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A phase I study of vincristine, escalating doses of irinotecan, temozolomide and bevacizumab (VIT-B) in pediatric and adolescent patients with recurrent or refractory solid tumors of non-hematopo...

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A phase I study of vincristine, escalating doses of irinotecan, temozolomide and bevacizumab (VIT-B) in pediatric and adolescent patients with recurrent or refractory solid tumors of non-hematopo...

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A PHASE I STUDY OF VINCRISTINE, ESCALATING DOSES OF IRINOTECAN,
TEMOZOLOMIDE AND BEVACIZUMAB (VIT-B) IN PEDIATRIC AND ADOLESCENT
PATIENTS WITH RECURRENT OR REFRACTORY SOLID TUMORS OF NON-
HEMATOPOIETIC ORIGIN

by

Rajkumar Venkatramani

___________________________________________________________________________

A Thesis Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(CLINICAL AND BIOMEDICAL INVESTIGATIONS)

December 2010

Copyright 2010 Rajkumar Venkatramani

ii

TABLE OF CONTENTS

List of Tables iii
Abstract iv
Chapter 1: Goals and Objectives (Scientific Aims) 1
Background 1
Chapter 2: Eligibility Criteria 12
Chapter 3: Treatment Program 22
Chapter 4: Required Observations 38
Chapter 5: Criteria for Removal from Protocol Therapy 41
and Off Study Criteria

Chapter 6: Statistical Considerations 44
Chapter 7: Evaluation Criteria 47
Chapter 8: Adverse Event Reporting Requirements 53
Bibliography 59
Appendix: Sample Research Informed Consent 65

iii

LIST OF TABLES

Table 1: Single Agent Studies with Irinotrecan 4

Table 2: Combination Studies with Irinotecan 5

Table 3: Threshold Serum Creatinine Value Based on Age 20

Table 4: Dose Levels 26

Table 5: Treatment Modification for Bevacizumab-Related Adverse Events 28

Table 6: Indications for Antibiotic Use (Cefpodoxime or Cefixime) for 37
GI Toxicities Due to Irinotecan

Table 7: Required Observations during Therapy 38

Table 8: Response Assessment Criteria 49

Table 9: Phase I Trial Expedited Reporting Requirements for Adverse Events 55
that Occur Within 30 Days of the Last Dose of Chemotherapy

iv

ABSTRACT

Vincristine, irinotecan and temozolomide have been used in various combinations to treat
pediatric solid tumors. These combinations, in general have been well tolerated. Outcomes for
patients with solid tumors who have been treated with various cytotoxic agents have reached a
plateau over the last two decades, with similar responses in various resistant cancers.
Incorporation of newer agents with different mechanisms of action with cytotoxic
chemotherapy may improve response rates and outcomes. Recently several agents that target
similar pathways in a broad range of cancers have become available. Only few of them have
been tested in the pediatric population. Bevacizumab, an inhibitor of vascular endothelial
growth factor (VEGF) is one such agent. The novel combination of vincristine, irinotecan,
temozolomide and bevacizumab with their unique mechanisms of action and non-overlapping
dose limiting toxicity could be useful in refractory solid tumors. This phase I study is designed
to determine the maximum tolerated dose of irinotecan given intravenous for 5 days every 3
weeks in combination with fixed doses of vincristine, temozolomide and bevacizumab (VIT-
B).
1

CHAPTER 1
GOALS AND OBJECTIVES (SCIENTIFIC AIMS)

Primary Aims
To determine the maximum tolerated dose of irinotecan in combination with fixed doses of
vincristine, temozolomide and bevacizumab and recommend a Phase II dose of the
combination.
To determine the rate of dose limiting toxicities of the combination of vincristine, irinotecan,
temozolomide and bevacizumab (VIT-B).

Secondary Aim
To preliminarily define the anti-tumor activity of the combination of, vincristine, irinotecan,
temozolomide and bevacizumab within the confines of a Phase I study.
BACKGROUND
Introduction
Over the past several decades, significant improvements in the outcome of children with
cancer have been documented. However, there are still some patients with poor prognoses,
especially those with metastatic sarcomas such as alveolar rhabdomyosarcoma, osteosarcoma,
Ewing sarcoma, hepatocellular carcinoma, high-risk neuroblastoma, and certain brain tumors.
Additionally, the outlook for most patients who have recurrent disease is dismal. It is because
of many years of life remaining for those pediatric patients who are cured of their malignancy,
2

limiting toxicity and long-term morbidity are also key factors in the treatment of children with
cancer. Recent advances in cancer therapy including discovery of various cancer pathways and
a plethora of molecular targets have led to introduction of newer anticancer drugs and their
combinations. We would like to test one such combination (vincristine, irinotecan,
temozolomide and bevacizumab) in this study.

We hypothesize that:
 The combination of vincristine, irinotecan, temozolomide and bevacizumab will be
tolerable.
 The combination of vincristine, irinotecan, temozolomide and bevacizumab will have
a superior response rate in target cancers when compared to vincristine, temozolomide
and irinotecan alone (Phase II).

Rationale
Mechanism of Action of Drugs in the Combination
Vincristine is a vinca alkaloid that inhibits microtubule formation, arresting mitosis in
metaphase. (Owellen et al., 1976) irinotecan is a camptothecin pro-drug that is de-esterified to
the more potent topoisomerase I inhibitor SN-38. Temozolomide is an oral methylating agent.
Bevacizumab is a humanized monoclonal neutralizing antibody binding all 5 isoforms of
human VEGF (Presta et al., 1997). The combination of these 4 drugs which have different
mechanisms of action and may be helpful in overcoming tumor resistance and improve
outcomes.

3

Rationale for the Use of Escalating Doses of Irinotecan
Irinotecan (CPT-11) is a water soluble analogue of camptothecin. Camptothecins interact
specifically with the enzyme topoisomerase I which relieves torsional strain in DNA by
inducing reversible single-strand breaks. Irinotecan and its active metabolite SN-38 bind to the
topoisomerase I-DNA complex and prevent religation of these single-strand breaks. Current
research suggests that the cytotoxicity of irinotecan is due to double-strand DNA damage
produced during DNA synthesis when replication enzymes interact with the ternary complex
formed by topoisomerase I, DNA, and either irinotecan or SN-38 (Redinbo et al., 1998).

Cytotoxicity of camptothecin mainly occurs in S-phase. Cells in S-phase are up to 1000-fold
more sensitive then cells in G1- or G2 phase, during brief exposures to the drug. These data
predict better antitumor activity with prolonged drug exposure, a phenomenon that has been
observed in preclinical models (Houghton P J et al., 1995). Significant antitumor activity has
been reported in xenografts derived from pediatric tumors such as neuroblastoma and
rhabdomyosarcoma, as well as in rhabdomyosarcoma xenografts selected in vivo for
resistance to vincristine, melphalan and topotecan (Komuro et al. 1994; Peter J. Houghton et
al. 1993).

Several clinical studies have utilized irinotecan alone or in combination with vincristine and/or
temozolomide. (See Tables 1 and 2)

4

Table 1: Single Agent Studies with Irinotecan
Authors Schedule MTD (maximum
tolerated dose)
DLT (dose limiting
toxicity)
Vassal et al. (2003) 120-720 mg/m
2
on day 1
every 21 days
600mg/m
2
Diarrhea and
leukopenia
Furman et al.
(1999)
20mg/m
2
(initial dose)
(qdx5)x2 every 21 days
20mg/m
2
diarrhea
Hirota et al. (2001) 100mg/m
2
/day(initial
dose) X3 every 21 days
180 mg/m
2
Diarrhea
Mugishima et al.
(2002)
50mg/m
2
/day(initial
dose) X3 every 25 days
160-180mg/m
2
Diarrhea and
myelosuppression
Blaney et al. (2001)

30mg/m
2
/day(initial
dose) x5 every 21 days
39mg/m
2
-heavily
treated patients
50mg/m
2
- less
heavily treated
patients
Myelosuppression –
heavily pretreated
patients
Diarrhea-less
heavily pretreated
patients
Turner et al. (2001)
Phase II
125mg/m
2
/week x 4
every 6 weeks
Phase II Myelosuppression
Bomgaars et al.

(2007) Phase II
50mg/m
2
/day x5 every
21 days
Phase II Diarrhea and
leukopenia

5

Table 2: Combination Studies with Irinotecan
Authors Schedule MTD DLT
Wagner et al.
(2004)
Irinotecan
10mg/m
2
(initial dose)
(qdx5)x2 every 21 days

Temozolomide 100
mg/m2 X 5d
10mg/m
2
Diarrhea and
neutropenia
Wagner et al.
(2007)
Irinotecan
10mg/m2(initial dose)
(qdx5)x2 every 21 days

Temozolomide 100
mg/m
2
X 5d
10-20mg/m
2
Diarrhea
Packer et al.
(2009)
Irinotecan 125mg/m
2

every 2 weeks

Bevacizumab 10mg/kg
every 2 week
125mg/m
2
Transient
leukoencephalopathy,
proteinuria
Wagner et al.
(2009)
Irinotecan 30mg/m
2
(initial dose) PO d1-5 and
d8-12 every 21 days

Temozolomide
100mg/m
2
/day PO d1-5
60mg/m
2

75mg/m
2

Neutropenia and
thrombocytopenia
Pappo et al. (2007) Irinotecan 20mg/m
2

(Qdx5)X2

Vincristine 1.5mg/m
2

weeks 0,1,3,4
Phase II Abdominal pain,
diarrhea

To summarize, irinotecan has been used in pediatric studies in various different doses and
schedules. Because the shorter schedule of irinotecan is likely to be a more appealing regimen
to patients and families, we propose to use the daily x 5 schedule for irinotecan. This schedule
(irinotecan 50 mg/m
2
/day iv daily x 5 with weekly vincristine) was studied in patients with
recurrent rhabdomyosarcoma (Mascarenhas L, 2008) and was determined to be as well

6

tolerated and as effective as the protracted (20 mg/m
2
/day daily x 5 x 2 with weekly
vincristine) schedule. Bomgaars et al. showed that irinotecan at 50 mg/m
2
/day x 5 days every
3 weeks was well tolerated in patients with refractory solid tumors (Bomgaars et al., 2007).

In a recently published abstract Wagner compared 2 different schedules of oral irinotecan (d x
5x 2 vs. d x 5x 1) in combination with vincristine and temozolomide in children with
refractory solid tumors (Wagner LM, 2009). They showed that d x 5x 1 schedule was well
tolerated at oral irinotecan dose of 90 mg/m2/day and no DLT was seen.

Blaney showed that the MTD of irinotecan, when given as single agent, was 39 mg/m2/day
x 5 days for heavily pretreated patients and 50 mg/m2/day x 5 days for less heavily pretreated
patients (Blaney et al., 2001). Kushner reported that 50 mg/m
2
/day x 5 of

irinotecan with
temozolomide 150 mg/m2/day x 5 days was tolerated by patients with recurrent
neuroblastoma (Kushner et al., 2006). However, the hematologic parameters for dosing on this
study were lower than what is generally accepted as standard. Based on the available data, the
MTD for irinotecan when given in combination with other drugs is yet to be firmly
established. Therefore we propose to test irinotecan at a dose of 30 mg/m
2
/day x 5 days and
subsequently escalate the dose to 50 mg/m2/day x 5 days if tolerated.

Rationale for the Use of Bevacizumab
Angiogenesis is the hallmark of tumor development and metastases. Vascular endothelial
growth factor (VEGF) is the most extensively studied proangiogenic factor. Tumor cells up
regulate the expression of VEGF when they grow in response to decreased levels of oxygen
7

and nutrients and the accumulation of metabolic waste. The binding of VEGF to its receptor
VEGFR-2 is a critical step that stimulates endothelial cell proliferation, migration, tube
formation, and capillary sprouting (Dvorak, 2002).

Bevacizumab (Avastin ®)
Bevacizumab is a humanized monoclonal neutralizing antibody binding all 5 isoforms of
human VEGF (Presta et al., 1997). It has been shown to bind to VEGF-A with high affinity
and neutralize its activity (Napoleone Ferrara & Davis-Smyth, 1997). Inhibition of
angiogenesis has resulted in reduced tumor growth in many ex vivo models of pediatric and
adult malignancies (McCrudden et al., 2003; Rowe, J Huang, Kayton, et al., 2000; Kim et al.,
1993; Rowe, J Huang, J Li et al., 2000; H P Gerber et al., 2000; Napoleone Ferrara et al.,
2004). This effect has also been independently demonstrated in RMS xenograft tumors
(Gerber H P et al., 2000). Animal toxicology studies of bevacizumab in cynomolgus monkeys
demonstrated no acute toxicities but evidence of physeal dysplasia, delayed wound healing
and proteinuria were noted (Ryan A M et al., 1999).

Administration of bevacizumab as a single agent to humans with metastatic clear cell
carcinoma of the kidney resulted in a significantly longer time to progression compared with
placebo (Yang et al., 2003). Furthermore, bevacizumab has been shown to have a direct anti-
vascular effect on tumors in patients with adenocarcinoma of the rectum (Willett et al., 2004).
Although anti-VEGF-A therapy alone appears to have a direct anti-tumor effect, there is
evidence from a variety of in vivo models that the combination of anti-VEGF-A therapy and
chemotherapy or radiotherapy has greater anti-tumor effects than either therapy alone (Lee et

8

al., 2000; Klement et al., 2000). Importantly, a recently reported trial in which adults with
metastatic colon cancer were randomized to receive irinotecan, fluorouracil, and leucovorin
alone or in combination with bevacizumab showed that those treated with bevacizumab plus
chemotherapy had a significantly better overall and progression-free survival (Hurwitz et al.,
2004). Toxicities noted in adults are hypertension, epistaxis, proteinuria and infusional
reactions. Serious but uncommon events, which appear to be agent specific, include
intratumoral bleeding, arterial and deep venous thrombosis, gastrointestinal perforation, nasal
septum perforation, impaired wound healing and reversible posterior encephalopathy
syndrome (Sandler et al., 2006; Shah et al., 2006). From these studies, the overall risk for
Grade III/IV toxicities is the 25% range, with Shah et al. reporting Grade III hypertension in
28% and thromboembolic events in 25%. These data suggest that bevacizumab alone and in
combination with conventional chemotherapy, has anti-tumor effects and despite some toxicity can
safely be given in combination with several standard chemotherapy regimens in adults. These data
also suggest that bevacizumab may be an effective therapeutic approach in multiple types of
human cancer in which VEGF-dependent angiogenesis plays an important role in tumor cell
survival.

ADVL0314 was a Phase I study of bevacizumab conducted by COG for children with
refractory solid tumors (Bender et al., 2008). This single agent study evaluated three dose
levels but did not escalate to a maximum tolerated dose (MTD). Side effects were limited to
mild infusional reactions, fever, rash, epistaxis, lymphopenia, and proteinuria, none of which
necessitated dose modification. There were no episodes of severe hemorrhage or thrombosis.
The maximum dose level of 15 mg/kg administered every 2 weeks over 30-90 minutes will be
9

the recommended dose and schedule for future studies of bevacizumab in children. There were
no objective responses on ADVL0314, but 5 of 18 patients with evaluable or measurable
disease experienced prolonged disease stabilization (> 3 months), one of which received
16 cycles of therapy prior to progression. All 5 of these patients had a diagnosis of bone or
soft tissue sarcoma. Results of a Phase III AVAIL trial in Non Small Cell Lung Cancer that
used bevacizumab combined with gemcitabine and cisplatin were recently published (Reck et
al., 2009). This trial supports the use of bevacizumab administered in a once every three week
schedule when administered in combination with cytotoxic chemotherapy.

Rationale for Combination of Vincristine, Irinotecan, Temozolomide, and Bevacizumab
(VIT-B)
The ideal combination chemotherapy is the one with additive clinical benefit and non additive
adverse effects. The dose limiting toxicity of vincristine (neurotoxicity) irinotecan (diarrhea,
myelosuppression), temozolomide (myelosuppression), and bevacizumab (none) combination
fits that description. Various combinations of the above agents have been tested in pediatric
and adult settings, though not all of them together in the same setting.

Wagner did a phase I study to estimate the maximum tolerated dose (MTD) of temozolomide
and irinotecan given on a protracted schedule in 28-day courses to pediatric patients with
refractory solid tumors (Wagner L M et al., 2004). Twelve heavily pretreated patients
received 56 courses of oral temozolomide at 100 mg/m
2
/day for 5 days combined with i.v.
irinotecan given daily for 5 days for 2 consecutive weeks at either 10 mg/m
2
/day (n = 6) or 15
10

mg/m2/day (n=6). Two patients experienced DLT (diarrhea, neutropenia) at the higher dose
level.

Packer treated 10 children with multiply recurrent low grade gliomas with bevacizumab (10
mg/kg every 2 weeks) and irinotecan (125 mg/m
2
every 2 weeks) (Packer et al., 2009).
Clinical improvements were noted in seven and the dose limiting toxicity included transient
leukoencephalopathy (1) and grade 3 proteinuria (1). The same combination (with a different
dosing regimen) was used by Vredenburgh in adults with glioblastoma multiforme
(Vredenburgh et al., 2007). Twenty of the 35 patients (57%; 95%

CI, 39% to 74%) had at least
a partial response. One patient

developed a CNS hemorrhage, which occurred in his 10th
cycle.

Four patients developed thromboembolic complications (deep venous

thrombosis and/or
pulmonary emboli).

The Children’s Oncology Group compared the combination of two cycles of irinotecan (20
mg/m
2
daily for 5 days for 2 weeks) and weekly vincristine with irinotecan alone in 21 newly
diagnosed patients with metastatic rhabdomyosarcoma or undifferentiated sarcoma (Pappo et
al., 2007). The vincristine and irinotecan combination was well tolerated and gastrointestinal
toxicity was the main side effect. The combination showed a lower rate of progressive disease
(8% vs. 42%).

Bevacizumab in combination with other chemotherapeutic agents has shown efficacy in adults
with colorectal cancer, non small cell lung cancer and breast cancer (Hurwitz et al. , 2004;
Kathy Miller et al., 2007; Kabbinavar et al., 2003; Johnson et al. ,2004; Kathy D. Miller et
11

al., 2005; Giantonio et al., 2007). There are no reported studies with bevacizumab that has
shown efficacy in pediatric solid tumors to date. This study will combine bevacizumab in
combination with cytotoxic chemotherapy and may provide some information on the anti-
tumor activity of this combination in the population studied.
12

CHAPTER 2
ELIGIBILITY CRITERIA
Screening and Study Enrollment Procedures
Physicians who wish to enroll patients should contact the research coordinator to determine if
the study is currently open for accrual.

IRB Approval
Local IRB approval should be confirmed prior to enrolling a patient.

Screening Procedures
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial
must only be done after obtaining written informed consent. Studies or procedures that were
performed for clinical indications (not exclusively to determine eligibility) may be used for
baseline values even if the studies were done before informed consent was obtained.

Informed Consent/Assent
The investigational nature and objectives of the trial, the procedures and treatments involved
and their attendant risks and discomforts, and potential alternative therapies will be carefully
explained to the patient or the patient’s parents or guardian if the patient is a child, and a
signed informed consent and assent will be obtained according to institutional guidelines.

13

Reservation and Contact Requirements
Before enrolling a patient on study, a reservation must be made with the research coordinator
at (323) 669-7148. The principal investigator or co-investigators will be contacted. Patients
must be enrolled within 5 days of making a reservation.

Patient Registration
The patient will be assigned a unique study identification number once the patient has been
enrolled on study.

Eligibility Checklist
Before the patient can be enrolled, the responsible attending physician must sign and date the
completed eligibility checklist.

Institutional Pathology Report
At the time of enrollment, the institutional pathology report for the diagnosis under which the
patient is being enrolled must be faxed to the research coordinator.

Study Enrollment
Patients may be enrolled on the study once all eligibility requirements for the study have been
met. Treatment must start within 5 calendar days of enrollment. Patients must not receive any
therapy as defined/determined by this protocol prior to enrollment and assignment of dose
level.

14

Dose Assignment
The dose level will be assigned by the Clinical Trials Office (CTO), confirmed by the
statistician and Principal Investigator and then communicated to the patient’s physician and
Principal Investigator in writing by the research coordinator.
Patient Eligibility
Inclusion Criteria
Tests to determine eligibility should be performed within one week before enrollment except
for disease staging scans that can be performed within two weeks before study enrollment.
Age
Patients must be > 12 months and < 21 years of age at the time of study entry.

Weight
Patient must be more than or equal to 10 Kilograms.

Histological Diagnosis
Patients must have had histological verification of the malignancy at some time prior to study
entry. All solid tumors are eligible with the exclusion of lymphomas. For patients with
neuroblastoma, diagnosis based on elevated catecholamines in the urine and tumor cells on
bone marrow aspirates/biopsies is acceptable. For patients with germ cell tumors, diagnosis
based on elevated tumor markers (serum alpha fetoprotein and/or serum beta human chorionic
gonadotropin) and radiographic evidence of disease is acceptable. Patients diagnosed with
diffuse brain stem gliomas by radiographic images alone will be eligible.
15

Disease Status
Disease must have failed standard therapy (therapies) or be a disease for which no standard
therapy exists. Patient with stable disease on other therapies are not eligible.

Performance Level
Karnofsky > 50% for patients >16 years of age and Lansky > 50 for children < 16 years of
age.

Life Expectancy
Must be > 8 weeks.

Prior Therapy
Patients must have fully recovered from the acute toxic effects of all prior chemotherapy,
immunotherapy, or radiotherapy before enrolling on this study:
a. Myelosuppressive chemotherapy: Must not have received within 2 weeks of
enrollment on this study (4 weeks if prior nitrosourea).
b. Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with a
biologic agent.
c. XRT:  2 wks for local palliative XRT (small port);  6 months must have elapsed if
prior craniospinal XRT or if  50% radiation of pelvis;  6 wks must have elapsed if
other substantial BM radiation.
16

d. Stem Cell Transplant (SCT): At least 6 months must have elapsed following
autologous stem cell transplant. Patients who received an allogeneic transplant are not
eligible for this study.
e. Peripheral Blood Stem Cell Infusion: ( PBSC) At least 6 months should have elapsed
following PBSC infusion for non brain tumor patients.

Patients must have recovered from any surgical procedure before enrolling on this study:
a. Patients with a documented, chronic non-healing wound, ulcer, or significant trauma
injury (those with bone fractures, including pathological fractures, or requiring
surgical intervention) within 28 days prior to beginning therapy should be excluded.
b. Minor surgical procedures (biopsies) for limited purposes of tissue retrieval will be
allowed. Minor procedures include indwelling IV catheter placement and needle
biopsy for diagnostic purposes.
1. For minor surgeries, patients should not receive the first planned dose of
bevacizumab until 7 days have elapsed or the wound is healed, whichever
is later.
2. For procedures such as the placement of an indwelling IV catheter, it is
recommended that bevacizumab not be given for at least 24 hours after
the procedure.
c. Patients who have had a major surgical procedure (such as laparotomy, thoracotomy
open biopsy or resection of tumor) can only be enrolled on study > 28 days from such
procedure.

17

Patients with unhealed wounds, bone fractures of other bone complications are NOT
ELIGIBLE for this study.

Other Conditions
Coagulopathy
a. Patients must not have had deep venous thrombosis (including pulmonary embolism)
within the last three months prior to study enrollment.
b. Patients on full-dose anticoagulants (e.g., warfarin) with PT INR > 1.5 are eligible if
both of these criteria are met:
 The patient has an in-range INR (usually between 2 and 3) on a stable dose of
oral anticoagulant or on a stable dose of low molecular weight heparin.
 The patient has no active bleeding or pathological condition that carries a high
risk of bleeding (e.g., tumor involving major vessels or known varices).

Cardiovascular Disease or Hypertension
a. Patients must not have had recent (within 6 months) arterial thromboembolic events,
including transient ischemic attack (TIA) or cerebrovascular accident (CVA)
b. Patients must not have a history of myocardial infarction, severe or unstable angina, or
peripheral vascular disease (Unlikely in the patient population being studied)
c. Hypertension must be well controlled on stable doses of medication for at least two
weeks prior to enrollment

18

Concomitant Therapy
a. Growth factor(s): Must not have received G-CSF within 1 week or PEG G-CSF within
2 weeks of entry onto this study. Growth factors may not be administered during the
course of this study except as described in the treatment section.
b. Study Specific: Patients may not receive any other chemotherapy or
immunomodulating agents, while enrolled on study. Radiation therapy may not be
given during the first two courses of chemotherapy. After two courses, radiation
therapy may be given after discussion with the Principal Investigator.
c. Chronic medications: Patients may be on chronic medications (e.g.: steroids,
narcotics, anti-epileptics) at the time of enrollment. Investigators should avoid, when
possible, increasing or decreasing the doses of these medications while the patient is
on study.
d. Enzyme-inducing anticonvulsants or other medications: Patients who are currently
taking phenobarbital, phenytoin, carbamazepine, oxcarbazepine (Trileptal), rifampin,
voriconazole, itraconazole, ketoconazole, aprepitant (Emend), or St. John’s Wort are
not eligible.

19

Organ Function Requirements
Adequate bone marrow function is defined as:
For patients with solid tumors including status post SCT:
- Peripheral absolute neutrophil count (ANC) >750/µL
- Platelet count >75,000/µL (transfusion independent)
- Hemoglobin > 8.0 gm/dL (may receive RBC transfusions)

For patients with tumor metastatic to bone marrow who have granulocytopenia, anemia,
and/or thrombocytopenia
- Peripheral absolute neutrophil count (ANC) > 500/µL
- Platelet count > 50,000/µL (Transfusion independent- should not have received a
platelet transfusion in the 5 days prior)
- Hemoglobin > 8.0 gm/dL (may receive RBC transfusions)
Hematologic toxicity will not be evaluable in these patients.

Adequate renal function defined as:
- Creatinine clearance or radioisotope GFR > 70ml/min/m2 OR
- A serum creatinine based on age as follows:

20

Table 3: Threshold Serum Creatinine Values Based On Age
AGE (years) Maximum creatinine
<5 0.8
5-10 1
10-15 1.2
>15 1.5

Urine protein should be screened by urine analysis for Urine Protein Creatinine (UPC) ratio.
For UPC ratio > 0.5, 24-hour urine protein should be obtained and the level should be < 1,000
mg for patient enrollment.
Note: UPC ratio of spot urine is an estimation of the 24 urine protein excretion – a UPC ratio
of 1 is roughly equivalent to a 24-hour urine protein of 1 gm. UPC ratio is calculated using
one of the following formulae:
o [urine protein]/[urine creatinine] – if both protein and creatinine are reported in mg/dL
o [(urine protein) x 0.088]/[urine creatinine] – if urine creatinine is reported in mmol/L

Adequate liver function defined as:
-Total bilirubin < 1.5 x upper limit of normal for age,
-SGPT (ALT) < 5 x upper limit of normal for age.

21

Adequate cardiac function defined as:
-Shortening fraction of > 28% by echocardiogram and qualitatively normal left ventricular
function, or
-Ejection fraction of > 55% by MUGA.
No prior history of cardiac failure or dysfunction attributed to anthracylines.

Exclusion Criteria
 Patients who have received bevazucimab and/or irinotecan previously are ineligible. Non
brain tumor patients who have previously received temozolomide are ineligible.
 Pregnancy or Breast-Feeding: Pregnant patients are ineligible for this study due to the
known teratogenic effects of the cytotoxic agents. Pregnancy tests must be obtained in
females of childbearing potential prior to enrollment.
 Lactating women must agree not to breast-feed.
 Males or females of reproductive age may not participate unless they have agreed to use
an effective contraceptive method.
 Patients Who Have an Uncontrolled Infection will not be eligible for enrollment until all
infections are under control.
 Clinically Significant Unrelated Systemic Illness: Patients with serious infections or
significant pulmonary, hepatic, renal, or other end-organ dysfunction which in the
judgment of the Principal Investigator would compromise the patient’s ability to tolerate
prescribed chemotherapy or are likely to interfere with the study procedures or results will
not be eligible.
22

CHAPTER 3
TREATMENT PROGRAM
Treatment Overview
Drug Administration
Dosing is based on body surface area. For administration of irinotecan, body surface area
should not exceed 2 square meters.

Administration Schedule for VIT-B (Cycles 1-12)
The administration schedule below describes 1 cycle of VIT-B and should be repeated 11
times. Each cycle is 21 days in duration.
The drug doses for VIT will be based on the patient’s body surface area (BSA).

Criteria to Start Each Cycle
ANC ≥ 750 /μL and platelet count ≥ 75,000/μL. The ANC often falls after discontinuing
myeloid growth factor support (filgrastim). If the ANC has risen to ≥ 750/μL after the nadir
but then falls to < 750/ μL, the next cycle, can be given despite ANC < 750/μL.

Temozolomide (TEM): P.O. once daily
Always administer temozolomide at least ONE hour before irinotecan
Days: 1-5 Dose: 100mg/m²/dose. Round to the closest 5 mg.

23

Administer with a glass of water preferably on an empty stomach to decrease nausea and
vomiting. Administer dose at approximately the same time each day. Antiemetic should be
given 30 minutes prior to the temozolomide dose. If emesis occurs within 10 minutes of taking
a given dose, then the dose may be repeated once.

Bevacizumab (BEVA): IV infusion
Day: 1.
Dose: 15 mg/kg
Initial infusion time should be over 90 minutes. If there is no reaction following the first
administration, it will be given over 60 minutes in the second administration and, if tolerated,
over 30 minutes for all subsequent doses
Bevacizumab is incompatible with D
5
W (the drug is inactivated).

Vincristine (VCR): IV push over one minute
Days: 1, 8
Dose: 1.5 mg/m
2
/dose. (Maximum dose 2 mg).
Avoid extravasation. Administration through a central line is recommended

Irinotecan (IRN): IV over 90 minutes
Days: 1-5
Dose: Level -1=20 mg/m
2

Level 1=30 mg/m
2

24

Level 1.5=40 mg/m
2

Level 2 =50 mg/m
2

Myeloid Growth Factor: SubQ
Filgrastim: (Neupogen) 5 mcg/kg SQ daily starting on Day 6 (at least 24 hours after
completion of previous dose of chemotherapy) and continued until ANC ≥ 2000/µL post
nadir. Discontinue at least 24 hours prior to next cycle of chemotherapy. Maximum dose of
GCSF administered should not exceed 300 micrograms per dose.

PEG Filgrastim: (Neulasta) 100 mcg/kg SQ X 1 24-36 hrs following the last dose of
irinotecan. Max dose: 6mg. If the treating physician chooses to not administer filgrastim or
PEG filgrastrim 24-48 hours following the last dose of irinotecan, filgrastrim must be started
if the ANC<1000/cmm at anytime during the cycle and continued until the ANC>2000/cmm.

If surgery is indicated to treat recurrent or progressive tumor, it should be performed no sooner
than 28 days after the most recent bevacizumab dose. Bevacizumab should not be reinstituted
sooner than 28 days after surgery. If there are significant postoperative wound complications
bevacizumab should be withheld for a further 3 weeks at investigator discretion. Elective surgery
should not be performed during the first two courses of chemotherapy.

If radiation is planned to treat recurrent or progressive disease, radiation should not be performed
during the first two courses of chemotherapy. Subsequently, radiation therapy is allowed.
Treating physicians must be aware agents used on this study are known to increase the toxicity of
25

radiation. Bevacizumab should be held for significant radiation induced complications and may
be reinstituted after 3 weeks at investigator discretion.

Definition of Course
A course will be considered 21-days from the start of the chemotherapy on day 1 or until the
time of hematopoietic recovery (ANC > 2000/cmm post nadir after growth factor
administration or ANC > 750/cmm if no myeloid growth factor is used) and platelet count >
75,000.cmm (without having received a platelet transfusion in the prior 5 days) or whichever
is longer. The interval between each course should not exceed 35 days.

Criteria for Retreatment
A course may be repeated no earlier than every 21 days if the patient has at least stable disease
and has recovered from the prior course of therapy to laboratory parameters defined in the
eligibility criteria. This is in addition to all non-hematological, non-dose limiting toxicities
returning to grade I level. The duration between courses should not exceed 35 days. (ANC
falling to <750/cmm after myeloid growth factor has been discontinued is an exception).
Patients with DLT who have no evidence of progressive disease may continue on protocol
therapy at the lower dose level as long as all toxicities have returned to baseline or < grade 1.

26

Dose Escalation
Table 4: Dose Levels
Dose Level 1 Irinotecan 30 mg/m
2
/day IV on day 1,2,3,4 and 5 (maximum dose
60mg/day)
Vincristine 1.5mg/m
2
(2mg max dose) IV on day 1,8
Temozolomide 100 mg/m
2
PO on day 1,2,3,4 and 5
Bevacizumab 15mg/kg IV on day 1
Dose Level
1.5*
Irinotecan 40 mg/m
2
/day IV on day 1,2,3,4 and 5 (maximum dose
80mg/day)
Vincristine 1.5mg/m
2
(2mg max dose) IV on day 1,8
Temozolomide 100 mg/m
2
PO on day 1,2,3,4 and 5
Bevacizumab 15mg/kg IV on day 1
Dose Level 2: Irinotecan 50 mg/m
2
/day IV on day 1,2,3,4 and 5 (maximum dose
100mg/day)
Vincristine 1.5mg/m
2
(2mg max dose) IV on day 1,8
Temozolomide 100 mg/m
2
PO on day 1,2,3,4 and 5
Bevacizumab 15mg/kg IV on day 1
Dose Level -1 Irinotecan 20 mg/m
2
/day IV on day 1,2,3,4 and 5 (maximum dose
40mg/day)
Vincristine 1.5mg/m
2
(2mg max dose) IV on day 1,8
Temozolomide 100 mg/m
2
PO on day 1,2,3,4 and 5
Bevacizumab 15mg/kg IV on day 1

1. Cycles will be repeated every 21 days
2. Filgrastim 5 mcg/kg SQ once daily, starting 24-48 hrs after last dose of irinotecan until ANC>
2000/cmm following nadir or PEG Filgrastim 100mcg/kg SQ X 1 dose 24-48 hrs following last
dose of irinotecan in each cycle. . If filgrastrim or PEG filgrastrim is not given 24-48 hrs after the
last dose of irinotecan, filgrastrim must be started if the ANC<1000/cmm at anytime during the
cycle and continued until the ANC>2000/cmm
3. Maximum number of cycles = 12
* Dose escalation will proceed from dose level 1 to dose level 2 and deescalate to dose level
1.5 if DLT is observed on dose level 2.

Intra-Patient Escalation
There will be no intra-patient escalation.

27

Concurrent Therapies
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general
supportive care are to be used as necessary. Other concurrent cancer therapy, including
chemotherapy, radiation therapy,* immunotherapy, or biologic therapy cannot be administered
to study patients. If these treatments are administered the patient will be removed from study.
(*Palliative or therapeutic radiation may be administered following recovery from at least 2
courses of chemotherapy after discussion with the Principal Investigator or Co- Investigators).

Investigational agents
No other investigational agents may be given while the patient is on study.

Dose Modifications for Toxicity
(NCI Common Terminology Criteria for Adverse Events [CTCAE v4.0])

Dose Modifications/Delays Guidelines for Bevacizumab
Note 1: There will be no dose reduction for bevacizumab. Treatment should be interrupted or
discontinued for certain adverse events, as described below.

28

Table 5: Treatment Modification for Bevacizumab-Related Adverse Events.
Event
CTCAE.v3.0
Grade
Action to be Taken
Allergic reactions,
or Acute infusional
reactions/ cytokine
release syndrome

Grades 1-2

If infusion-related or allergic reactions occur,
premeds should be given with the next dose,
and infusion time may not be reduced for the
subsequent infusion.
Grade 3 Bevacizumab infusion should be stopped and
not restarted on the same day. At the
physicians’ discretion, bevacizumab may be
permanently discontinued or re-instituted with
premeds and at a rate of 90+15 min a
minimum of 24 hours following the initial
reaction and before the completion of the last
dose of irinotecan for that course. If
bevacizumab is re-instituted, the patient should
be closely monitored for duration comparable
to or longer than the duration of the previous
reactions.
Grade 4 Discontinue bevacizumab
Arterial Thrombosis
- Cardiac ischemia/
infarction
- CNS ischemia (TIA,
CVA)
- any peripheral or
visceral arterial
ischemia/thrombosis
Grade 2 ( if new
or worsened
since
bevacizumab
therapy)
Discontinue bevacizumab.
Grades 3-4 Discontinue bevacizumab

29

Table 5, Continued
Venous Thrombosis
*

*for grade 3 catheter
related thrombosis the
catheter will be removed
and bevacizumab
continued as per schedule

Grade 3
(non catheter
related)

 Hold bevacizumab treatment. If the planned
duration of full-dose anticoagulation is <2
weeks, bevacizumab should be held until the
full-dose anticoagulation period is over.
 If the planned duration of full-dose
anticoagulation is > 2 weeks, bevacizumab
may be resumed during the period of full-
dose anticoagulation IF all of the criteria

below are met:
- The subject must have an in-range INR
(usually 2-3) on a stable dose of warfarin or
on stable dose of heparin prior to restarting
bevacizumab.
- The subject must not have pathological
conditions that carry high risk of bleeding
(e.g. tumor involving major vessels or other
conditions)
- The subject must not have had hemorrhagic
events while on study
If thromboemboli worsen/recur upon
resumption of study therapy, discontinue
bevacizumab
Grade 4
(symptomatic)
Discontinue bevacizumab

Hypertension
Use age and gender
appropriate normal
values >95th percentile
ULN for pediatric
patients.
[Treat with anti-hypertensive medication as needed. The goal
of BP control should be consistent with general medical
practice]
Grade 1: Consider increased BP monitoring
Grade 2 Begin anti-hypertensive therapy and continue
bevacizumab
Grade 3- Discontinue bevacizumab
Grade 4: Discontinue bevacizumab.
Congestive Heart
Failure
Grade 3
(symptomatic)
Discontinue bevacizumab
Grade 4 Discontinue bevacizumab
30

Table 5, Continued
Proteinuria

[Proteinuria should be monitored by urine analysis for urine
protein creatinine (UPC) ratio prior to every other dose of
bevacizumab]
UPC ratio
< 3.5
Continue bevacizumab.
UPC ratio
> 3.5
Discontinue bevacizumab.
Grade 4 or
nephrotic
syndrome
Discontinue bevacizumab.
Hemorrhage (CNS or
pulmonary)
Grade 2-4 Discontinue bevacizumab
Hemorrhage(non-
CNS; non-
pulmonary)
Grade 3

Discontinue bevacizumab
Grade 4 Discontinue bevacizumab
RPLS (Reversible Posterior
Leukoencephalopathy syndrome or
PRES (Posterior Reversible
Encephalopathy Syndrome)
 Hold bevacizumab in patients with
symptoms/signs suggestive of RPLS;
subsequent management should include MRI
scans and control of HTN.
 Discontinue bevacizumab upon diagnosis of
RPLS.
Wound dehiscence requiring medical or
surgical intervention
Discontinue bevacizumab
GI perforation, GI leak or fistula

Discontinue bevacizumab
Bowel obstruction

Grades 3-4
 Hold bevacizumab until complete resolution
 If surgery is required, patient may restart
bevacizumab after full recovery from surgery,
and at investigator’s discretion adhering to the
guidelines in Section 5.1.3.
Other Unspecified
bevacizumab-related
AEs (except controlled
nausea/vomiting).
Grade 3
 Hold bevacizumab until symptoms resolve to
< Grade 1
Grade 4
 Discontinue bevacizumab
 Upon consultation with the study chair,
resumption of bevacizumab may be considered
if a patient is benefiting from therapy, and the
Grade 4 toxicity is transient, has recovered to <
Grade 1 and unlikely to recur with retreatment.
31

Other Modifications
Hyperbilirubinemia
If the total bilirubin is 1.5-3 X ULN (grade 2) then hold vincristine dose for one week. When
due next, give full dose if resolved to Grade 1 or less, 50% of dose if still grade 2; if the total
bilirubin is >3 X ULN (grade 3 or 4) then hold vincristine dose until resolved to Grade 1 or
less and dose as above.

Vincristine Neuropathy
Grades 1 and 2 neurotoxicity requires no dose modification. For Grades 3 and 4 (interfering
with activities of daily living) hold until symptoms decrease to Grade 1 (present on
exam/testing but not symptomatic) or less and resume at 50% dose. Increases to 75% and full
dose should be considered at the start of each vincristine containing cycle based on patients’
symptoms.

Anticipate autonomic neuropathy resulting in constipation. Laxatives and/or stool softeners
should be used preemptively during vincristine containing cycles. If severe paralytic ileus
occurs vincristine should be stopped until normal bowel movements are re-established and
then resumed at 50% dose. Mild to moderate constipation (< 4 days) is not an indication for
interrupting vincristine.

While vincristine may be associated with jaw pain this should be treated with analgesics and
should not require dose modification.

32

Renal toxicity
Vincristine and irinotecan are not dose adjusted for renal dysfunction. Caution should be
exercised when temozolomide is administered to patients with severe renal impairment
(Creatinine clearance<40ml/min/1.73m2.)

Hematopoietic toxicity
Irinotecan and Temozolomide
Prescribe myeloid growth factor routinely as recommended in the treatment plan. If at the time
of scheduled therapy the absolute neutrophil count (ANC: PMNS, bands) is < 750/µL on
myeloid growth factor, or if the platelet count is < 75,000/µL, further therapy should be
delayed until ANC is ≥ 2000/µL on growth factor and platelets ≥ 75,000/µL. If the ANC is <
750µL on myeloid growth factor or platelets < 75,000/µL more than 14 days beyond the time
for the next treatment reduce the treatment to the next lower dose level as long as the patient
continues to have responsive disease. If similar delays occur, secondary to hematopoietic
toxicity with subsequent cycles continue to decrease to the next lower dose level. If already at
dose level -1, then decrease temozolomide dose by 25%. The ANC often falls after
discontinuing myeloid growth factor support (filgrastim). If the ANC has risen to ≥ 750/μL
after the nadir but then falls the next cycle can be given despite ANC< 750/μL.

Vincristine
No dose adjustment for vincristine is indicated for hematopoietic toxicity.

33

Febrile neutropenia
Twenty-five percent dose reductions should also take place in the event of life threatening
infection (e.g., septic shock, multiple documented episodes of gram negative sepsis).
Uncomplicated febrile neutropenia is not a reason to dose reduce.

Gastrointestinal toxicity secondary to irinotecan
Patients will receive prophylactic antibiotics and anti-diarrheals to prevent irinotecan induced
diarrhea. If patients continue to experience Grade 4 diarrhea or grade 3 diarrhea lasting >3
days despite maximum supportive care measures with prophylactic antibiotics and anti-
diarrheals, subsequent irinotecan doses should be reduced to the lower dose level.

Surgical procedures
Patients may not have had a planned major surgical procedure (such as resection of recurrent
disease) within 28 days of initiating bevacizumab. If major surgery for local control is planned
during study therapy for a patient on bevacizumab, then the bevacizumab should be held for
one cycle prior and for 28 days post definitive resection, unless the patient has had a
significant post-operative wound complication that in the opinion of the investigator would
preclude bevacizumab administration. In this clinical situation post-operative bevacizumab
should be withheld for longer. These restrictions are due to concerns of delayed wound
healing and hemorrhage. Minor surgical procedures (biopsies) need to either have healed or
occurred > 7 days prior to initiating bevacizumab. For other surgical procedures (such as a line
placement) initial and subsequent doses of bevacizumab should be postponed for at least 24
hours after the procedure.
34

Radiation therapy
No radiation therapy is allowed during the first two cycles of chemotherapy. If radiation
therapy is used for treating target lesions, those patients will not be eligible for response
evaluation. Radiation therapy should be held for severe chemotherapy related complications at
the discretion of the treating oncologist.

Supportive Care
General
Appropriate antibiotics, blood product support, and general supportive care measures will be
used as indicated according to institutional guidelines and standard of care. Prophylaxis
against Pneumocystis jiroveci pneumonia is recommended in all patients. If trimethoprim-
sulfamethoxazole is used for prophylaxis, it should be administered on two consecutive days
at a dose equivalent to 5 mg/kg of trimethoprim divided BID.

Diarrhea Secondary to Irinotecan
Patients are to receive anti-diarrheals and prophylactic antibiotics (Cefpodoxime or Cefixime)
per the supportive care guidelines below.

Patients who have the onset of diarrhea during the irinotecan infusion or in the several hours
following completion of the irinotecan infusion should receive a dose of atropine
(suggested dose 0.01 mg/kg IV, maximum dose 0.4 mg). Each family should be instructed
to have antidiarrheal medication available and begin treatment at the first episode of poorly

35

formed or loose stools or the earliest onset of bowel movements more frequent than
normally expected for the patient. Patients should also be instructed to contact their
physician if any diarrhea occurs.

Loperamide dosing recommendations for late diarrhea which occurs 8 hours after irinotecan
(based on body weight):
Under 13 kg: Take 0.5 mg after the first loose bowel movement, followed by 0.5 mg
every 3 hours. During the night, the patient may take 0.5 mg every 4 hours. Do not exceed 4
mg per day.
From 13 kg to less than 20 kg: Take 1 mg after the first loose bowel movement, followed by
1 mg every 4 hours. Do not exceed 6 mg per day.
From 20 kg to less than 30 kg: Take 2 mg after the first loose bowel movement, followed by 1
mg every 3 hours. During the night, the patient may take 2 mg every 4 hours. Do not exceed 8
mg per day.
From 30 kg to less than 43 kg: Take 2 mg after the first loose bowel movement, followed by 1
mg every 2 hours. During the night, the patient may take 2 mg every 4 hours. Do not exceed
12 mg per day.
->12 years old and adults: Take 4 mg after the first loose bowel movement, followed by 2
mg after each loose stool. Do not exceed 16 mg per day.
Failure of loperamide to control diarrhea within 24 hours of onset:
Begin subcutaneously or intravenously administered octreotide (Sandostatin
®
), 1-2
mcg/kg/dose every 12 hours. If needed, the dose may be titrated up to 10 mcg/kg/dose
(maximum dose: 500 mcg) every 8 hours.
36

Antibiotics for GI Toxicities
For patients who develop Grade 3 or 4 gastrointestinal (GI) toxicity (see table below for the
indications for antibiotic use) following irinotecan therapy, administration guidelines are
provided for Cefpodoxime (Vantin
®
) and cefixime (Suprax
®
).

Cefpodoxime: 10 mg/kg/day, divided in 2 oral doses; maximum daily dose 400 mg for
children < 12 years and maximum daily dose 800 mg for those ≥ 12 years) OR
Cefixime: (8 mg/kg/day as a single daily oral dose; maximum daily
dose 400 mg).

The antibiotic should be started 5 days prior to the start of irinotecan therapy only if
the patient experienced Grade 3 or 4 colitis, dehydration, diarrhea, abdominal pain, weight
loss or vomiting during prior therapy with irinotecan. If it is not feasible to start
Cefpodoxime or cefixime 5 days prior to therapy with irinotecan, give at least 1 full day of
Cefpodoxime or cefixime prior to the start of irinotecan course.

37

Table 6: Indications for Antibiotic Use (Cefpodoxime or Cefixime) for GI Toxicities

Due to Irinotecan

Toxicity Defined as
Abdominal
Pain
Severe pain, pain or analgesics severely interfering with activities
of daily living, disabling.
Colitis
(Grade 3 or 4)
Abdominal pain, fever, change in bowel habits with ileus or
peritoneal signs, and radiographic or biopsy documentation of
perforation or requiring surgery or toxic megacolon.
Dehydration Requiring IV fluid replacement (sustained), physiologic
consequences requiring intensive care, hemodynamic collapse.
Diarrhea Increase of ≥ 7 stools/day or incontinence; or need for
parenteral support for dehydration, severe increase in loose stool,
physiologic consequences requiring intensive care, hemodynamic
collapse, or watery stool output compared with pretreatment,
interfering with normal activity, physiologic consequences
requiring intensive care, hemodynamic collapse.
Vomiting ≥ 6 episodes in 24 hours over pretreatment, or need for IV
fluids requiring parenteral nutrition, or physiologic
consequences requiring intensive care, hemodynamic collapse.
Weight Loss > 20%

38

CHAPTER 4
REQUIRED OBSERVATIONS

Clinical and Laboratory Studies and Disease Evaluation
All entry/eligibility studies must be performed within 1 week prior to entry onto the trial
(unless otherwise specified). Imaging studies are required within 2 weeks of study entry. An
echocardiogram/MUGA may be done up to a month prior to study enrollment.
Table 7: Required Observations during Therapy

STUDIES TO BE
OBTAINED
Pre-
Study*
Course 1 Course 2 Subsequent
Courses
Off
Study
History X X X X X
Physical Exam (Ht, Wt,
BSA, VS)
X X X X X
Blood Pressure X X X X X
Performance Status X X X
CBC, differential,
platelets
1

X Two
times/week
Two
times/week
Two
times/week
2
X
PT, PTT, INR, D-dimer X X X X
Urine for UPC ratio
3
X X X X
BUN/Creatinine/Glucose X Weekly X X X
Electrolytes including
Ca++, PO
4
, Mg++
X X X X X
SGPT, Alk Phos, Bilirubin X Weekly X X
Echocardiogram/MUGA X End of
Course
X
Tumor Disease Evaluation
–By CT or MRI
4
X End of
course
End of 5
th

and 8
th

course
X
Nuclear Medicine Scan(s)
5
X End of
course
End of 5
th

and 8
th

course
X
39

Table 7, Continued
 Pre-study evaluation can be used as the initial evaluation for course 1.
1. CBC can be discontinued after hematological recovery
2. In patients who have received peg-filgastrim, CBC can be done once a week from 3
rd
cycle
3. If UPC (Urine Protein Creatinine) ratio > 0.5, 24-hour urine protein should be < 1,000 mg for
enrollment
4. Head CT or MRI at baseline is strongly encouraged at baseline to rule out occult brain metastases for
non brain tumor patients.
5. Nuclear medicine scans are only required in patients with evaluable disease but without measurable
disease. If initially negative, repeat scans are not required unless clinically indicated.
6. If there is suspected BM disease, a BM aspirate and biopsy must be performed within 4 weeks of
enrollment. If positive repeated after the 2
nd
, 5
th
and 8
th
course until clear of tumor cells.
7. If patients are found to have an open tibial growth plate, and then repeat plain AP radiographs of the
same tibial growth plate will be obtained at the end of 2
nd
, 5th, 8
th
course and at the end of the study.
8. Female patients with childbearing potential require a negative pregnancy test prior to starting
treatment.

Growth Plate Evaluation
Patients receiving bevacizumab will have a plain AP radiograph of a single tibial growth plate
obtained prior to initial treatment. If patients are found to have a closed tibial growth plate, no
further radiographs will be required. If patients are found to have an open tibial growth plate,
then repeat plain AP radiographs of the same tibial growth plate will be obtained at the end of
2
nd
, 5
th
, 8
th
course and at the end of study. The baseline radiograph will be compared with each
radiograph performed during follow-up. Patients with evidence of growth plate thickening or
Urinary Catecholamines
(Neuroblastoma patients
only)
X End of
Course
End of 5
th

and 8
th

course
X
Bone marrow aspirate and
biopsy
6

X
^
X
^
End of 5
th

and 8
th

course if
positive
X if
positive
Growth Plate Evaluation
7
X End of
Course
End of 5
th

and 8
th

course
X
Pregnancy Test
8
X
40

other changes should have a knee MRI performed to further assess the degree of physeal
pathology. Patients with abnormalities by MRI should continue to have radiographs of the
same tibial growth plate before odd-numbered cycles.
41

CHAPTER 5
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND
OFF STUDY CRITERIA

Criteria for Removal from Protocol Therapy
a. Progressive disease
b. Irreversible dose-limiting toxicity
c. Patient withdrawal from protocol
d. Physician determines it is not in the patient’s best interest to continue on protocol
therapy.
e. Entry onto another therapeutic study.
f. Diagnosis with a second malignant neoplasm
g. Thirty days after the last dose of the study drugs are given (but note that patients with
ongoing toxicity should be followed until the toxicity resolves even if it is longer than
30 days).
Patients who are off protocol therapy are to be followed until they meet the criteria for off
study (see below).

Off Study Criteria
a. Death
b. Lost to follow-up
c. Study closure*
42

* Following completion of protocol therapy vital status and disease status will be followed
based on routine clinical visits (not protocol specific visits) for a period of one year after all
enrolled subjects have completed therapy. At this time the study will be closed.

Definitions of Dose-Limiting Toxicity
Dose limiting toxicities are toxicities that occur in the first two courses of therapy, that are
possibly, probably or definitely attributable either to vincristine, irinotecan, temozolomide,
bevacizumab or their combination as defined below, with specific exceptions as enumerated.

Toxicity will be graded using the CTCAE criteria, version 4.0. A copy of the CTCAE can be
down loaded from the CTEP home page (http://ctep.cancer.gov).

Dose limiting hematologic and non-hematologic toxicities are defined separately.

Non-Hematologic Dose-Limiting Toxicity
1. Any Grade 3 or Grade 4 non-hematological toxicity possibly, probably or definitely
attributable to the investigational drug with the specific exclusion of:
a. Grade 3 nausea, vomiting or dehydration
b. Grade 3 diarrhea < 3 days, Grade 3 diarrhea regardless of duration if patient
did not receive appropriate Supportive care (cefixime, loperamide, or atropine
as outlined in Section 7.5)
c. Grade 3 transaminase (AST/ALT) elevation that returns to Grade ≤ 1 or
baseline prior to the time for the next treatment course
43

d. Grade 3 GGT
e. Grade 3 fever, febrile neutropenia, or infection
f. Grade 3 electrolyte abnormalities (Na, K, Cl, CO2, Ca, Mg, Phosphate) that
improve to ≤ Grade 2 within 7 days, with or without supplements
g. Vincristine-related neuropathy will NOT be considered DLT for the purposes
of this study
h. Grade 3 catheter related venous thrombosis
2. Grade 2 arterial thrombosis
3. Grade 2 pulmonary/CNS hemorrhage

Hematologic Dose Limiting Toxicity
 Grade IV neutropenia or Grade IV thrombocytopenia lasting > 14 days following the
combination vincristine, irinotecan, temozolomide and bevacizumab chemotherapy.
 Hematologic toxicity that causes a delay of ≥ 14 days beyond the planned interval
between treatment courses.

Suspected DLT requires a telephone call to the Principal Investigator or Co investigators as
soon as suspected. The requirement is that DLT are reported immediately to the research
coordinator via DLT- reporting CRF in addition to a telephone call to the PI or Co- PI. The
CRC, statistician and PI will immediately convene to review the DLT and determine whether
the study should continue or be suspended.
44

CHAPTER 6
STATISTICAL CONSIDERATIONS

Sample Size and Study Duration
This trial is a phase I evaluation of irinotecan, vincristine, temozolomide and bevacizumab and
G-CSF for hematopoietic support with the starting dose and schedule as stated in the treatment
plan section.

It is anticipated that 1-2 patients per month are available for enrollment, of which
approximately one half are less than 12 years of age at enrollment. The study will follow a
standard 3+3 patient cohort escalation design, with escalation through two dose levels and
possible de-escalation to one level below the starting dose level and one level below the
second dose level. A minimum of 6 patients and a maximum of 24 patients will therefore be
required to establish a recommended phase II dose (RP2D). Patients who do not receive a
complete course of treatment for reasons unequivocally unrelated to toxicity are considered
not evaluable for DLT evaluation and will be replaced.

Definitions
Evaluable For Toxicity
Dose escalation will not be considered until at least 3 evaluable patients have been entered at
the current dose level. For the purpose of dose escalation, a patient who experiences no DLT
will be evaluable for toxicity if the patient completes the first 2 courses.

45

Dose Escalation
Dose escalations will follow a standard 3-cohort escalation plan.
1. Three patients are studied at the first dose level.
a. If none of these three patients experience DLT, then the dose is escalated to the next
higher level in the three subsequent patients.
b. If one of three patients experiences DLT at the current dose, then up to three more
patients are accrued at the same level.
I. If none of these three additional patients experience DLT, then the dose is
escalated in subsequent patients.
II. If one or more of these three additional patients experiences DLT, then patient
entry at that dose level is stopped, the MTD has been exceeded and dose
escalation will be stopped. Three more patients are treated at the next lower
dose (unless six patients have already been treated at that prior dose).
c. If two or more patients experience DLT, then the MTD has been exceeded and dose
escalation will be stopped. Three more patients are treated at the next lower dose
(unless six patients have already been treated at that prior dose).

The estimated MTD is the highest dose level at which no more than 1/6 patients experience
DLT.
If the MTD has been exceeded at the dose level 1, then the subsequent cohort of patients will
be treated at dose level –1.

46

If the MTD has been exceeded at the dose level 2, then the subsequent cohort of patients will
be treated at dose level 1.5.
Patients are evaluable for DLTs only during the first two courses of therapy.
47

CHAPTER 7
EVALUATION CRITERIA

Common Terminology Criteria for Adverse Events v4.0 (CTCAE)
This study will utilize the National Cancer Institute (NCI) CTC Version 4.0. A copy of the
NCI-CTC version 4.0 can be downloaded from the CTEP home page
(http://ctep.info.nih.gov). Additionally, the toxicities are to be reported on the appropriate data
collection forms.

Response Criteria for Non CNS Solid Tumors
This study will use the (RECIST) Response Evaluation Criteria in Solid Tumor version 1.1
from the NCI. Response will be assessed using radiographic studies.

Measurable Disease
The presence of at least one lesion that can be accurately measured in at least one dimension
with the longest diameter at least 20 mm. With spiral CT scan, lesions must be at least 10 mm.
The investigator will identify up to 5 measurable lesions to be followed for response. Serial
measurements of lesions are to be done with CT or MRI. The same method of assessment is to
be used to characterize each identified and reported lesion at baseline and during follow-up.

Quantification of Disease Burden
The sum of the longest diameter (LD) for all target lesions will be calculated and reported as
the disease measurement.
48

Complete Response (CR)
Disappearance of all target lesions. If immunocytology is available, no disease must be
detected by that methodology.

Partial Response (PR)
At least a 30% decrease in the disease measurement, taking as reference the disease
measurement done to confirm measurable disease at study entry.

Progressive Disease (PD)
At least a 20% increase in the disease measurement, taking as reference the smallest disease
measurement recorded since the start of treatment; or the appearance of one or more new
lesions.

Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking
as reference the smallest disease measurement since the treatment started.

Response Assessment
Each patient will be classified according to their “best response” for the purposes of analysis
of treatment effect. Best response is determined from the sequence of the objective statutes
described above.

49

Best Response
Two objective status determinations of CR before progression are required for best response
of CR. Two determinations of PR or better before progression, but not qualifying for a CR, are
required for a best response of PR. Two determinations of stable/no response or better before
progression, but not qualifying as CR or PR are required for a best response of stable/no
response; if the first objective status is unknown, only one such determination is required.
Patients with an objective status of progression on or before the second evaluations will have a
best response of progressive disease. Best response is unknown if the patient does not qualify
for a best response of increasing disease and if all objective statuses after the first
determination and before progression are unknown.

Sequences of objective statuses with corresponding best response.
Table 8: Response Assessment Criteria
1
st
Status

2
nd
Status 3
rd
Status Best Response
Progression
Stable, PR, CR
Unknown
Stable
Stable, Unknown
Stable, Unknown
PR
PR
PR, CR
CR
Unknown

Progression
Progression
Stable
PR, CR
Unknown
PR
CR
Unknown
CR
Stable

Progression
Progression
Progression
Progression
Progression
Progression
Progression
Progression
Increasing Disease
Increasing Disease
Increasing Disease
Stable
Stable
Unknown
PR
PR
Unknown
CR
Stable

50

Patients with Evaluable, but not Measurable Disease Only
For patients with evaluable but not measurable disease, only CRs will be considered a
response, except for patients with neuroblastoma and germ cell tumors.

For patients with neuroblastoma who only had evaluable disease (i.e. limited to positive bone
scan, positive MIBG, or bone marrow) with elevated urinary catecholamine(s)
(Dopamine, HMMA/VMA or HVA), all of the following criteria must be met for at least 4
weeks to qualify as an objective response:
 MIBG - must show a decrease in activity if initially abnormal
 Urinary catecholamines - Dopamine, HMMA/VMA and HVA must decrease ≤ 50%
of baseline if initially abnormal
 Bone Marrow - if initially positive, must clear on biopsy
Progression (any of the following)
 Appearance of new areas of malignant disease.
 Worsening of symptoms directly attributable to malignant disease
 In the opinion of the investigator, progression of known sites of disease
 Sequences of objective statuses with corresponding best responses

For patients with germ cell tumors limited to positive bone scan or disease that is not
measurable and with elevated tumor markers, all of the following qualify as an objective
response:
 Sustained decline in tumor markers between chemotherapy courses
 Pre- course tumor marker level lower than the previous tumor marker level
51

Progression (any of the following)*
 Appearance of new areas of malignant disease.
 Worsening of symptoms directly attributable to malignant disease.
 In the opinion of the investigator, progression of known sites of disease.
 Sequences of objective statuses with corresponding best responses.
* For patients with large tumor burdens and responsive disease, tumor markers may first
increase before declining. In this case, response is based on radiographic imaging.

Response Criteria for CNS tumors (Macdonald et al., 1990)
Complete Response (CR)
No evidence of disease at the primary tumor site. Off all steroids with stable or improving
neurologic examination.

Partial Response (PR)
A greater than 50% reduction in the product of the greatest tumor diameter and its
perpendicular diameter on MRI scan, on a stable or decreasing dose of steroids with a stable or
improving neurologic examination.

Minor Response (MR)
A greater than or equal to 25% but less than or equal to 50% reduction in the product of the
greatest tumor diameter and its perpendicular diameter on MRI scan, on a stable or decreasing
dose of steroids with a stable or improving neurologic examination.

52

Stable Disease (SD)
A less than 25% reduction in the product of the greatest tumor diameter and its perpendicular
diameter on MRI scan, on a stable or decreasing dose of steroids with a stable or improving
neurologic examination.

Progressive Disease (PD)
A more than 25% increase in tumor size radiographically or the emergence of new lesions or
CSF positivity.
53

CHAPTER 8
ADVERSE EVENT REPORTING REQUIREMENTS

Adverse event data collection and reporting which are required as part of every clinical trial,
are done to ensure the safety of patients enrolled in the studies as well as those who will enroll
in future studies using similar agents. Adverse events are reported in a routine manner at
scheduled times during a trial. Additionally, certain adverse events must be reported in an
expedited manner to allow for optimal monitoring of patient safety and care. The following
sections provide information about expedited reporting.

Reporting requirements may include the following considerations:
1) The characteristics of the adverse event including the grade (severity), the relationship to
the study therapy (attribution), and the prior experience (expectedness) of the adverse event;
2) Whether or not hospitalization or prolongation of hospitalization was associated with the
event.

Steps to Determine If an Adverse Event Is to Be Reported In an Expedited Manner
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria for
Adverse Events (CTCAE, V4.0). The CTCAE provides descriptive terminology and a grading
scale for each adverse event listed. A copy of the CTCAE can be downloaded from the CTEP
home page (http://ctep.cancer.gov/reporting/ctc.html). Additionally, if assistance is needed,
the NCI has an Index to the CTCAE that provides help for classifying and locating terms. All
appropriate treatment locations should have access to a copy of the CTCAE.
54

Step 2: Grade the adverse event using the NCI CTCAE.
Step 3: Determine whether the adverse event is related to the protocol therapy
Attribution categories are as follows:
Unrelated, Unlikely, Possible, Probable, and Definite.
Note: This includes all events that occur within 30 days of the last dose of protocol treatment.
Any event that occurs more than 30 days after the last dose of treatment and is attributed
(possibly, probably, or definitely) to the agent(s) must also be reported according to the
instructions above.
Step 4: Determine the prior experience of the adverse event. Expected events are those that
have been previously identified as resulting from administration of the agent. An adverse
event is considered unexpected, for expedited reporting purposes only, when either the type of
event or the severity of the event is not listed in the drug information section of the protocol.

Review the Table below in this section to determine if:
• There are any protocol-specific requirements for expedited reporting of specific adverse
events that require special monitoring; and/or
• There are any protocol-specific exceptions to the reporting requirements.

55

Table 9: Phase I Trial Expedited Reporting Requirements for Adverse Events That
Occur Within 30 Days
1
of the Last Dose of Chemotherapy
Grade
1
Grade 2 Grade
3
Grade 3 Grade 3 Grades 4
& 5
2

Unexpe
cted
and
Expecte
d
Unexpect
ed
Expect
ed
Unexpected
With
Hospitalizat
ion
Unexpected
Without
Hospitalizat
ion
Expected
With
Hospitalizat
ion
Expected
Without
Hospitalizat
ion
Unexpect
ed and
Expected
Unrelate
d
Unlikely
Not
Require
d
Not
Required
Not
Requir
ed
5 Calendar
Days
Not
Required
5 Calendar
Days
Not
Required
24-Hour;
5
Calendar
Days
Possible
Probable
Definite
Not
Require
d
5
Calendar
Days
Not
Requir
ed
24-Hour;
5 Calendar
Days
24-Hour;
5 Calendar
Days
5 Calendar
Days
Not
Required
24-Hour;
5
Calendar
Days
1
Adverse events with attribution of possible, probable, or definite that occur greater than 30 days
after the last dose of treatment require reporting as follows:
24-hour notification (via E-mail or Telephone ) to Principal Investigator followed by complete
report within 5 calendar days for:
 Grade 3 unexpected events with hospitalization or prolongation of hospitalization
 Grade 4 unexpected events
 Grade 5 expected events and unexpected events
2
Although 24-hour notification is not required for death clearly related to progressive disease; a
full report is required as outlined in the table.

All deaths on study require both routine and expedited reporting regardless of causality.
Attribution to treatment or other cause should be provided.
• Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or
prolongation of existing hospitalization) must be reported regardless of attribution and
designation as expected or unexpected with the exception of any events identified as protocol
specific expedited adverse event reporting exclusions.
56

• Any event that results in persistent or significant disabilities/incapacities, congenital
anomalies, or birth defects must be reported if the event occurs following treatment on this
study.
• Any death that occurs more than 30 days after the last dose of treatment with an
investigational agent which can be attributed (possibly, probably, or definitely) to the agent
and is not due to cancer recurrence/progression must be reported.
• Grade 3 or 4 myelosuppression and ≤ Grade 3 febrile neutropenia do not require expedited
reporting

When to Report an Event in an Expedited Manner
• Some adverse events require notification within 24 hours (refer to Table A) to the Principal
Investigator/ Co-Principal Investigator via E-mail or telephone.
• When the adverse event requires expedited reporting, submit the report within 5 calendar
days of learning of the event.

Definition of Onset and Resolution of Adverse Events
a. If an adverse event occurs more than once in a course (cycle) of therapy only the most
severe grade of the event should be reported.
b. If an adverse event progresses through several grades during one course of therapy,
only the most severe grade should be reported.
c. The duration of the AE is defined as the duration of the highest (most severe) grade of
the Adverse Effects.
57

d. The resolution date of the AE is defined as the date at which the AE returns to
eligibility criteria level (note that the resolution date may therefore be different from
the date at which the grade of the AE decreased from its highest grade). If the AE
does not return to baseline the resolution date should be recorded as "ongoing."
e. An adverse event that persists from one course to another should only be reported
once unless the grade becomes more severe in a subsequent course. An adverse event
which resolves and then recurs during a different course, must be reported each course
it recurs.
f. Adverse events determined to be reportable must be reported according to the local
policy and procedures to the Committee on Clinical Investigations at Childrens
Hospital Los Angeles.

Reporting Secondary AML/MDS
All cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) that occur
in patients following their chemotherapy for cancer must be reported immediately to the
principal investigator.

Records and Reporting
Categories or Research Records
Study specific CRF in electronic form will be used. These will be stored in password protected
computers accessible only to investigators and study committee members.
When electronic forms are not available paper forms will be used. Research records for this
study will be maintained in locked cabinets accessible only to the investigators and study
58

committee members. Subject specific data will be maintained. Data will be retained at least for
three years following completion of the research study.

Data and Safety Monitoring Plan
The Principal Investigator or designee will be available at all times to answer questions that
may rise with patients on the research protocol. Regular meeting will be held with the entire
study committee at least once a month, once the first patient is accrued to review study
progress. Strict attention will be paid to the conduct of the study according to the protocol
since this is a Phase I study. Protocol procedures for safety monitoring have been delineated in
the previous sections. The study will continue only if there is unanimous agreement with
proceeding after each meeting. In addition, the external Data Safety Monitoring Committee of
the Children’s Center for Cancer and Blood Diseases will review the conduct of the study at 6
monthly intervals and as needed.

59

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Wagner, Lars M., Kristine R. Crews, Lisa C. Iacono, Peter J. Houghton, Christine E. Fuller,
M. Beth McCarville, Robert E. Goldsby, Karen Albritton, Clinton F. Stewart, and Victor M.
Santana. 2004. Phase I Trial of Temozolomide and Protracted Irinotecan in Pediatric Patients
with Refractory Solid Tumors. Clin Cancer Res 10, no. 3 (February 1): 840-848.
doi:10.1158/1078-0432.CCR-03-0175.

Wagner, Lars M., Nancy McAllister, Robert E. Goldsby, Aaron R. Rausen, Ren Y. McNall-
Knapp, M. Beth McCarville, and Karen Albritton. 2007. Temozolomide and intravenous
irinotecan for treatment of advanced Ewing sarcoma. Pediatric Blood & Cancer 48, no. 2:
132-139. doi:10.1002/pbc.20697.

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Wagner, Lars M., Judith G. Villablanca, Clinton F. Stewart, Kristine R. Crews, Susan
Groshen, C. Patrick Reynolds, Julie R. Park, et al. 2009. Phase I Trial of Oral Irinotecan and
Temozolomide for Children With Relapsed High-Risk Neuroblastoma: A New Approach to
Neuroblastoma Therapy Consortium Study. J Clin Oncol 27, no. 8 (March 10): 1290-1296.
doi:10.1200/JCO.2008.18.5918.

Willett, Christopher G, Yves Boucher, Emmanuelle di Tomaso, Dan G Duda, Lance L Munn,
Ricky T Tong, Daniel C Chung, et al. 2004. Direct evidence that the VEGF-specific antibody
bevacizumab has antivascular effects in human rectal cancer. Nature Medicine 10, no. 2
(February): 145-147. doi:10.1038/nm988.

Yang, James C., Leah Haworth, Richard M. Sherry, Patrick Hwu, Douglas J.
Schwartzentruber, Suzanne L. Topalian, Seth M. Steinberg, Helen X. Chen, and Steven A.
Rosenberg. 2003. A Randomized Trial of Bevacizumab, an Anti-Vascular Endothelial Growth
Factor Antibody, for Metastatic Renal Cancer. N Engl J Med 349, no. 5 (July 31): 427-434.
doi:10.1056/NEJMoa021491.
65

APPENDIX
SAMPLE RESEARCH INFORMED CONSENT

Childrens Hospital Los Angeles
CONSENT/PERMISSION/ASSENT
1
TO PARTICIPATE IN A RESEARCH STUDY

TREATMENT OF RELAPSED OR RESISTANT SOLID TUMORS
USING INCREASING DOSES OF INTRAVENOUS IRINOTECAN IN
COMBINATION WITH VINCRISTINE TEMOZOLOMIDE AND BEVACIZUMAB

PROTOCOL TITLE: A PHASE I STUDY OF VINCRISTINE, IRINOTECAN,
TEMOZOLOMIDE AND BEVACIZUMAB IN PEDIATRIC AND ADOLESCENT
PATIENTS WITH RECURRENT OR REFRACTORY SOLID TUMORS OF
NON- HEMATOPOIETIC ORIGIN

Subject’s Name:
CHLA# :
Birth
Date:

Introduction

You are being asked to participate in a research study conducted by Rajkumar
Venkatramani, M.D. from the Children’s Center for Cancer and Blood Diseases at
Children’s Hospital Los Angeles (CHLA). You are being asked to participate in this
study because your cancer has grown back (relapsed) or is not responding to standard
treatment. Standard treatment may have included chemotherapy, surgery, radiation
therapy and/or high-dose chemotherapy using your stem cells (called an autologous
stem cell transplant). It is expected that approximately 6-24 children and adolescents
will take part in this study. Participation in this study is completely voluntary. Please
read the information below, and ask questions about anything you do not understand,
before deciding whether or not to participate.

1
This form will also serve as the “Consent/Permission for Child to Participate in Research” form for the
parents to read and sign. In this case, “You” refers to “your child.”
66

Purpose of the Study

This research study is not designed to improve your condition. The goal of this
research is to find out the highest amount of study drugs you can tolerate. At this time,
there is no known effective treatment for your cancer once it becomes resistant to
standard therapy. This study will examine the effects of combining four chemotherapy
drugs, vincristine, irinotecan, temozolomide and bevacizumab (VIT-B) together.
These are chemotherapy drugs that have been given before to children with cancer.
The side effects and dose of these medications are known. These drugs have been used
before in various combinations. However, the combination of all four drugs has not
been studied before in adults or children. This is the first clinical research study to test
these four drugs together. Hopefully, this study will help find the highest dose of
irinotecan that can be safely given with vincristine, temozolomide and bevacizumab in
children and adolescents who have resistant or relapsed cancer.

Procedures

If you agree to be on this study, we will ask you to do the following things: Take some
blood tests and scans to see if your body can tolerate the study drugs and to see how
much cancer is in your body. If these tests have been done recently, they do not need
to be repeated. All these tests are not research tests, but are needed to safely give you
chemotherapy

Treatment Plan

Drug
How the drug will be
given
Days
Bevacizumab (B) IV (intravenous: given
through a vein)
Day 1 of each cycle
Vincristine (V) IV Days 1,8 of each cycle
Irinotecan (I) IV Days 1-5 of each cycle
Temozolomide (T) Orally Days 1-5 of each cycle

*The first dose of bevacizumab will be given over about 90 minutes, and if you do not have any bad
effects, the next time it is given the drug will be given over 60 minutes. If you do not have any bad
effects, the third dose and all the rest of the doses you get will be given over 30 minutes. Also, you
cannot have a bevacizumab dose close to the time of any surgical procedure (the time the dose must be
held depends on whether you need just a biopsy or a surgery to remove tumor).

67

The first group of subjects will get a dose of irinotecan that we think will be most safe.
The irinotecan dose will then be increased (“dose escalation”) in the second group of
research patients if no bad side effects are seen in the first group. This will be the last
group of subjects studied if no bad side effects are seen. 3-6 subjects will be treated on
each group as long as there are no harmful side effects noted. Your doctor will tell you
what dose you will get. If harmful side effects are seen, future research patients will be
treated with lower doses of irinotecan in combination with the other chemotherapy
medications.

If you have bad side effects, you can continue treatment with a lower dose of
irinotecan along with vincristine, temozolomide and bevacizumab provided your side
effects have gone away and your tumor is not getting worse or is getting better.

Other medications to help your blood counts recover or prevent complications may be
administered. Your doctor will decide if you will receive GCSF or a similar
medication to help with recovery of the white blood cell count.

Required Medical Tests

You will have a series of standard medical tests before, during and following
treatment. Researchers will use these tests to measure the effectiveness of the
treatment and what it is doing to your body.

Medical Tests Before and During Treatment

Physical exam
Bone marrow tests#
Blood tests
Various scans*
Pregnancy test (for females of child- bearing age -done only before starting treatment)
Urine tests
Echocardiogram (a test that uses sound waves to measure heart function)

# Bone marrow tests are done by inserting a needle into the hipbone to remove the
marrow, which is inside the bone. Sedation and pain medicine will be provided during
this test.

* Various scans are done for diagnosis and checking the response of the tumor to
treatment. These may include CT and /or MRI scans, MUGA scans (a scan that shows
the heart beating) and MIBG scans. We will recommend scans specific for your case
and we will answer your questions about these scans.
68

Medical Tests Following Treatment

Physical exam
Bone marrow tests#
Blood tests
Various scans*
Urine tests

The chart at the end of this form tells you when these tests need to be done. These
tests are not in excess of those that would be performed if you were seeking a similar
treatment.

You can continue to get treatment courses every 21-28 days for as long as your cancer
responds to the treatment or you do not have bad side effects and for a maximum of 12
courses. After you stop treatment, you will continue to have tests and scans done to
measure how much tumor is left. Your doctor will tell you how often these tests will
be done. Information on how you are doing will be recorded for one year after all
patients on this study have finished treatment. You can remove yourself from this
study at any time. In addition, your doctor may remove you from this study at any
time if he/she does not feel it is in your best medical interest.

Potential Risks and Discomforts

This is a Phase I study. A Phase I study gives increasing doses in successive groups of
patients until significant side effects occur. It is possible that no serious side effects
occur at the highest dose to be tested. Some side effects may be severe or even life
threatening. It is possible that death could occur due to side effects from this
treatment. Since this drug combination has not been studied before, there may be side
effects other than those listed which we cannot predict. You should discuss these risks
with your doctor. Patients are watched carefully and treatment will be stopped if
serious side effects occur. Treatment will be given to make the side effects less severe.

Many side effects go away shortly after the treatment is stopped, but in some cases
side effects may be long lasting or permanent. It is also possible that you may receive
a dose that is less than the one found to be most effective against tumors. While on
the study, you are at risk for the side effects listed below:

69

Risks and side effects related to Irinotecan include those which are:

Likely Less Likely Rare but Serious
 Diarrhea that can occur
during the infusion of
irinotecan or immediately
after and may be
associated with abdominal
cramping, a runny nose,
tearing, salivation,
sweating, flushing (feeling
of warmth and red cheeks),
and difficulty adjusting your
eyes to light.
 Nausea
 Vomiting
 Loss of appetite
 Fewer white blood cells
in the blood.
○A low number of white
blood cells can make it
easier to get infections
 Fever
 A feeling of weakness
and tiredness
 Hair loss
 Elevation in the blood of
certain enzymes or
bilirubin found in the liver
which could indicate liver
irritation or damage
 An increase in the blood
of a type of white blood cell
called an eosinophil. These
are sometimes associated
with allergic reactions.
 Inflammation and/or
sores in the mouth, throat
and/or esophagus
 Infections
 Fewer red blood cells and
platelets in the blood.
○A low number of red blood
cells can make you feel tired
and weak
○A low number of platelets
causes you to bruise and
bleed more easily
 Diarrhea that may occur
later from 1 day to 2 weeks
after irinotecan which could
cause excessive loss of
water and salts from the
body
 Constipation
 Pain at the injection site
 A slow heart beat
 Low blood pressure
 Shortness of breath with
cough
 Rash
 Headache
 Acid or an upset stomach
(heartburn)
 Confusion or sleepiness

 Severe allergic reaction
which can be life
threatening with shortness
of breath, low blood
pressure and a rapid heart
rate
 Severe loss of water from
the body (dehydration)
which if untreated may
cause low blood pressure
and severe loss of salts
such and sodium and
potassium from the body
and could lead to the
kidneys failing which could
be life-threatening
 Inflammation of the lungs
which could lead to chest
pain and shortness of
breath and which may be
life-threatening
 Inflammation of the part of
the intestine known as the
colon which can lead to
infection, blood in the
stools and abdominal pain
 Blood clots which may be
in rare cases life-
threatening
 A stoppage (or blockage)
of the intestine which may
require treatment

Irinotecan can cause bad diarrhea or other digestive problems. Not all subjects will
have bad diarrhea or other digestive problems. Using the supportive care drug
loperamide (also known as Imodium) may help prevent diarrhea. Using an
antibiotic might also help prevent diarrhea when irinotecan is given.

70

Risks and side effects related to Bevacizumab include those which are:

Likely Less Likely Rare but Serious
 A feeling of weakness
and/or tiredness
 Headache
 Bloody nose
 Protein in the urine
which may indicate kidney
damage
 Infections
 High blood pressure
 Diarrhea or Constipation
 Aches and pains in the
muscles and joints
 Nausea and/or vomiting
 Loss of appetite
 Cough
 Shortness of breath
 Itching
 Low white blood count
in combination with other
chemotherapy drugs

 Too much gas produced
in the intestines
 Acid or upset Stomach
(heartburn)
 Dry mouth or taste
changes
 Excessive tearing from
the eyes (watery eyes)
 Dizziness or fainting
 Numbness and tingling
in the fingers and toes
and/or increased sensitivity
to feeling such as touch or
pain
 Clotting of veins which
can lead to pain and
swelling in the area of the
clot. Such clots may also
break loose and cause
damage or be life-
threatening depending on
where they go.
 Irregular heart rate
 Loss of weight
 Fever, chills including
shaking chill
 Rash, hives, skin sores
 Hair loss
 Hoarseness or other
change in voice
 Pain in the chest, back
or abdomen (belly)
 Inflammation and/or
sores in the mouth that
may make swallowing
difficult and are painful
(painful mouth sores)
 Throat or sinus
inflammation or infection

 Bladder or kidney
infection
 Feelings of depression
 Drowsiness
 Severe allergic reaction
with the infusion which can
be life threatening with
shortness of breath,
wheezing, a very high blood
pressure, chills, sweating
and a headache
 Blood clots in the arteries
which can block the blood
flow to such areas as the
brain leading to strokes, the
heart with possible heart
attack, the intestines or the
legs. The lack of blood flow
can damage these organs.
These are more common in
older people with pre-
existing problems such as
heart or blood vessel
disease.
 Severe rashes which can
result in loss of skin and
damage to mucous
membranes and which may
be life-threatening
 Severe bleeding which
can occur in the head, lungs,
stools, urine and other parts
of the body and which may
be life threatening
 Inflammation of the part
of the intestines known as
the colon which can lead to
infection, blood in the stools
and abdominal (belly) pain
 An abnormal opening
(hole) in the wall of the
bowel that causes the
contents of the bowel to spill
into the abdominal cavity

 An abnormal connection
between the tube that goes
from the mouth and the
lining of the windpipe in
patients who have had
radiation to the head and
71

 Runny nose, sneezing
 Low blood pressure
 Bleeding the intestines
 Fewer white blood cells,
red blood cells and
platelets in the blood
o a low number of
white blood cells can make
it easier to get infections
o a low number of
red blood cells can make
you feel tired and weak
o a low number of
platelets causes you to
bruise and bleed more
easily
 Abnormal levels of
potassium in the body
which may require that you
take extra potassium by
mouth or vein
 Condition where the
blood contains more acid
than normal
 Increase in the blood of
certain enzymes or bilirubin
(a substance that comes
from the liver breaking
down waste products)
which could indicate liver
irritation or damage
 Increased levels of a
chemical (creatinine) in the
blood which could mean
kidney damage
A hole in the nasal septum,
the wall inside the nose
that runs down the middle
dividing it into two sides.
neck in combination with this
drug.
 Development of ulcers
(Erosion (ulceration) of the
lining of the intestines which
can result in pain and/or
bleeding)
 A bursting open or
splitting along
http://www.biology-
online.org/dictionary/surg
ical surgical suture lines
allowing a wound to reopen
 A stoppage (or blockage)
of the intestine which may
require treatment
 Damage to the heart
muscle which may make you
tired, weak, feel short of
breath, and retain fluid
 Damage to the kidneys
that causes protein to be lost
from the blood by leaking
from the kidneys into the
urine and causing swelling
usually in the legs and
ankles from fluid build-up in
body tissues
 Severe kidney damage
(which may be permanent)
 Damage to the brain
which may lead to difficulty
thinking, carrying out normal
tasks, seizures
(convulsions), difficulty
seeing, blindness, or other
visual changes, which if
caught early can be
reversed.

We do not know the effects of bevacizumab on bone growth in children taking
this medication.

72

Risks and side effects related to Temozolomide include those which are:

Likely Less Likely Rare But Serious
 Fewer red and white
blood cells and platelets in
the blood
o a low number of
red blood cells can make
you feel tired and weak
o a low number of
white blood cells can make
it easier to get infections
o a low number of
platelets causes you to
bruise and bleed more
easily
 Nausea
 Vomiting
 Constipation
 Loss of appetite

 Diarrhea
 Headache
 Tiredness
 Difficulty swallowing
 Dizziness
 Anxiety or depression
 Difficulty sleeping
 Rash
 Itching
 Increased need to
urinate
 Urinary tract infections
 Mouth sores
 Fluid buildup in legs
and arms
 Hair loss
 Elevation in the blood of
certain enzymes found in
the liver
 Visual disturbances that
may cause double vision
 Forgetfulness or
confusion
 Aches and pains in
muscles and joints
 Pain in the abdomen
 Convulsions
 Severe allergic reaction
which can be life
threatening with shortness
of breath, low blood
pressure, rapid heart rate,
chills and fever
 Low numbers of white
blood cells called
lymphocytes that may last
a long time and make it
easier to get infections
which may be life-
threatening
 Partial paralysis or
weakness of one side of
the body
 Blood clots which may
be life-threatening
 A new cancer or
leukemia resulting from this
treatment

73

Risks and side effects related to Vincristine include those which are:

Likely Less Likely Rare but Serious
 Hair loss
 Reversible nerve
problem that may affect
the way you walk or the
feelings in your fingers or
toes
 Constipation

 Jaw pain
 Headache
 Muscle Weakness
 Pain and bloating in your
abdomen
 Numbness and tingling
 Wrist or foot drop
 Drooping eyelids
 Double vision, difficulty
seeing at night
 Hoarseness of your
voice
 Difficulty sweating
 Abnormal walk with foot
slapping
 Difficulty with urination or
increased desire to urinate
 Dizziness and low blood
pressure when you stand
 Abnormal hormone
function which may lower
the level of salt in the blood
 A mild drop in white
blood cells, red blood cells
and platelets in the blood
o a low number of red
blood cells can make you
feel tired and weak
o a low number of
white blood cells can make
it easier to get infections
o a low number of
platelets causes you to
bruise and bleed more
easily

Complete stoppage of your
intestinal activity which can
result in intestinal blockage
 If the drug leaks out of
the vein when being
administered it will cause
damage to nearby tissue
 Seizures
 Vocal cord paralysis
 Difficulty breathing
 Inability to walk
 Decreased ability to hear
clearly
 Damage to the nerve of
the eye (optic nerve) leading
to decreased vision and
possible blindness
 In combination with other
chemotherapy drugs:
damage to the liver which
can lead to inflammation
and/or scarring which could
lead to a yellow appearing
skin, and fluid collection in
the abdomen (belly) which
makes it look larger

In addition to the risks described above, there may be unknown risks, or risks
that we did not anticipate, associated with being in this study.

You should not become pregnant or father a child while on this study. The medicines
used in the study may be dangerous to an unborn child. Patients and their sexual
partners should use abstinence and/or an effective method of birth control that is
74

medically appropriate based on your personal doctor’s recommendation. Please ask
about counseling and more information about preventing pregnancy.

The risks from having your blood taken are minimal, but can include an infection or a
blood clot. Experienced doctors or nurses will perform these blood draws to minimize
this risk.

There is the potential for unintentional disclosure of confidential information.

Anticipated Benefits to Subjects

This research is not being done to improve your cancer. It is being done to find out the
highest dose of vincristine, irinotecan, temozolomide and bevacizumab that can be
given to children and young adults without causing bad side effects. Your cancer may
not have any response to this treatment. However, no one can know in advance if
vincristine, irinotecan, temozolomide and bevacizumab will be helpful in your
particular case. Researchers believe that the combination of vincristine, irinotecan,
temozolomide and bevacizumab may shrink cancers that have relapsed or are no
longer responding to standard therapy. The potential benefits may be that the size of
your tumor may stay the same or become smaller for a short time.

Anticipated Benefits to Society

The information learned from this study may or may not benefit other children or
adolescents with cancer in the future.

Alternatives to Participation

Yes, there are other options for treatment. Instead of being in this study, you have
these options:

- All medications used in this clinical trial are commercially available. Various
combinations of these drugs can be used to treat you without participation on this
study.
- Treatment with other established chemotherapy medicines if available.
- Treatment with other experimental medicines that may be available.
- No cancer treatment at this time, but still receive medicines to help you feel
more comfortable.

Please talk about these options with your doctor.

75

Financial Obligation

All the drugs used on this study are commercially available. You and/or your
insurance company will need to pay for medicine needed to complete the study.

You and/or your insurance company will be charged for continuing medical care or
hospitalization.

Taking part in this study may lead to added costs that may be covered by your
insurance company. Please ask about any expected added costs or insurance problems.

You may have to pay for other things during this study, such as but not limited to,
your time, the cost of food you buy while you are being treated at the hospital, car
fare, parking, and babysitter fees.

Emergency Care and Compensation for Injury

The investigators and CHLA are not able to offer any financial compensation or
absorb the costs of treatment should you be injured as a result of participating in this
research.

If you believe that injury has been suffered as a result of participation in this study,
you should contact Dr. Rajkumar Venkatramani at 323-361-xxxx.

Privacy and Confidentiality

Members of the research team and, if appropriate, your physicians and nurses will
know that you are a research subject. All results will be kept confidential, but may be
made available to you, and/or your physician if you wish. Authorized representatives
from the Department of Health and Human Services (DHHS) and the CHLA
Committee on Clinical Investigations may need to review records of individual
subjects. As a result, they may see your name; but they are bound by rules of
confidentiality not to reveal your identity to others. No information about you, or
provided by you during the research will be disclosed to others without your written
permission, except:

- If necessary to protect your rights or welfare (for example, if you are injured and
need emergency care); or

76

- If required by law (i.e., child abuse, reports of certain infectious diseases).

When the results of the research are published or discussed in conferences, no
information will be included that would reveal your identity.

This study involves the treatment of a medical condition. Therefore, a copy of this
consent form will be placed in your medical record. This will allow the doctors that
are caring for you to obtain information about what medications or procedures you are
receiving in the study and treat you appropriately.

Participation and Withdrawal

Your participation in this research is VOLUNTARY. Your choice about whether or
not to participate will have no affect on your care, services or benefits at Childrens
Hospital Los Angeles. If you agree to participate, but later decide to withdraw from
this study, you may do so without affecting your rights to health care, services or other
benefits at Childrens Hospital Los Angeles.

Withdrawal of Participation by the Investigator

The investigator may withdraw you from participating in this research if necessary to
protect your health or if other situations arise that make it necessary to do so. If you
experience any serious following side effects or become ill during the research, you
may have to drop out, even if you would like to continue. The investigator, Dr.
Rajkumar Venkatramani will make the decision and let you and your parents know if
it is not possible for you to continue. The decision may be made either to protect your
health and safety, or because it is part of the research plan that people who develop
certain conditions may not continue to participate.

New Findings

If there is significant new information found during the course of the study or the
study plan is changed in ways that might affect your decision to participate in the
study, you will be informed, and your consent to continue participating in the study
may be obtained again.

Identification of Investigators

In the event of a research related injury or if you experience side effects, please
immediately contact one of the investigators listed below.
77

Daytime, Monday through Friday, 8:00 A.M. through 4:30 P.M. you may call Dr.
Rajkumar Venkatramani at 323-361-xxxx.

Evenings, nights, weekends or holidays you may call the hospital number, 323-660-
xxxx and ask for the Hematology-Oncology doctor on-call.

If your questions are not an emergency, you can obtain better information by calling
Dr. Rajkumar Venkatramani, Monday through Friday, 8:00 a.m. through 4:30 p.m.,
than by calling Hematology- Oncology on call service after hours.

Financial Interest of the Investigator

There is no funding for the conduct of this study provided by any governmental or
private agencies. If your physician is an investigator for this study s/he is interested in
both your healthcare and the conduct of this research. You are not under any
obligation to participate in a research study conducted by your doctor.

Rights of Research Subjects

You may withdraw from this study at any time and discontinue participation without
penalty. You are not waiving any legal claims, rights or remedies because of your
participation in this research study. If you have questions regarding your rights as a
research subject, you may contact the CHLA Office for Protection of Human Subjects
at (323) 361-xxxx.

78

SIGNATURE OF RESEARCH SUBJECT (If the subject is 14 years or older)

Your signature below indicates
 You have read this document and understand its meaning;
 You have had a chance to ask questions and have had these questions
answered to your satisfaction;
 You consent/assent to your participation in this research study; and
 You will be given a signed copy of this form, the Experimental Subject’s Bill
of Rights and the HIPAA authorization form.

__________________________________________
Name of Subject

__________________________________________ _____________________
Signature of Subject Date

SIGNATURE OF PARENT(S)/LEGAL GUARDIAN(S) (If the subject is a minor)
Your signature(s) below indicates
 You have read this document and understand its meaning;
 You have had a chance to ask questions and have had these questions answered
to your satisfaction;
 You agree to your child’s participation in this research study;
 You will be given a signed copy of this form, the Experimental Subject’s Bill
of Rights and the HIPAA authorization form.

____________________________ _________________________________
Name(s) of Parent(s)/Legal Guardian

________________________________________ _________________________
Signature of Parent (Legal Guardian) Date

________________________________________ _________________________
Signature of Parent (Legal Guardian) Date

79

SIGNATURE OF INVESTIGATOR/PERSON OBTAINING CONSENT
I have explained the research to the subject and/or the subject’s parent(s)/legal
guardian(s) and have answered all of their questions. I believe that they understand all
of the information described in this document and freely give
assent/consent/permission to participate.

________________________________________
Name of Investigator/Person obtaining consent

________________________________________ ____________________
Signature of Investigator/Person obtaining consent Date (must be the same date as
subject’s)

SIGNATURE OF WITNESS (if applicable)
My signature as Witness indicates that the subject and/or the subject’s
parent(s)/guardian(s) voluntarily signed this assent/consent/permission form in my
presence.

________________________________
Name of Witness

________________________ _________________________________
Signature of Witness Date (must be the same date as subjects)

80

SIGNATURE OF INTERPRETER (if applicable)

________________________________
Name of Interpreter

________________________________ _________________________________

Signature of Interpreter Date (must be the same date as subjects)

Complete if applicable (i.e. form is being used as parental permission and
assent was not obtained):
Please check appropriate box and sign below.

Investigator/person obtaining consent’s statement of certification for subjects less
than seven years of age (assent):

The undersigned, _____________________, hereby certifies that he/she has
discussed all the information contained in the study consent to the subject, and has
explained all the information in the study consent to the participant/patient,
including any risks that may reasonably be expected to occur. The undersigned
further certifies that the subject was encouraged to ask questions, that all questions
were answered, and that assent was obtained.

Assent was not obtained for a subject under 18 years of age. (Please state the
reason. Examples include: child is an infant; child is comatose; child lacks cognitive
abilities to understand the information.)

____________________________________________________________________
____________________________________________________________________

Date:_____________

Time:______________
Signature_________________________________________

81

Routing of signed copies of the consent form:
1) Give to the parent/adult subject (copy)
2) Place in the CHLA Medical Record (copy)
3) Place in the Principal Investigator's research file (original)

Consent Addendum: Tests to be done while on this research study

STUDIES TO BE
OBTAINED
Pre-Study Course 1 Course 2 Subsequent
Courses
Off
Study
History X X X X X
Physical Exam (Ht, Wt,
BSA, VS)
X X X X X
Blood Pressure X X X X X
Performance Status X X X
CBC, differential,
platelets
1

X Two
times/week
Two
times/week
Two
times/week
2
X
PT, PTT, INR, D-dimer X X X X
Urine for UPC ratio
3
X X X X
BUN/Creatinine/Glucose X Weekly X X X
Electrolytes including
Ca++, PO
4
, Mg++
X X X X X
SGPT, Alk Phos,
Bilirubin
X Weekly X X
Echocardiogram/MUGA X End of
Course
X
Tumor Disease
Evaluation –
By CT or MRI
4
X End of
course
End of 5
th
and
8
th
course
X
Nuclear Medicine
Scan(s)
5
X End of
course
End of 5
th
and
8
th
course
X
Urinary Catecholamines
(Neuroblastoma patients
only)
X End of
Course
End of 5
th
and
8
th
course
X
Bone marrow aspirate
and biopsy
6

X
^
X
^
End of 5
th
and
8
th
course if
positive

Growth Plate Evaluation
7
X End of
Course
End of 5
th
and
8
th
course
X
Pregnancy Test
8
X
82

OBTAIN OTHER STUDIES AS NEEDED FOR GOOD PATIENT CARE

1. CBC can be discontinued after hematological recovery.

2. In patients who have received peg-filgastrim, CBC can be done once a week from
3
rd
cycle.

3. If UPC (Urine Protein Creatinine) ratio > 0.5, 24-hour urine protein should be <
1,000 mg for enrollment.

4. Head CT or MRI at baseline is strongly encouraged at baseline to rule out occult
brain metastases for non brain tumor patients.

5. Nuclear medicine scans are only required in patients with evaluable disease but
without measurable disease. If initially negative, repeat scans are not required unless
clinically indicated.

6. If there is suspected BM disease, a BM aspirate and biopsy must be performed
within 4 weeks of enrollment. If positive repeated after the 2nd, 5th and 8th course
until clear of tumor cells.

7. If patients are found to have an open tibial growth plate, and then repeat plain AP
radiographs of the same tibial growth plate will be obtained at the end of 2nd, 5th, 8th
course and at the end of the study.

8. Female patients with childbearing potential require a negative pregnancy test prior
to starting treatment.

Abstract (if available)

Abstract Vincristine, irinotecan and temozolomide have been used in various combinations to treat pediatric solid tumors. These combinations, in general have been well tolerated. Outcomes for patients with solid tumors who have been treated with various cytotoxic agents have reached a plateau over the last two decades, with similar responses in various resistant cancers. Incorporation of newer agents with different mechanisms of action with cytotoxic chemotherapy may improve response rates and outcomes. Recently several agents that target similar pathways in a broad range of cancers have become available. Only few of them have been tested in the pediatric population. Bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF) is one such agent. The novel combination of vincristine, irinotecan, temozolomide and bevacizumab with their unique mechanisms of action and non-overlapping dose limiting toxicity could be useful in refractory solid tumors. This phase I study is designed to determine the maximum tolerated dose of irinotecan given intravenous for 5 days every 3 weeks in combination with fixed doses of vincristine, temozolomide and bevacizumab (VIT-B).

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Asset Metadata

Creator Venkatramani, Rajkumar (author)

Core Title A phase I study of vincristine, escalating doses of irinotecan, temozolomide and bevacizumab (VIT-B) in pediatric and adolescent patients with recurrent or refractory solid tumors of non-hematopo...

School Keck School of Medicine

Degree Master of Science

Degree Program Preventive Medicine (Health Behavior)

Publication Date 10/21/2010

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag bevacizumab,clinical trial,OAI-PMH Harvest,phase I study

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Siegel, Stuart E. (committee chair), Azen, Stanley Paul (committee member), Mascarenhas, Leo (committee member)

Creator Email rajkumav@usc.edu,rvenkatramani@chla.usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-m3508

Unique identifier UC196566

Identifier etd-Venkatramani-4152 (filename),usctheses-m40 (legacy collection record id),usctheses-c127-409812 (legacy record id),usctheses-m3508 (legacy record id)

Legacy Identifier etd-Venkatramani-4152.pdf

Dmrecord 409812

Document Type Thesis

Rights Venkatramani, Rajkumar

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Repository Name Libraries, University of Southern California

Repository Location Los Angeles, California

Repository Email cisadmin@lib.usc.edu