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Eribulin in advanced bladder cancer patients: a phase I/II clinical trial

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Eribulin in advanced bladder cancer patients: a phase I/II clinical trial

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Content 1

ERIBULIN IN ADVANCED BLADDER CANCER PATIENTS:
A PHASE I/II CLINICAL TRIAL

by

Chuqing Yao

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
(BIOSTATISTICS)

December 2015

2

Acknowledgement

I would like to express my deep and sincere gratitude to my thesis chair Dr. Susan Groshen for
her patience, encouragement and enthusiastic supervision during this process. She has been an
excellent mentor to me. I would like to thank my thesis committee members Dr. Richard Sposto
and Dr. Wendy Mack for their helpful suggestions and support.

3

Table of Contents
1. Introduction ................................................................................................................................ 5
1.1. Bladder Cancer............................................................................................................. 5
1.2. Halichondrin analog, Eribulin ...................................................................................... 5
1.3. Phase I and Phase II Studies ....................................................................................... 6
1.3.1. The Initial Phase I/II Study of Eribulin in Metastatic Bladder Cancer ........ 6
1.3.2. Rationale/Background for Extended Phase II Study ................................... 7
1.3.3. Rationale/Background for Extending Accrual of Women to Compare Men
and Women .............. .............................................................................................. 7
1.4. Purpose of this Thesis .................................................................................................. 7
2. Methods...................................................................................................................................... 8
2.1. Patient .......................................................................................................................... 8
2.2. Treatment Plan ........................................................................................................... 11
2.3. Study Calendar ........................................................................................................... 11
2.4. Phase I Design............................................................................................................ 12
2.4.1. Definition of Dose Limiting Toxicity (DLT)............................................. 12
2.4.2. Definition of Maximum Tolerated Dose (MTD) ....................................... 13
2.4.3. Definition of Evaluable for Assessment of Toxicity and DLT .................. 13
2.4.4. The Modified 3+3 Design .......................................................................... 14
2.5. Phase II Design .......................................................................................................... 15
2.5.1. Definition of Evaluable .............................................................................. 16
2.5.2. Response Criteria ....................................................................................... 16
2.5.3. Simon Optimum two-stage design ............................................................. 17
3. Data Analysis Plan ................................................................................................................... 18
3.1. Definition of Analysis Sets ........................................................................................ 18
3.2. Endpoint Data Analysis ............................................................................................. 18
3.2.1. Demographics ............................................................................................ 18
3.2.2. Summary of Trial Status ............................................................................ 18
3.2.3. Treatment Administration .......................................................................... 19
3.2.4. Safety Endpoint .......................................................................................... 19
3.2.5. Outcome ..................................................................................................... 20
4

4. Results ...................................................................................................................................... 22
4.1. Demographics ............................................................................................................ 22
4.2. Summary of Trial Status ............................................................................................ 23
4.3. Treatment Received ................................................................................................... 25
4.4. Summary of Toxicities ............................................................................................... 26
4.5. Progression Free Survival and Overall Survival ........................................................ 28
5. Discussion ................................................................................................................................ 34
Bibliography ................................................................................................................................. 36
Appendix........................................................................................................................................38

5

1. Introduction
1.1. Bladder Cancer
Approximately 110,500 men and 70,000 women worldwide are diagnosed with new cases of
urothelial bladder cancer each year.
1
Of the new tumors, 25% are muscle-invasive; the majority
of deaths due to bladder cancer involve muscle-invasive disease.
2
Currently, the regimens
methotrexate-vinblastine-adriamycin-cisplatin (MVAC) and gemcitabine, cisplatin (GC) are the
standard of care for patients with advanced bladder cancer.
3
However, for both regimens, the
overall median survival is still only between 12 and 17 months with response rates of 40% to
50%.
4
In addition, patients who have significant kidney dysfunction are often ineligible for these
platinum-based therapies due to toxic side effects. There is no standard of care yet to treat
advanced and metastatic bladder cancer patients with renal dysfunctions. Eribulin is a novel
chemotherapy agent that can potentially fulfill this unmet need. Eribulin is primarily
metabolized in the liver; therefore, it is expected to be well tolerated by patients with renal
dysfunction.
5

1.2. Halichondrin analog, Eribulin
Eribulin is a synthetic analogue of the marine sponge natural product halichondrin B.
6
It inhibits
tumor cell proliferation by targeting tubulin and microtubules responsible for proper function of
the mitotic spindle.
7
Data from previous Phase I and Phase II trials have shown that the dose of
1.4mg/m
2
given on days 1 and 8 on a 21 day cycle was well tolerated in patients with normal
kidney functions.
8,9

6

1.3. Phase I and Phase II Studies
In general, the purpose of Phase I study is to understand drug tolerance, determine the organ
systems that are affected by the drug, estimate maximum tolerated dose (MTD), and recommend
a dose for next testing. Because of the uncertainty about safety, only a small number of subjects
are tested and they are usually people whose tumors fail to respond to existing standard
therapies. The Phase II trial is designed to gather information on feasibility and efficacy, refine
estimates of toxicity and side effects and provide further information on drug pharmacology.
Phase II study uses a fixed dose established from Phase I to decide whether a larger Phase III
trial is warranted.

1.3.1. The Initial Phase I/II Study of Eribulin in Metastatic Bladder Cancer
When the protocol was first written, this trial was referred to as a Phase I/II trial; but more
appropriately, this is a Phase II clinical trial of Eribulin in Patients with advanced or metastatic
bladder cancer, with a safety lead-in Phase I trial in patients with moderate and severe renal
dysfunction. The objective of the safety lead-in Phase I portion of this trial was to establish that
Eribulin can be given safely to patients with advanced or metastatic bladder cancer and moderate
or severe renal dysfunction at 1.4 mg/m²/week (the dose recommended previously for patients
with normal renal function) on days 1 and 8 of a 21-day cycle. The objectives of the Phase II
portion of this study include:
 Document the toxicity attributed to the administration of Eribulin to patients with
advanced bladder cancer and varying degrees of renal dysfunction.
 Determine the response rate of patients with untreated bladder cancer to Eribulin.
7

 Determine the progression free survival and overall survival of patients with advanced
bladder cancer treated with Eribulin at 6, 12, and 24 months.

1.3.2. Rationale/Background for Extended Phase II Study
Given the potential of Eribulin as a second line therapy, a protocol amendment to the original
Phase II trial was made to accrue patients previously treated with up to two lines of treatment for
advanced bladder cancer. Since Eribulin is a tubulin inhibitor, two cohorts were selected based
on whether the patients had received a prior tubulin inhibitor treatment or not.

1.3.3. Rationale/Background for Extending Accrual of Women to Compare Men and
Women
The Phase II trial was expanded to accrue more female patients to study the effects of Eribulin
on female patients compared to male patients. The rationale for this expansion is that although
bladder cancer is much more common in men than women, women with muscle invasive bladder
cancer have consistently worse outcomes compared to men.
10
Few prospective evaluations of
toxicity, response, and survival have been carried out to investigate this gender-based disparity in
bladder cancer mortality.

1.4. Purpose of this Thesis
The goal of this thesis was to summarize the results of a Phase I and II clinical trial by describing
patient characteristics, amount of treatment given, toxicity, response rate, progression free
survival and overall survival. The associations of progression free survival and overall survival
with covariates: prior treatment, gender and renal function were explored.
8

2. Methods
2.1. Patient
Patients were recruited from the University of Southern California (USC), City of Hope Cancer
Center (COH) and the Cancer Center at UC Davis (UCD). To be eligible for the trial, they had to
have locally advanced or metastatic bladder cancer that could not be treated with surgeries. The
Phase I portion included patients with moderate or severe renal dysfunction – regardless of
amount of prior therapy. The original Phase II included patients with normal renal function who
had no prior treatment. Patients from Phase I who were treated at the highest dose (1.4 mg/m
2
)
and who did not have prior treatment were also included in Phase II (6 patients) for analysis. The
extended Phase II included patients who had received at least one platinum-based chemotherapy
for recurrent/advanced disease: one cohort for patients who received a prior tubulin-inhibitor
treatment and another cohort for patients who were tubulin-naive. Please refer to Appendix A for
detailed inclusion and exclusion criteria.

This trial is ongoing. For the purpose of this thesis, additional accrual of female patients was not
included because it is too early for evaluation. However, gender-based differences were analyzed
based on the original accrual that was completed for preliminary results.

9

Figure 1 summarizes the flow of the study. The Phase I portion (for patients with renal
impairments and with or without prior therapy) and the original Phase II portion (for untreated
patients with no renal impairment) opened at the same time. Once the Phase I portion was
completed, patients treated at 1.4 mg/m²/week without prior therapy from Phase I were folded
into Phase II. The Phase II portion was opened to include patients with renal impairment;
Phase II was additionally extended to include patients with prior treatments. A total of 154
patients were presented in this figure. There were 23 patients in the Phase I portion and there
were 137 patients in the Phase II portion. 6 patients were included in both the Phase I portion and
the Phase II portion since these patients from the Phase I portion also meet the eligibility criteria
for the Phase II portion.

10

Figure 1. Study Flow Schema

11

2.2. Treatment Plan
For Phase I, Eribulin was given at a dose of 0.7 mg/m
2
/week, 1.0 mg/m
2
/week, or 1.4
mg/m
2
/week on days 1 and 8 of a 21-day cycle. For Phase II, Eribulin was given at 1.4
mg/m
2
/week on days 1 and 8 of a 21-day cycle. A total of three courses were given during each
cycle.

2.3. Study Calendar
Eribulin was administered, adverse events were evaluated, and tumor response were measured
according to the study calendar below.

Pre-
study
Day
1
Day
8
Day
21

Day
1
Day
8
Day
21

Off-
study

Cycle 1
(21 days)

Cycle 2, 3, 4,…
(each cycle =21 days

Eribulin X X X X
Informed Consent X
Adverse Event
Evaluation
X X X X X X X X
Tumor Measurements X
Tumor measurements are repeated every six weeks
(after every 2 cycles). Documentation (radiologic)
must be provided for patients removed from study
for progressive disease.
X

12

2.4. Phase I Design
Eribulin was given to patients with advanced or metastatic bladder cancer and moderate or
severe renal dysfunction at 1.4 mg/m²/week (the dose recommended previously for patients with
normal renal function) on days 1 and 8 of a 21-day cycle. The modified 3+3 design was used
(described in section 2.4.4). The dose levels were escalated from 0.7 mg/m²/week, to 1.0
mg/m²/week, and to 1.4 mg/m²/week. Patients were stratified into two groups:
Group A – moderate renal dysfunction:
 calculated creatinine clearance ≥40 and <60 mL/min
Group B – severe renal dysfunction:
 calculated creatinine clearance ≥20 and <40 mL/min.

2.4.1. Definition of Dose Limiting Toxicity (DLT)
Toxicities were graded according to the NCI Common Terminology Criteria for Adverse Events
(CTCAE). Toxicities experienced in the Phase I trial and the initial Phase II trial used CTCAE
v3; toxicities experienced in the extended initial Phase II trial used CTCAE version 4 . Patients
could continue being treated until they experienced unacceptable toxicity or disease progression.
However, for the Phase I trial, to select a starting dose for future studies, we focused on the 1
st

21-day cycle. DLTs occurring during the first cycle of treatment were used in the decisions to
dose escalate, expand the dose, or terminate dose escalation. As specified in protocol v.4, the
following treatment-related adverse events (AEs) were considered dose limiting toxicities in
patients with renal dysfunction:
 Any grade 3 or greater non-hematologic toxicity (excluding alopecia, hypersensitivity,
fatigue and renal abnormalities)
13

 Uncomplicated grade 4 neutropenia lasting more than 7 days (Note: lymphopenia and
leucopenia of any grade are not DLTs.)
 Occurrence of neutropenic fever with ANC < 1.0 x 109/L
 Grade 4 thrombocytopenia
 Grade 3 nausea and vomiting if it occurs despite maximal (5HT antagonist and
corticosteroid) antiemetic therapy, and if hydration is required for >24 hours.
 Grade 3 diarrhea despite patient compliance with loperamide therapy.
 Renal toxicity thought to be related to Eribulin
- Patients in moderate dysfunction group (Group A): 1.5 times increase from
baseline serum creatinine, lasting for >2 weeks.
- Patients in severe dysfunction group (Group B): 1.5 times increase from baseline
serum creatinine for > 2 weeks.
 Treatment delays of 2 weeks due to treatment-related toxicity constituted a DLT.
2.4.2. Definition of Maximum Tolerated Dose (MTD)
The MTD is the highest dose at which no more than one instance of DLT is observed (among 6
patients treated).

2.4.3. Definition of Evaluable for Assessment of Toxicity and DLT
 To be evaluable for a dose escalation or expansion decision: patient must had completed 1
course (i.e. receive 2 full doses) or experienced a DLT
 To be evaluable for toxicity: a patient must had started treatment (i.e. received any amount
of Eribulin)
14

Toxicities attributed to a patient's primary renal dysfunction were not considered in the
determination of DLT, MTD, and dosing recommendations, unless sudden changes in these
parameters occurred in a temporal relationship to administration of Eribulin.
2.4.4. The Modified 3+3 Design
In this Phase I trial, the standard 3+3 design was used with modification. The standard 3+3
design uses the following rules to decide when to dose escalate, dose expand, and dose de-
escalate:
 Pre-specify doses to consider
 Treat 3 patients at dose level X
o If 0 patients experience DLT, escalate to dose level X+1
o If 1 patient experiences DLT, treat 3 more patients at dose level X.
 If ≥2 of 6 experiences DLT, de-escalate to dose level X-1
 If 1 of 6 experience DLT, escalate to dose level X+1
o If ≥2 patients experience DLT, de-escalate to dose level X-1
The modification to the 3+3 design was based on the assumption that patients with moderate
renal insufficiency would tolerate Eribulin better than patients with severe renal insufficiency.
Therefore, patients with severe renal insufficiency could not be treated at a dose that was not
tolerated in the moderate renal insufficiency group; and conversely, if a dose was found to be
well tolerated in the severe renal insufficiency group, patients in the moderate renal insufficiency
group could be escalated to that dose.
The standard 3+3 design is a rule-based design, rather than a model-based design. This design is
very commonly used for cancer research in an ad hoc manner.
11
A simulation study comparing
15

nine Phase I designs have demonstrated that the toxicity of the 3+3 design was the lowest among
these nine designs; however, the 3+3 design treated half of the patients at sub-therapeutic dose
levels of toxicity ≤10%.
12
New trial designs are sometimes more efficient than the standard 3+3
design in treating higher proportion of patients at or near the recommended dose for Phase II
trials and/or reducing the duration of accrual.
13
Our modification to the 3+3 design, based on the
assumption that if Eribulin is tolerated in patients with severe renal dysfunction at a specific dose
level, then Eribulin would also be tolerated in patients with moderate renal dysfunction at the
same dose level, allowed us to reduce the number of patients treated below the recommended
dose level and resulted in faster completion of accrual. It is crucial to continue to assess toxicity
in subsequent Phase II trials.

2.5. Phase II Design
Accrual of patients with normal renal function to the Phase II portion of the study began at the
same time as accrual of patients with abnormal renal function to the Phase I portion of the study.
The Phase II portion of the study was expanded to include patients with renal insufficiency once
it was shown that 1.4 mg/m
2
/week on days 1 and 8 of a 21-day cycle could be given safely to
patients with renal insufficiency. The original Phase II study was directed towards patients with
advanced bladder cancer with normal renal function who had not received any chemotherapy for
the advanced disease; once the Phase I portion was completed, patients with moderate or severe
renal insufficiency (calculated creatinine clearance > 20 mL/min) were also eligible. A Simon
two-stage design (described in section 2.5.3) was used to establish whether there was a robust
signal of anti-tumor activity (based on objective tumor response). Based on the encouraging
results of the initial Phase II trial, an amendment to protocol was made to perform an additional
16

(extended) Phase II trial which would include patients with advanced bladder cancer, who had
received a platinum-based chemotherapy for advanced bladder cancer, and who have a
calculated creatinine clearance > 20 mL/min. In this second Phase II trial, two cohorts of patients
were evaluated separately based on prior tubulin inhibitor exposure: (Cohort 1) patients who
were previously treated with a tubulin-inhibitor for the recurrent/advanced disease and (Cohort
2) patients who had no prior a tubulin-inhibitor treatment for the recurrent/advanced disease.
These cohorts followed the same Simon Optimum two-stage design as the original trial with a
target rate for response of 20% to warrant further study.

2.5.1. Definition of Evaluable Patients
 Evaluable for response: all eligible patients who start treatment were counted in the
summaries of response (and progression-free and overall survival)

2.5.2. Response Criteria
The established response criteria for solid tumors (RECIST v1) was used to assess tumor burden
and changes to tumor burden after treatment as specified in the protocol v.4. The response
categories are summarized briefly below:
 Complete Response (CR): Disappearance of all tumor lesions
 Partial Response (PR): At least a 30% decrease in the sum of the longest diameters (LD) of
target (measureable) lesions, and no unequivocal increase in the size of lesions that cannot be
reliably measured, and no new tumor lesions
17

 Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions,
taking as reference the smallest sum LD recorded since the treatment started, 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
Definition of Objective response: CR or PR that is confirmed to persist for at least 4 weeks
2.5.3. Simon Optimum two-stage design
A Simon Optimum two-stage design was used for the initial Phase II trial and for each cohort in
the Extended Phase II Trial. If the response rate (defined as the percent of patients who start
treatment and experience a complete response or partial response) is clearly greater than 5%, it
would indicate clinical activity as a single agent in treating bladder cancer; if the response rate is
clearly less than or equal to 20%, further testing as a single agent would not be pursued. This
design allows early stopping for futility. Formally, in terms of statistical hypothesis testing, this
can be stated as:
H
0
: p ≤ 5%
H
a
: p ≥ 20%
This design has a type I error rate of 5% (when the true response rate is 5%) and a power of 90%
(when the true response rate is 20%).
Stage 1: continue if more than 2 eligible patients experience objective response out of the
initial 21 patients
Stage 2: recommend further study if more than 5 patients experience objective response
out of 41 patients
18

3. Data Analysis Plan
3.1. Definition of Analysis Sets
 Safety analysis set: All enrolled subjects who received any amount of the study drug
(n=154).
 Outcome analysis set*: All eligible subjects who received any amount of the study
drug (n=137).
*Note: 6 patients from Phase I who met the eligibility criteria for Phase II were
included in the analysis of response rate, progression free survival, and overall
survival. For descriptive statistics, these 6 patients were kept in their original
assignment (Phase I).

3.2. Endpoint Data Analysis
3.2.1. Demographics
Demographic and clinical characteristics including gender, race, age and renal function were
summarized by trial Phase and prior treatments. These variables were presented as categorical
variables and summarized by frequencies and percentages.

3.2.2. Summary of Trial Status
Accrual to each dose level and treatment cohort was summarized by number of patients entered,
number of patients eligible, number of patients evaluable for toxicity, number of patients with
DLT, and number of patients who completed the first course for Phase I. Number of patients
entered, number of patients eligible, number of patients evaluable for response, number of
patients completed first course, number of patients with objective response, and response rate
19

with 95% confidence interval were summarized for each cohort in the Phase II trial. In addition
to the original analysis plan, exploratory analysis was performed to compare response rates
among prior treatment cohorts using Fisher's exact test. Two-tailed p-values with a significance
level of 0.05 were reported.

3.2.3. Treatment Administration
For each dose level and treatment cohort, the number of courses started, number of courses
completed, ratio of actual dose received vs. expected dose for first course, and ratio of actual
dose received vs. expected dose for all courses were be summarized using median, minimum,
maximum, first quartile (25th percentile) and third quartile (75th percentile).

3.2.4. Safety Endpoint
Safety was evaluated through summarization of adverse events. The frequency of adverse events
at least possibly (possible, probably, definitely) attributable to Eribulin, for the first course, was
reported by study Phase and prior treatment. Summaries were presented by the severity of the
adverse events from grade 1 to grade 5, with grade 5 being the most severe, per Common
Terminology Criteria for Adverse Events [CTCAE]. Although CTCAE version 3 was used in
the Phase I and the initial Phase II trial, these toxicity grades were converted over to version 4, in
order to be combined with the toxicities observed and reported in the extended Phase II portion
which used version 4.

20

3.2.5. Outcome
All eligible patients who started treatment in the Phase II portion and the 6 patients from the
Phase I portion who met the Phase II eligibility criteria were included in the analysis set for
progression free survival and overall survival. A total of 137 patients were included. Intent to
treat analysis was used.

Response rate
The overall response rate was calculated as the ratio of the number of eligible patients who
experienced a confirmed CR or PR (by RECIST v1.1) divided by the total number of eligible
patients who began treatment.

Progression-free Survival
Progression-free Survival (PFS) was defined as the interval from the start of treatment on Day 1
to the first documentation of disease progression or death from any cause. For patients who had
not progressed or died at the time of analysis, PFS was censored on the date of last disease
assessment. The Kaplan-Meier product-limit method was used to estimate the probability of
remaining alive and progression free after start of treatment. These Kaplan-Meier curves were
used to estimate the median PFS and the associated 95% confidence interval (using the linear
transformations). Estimates of PFS probability and associated 95% confidence interval (using
Greenwood’s formula for the standard error) at 6 and 12 and 24 months, were calculated (Table
6). The log rank test was used to test for differences in PFS on each of the following variables:
prior treatment, gender and renal function.

21

Overall Survival
Overall survival (OS) was defined as the time from the start of treatment on day 1 to the date of
death due to any cause. Subjects who were known to be alive or whose survival status was
unknown were censored at the date of last contact. Overall survival was described and analyzed
in a manner similar to that for progression-free survival.

Data were cleaned, restructured, and analyzed using SAS v. 9.4 (SAS Institute, Cary, N.C.)

22

4. Results
4.1. Demographics
Demographic characteristics including gender, race, age, and renal function are displayed in
Table 1, stratified by trial Phase and prior treatment. A total of 154 patients were treated in this
Phase I/II study. The median age was 68 years (range: 25 - 87), and 75% were male. 75% were
non-Hispanic white, 12% were Asian, 9% were Hispanic, 2% were Black and 3% were other
races. 76% of the patients had normal renal function, 14% had moderate renal dysfunction, and
10% had severe renal dysfunction.
Table 1. Summary of Demographic Characteristics
Characteristics Phase I Phase II
Untreated
Phase II Phase II Total
Tubulin No Tubulin
n % n % n % n % n %
Gender
Female 2 9% 16 35% 7 16% 14 34% 39 25%
Male 21 91% 30 65% 37 84% 27 66% 115 75%
Race
Asian 3 13% 7 15% 4 9% 4 10% 18 12%
Black 1 4% 1 2% 1 2% 3 2%
Non-Hispanic
White
18 78% 30 65% 36 82% 31 76% 115 75%
Hispanic 1 4% 7 15% 3 7% 3 7% 14 9%
Other 1 2% 3 7% 4 3%
Age (yrs.)
<=45 1 2% 1 2% 2 5% 4 3%
46-55 1 4% 9 20% 11 25% 5 12% 26 17%
56-65 4 17% 11 24% 10 23% 9 22% 34 22%
66-75 11 48% 15 33% 5 11% 19 46% 50 32%
>75 7 30% 10 22% 17 39 6 15% 40 26%
Renal Dysfunction
Moderate 11 48% 1 2% 5 11% 4 10% 21 14%
Severe 12 52% 3 7% 15 10%
Normal 45 98% 36 82% 36 88% 117 76%
Missing 1 2% 1 1%

23

4.2. Summary of Trial Status
Table 2 summarizes the accrual to different dose levels for the Phase I portion. Number of
patients entered, number of patients eligible, number of patients evaluable for toxicity, number of
patients with DLT and number of patients started/completed first course are displayed. Of 23
patients evaluable for toxicity, 1 DLT was experienced at the 1.4mg/m
2
/week level in the severe
renal dysfunction group.

Table 2. Phase I Summary
Renal
Insufficiency
Group
Dose Level
Patients
Entered
Patients
Eligible
Evaluable
for
toxicity
Patients
with
DLT
Patients
Completed 1st
Course
Moderate
0.7mg/m
2
/week 2* 2* 2* 0 2*
1.0mg/m
2
/week 3 3 3 0 3
1.4mg/m
2
/week 6 6 6 0 6
Severe
0.7mg/m
2
/week 3 3 3 0 2
1.0mg/m
2
/week 4*** 4*** 3 0 3
1.4mg/m
2
/week 6 6 6 1 5**

* Recruitment of patients with severe renal dysfunction to the 0.7mg/m
2
/week dose level was
completed before recruitment of patients with moderate renal dysfunction to the 0.7mg/m
2
/week
dose level. Since the result showed 0.7mg/m
2
/week was well tolerated in the severe renal
dysfunction group, and since none of the 2 patients in the moderate dysfunction group
experienced DLT, the study committee decided to escalate the moderate renal dysfunction group
at the same time as the severe renal dysfunction group.
* *Patient with DLT did not complete the 1st course.
*** One patient never started treatment.

24

Table 3 summarizes the accrual to different treatment cohorts for the Phase II portion. Number
of patients entered, number of patients eligible, number of patients evaluable for response,
number of patients who completed the first course, number of patients with objective response,
and the response rate with 95% confidence interval are displayed. 19 of the 46 previously
untreated patients reached an objective response. The response rate was 37% (95% CI: 24%,
50%). 15 of the 44 previously treated tubulin-naive patients achieved an objective response,
resulting in a response rate of 34% (95% CI: 20%, 48%). 7 of the 41 tubulin-inhibitor treated
patients demonstrated an objective response, resulting in a response rate of 17% (95% CI: 6%,
28%). There was no statistical difference among response rates for these three treatment cohorts
at the 0.05 significance level using Fisher's exact test (p=0.09). There were sufficient responses
in both tubulin-naive and tubulin-exposed cohorts, as well as the untreated cohort, to warrant
continuation of the two-stage design to complete accrual as planned. The overall response rate of
the Phase II portion was 30% (95% CI: 22%, 38%).
Table 3. Phase II Summary
Treatment
Patients
Entered
Patients
Eligible
Evaluable
for
Response
Patients
with
Objective
Response
Response Rate %
(95% CI)
Untreated 52* 52* 52* 19 37% (24%, 50%)
Tubulin-Naïve 44 44 44 15 34% (20%, 48%)
Prior Tubulin
Inhibitor Treatment
41 41 41 7 17% (6%, 28%)
* 6 of the subjects from the Phase I portion (Dose Level 1.4 mg/m
2
) were added to the Phase II
untreated portion for analysis of response.
25

0.7mg/m
2
1.0mg/m
2
1.4mg/m
2
0.7mg/m
2
1.0mg/m
2
1.4mg/m
2
Number of Course started
N 2 3 6 3 3 6 46 44 41 154
Median 7 13 6 4 9 5 4 4.5 4 4
Min, Max 2,12 2,15 4,12 2,6 2,16 1,7 1,25 1,54 1,21 1,45
q1,q3 2,12 2,15 6,10 2,6 2,16 3,6 2,6 3,8 2,6 2,8
Number of Courses Completed
N 2 3 6 3 3 5 45 44 38 149
Median 7 13 6 4 9 5 4 4.5 4 4
Min, Max 2,12 2,15 4,12 2,6 1,16 2,7 1,25 1,54 1,21 1,54
q1,q3 2,12 2,15 6,10 2,6 1,16 4,6 2,6 2,8 2,7 2,8
Ratio of Expected Dose
Received for First Course
N 2 3 6 3 3 6 46 44 41 154
Median 0.76 1.01 0.99 1.00 0.99 1.00 1.00 1.00 1.00 1.00
Min, Max 0.49,1.03 0.98,1.01 0.97,1.01 0.99,1.29 0.98,1.00 0.50,1.02 0.24,1.14 0.49,1.09 0.48,1.05 0.24,1.2
q1,q3 0.49,1.03 0.98,1.01 0.98,1.00 0.99,1.29 0.98,1.00 0.98,1.02 0.98,1.01 0.99,1.01 0.98,1.01 0.98,1.0
Ratio of Expected Dose
Received for All Courses
N 2 3 6 3 3 6 46 44 41 154
Median 0.95 1.00 0.99 0.99 1.00 0.96 0.99 0.91 0.87 0.98
Min, Max 0.88,1.02 0.98,1.01 0.98,1.00 0.95,1.02 0.74,1.05 0.50,1.00 0.24,1.14 0.66,1.03 0.49,1.03 0.24,1.1
q1,q3 0.88,1.02 0.98,1.01 0.99,0.99 0.95,1.02 0.74,1.05 0.84,1.00 0.91,1.00 0.76,1.00 0.77,1.00 0.80,1.0
Overall
Phase I Moderate Phase I Severe Phase II
Untreated
Phase II
Tubulin Naïve
Phase II
Tubulin
Treated
4.3. Treatment Received
The amount of treatment received is described in Table 4 for each trial Phase and treatment
cohort. Overall, the median number of courses started and median number of courses completed
was 4 (range: 1-54) courses. The median ratio of actual dose received vs. expected dose for the
first course was 1 (range: 0.24-1.20). The median ratio of actual dose received vs. expected dose
for all courses was 0.98 (range: 0.24-1.10).

Table 4. Treatment Received, Stratified by Trial Phase and Treatment Cohorts

26

4.4. Summary of Toxicities
Table 5 summarizes toxicities that were rated as at least possibly (possibly, probably, definitely)
attributable to Eribulin, for all courses. Toxicities were scored 0-4 according to CTCAE. No
grade 5 adverse events were observed. The toxicity profile was considered acceptable in both
Phase I and II components, as well as in both tubulin-naive and tubulin-exposed cohorts.
Table 5. Summary of Toxicities (n=154 Patients with at Least the 1
st
Course Data Entered)
Phase/Treatment System Grade 1
& 2
Grade
3
Grade
4
Phase I
Blood and lymphatic system disorders 3
Cardiac disorders 1
Gastrointestinal disorders 18 1
General disorders and administration site conditions 18 2
Infections and infestations 2 1
Investigations 13 6 3
Metabolism and nutrition disorders 16 4
Musculoskeletal and connective tissue disorders 5 1
Nervous system disorders 11
Renal and urinary disorders 1
Respiratory, thoracic and mediastinal disorders 3
Skin and subcutaneous tissue disorders 19
Phase II Untreated
Blood and lymphatic system disorders 10
Cardiac disorders 1
Eye disorders 1
Gastrointestinal disorders 31 1
General disorders and administration site conditions 34 5
Infections and infestations 1 3 1
Investigations 18 10 12
Metabolism and nutrition disorders 28 8
Musculoskeletal and connective tissue disorders 9
Nervous system disorders 23 3
Renal and urinary disorders 1
Respiratory, thoracic and mediastinal disorders 2 1
Skin and subcutaneous tissue disorders 38
Vascular disorders 1 1
Phase II Tubulin Naïve
Blood and lymphatic system disorders 24 12
Cardiac disorders 4
Eye disorders 1
27

Gastrointestinal disorders 29 2
General disorders and administration site conditions 38 2
Infections and infestations 5 6 2
Investigations 9 12 23
Metabolism and nutrition disorders 30 6 1
Musculoskeletal and connective tissue disorders 20 1
Nervous system disorders 24
Psychiatric disorders 2
Renal and urinary disorders 3
Reproductive system and breast disorders 3
Respiratory, thoracic and mediastinal disorders 12 1
Skin and subcutaneous tissue disorders 24
Vascular disorders 12 2
Phase II Tubulin
Treated
Blood and lymphatic system disorders 23 6
Cardiac disorders 2
Eye disorders 1
Gastrointestinal disorders 17 1
General disorders and administration site conditions 23 4
Infections and infestations 2 1
Injury, poisoning and procedural complications 1
Investigations 11 8 15
Metabolism and nutrition disorders 21 2 2
Musculoskeletal and connective tissue disorders 13 1
Nervous system disorders 18
Renal and urinary disorders 1 1
Respiratory, thoracic and mediastinal disorders 4
Skin and subcutaneous tissue disorders 6
Vascular disorders 6

28

4.5. Progression Free Survival and Overall Survival
Only patients in the Phase II portion and the 6 patients from Phase I who met the Phase II
eligibility criteria were included in the analysis for progression free survival and overall survival.
A total of 137 patients were included. PFS and OS medians and their 95% confidence intervals
were calculated based on the Kaplan-Meier estimates using the linear transformations.
Cumulative survival probabilities at 6, 12, and 24 months were estimated using the Kaplan-
Meier calculations; 95% confidence intervals used Greenwood’s formula.

Table 6 summarizes probabilities of progression free survival at 6 and 12 months (patients at 24
month were not evaluable), and probabilities of overall survival at 6, 12 and 24 months, stratified
by treatment cohorts (all patients treated with Eribulin at 1.4 mg/m
2
). The probability of
progression free survival at 6 and 12 months was 0.30 (95% CI: 0.22, 0.38) and 0.14 (95% CI:
0.07, 0.20), respectively. The probability of overall survival at 6,12 and 24 months was 0.67 (95%
CI: 0.59, 0.76), 0.40 (95% CI: 0.31, 0.50) and 0.21 (95% CI: 0.12, 0.30), respectively.

Table 6. Progression Free Survival at 6 and 12 Months, and Overall Survival at 6, 12 and
24 Months, Stratified by Treatment Cohort

n
Estimated
Probability of
PFS at 6
months (95%
CI)
Estimated
Probability of
PFS at 12
months (95%
CI)
Estimated
Probability of
OS at 6 months
(95% CI)
Estimated
Probability of
OS at 12
months (95%
CI)
Estimated
Probability of
OS at 24
months (95%
CI)
Untreated 52 0.24 (0.12, 0.35) 0.15 (0.05, 0.25) 0.66 (0.53, 0.80) 0.39 (0.24, 0.53) 0.22 (0.09, 0.35)
Tubulin
Naïve
44 0.40 (0.25, 0.54) 0.14 (0.02, 0.26) 0.67 (0.52, 0.81) 0.38 (0.22, 0.55) 0.13 (0.00, 0.32)
Tubulin
Treated
41 0.22 (0.08, 0.36) N/A 0.64 (0.48, 0.80) 0.38 (0.19, 0.57) 0.00 (0.00, 0.00)
Overall 13 0.30 (0.22, 0.38) 0.14 (0.07, 0.20) 0.67 (0.59, 0.76) 0.40 (0.31, 0.50) 0.21 (0.12, 0.30)

29

Legends for Figures 2-9
Figures 2 and 3 display the Kaplan-Meier curves describing progression free survival and
overall survival. Median progression free survival was 4.1 months (95% CI: 3.2, 4.5; 118
patients progressed). Median overall survival was 9.6 months (95% CI: 7.6, 12.4; 90 patients
died).

In Figures 4 and 5, progression free survival and overall survival were stratified by treatment
cohort (untreated: n=52, tubulin naive: n=44, tubulin treated: n=41). There were no statistically
significant differences in the progression free survival among the treatment cohorts (log-rank
p=0.19). There was also no statistically significant differences in overall survival among the
treatment cohorts (log-rank p=0.41).

Figures 6 and 7 display the Kaplan-Meier curves describing progression free survival and
overall survival, stratified by gender (female: n=37, male: n=100). Gender disparity was not
detected for progression free survival and overall survival (log-rank p=0.69, log-rank p=0.44,
respectively).

Figures 8 and 9 display the progression free survival and overall survival stratified by renal
function (severe renal dysfunction : n=15, moderate renal dysfunction n= 4, normal renal
function: n=117). Progression free survival and overall survival were not affected by the patient's
renal function (log-rank p=0.50, log-rank p=0.37, respectively).

30

0 5 10 15 20 25 30 35 40 45 50
Start of Treatment to Event (Months)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Progression Free Survival Probability
Median PFS: 4.1 (95% CI: 3.2, 4.5) months
Figure2. Progression Free Survival
0 5 10 15 20 25 30 35 40 45 50
Start of Treatment to Event (Months)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Overall Survival Probability
Median OS: 9.6 (95% CI: 7.6, 12.4) months
Figure 3. Overall Survival

31

0 5 10 15 20 25 30 35 40 45 50
Start of Treatment to Event (Months)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Progression Free Survival Probability
Log-rank P=0.19
Tubulin Treated, Median PFS: 3.9 ( 95% CI: 2.8, 4.5) months
Tubulin Naive,Median PFS: 4.4 ( 95% CI: 3.0, 6.4) months
Untreated, Median PFS: 4.0 (95% CI: 2.8, 5.5) months
Figure 4. Progression Free Survival Stratified by Treatment
0 5 10 15 20 25 30 35 40 45 50
Start of Treatment to Event (Months)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Overall Survival Probability
Log-rank P=0.41
Tubulin Treated, Median OS: 8.4 (95% CI: 6.0, 15.4) months
Tubulin Naïve, Median OS: 9.6 (95% CI: 6.4, 14.0) months
Untreated, Median OS: 10.0 (7.1, 17.4) months
Figure 5. Overall Survival Stratified by Treatment

32

0 5 10 15 20 25 30 35 40 45 50
Start of Treatment to Event (Months)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Overall Survival Probability
Log-rank P=0.44
Male, Median OS: 9.6 (95% CI: 7.6, 12.5) months
Female, Median OS: 9.5 (95% CI: 5.8, 21.2) months
Figure 7. Overall Survival Stratified by Gender

0 5 10 15 20 25 30 35 40 45 50
Start of Treatment to Event (Months)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Progression Free Survival Probability
Log-rank P=0.69
Male, Median PFS: 4.0 (95% CI: 2.9, 5.0) months
Female, Median PFS: 4.2 (95% CI: 3.0, 5.5) months
Figure 6. Progression Free Survival Stratified by Gender
33

0 5 10 15 20 25 30 35 40 45 50
Start of Treatment to Event (Months)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Progression Free Survival Probability
Log-rank P=0.50
Normal, Median PFS: 4.0 (95% CI: 3.0, 5.0) months
Severe, Median PFS: 5.0 (95% CI: 1.5, 6.1) months
Moderate, Median PFS: 4.2 (95% CI: 2.8, 8.8) months
Figure 8. Progression Free Survival Stratified by Renal Function
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80
Start of Treatment to Event (Months)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Overall Survival Probability
Log-rank P=0.37
Normal, Median OS: 9.5 (95% CI: 7.13, 12.4) months
Severe, Median OS: 9.0 (95% CI: 5.1, 10.5) months
Moderate, Median OS: 36.3 (95% CI: 4.3,40.0) months
Figure 9. Overall Survival Stratified by Renal Function
34

5. Discussion
In this trial, the Phase I portion showed that 1.4mg/m
2
/week is well tolerated in patients with
moderate and severe renal dysfunction. We concluded that it is safe to give Eribulin to patients
with renal dysfunctions. For the Phase II portion, a response rate of 30% and a median overall
survival of 9.6 months compares well with single agent activity for standard treatments. For
example, with gemcitabine alone, the response rate is 22.5- 28% and the overall survival is 5-
12.5 months; with cisplatin alone, the response rate is 12% and the overall survival is 8.2
months.
14,15,16
The observed responses rates were well beyond 5% in untreated, tubulin-naive
and tubulin-exposed cohorts, indicating that future evaluation of this agent is warranted, and that
Erubulin could be used as a second line agent in bladder cancer. Previously untreated and
previously treated cohorts had similar response rates and survival outcomes. The commonly
documented gender disparity in bladder cancer survival was not observed in this study of
Eribulin treatment, although the limited sample size for females (n=37) may not have allowed
the previously observed difference to be detected. Nonetheless, the gender-specific survival
curves showed no obvious differences (Figure 7). Another possibility is that Eribulin truly
reduces or eliminates gender disparity in bladder cancer mortality. Extended accrual of females
to this trial is ongoing. We plan to explore the implications of how female patients should be
treated in bladder cancer. The number of patients with renal dysfunctions was limited in the
Phase II portion. Based on this limited sample size, our exploratory analysis indicates that
patients with renal dysfunctions have similar survival outcomes as patients with normal renal
function. Future studies expanding the number of patients with renal dysfunctions would help us
confirm this conclusion. Eribulin exhibits promising single agent activity. Although the standard
regimens, MVAC and GC, still lead to better response rates and overall survival compared to
35

Eribulin alone, future studies including Eribulin into a combination regimen might potentially
demonstrate further benefits.

36

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validation study of the novel anti-tubulin agent E7389. Proc Am Soc Clin Oncol; 2005;
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73.

38

Appendix A
PATIENT SELECTION
1.1. Eligibility Criteria (for all Patients)
1.1.1. Patients must have locally advanced or metastatic urothelial carcinoma that is not
amenable to surgical treatment
1.1.2. Patients must have histologically or cytologically confirmed urothelial tract
carcinoma.
1.1.3. Patients with renal dysfunction that are entered into the safety lead-in portion of the
study at dose levels below 1.4mg/m
2
/ week [i.e. to be treated with 0.7mg/m
2
/week
and 1.0mg/m
2
/week] may have received up to two prior lines of therapy.
1.1.4. Patients must be 18 years of age or older because no dosing or adverse event data are
currently available on the use of E7389 Halichondrin analog in patients <18 years of
age. Children are excluded from this study but will be eligible for future pediatric
single-agent trials, if applicable.
1.1.5. Life expectancy of greater than 6 months.
1.1.6. ECOG performance status 0-2 and Karnofsky > 60% (see Appendix A).
1.1.7. Patients must have normal hepatic and marrow function as defined below:
• absolute neutrophil count >1,000/mcL
• platelets >100,000/mcL
• hemoglobin ≥ 9g/dL
• total bilirubin ≤ 1.5 institutional upper limit of normal (IULN)
• AST(SGOT)/ALT(SGPT) ≤ 2.5 X IULN
39

1.1.8. The Phase II portion of the study will be open initially to patients with normal kidney
function (i.e. creatinine ≤ 1.5 X IULN OR calculated creatinine clearance>60 mL/min
by the modified Cockcroft and Gault Formula – see Appendix C.) Once the Phase I
escalation in (a) patients with moderate renal insufficiency (i.e. calculated creatinine
clearance ≥40-59 mL/min) and (b) patients with severe renal insufficiency (i.e.
calculated creatinine clearance <40 mL/min) have been completed, patients with
moderate and severe renal insufficiency will enter the Phase II portion of the study.
Patients on dialysis are not eligible. Patients with symptomatic uremia, uncontrolled
edema or unstable serum electrolytes should not enter the trial until such time as they
have been stabilized – such patients should be discussed with the Principal
Investigator (diquinn@usc.edu, phone 323 865 3956).
1.1.9. Eligibility of patients receiving any medications or substances known to affect or with
the potential to affect the activity or pharmacokinetics of E7389 Halichondrin analog
(see Appendix H) will be determined following review of their case by the Principal
Investigator.
1.1.10. The effects of E7389 Halichondrin analog on the developing human fetus at the
recommended therapeutic dose are unknown. For this reason and because tubulin
inhibitors are known to be teratogenic, women and men of child-bearing potential
must agree to use adequate contraception (hormonal or barrier method of birth
control; abstinence) prior to study entry and for the duration of study participation.
Should a woman become pregnant or suspect she is pregnant while participating in
this study, she should inform her treating physician immediately.
40

1.1.11. Patients must have the ability to understand and the willingness to sign a written
informed consent document.

1.2. Eligibility Criteria (for all Patients in the Extended Phase II Trial per Amendment
6)
1.2.1. Patients must have locally advanced or metastatic urothelial cancer that is not
amenable to surgical treatment
1.2.2. Patients must have histologically or cytologically confirmed urothelial tract
carcinoma.
1.2.3. Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as >
20 mm with conventional techniques or as > 10 mm with spiral CT scan. See section
11.2 for the evaluation of measurable disease (RECIST v1.1).
1.2.4. All patients may have received up to two prior lines of chemotherapy for
recurrent/advanced disease.
1.2.4.1. Patients must have received at least one platinum-based chemotherapy for
recurrent/advanced disease. Recurrent disease is defined as having recurred
after definitive therapy and advanced disease is defined as T4 and/or N2
and/or M1. In addition, for completion of Cohort #2, patients must also have
received a tubulin inhibitor as part of their therapy for urothelial cancer. For
purposes of this evaluation, treatment with chemotherapy regimens where
carboplatin or similar is substituted for cisplatin or where a taxane is added or
removed will be considered the same regimen. Tubulin inhibitors in common
41

use include paclitaxel, docetaxel, and vinblastine. The exception to this
requirement applies to women as stated below in 2.2.4.2:
1.2.4.2. Women with and without prior therapy are also eligible. Priority will be given
to those who consent to participating in the pharmacokinetic studies.
1.2.5. Patients must be 18 years of age or older because no dosing or adverse event data are
currently available on the use of E7389 Halichondrin analog in patients < 18 years of
age. Children are excluded from this study but will be eligible for future pediatric
single-agent trials, if applicable.
1.2.6. Life expectancy of greater than 6 months.
1.2.7. ECOG performance status 0-2 and Karnofsky  60% (see Appendix A).
1.2.8. Patients must have normal hepatic and marrow function as defined below:
 absolute neutrophil count >1,000/mcL
 platelets >100,000/mcL
 hemoglobin  9g/dL
 total bilirubin  1.5 institutional upper limit of normal (IULN)
 AST(SGOT)/ALT(SGPT)  2.5 X IULN
1.2.9. Patients must have either (a) normal kidney function (i.e. creatinine ≤ 1.5 X ULN OR
calculated creatinine clearance > 60 mL/min by the modified Cockcroft and Gault
Formula – see Appendix C, OR a creatinine clearance > 60 mL/min obtained from a
24-hour urine collection) or (b) moderate or severe renal dysfunction (i.e. creatinine
clearance < 60 mL/min and ≥ 20 mL/min)
42

1.2.9.1. Patients with symptomatic uremia, uncontrolled edema or unstable serum
electrolytes should not enter the trial until such time as they have been
stabilized – such patients should be discussed with the Principal Investigator
(diquinn@usc.edu, phone 323 865 3956).
1.2.10. Eligibility of patients receiving any medications or substances known to affect or with
the potential to affect the activity or pharmacokinetics of E7389 Halichondrin analog
(see Appendix H) will be determined following review of their case by the Principal
Investigator.
1.2.11. The effects of E7389 Halichondrin analog on the developing human fetus at the
recommended therapeutic dose are unknown. For this reason and because tubulin
inhibitors are known to be teratogenic, women and men of child-bearing potential
must agree to use adequate contraception (hormonal or barrier method of birth
control; abstinence) prior to study entry and for the duration of study participation.
Should a woman become pregnant or suspect she is pregnant while participating in
this study, she should inform her treating physician immediately.
1.2.12. Patients must have the ability to understand and the willingness to sign a written
informed consent document.

1.3. Eligibility Criteria (Patients with Moderate Renal Dysfunction Receiving
1.4mg/m
2
/week and Patients with Normal Renal Function
1.3.1. For Patients with Moderate Renal Dysfunction Receiving 1.4 mg/m
2
/week (Dose
Level 3 of the Phase I portion) and all Patients in the Phase II portion: Patients
must have measurable disease, defined as at least one lesion that can be accurately
43

measured in at least one dimension (longest diameter to be recorded) as >20 mm with
conventional techniques or as >10 mm with spiral CT scan. See section 11.2 for the
evaluation of measurable disease.

1.3.2. For Patients with Moderate Renal Dysfunction Receiving 1.4 mg/m
2
/week (Dose
Level 3 of the Phase I portion) and all Patients in the Phase II portion: Patients
are not allowed to have received any prior chemotherapy for advanced disease.
Patients are allowed to have received chemotherapy in the adjuvant setting, provided
the last dose of treatment was more than 6 months from the date of enrollment to this
study.

1.4. Exclusion Criteria (for all Patients)
1.4.1. Patients may not be receiving any other investigational agents.
1.4.2. Patients with brain metastasis that are unstable (i.e. presenting with neurologic
symptoms that progress or require increasing doses of steroids within a 4-week
period) or are untreated (i.e. not radiated) should be excluded.
1.4.3. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.
1.4.4. Pregnant women are excluded from this study because E7389 Halichondrin analog is
tubulin inhibitor agent with the potential for teratogenic or abortifacient effects.
Because there is an unknown but potential risk for adverse events in nursing infants
44

secondary to treatment of the mother with E7389 Halichondrin analog, breastfeeding
should be discontinued if the mother is treated with E7389.
1.4.5. HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with E7389 Halichondrin analog. HIV-
positive patients with CD4+ ≤ 500/mm3 are ineligible because they are at increased
risk of lethal infections when treated with marrow suppressive therapy. Appropriate
studies will be undertaken in this group of patients when indicated.

3.3 Inclusion of Women and Minorities
Both men and women and members of all races and ethnic groups are eligible for this trial.
After enrollment of 41 evaluable patients to Cohort #2 (Tubulin exposed), accrual will be
restricted to women with the following targets:
(1) 50 females enrolled and treated
(2) PK studies on 10 women who had previously received a platinum-containing
chemotherapy regimen for their advanced/metastatic disease, and
(3) PK studies on 10 women who had never received a chemotherapy for their
advanced/metastatic disease.
We anticipate enrolling an additional 20 women to achieve these goals.

Abstract (if available)

Abstract This thesis summarized the results of a Phase I/II clinical trial of Eribulin in patients with locally advanced or metastatic bladder cancer and varying degrees of renal dysfunction. The objective of the safety lead‐in Phase I portion of this trial was to establish that Eribulin can be given safely to advanced bladder cancer patients with moderate or severe renal dysfunction at 1.4 mg/m²/week on days 1 and 8 of a 21‐day cycle. The objectives of the Phase II portion of this study included describing toxicity, response rate, progression free survival and overall survival in these patients. The associations of progression free survival and overall survival with covariates: prior treatment, gender and renal function were explored. A total of 154 patients were included in this study. The Phase I trial followed a modified 3+3 design. The dose was escalated from 0.7 mg/m²/week, 1.0 mg/m²/week, to 1.4 mg/m²/week. The Phase II trial followed a Simon Optimum two‐stage design. No serious Eribulin‐related adverse events have been reported. The overall response rate was 30%. Median progression free survival was 4.1 months (95% CI: 3.2, 4.5). Median overall survival was 9.6 months (95% CI: 7.6, 12.4). The probability of progression free survival at 6 and 12 months was 0.30 (95% CI: 0.22, 0.38) and 0.14 (95% CI: 0.07, 0.20), respectively. The probability of overall survival at 6,12 and 24 months was 0.67 (95% CI: 0.59, 0.76), 0.40 (95% CI: 0.31, 0.50) and 0.21 (95% CI: 0.12, 0.30), respectively. We did not identify any parameter that significantly correlated with better progression free survival or overall survival. Eribulin is a safe chemotherapy drug with promising single agent activity in bladder cancer patients with renal dysfunction.

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Asset Metadata

Creator Yao, Chuqing (author)

Core Title Eribulin in advanced bladder cancer patients: a phase I/II clinical trial

School Keck School of Medicine

Degree Master of Science

Degree Program Biostatistics

Publication Date 11/02/2016

Defense Date 10/28/2015

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

Tag bladder cancer,clinical trial,OAI-PMH Harvest,renal dysfunction

Format application/pdf (imt)

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Groshen, Susan (committee chair), Mack, Wendy (committee member), Sposto, Richard (committee member)

Creator Email carolchuyao@gmail.com,chuqingy@usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c40-195258

Unique identifier UC11278467

Identifier etd-YaoChuqing-4008.pdf (filename),usctheses-c40-195258 (legacy record id)

Legacy Identifier etd-YaoChuqing-4008.pdf

Dmrecord 195258

Document Type Thesis

Format application/pdf (imt)

Rights Yao, Chuqing

Type texts

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

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the a...

Repository Name University of Southern California Digital Library

Repository Location USC Digital Library, University of Southern California, University Park Campus MC 2810, 3434 South Grand Avenue, 2nd Floor, Los Angeles, California 90089-2810, USA