Clinical trial NCT02178241
Conditions: Metastatic Ureter Carcinoma Metastatic Urethral Carcinoma Stage III Bladder Urothelial Carcinoma AJCC v6 and v7 Stage III Ureter Cancer AJCC v7 Stage III Urethral Cancer AJCC v7 Stage IV Bladder Urothelial Carcinoma AJCC v7 Stage IV Ureter Cancer AJCC v7 Stage IV Urethral Cancer AJCC v7 Ureter Urothelial Carcinoma Urethral Urothelial Carcinoma
Sponsor: National Cancer Institute (NCI)
Start date: 2014-12-11; Completion date: 2019-07-11
Enrollment: 26 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well gemcitabine hydrochloride and eribulin mesylate work in treating patients with bladder cancer that has spread to other places in the body or cannot be removed by surgery. Drugs used in chemotherapy, such as gemcitabine hydrochloride and eribulin mesylate, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the objective response rate of gemcitabine (gemcitabine hydrochloride)-eribulin (eribulin mesylate) (GE) when given to cisplatin ineligible patients with advanced or unresectable urothelial carcinoma who have not received any prior chemotherapy for the advanced disease.

SECONDARY OBJECTIVES:

I. To estimate the median progression-free survival (PFS). II. To summarize the toxicity profile (using Common Terminology Criteria for Adverse Events \[CTCAE\] version \[v\] 4 criteria) of the GE regimen in these patients.

OUTLINE:

Patients receive gemcitabine hydrochloride intravenously (IV) over 30 minutes on days 1 and 8 and eribulin mesylate IV over 2-5 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 36 months.

Arms: arm 1: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 and eribulin mesylate IV over 2-5 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Eribulin Mesylate intervention 2: Gemcitabine Hydrochloride
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
NCI Protocol #: 9653 
Version Date: February 20, 2017 
 
i 
SUMMARY OF CHANGES 
 
Date: 
 
February 20, 2017 
Document: 
NCI Protocol #9653, PhII-130: “Phase II Trial of Gemcitabine-Eribulin 
(GE) in Cisplatin Ineligible Patients with Advanced or Unresectable 
Urothelial Carcinoma of the Bladder.” 
Note: 
The following is a Summary of Changes between the 5.2.16 and 2.20.17 
versions of protocol 
 
Section 
Description of Change (v. 5.2.16 and v. 2.20.17) 
Face page  
• Changed protocol version and headers to February 20, 2017   
• Removed P2C-IL07 
TOC 
Updated page numbers 
4.2 
Updated verbiage per current CTEP template. 
8.1 
Added section 8.1.2.3 - Investigator Brochure information. 
Added section 8.1.2.4 – Useful links and contacts 
12 
Revised this section in accordance with recent changes to the ETCTN template language. 
12.1.1 – Updated CTMS language per CTEP 
12.1.2 – Removed CDUS language as study is using CTMS 
12.2 – Deleted the section as multicenter guidelines do not apply to ETCTN trials 
13 
Updated the statistics to state: 
 
Study enrollment will be extended if the following 2 conditions hold:  (1) 7 or more 
patients of the 21 eligible patients experience a CR or PR, AND (2) there are patients who 
failed to receive 2 courses of treatment and undergo radiographic evaluation of tumor 
burden after the 2nd course for reasons be unrelated to disease progression.  Thus accrual 
will be extended to “replace” patients who terminated treatment early for reasons of 
adverse events or toxicity or decisions unrelated to disease progression; patients who fail to 
receive 2 courses because of early progression will not be “replaced”.  Although all eligible 
patients who begin treatment will be included in the primary analysis, this extension will 
permit an estimate of the response rate in those patients who could receive 2 courses of 
therapy. 
 
Appendix B 
Deleted this Appendix as multicenter guidelines do not apply to ETCTN trials. 
 
  
 
 


NCI Protocol #: 9653 
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NCI Protocol #: 
9653 
 
Local Protocol #: 
PhII-130 
 
TITLE:  Phase II Trial of Gemcitabine-Eribulin (GE) in Cisplatin Ineligible Patients with 
Advanced or Unresectable Urothelial Carcinoma of the Bladder 
 
 
Coordinating Center: 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
 
1500 E. Duarte Road 
 
Duarte, California 91010  
 
Phone:  626-256-HOPE(4673), extension 65928 
 
Fax:      626-256-8654 
 
 
 
 
 
 
 
 
Email:  cccp@coh.org  
 
 
*Principal Investigator: 
Sarmad Sadeghi, MD, PhD 
 
USC Norris Comprehensive Cancer Center 
 
1441 Eastlake Ave, Suite 3440 
 
Los Angeles, CA 90033 
 
Phone:  323-865-0553 
 
Fax: 323-865-0061 
 
Email:  sarmad.sadeghi@usc.edu  
 
Participating Organizations  
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-MN026 / Mayo Clinic Cancer Center LAO 
LAO-NC010 / Duke University - Duke Cancer Institute LAO 
LAO-NJ066 / Rutgers University - Cancer Institute of New Jersey LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
 
 
NCI-Supplied Agent(s):  E7389 (Halichondrin B Analog) eribulin (NSC 707389) 
 
Other Agent(s):  Gemcitabine (Gemzar™), Lilly Oncology  


NCI Protocol #: 9653 
Version Date: February 20, 2017 
 
2 
 
IND #:  64395 
 
IND Sponsor:  DCTD, NCI 
 
Protocol Type / Version # / Version Date: 
May 27, 2014  
Initial Protocol 
 
 
 
 
July 10, 2014  
Consensus Review 
 
 
 
 
August 4, 2014 
Follow Up Review 
 
 
 
 
August 14, 2014 Follow Up Review 
 
 
 
 
September 24, 2014 Amendment 
 
 
 
 
May 11, 2015  
Amendment 
 
 
 
 
February 8, 2016 Amendment 
 
 
 
 
February 25, 2016 Amendment 
 
 
 
 
May 2, 2016  
Amendment – RRA 
 
 
 
 
February 20, 2017 Amendment 
 


NCI Protocol #: 9653 
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SCHEMA 
 
 


NCI Protocol #: 9653 
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TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................3 
1. 
OBJECTIVES ......................................................................................................................6 
1.1 
Primary Objective ....................................................................................................6 
1.2 
Secondary Objectives...............................................................................................6 
2. 
BACKGROUND .................................................................................................................6 
2.1 
Study Disease(s).......................................................................................................6 
2.2 
Eribulin E7389 .........................................................................................................7 
2.3 
Gemcitabine .............................................................................................................8 
2.4 
Rationale ..................................................................................................................9 
2.5 
Correlative Studies Background ............................................................................10 
3. 
PATIENT SELECTION ....................................................................................................10 
3.1 
Eligibility Criteria ..................................................................................................10 
3.2 
Exclusion Criteria ..................................................................................................12 
3.3 
Inclusion of Women and Minorities ......................................................................13 
4. 
REGISTRATION PROCEDURES ...................................................................................13 
4.1 
Investigator and Research Associate Registration with CTEP ..............................13 
4.2 
Site Registration .....................................................................................................14 
4.3 
Patient Registration ................................................................................................16 
4.4 
General Guidelines.................................................................................................17 
5. 
TREATMENT PLAN ........................................................................................................17 
5.1 
Agent Administration.............................................................................................17 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................18 
5.3 
Duration of Therapy ...............................................................................................19 
5.4 
Duration of Follow Up ...........................................................................................19 
5.5 
Criteria for Removal from Study ...........................................................................19 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................20 
6.1 
Retreatment criteria and dosing delays ..................................................................20 
6.2 
Dose modifications for eribulin .............................................................................20 
6.3 
Dose modifications for gemcitabine ......................................................................21 
6.4 
Dose Modifications for Eribulin and Gemcitabine for Nausea, Vomiting, 
Diarrhea, Neutropenia and Thrombocytopenia ......................................................22 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................24 
7.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) ...............24 
7.2 
Adverse Event Characteristics ...............................................................................29 
7.3 
Expedited Adverse Event Reporting ......................................................................30 
7.4 
Routine Adverse Event Reporting .........................................................................32 
7.5 
Secondary Malignancy...........................................................................................32 
7.6 
Second Malignancy ................................................................................................32 


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8. 
PHARMACEUTICAL INFORMATION ..........................................................................32 
8.1 
CTEP IND Agent(s) ...............................................................................................33 
8.2 
Gemcitabine ...........................................................................................................35 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................35 
9.1 
Collection of Specimens ........................................................................................35 
9.2 
Shipping of Specimens ..........................................................................................36 
9.3 
Biomarker Studies ..................................................................................................36 
10. 
STUDY CALENDAR .......................................................................................................37 
11. 
MEASUREMENT OF EFFECT........................................................................................38 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................38 
12. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS .............................................................................................................44 
12.1 
Study Oversight .....................................................................................................44 
12.2 
Data Reporting .......................................................................................................45 
12.3 
Collaborative Agreements Language .....................................................................46 
13. 
STATISTICAL CONSIDERATIONS...............................................................................48 
13.1 
Study Design / Endpoints.......................................................................................48 
13.2 
Sample Size/Accrual Rate ......................................................................................50 
13.3 
Stratification Factors ..............................................................................................50 
13.4 
Analysis of Results ................................................................................................50 
13.5 
Reporting and Exclusions ......................................................................................51 
14. 
CCCP POLICIES FOR MONITORING CONSORTIUM TRIALS .................................52 
14.1 
Oversight ................................................................................................................52 
15. 
REFERENCES ..................................................................................................................54 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................58 
 


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1. OBJECTIVES 
 
This is a phase II clinical trial of eribulin given with gemcitabine in patients with advanced or 
unresectable urothelial carcinoma who have not received any prior chemotherapy for the 
advanced disease and who are not eligible to receive cisplatin-based chemotherapy.  
 
1.1 Primary Objective 
The primary objective of this study is to estimate the objective response rate of gemcitabine-
eribulin (GE) when given to cisplatin ineligible patients with advanced or unresectable urothelial 
carcinoma who have not received any prior chemotherapy for the advanced disease.  Objective 
response is defined as either a complete response (CR) or a partial response (PR) based on 
RECIST v1.1.  
 
1.2 Secondary Objectives 
The secondary objectives are (1) to estimate the median progression-free survival (PFS), and (2) 
to summarize the toxicity profile (using CTCAE v4 criteria) of the GE regimen in these patients. 
 
2. BACKGROUND 
 
2.1 Study Disease(s) 
Urothelial carcinoma of the bladder remains one of the most challenging and lethal urologic 
cancers. It is the second most common genitourinary (GU) cancer next to prostate cancer with a 
2013 estimated incidence of 72,570 (69,250 in 2011) and has risen to be the second most deadly 
GU cancer with 15,210 estimated deaths in 2013 (14,990 estimated bladder cancer deaths in 
2011)1,2. Many of these patients will have superficial disease at diagnosis (75-80%); however, 
approximately two thirds of those who present with muscle invasion will go on to develop 
regional or systemic disease. Despite improvements in surgical techniques and multimodal 
therapy, 5-year survival rates for patients with invasive bladder cancer remain suboptimal 3. 
Virtually all deaths from bladder cancer result from muscle invasive disease that recurs or 
metastasizes after local therapy4. 
 
Platinum-based regimens are the mainstay of treatment for recurrent or metastatic bladder 
cancer5. The MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) regimen has 
produced response rates of 40 to 70% with 13 to 28% of patients having complete responses in 
Phase II and III trials6,7. The gemcitabine-cisplatin (GC) doublet has shown a similar response 
rate and survival as the MVAC combination, but a reportedly better toxicity profile7. However, 
the median overall survival of patients treated with either regimen is still only between 12 and 14 
months and less than 10% of patients become long term disease-free survivors7-10.  
 
In addition, patients affected with this disease are often elderly and have multiple comorbid 
conditions such as renal insufficiency and congestive heart failure, which preclude them from 
receiving platinum-based therapy. It is estimated that 50% of patients are cisplatin-ineligible due 
to renal function impairment, compromised performance status, and/or comorbid conditions 
(such as congestive heart failure, among others) preventing them from receiving high volume 
hydration11. While it is less clear what precise proportion of the cisplatin-ineligible patients have 


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renal impairment as the sole reason for ineligibility, data from the adjuvant setting (i.e., patients 
fit enough to undergo radical surgery) suggest that between 25-50% of patients had a creatinine 
clearance of <60ml/min depending on the formula used for calculation and up to 40% of patients 
over 70 years of age using Cockroft-Gault formula12. Thus, there is an unmet medical need for 
treatment in patients who have significant comorbidities, particularly renal dysfunction.  
 
Although the use of taxane combinations has been explored by ECOG as a first line alternative in 
patients with renal dysfunction, but there is still no widely accepted standard of care. There still 
is an ongoing need for the development of active agents to fill this void. Eribulin is a notable 
candidate to fulfill this role, given its reliance principally on hepatic metabolism and its 
promising single agent activity in early clinical trials13. 
 
2.2 Eribulin E7389 
Halichondrin B is a potent antimitotic agent due to its inhibition of tubulin polymerization and 
microtubule assembly. It has remarkable in vitro and in vivo activity in a number of human 
tumor models, including melanoma, osteogenic sarcoma, lung and colon cancer14,15. 
Of the 180 compounds that were screened, eribulin (previously E7389, ER 086526, and NSC-
707389) was shown to retain significant in vitro as well as in vivo efficacy in a variety of human 
tumor xenograft models, including breast, colon, melanoma and ovarian cancer models16. 
Eribulin showed sub-nM in vitro growth inhibition against several human cancer cell lines and 
was found to induce a G2-M cell cycle arrest in association with the disruption of mitotic 
spindles17. Further studies showed that prolonged mitotic blockage by eribulin led to apoptotic 
cell death in cancer cells in vitro18. The studies in xenograft models demonstrated 20-100 fold 
potency of eribulin when compared to paclitaxel, with frank regressions and increased lifespans 
shown in the mice, together with a significantly wider therapeutic window17. In vivo activity was 
found to be schedule dependent, with intermittent dosing demonstrating the best antitumor 
efficacy and also the least toxicity19. 
 
In light of this very promising anticancer activity, preclinical studies with eribulin were 
undertaken in rats and dogs. These studies showed that eribulin exhibits rapid and extensive 
tissue distribution in rats and dogs with an extended terminal t1⁄2 and that it does not bind 
strongly to plasma protein. Reversible bone marrow suppression was the dose-limiting toxicity in 
both rats and dogs20. 
 
Three phase I and two phase II trials with eribulin are ongoing or have completed accrual. In a 
CTEP sponsored phase I trial conducted by the California Cancer Consortium, eribulin was 
given as a weekly bolus intravenous injection three weeks out of four, starting at 0.125 
mg/m2/wk. The first part of the trial was a rapid escalation phase, which ended with a grade 3 
alkaline phosphatase elevation at 0.5 mg/m2/wk. The second part of the trial consisted of a 
standard 3x3 dose escalation, which ended at 2.0 mg/m2/wk with one grade 3 febrile neutropenia 
and one grade 4 neutropenia. The MTD was 1.4 mg/m2/wk. Non-hematological toxicities 
included hypoglycemia, hypophosphatemia and fatigue. Of 38 evaluable patients who had 
refractory or advanced solid tumors, two had a partial response (one bladder, see below), three 
had minor responses and twelve had stable disease lasting a median of 4 months (range 2-14)13. 
Of these, three patients had heavily pretreated bladder cancer. One experienced a partial response 
and the other two had stable disease for 24 weeks. 


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The pharmacokinetic studies undertaken in this study demonstrated tri-phasic elimination with a 
rapid distributive phase followed by a prolonged elimination from plasma resulting in a terminal 
t1/2 of 36-48 hours. At the MTD, plasma levels remained at concentrations (median of 0.8 nM, 
range 0.2- 2.5 nM) well above those required for in vitro toxicity for more than one week. A 
small fraction of drug (< 10%) was excreted unchanged into the urine and no circulating 
metabolites were detected13. 
 
The two Eisai-sponsored trials are looking at different schedules of administration of a 1-hour 
intravenous infusion of eribulin. In one, the drug is given weekly for three weeks out of four 
(study #101), and in the other the drug is given once every three weeks (study #102). Twenty-six 
patients have been enrolled to the first study (#101), with doses ranging from 0.5 to 2.8 mg/m2. 
Grade 3 neutropenia and grade 3 fatigue were reported at the 0.5 mg/m2 dose level but the MTD 
for this schedule has not been reported21. Eighteen patients have been enrolled to the second 
study (#102), with doses ranging from 0.25 to 4 mg/m2. Neutropenia was found to be the dose-
limiting toxicity in this study, with the MTD expected to be at 2mg/m2 on this schedule. Four 
patients have had stable disease for more than 4 cycles22. The pharmacokinetic analyses 
conducted in these studies also confirmed a rapid distribution and a prolonged elimination 
phase23. The two Eisai-sponsored phase II trials in breast and lung cancer that are ongoing are 
evaluating the 1.4 mg/m2/wk dose administered as an intravenous bolus for three out of every 
four weeks. Accrual to these trials is ongoing but the safety data collected up until this point 
suggests that dosing 2 weeks out of every 3 weeks is more tolerable than dosing 3 out of every 4 
weeks. Based on these data, Eisai has recommended that a day 1 and 8 dosing every 21 days be 
used instead of the day 1, 8 and 15 dosing every 28 days, in future studies. 
 
Most recently, a CTEP sponsored phase I trial of GE demonstrated safety of the combination at 
1000 mg/m2 of gemcitabine and 1.4 mg/m2, of eribulin where each of the agent was given on 
days 1 and 8 of a 21 day cycle24. More details on this study are discussed in 2.4. 
 
2.3 Gemcitabine 
Gemcitabine is a pyrimidine antimetabolite, 2'deoxy -2'difluoro-cytidine (gemcitabine) has been 
introduced into clinical practice for urothelial and a range of other tumors. In preclinical systems 
gemcitabine showed very significant activity against experimental solid tumors 25 and human 
tumor xenografts 26. It is activated intracellularly to the triphosphate, 2'deoxy -2'difluoro-cytidine 
5'-triphosphate (dFdCTP) and in this form is incorporated into DNA 27-29.  Gemcitabine entry to 
cells requires the presence of the nucleoside transporter system, with cells deficient in this 
transporter being gemcitabine resistant 27. The activity of gemcitabine is cell cycle specific with 
blockade at the G1/S phase transition, perhaps suggesting that RR inhibition is an important 
contributor to gemcitabine antineoplastic effect. 
 
In the initial phase I clinical trial, the drug was given over a 30 minute infusion weekly for three 
weeks every four weeks.  The maximum tolerated dose was 790 mg/m2 with myelosuppression 
predominantly thrombocytopenia and anemia being the dose limiting toxicity 7,30. However, 
subsequent studies have shown that considerably higher doses can be given safely, particularly to 
patients with little or no prior therapy.  In patients with non-small cell lung cancer and no prior 
therapy, O'Rourke  et al. found that 2500 mg/m2 given over 4 hours every two weeks was below 


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9 
the MTD 31.  Initial pharmacokinetic studies showed a rapid elimination of the drug with a 
median half life of eight minutes.  The drug was rapidly converted to the corresponding uracil 
metabolite 2',2'-difluorodeoxyuridine which had a longer half life, with a median of 14 hours.  
Antitumor activity for gemcitabine against bladder cancer was noted in the phase I study by 
Pollera et al. in 14 patients receiving gemcitabine at doses greater than 875 mg/m2, they 
observed 1 CR and 2 PR 32.  A response rate of 28% was observed in a phase II trial in 
previously untreated patients with bladder cancer 33.  Subsequently, the combination of 
gemcitabine and cisplatin was assessed in a phase II trial with a response rate of 41% 34. This 
combination was then compared to MVAC in a randomized phase III trial and found to produce 
equivalent response and survival with better quality of life 7. De Mulder et al. noted response rate 
of 8.1% or 3 of 39 evaluable patients in a phase II study of gemcitabine in renal cell carcinoma, 
with durable responses exceeding 12 months in 2 patients 35. 
 
Gemcitabine is part of most combination regimens for urothelial cancer including MVAC36,37, 
GC7, PGC38 and MCAVI11 as well as single agent39 and as will be discussed was tried in 
combination with eribulin in a CTEP sponsored trial- see 2.4. 
 
2.4 Rationale 
Based on the preliminary evidence of clinical activity of eribulin in metastatic urothelial 
carcinomas, we propose a phase II study of this drug given at a dose of 1.4 mg/m2 in 
combination with gemcitabine 1000mg/m2 on days 1 and 8 of a 21 day cycle in patients with 
metastatic or unresectable urothelial carcinoma of the bladder who are not candidates for 
cisplatin therapy.  
 
Eribulin is metabolized primarily in the liver and no renal toxicity has been observed in the phase 
I studies performed with this agent to-date, therefore, we expect eribulin to be well-tolerated in 
patients with renal dysfunction at the MTD previously defined for patients with normal renal 
function (i.e. 1.4 mg/m2/week). Gemcitabine can be given at full doses to patients with a CrCl > 
30ml/min. 
 
The Phase II study of single agent eribulin in first line advanced urothelial cancer patients was 
completed and presented at ASCO 2010 with a response rate of 38%, median TTP 3.9 months 
and median OS 9.4 months40. This compares favorably with prior single agent activity for drugs 
that are standard of care for urothelial cancer, for example with gemcitabine: response rate 22.5-
28% and overall survival 5-12.5 months, and cisplatin: response rate 12% and overall survival 
8.2 months33,37,39. 
 
The phase I study in renal impaired patients was also presented at ASCO 2010 suggesting that 
full dosing of eribulin is feasible and efficacious in patients with creatinine clearance values 
down to 20 mL/min41. Eribulin also has significant activity in patients who have progressed after 
platin regimens for advanced or metastatic disease. In a recent NCI-CTEP sponsored phase II 
study of eribulin in platinum-treated tubulin naive advanced urothelial cancer, overall RR was 
36% (95%CI: 21, 53%), including 1 CR, 7 PR, and 6 unconfirmed PR. [Confirmed RR was 21% 
(95%CI: 9, 36%)]. Stable disease for ≥12 weeks was seen in 12 patients (31%). PD was best 
response in 11 patients (28%). At median follow-up of 5.9 (1.4, 17.1) months, median PFS was 
4.1 months (2.6, 6.4). Median OS was 9.6 months (5.3, ∞) (16 patients died). PFS was associated 


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with Bajorin risk group (p=0.005 for trend). Toxicities included grade 3/4 neutropenia (24), 
grade 3 febrile neutropenia (3), grade 1/2 sensory neuropathy (14), grade 3 hyperglycemia (1), 
grade 1 hyponatremia (8), grade 1/2 alopecia (16), grade 1 leg fatigue & aching (2)42. 
 
Most recently a CTEP-sponsored phase I dose escalation trial of GE has been conducted which 
tested four dose levels of this doublet. Gemcitabine-Eribulin doses were as follows: 800-0.7, 
1000-0.7, 1000-1.0 and 1000-1.4 mg/m2. Safety for the highest dose level was established and 
evidence of antitumor activity for this regimen was seen24. A summary of the findings in this 
trial is provided courtesy of Dr. Rakesh Goel from the Ottawa Hospital (personal 
communication)24. In this trial, 45 patients were included in the study in 3 cohorts: pretreated 
(n=21), gynecologic cancers expansion cohort (n=10), and chemo-naïve (n=14). The initially 
planned Day 1, 8, and 15 in a 28 day cycle was not tolerated at dose level 1 and therefore 
remainder of the trial used a 21 day schedule with treatment on days 1 and 8. The most common 
grade 3-4 toxicities included: neutropenia (24), leukopenia (16), lymphopenia (12), ALT rise (7), 
fatigue (7), AST rise (5), thrombocytopenia (4), anemia, diarrhea, nausea, and vomiting (2 each). 
Non-hematological toxicities and specifically neuropathy were minimal. Efficacy assessments 
showed evidence for anti-tumor activity in each of the pre-defined cohorts. In the pretreated 
cohort, disease control rate (DCR) was 48% (SD 8, PR 2, PD 7, inevaluable 4, n=21).  In the 
gynecologic cancers expansion cohort, DCR was 80%, including 9 ovarian cancers (SD 6, PR 1, 
PD 2) and 1 endometrial cancer with SD.  In the chemo-naïve cohort, DCR was 57% (SD 8, PR 
2, PD 3, inevaluable 1).  
 
Eribulin is approved by the FDA for use in metastatic breast cancer previously treated with 
chemotherapy after demonstrating an overall survival advantage over physicians’ choice in the 
EMBRACE trial43. 
 
2.5 Correlative Studies Background 
 
N/A 
 
3. PATIENT SELECTION 
 
3.1 Eligibility Criteria  
 
This trial is open to cisplatin-ineligible patients with advanced or unresectable urothelial 
carcinoma who have not received any prior chemotherapy for advanced disease.   
 
3.1.1 
Patients must have locally advanced or metastatic predominantly urothelial 
carcinoma of the bladder, ureter, or urethra that is not amenable to curative surgical 
treatment. 
 
3.1.2 Patients must have histologically confirmed predominantly urothelial 
carcinoma of the bladder, ureter, or urethra. 
 


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11 
3.1.3 
Patients must have measurable disease per RECIST 1.1 criteria , defined as at least 
one lesion that can be accurately measured in at least one dimension (longest diameter to 
be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm with 
conventional techniques or as ≥10 mm with spiral CT scan, MRI, or calipers by clinical 
exam.  See Section 11 for the evaluation of measurable disease. 
 
3.1.4 
Patients must be ineligible for treatment with cisplatin, based on one of:  
− 
Calculated creatinine clearance (CrCl) ≥ 30 and <60 mL/min 
(Cockcroft-Gault) 
− 
CTCAE Gr ≥ 2 hearing loss 
− 
CTCAE Gr ≥ 2 neuropathy 
 
3.1.5 
Patients must not have received prior systemic therapy for their advanced cancer. 
Prior intravesical therapy completed 4 weeks prior to enrollment and 
adjuvant/neoadjuvant chemotherapy completed more than 6 months prior to diagnosis of 
advanced disease are permitted.  
 
3.1.6 
Patients must be 18 years of age or older.  Because no dosing or adverse event data 
are currently available on the use of eribulin in combination with gemcitabine in patients 
<18 years of age, children are excluded from this study.  In addition, urothelial cancer of 
the bladder is extremely rare in pediatric patients. 
 
3.1.7 
Zubrod performance status ≤2 (Karnofsky ≥60%, see Appendix A). 
 
3.1.8 
Life expectancy of greater than 3 months 
 
3.1.9 
Patients must have adequate organ and marrow function as defined below: 
 
− 
leukocytes 
≥3,000/mcL 
− 
absolute neutrophil count 
≥1,500/mcL 
− 
platelets 
≥100,000/mcL 
− 
total bilirubin 
< 1.5 times the upper limit of normal (x ULN) for the 
institution 
− 
AST(SGOT)/ALT(SGPT) 
≤3 × institutional upper limit of normal 
− 
creatinine clearance 
calculated creatinine clearance (CrCl) ≥ 30 mL/min and 
<60 mL/min (Cockroft-Gault) unless the patient 
qualified based on hearing loss or neuropathy (see 
3.1.4) 
 


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12 
3.1.10 
The effects of gemcitabine and eribulin on the developing human fetus are 
unknown.  For this reason and because tubulin inhibiting agents as well as other 
therapeutic agents used in this trial are known to be teratogenic, women of child-bearing 
potential and men 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 she or 
her partner is participating in this study, she should inform her treating physician 
immediately.  Men treated or enrolled on this protocol must also agree to use adequate 
contraception prior to the study, for the duration of study participation, and 4 months 
after completion of gemcitabine and eribulin administration. 
 
3.1.11 
Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.2 Exclusion Criteria 
 
3.2.1 
Patients with a small cell component in their histology are excluded.  
 
3.2.2 
Patients who have had chemotherapy for the treatment of the advanced or 
unresectable urothelial cancer of the bladder are not eligible; patients who were 
previously treated for local disease must not have received radiotherapy or chemotherapy 
within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study and 
must have recovered from adverse events due to agents administered more than 4 weeks 
earlier. Patients who have received neoadjuvant or adjuvant chemotherapy must have 
completed treatment at least 6 months prior to diagnosis of metastatic disease.  
 
3.2.3 
Patients who are receiving any other investigational agents. 
 
3.2.4 
Patients with known brain metastases should be excluded from this clinical trial 
because of their poor prognosis and because they often develop progressive neurologic 
dysfunction that would confound the evaluation of neurologic and other adverse events. 
 
3.2.5 
History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to gemcitabine and eribulin. 
 
3.2.6 
Uncontrolled intercurrent illness including, but not limited to, a second cancer 
diagnosis within the past 5 years, or a cancer undergoing any treatment, 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. 
 


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13 
3.2.7 
Pregnant women are excluded from this study because eribulin is an anti-tubulin 
agent with the potential for teratogenic or abortifacient effects. Because there is an 
unknown but potential risk for adverse events in nursing infants secondary to treatment of 
the mother with eribulin and gemcitabine, breastfeeding should be discontinued if the 
mother is treated with eribulin and gemcitabine.  
 
3.2.8 
Human immunodeficiency virus (HIV)-positive patients with inadequate CD4 
counts or those who are on combination antiretroviral therapy with strong CYP3A4 
effects are ineligible for this trial 
 
3.2.9 
QT prolongation has been observed in patients that received Eribulin and 
therefore: 
• Patients with baseline QTc prolongation greater than grade 1 are excluded 
from this study. Patients with grade 1 QTc elevation are eligible but must 
be monitored with ECG (EKG) exams, for the first 3 cycles of treatment. 
Eribulin time to Cmax after infusion is about 10 minutes, and half life is 
40 minutes44. ECG (EKG) should be performed between 10 to 40 minutes 
after eribulin administration (on day 1 and day 8 of treatment). Continued 
ECG (EKG) monitoring beyond cycle 3 can be done at the discretion of 
the treating physician. 
• Patients with congenital long QT syndrome are excluded from this study. 
• Other medications known to prolong QT interval should be discontinued 
and if not possible, patient is excluded from this study.  Refer to 
http://crediblemeds.org for lists of drugs that may cause QT prolongation. 
 
3.3 Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
4. REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 
4.1.1 
CTEP Registration Procedures 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all investigators participating in any NCI-sponsored clinical trial to register 
and to renew their registration annually. 
 
Registration requires the submission of: 
 
• a completed Statement of Investigator Form (FDA Form 1572) with an original 
signature 
• a current Curriculum Vitae (CV) 
• a completed and signed Supplemental Investigator Data Form (IDF) 
• a completed Financial Disclosure Form (FDF) with an original signature 


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14 
 
Fillable PDF forms and additional information can be found on the CTEP website at 
http://ctep.cancer.gov/investigatorResources/investigator_registration.htm. For questions, 
please contact the CTEP Investigator Registration Help Desk by email at 
pmbregpend@ctep.nci.nih.gov. 
 
4.1.2 
CTEP Associate Registration Procedures / CTEP-IAM Account 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) application is a web-based application intended for use by both Investigators (i.e., 
all physicians involved in the conduct of NCI-sponsored clinical trials) and Associates 
(i.e., all staff involved in the conduct of NCI-sponsored clinical trials). 
 
Associates will use the CTEP-IAM application to register (both initial registration and 
annual re-registration) with CTEP and to obtain a user account. 
 
Investigators will use the CTEP-IAM application to obtain a user account only. (See 
CTEP Investigator Registration Procedures above for information on registering with 
CTEP as an Investigator, which must be completed before a CTEP-IAM account can be 
requested.) 
 
An active CTEP-IAM user account is needed to access all CTEP and CTSU (Cancer 
Trials Support Unit) websites and applications, and is critical to the conduct of this study, 
including document access, patient enrollment, and clinical data submission. 
 
Additional information can be found on the CTEP website at 
http://ctep.cancer.gov/branches/pmb/associate_registration.htm.  For questions, please 
contact the CTEP Associate Registration Help Desk by email at 
ctepreghelp@ctep.nci.nih.gov. 
 
4.1.3 
For Questions and Support 
 
For questions about Investigator Registration, please contact the CTEP Investigator 
Registration Help Desk: pmbregpend@ctep.nci.nih.gov. 
 
For questions about Associate Registration or CTEP-IAM Account Creation, please 
contact the CTEP Registration Help Desk: ctepreghelp@ctep.nci.nih.gov. 
 
4.2 
Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office 
before they can be approved to enroll patients.  Assignment of site registration status in the 
CTSU Regulatory Support System (RSS) uses extensive data to make a determination of whether 
a site has fulfilled all regulatory criteria including but not limited to: an active Federal Wide 


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15 
Assurance (FWA) number, an active roster affiliation with the Lead Network or a participating 
organization, a valid IRB approval, and compliance with all protocol specific requirements. 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are 
not required to submit IRB approval documentation to the CTSU Regulatory Office. For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in 
an automated process.  Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRBManager to indicate their intent to open the study locally.  
The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office.  In 
order for the SSW approval to be processed, the Signatory Institution must inform the CTSU 
which CIRB-approved institutions aligned with the Signatory Institution are participating in the 
study. 
 
4.2.1 Downloading Regulatory Documents 
 
Site registration forms may be downloaded from the NCI# 9653 protocol page located on 
the CTSU Web site.  Permission to view and download this protocol is restricted and is 
based on person and site roster data housed in the CTSU RSS.  To participate, 
Investigators and Associates must be associated with the Corresponding or Participating 
protocol organization in the RSS.  
 
• Go to https://www.ctsu.org and log in using your CTEP IAM username and 
password 
• Click on the Protocols tab in the upper left of your screen  
• Click on the ETCTN link to expand, then select Phase 1 Grants followed by 
LAO-CA043, and protocol #9653 
• Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided.  (Note: For sites under the CIRB 
initiative, IRB data will automatically load to RSS.) 
 
4.2.2 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will 
be entered and tracked in the CTSU RSS. 
 
ONLINE: www.ctsu.org (members’ section) → Regulatory Submission Portal 
 
4.2.3 Checking Site Registration Status 
 


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16 
You can verify your site registration status on the members’ section of the CTSU 
website.   
• Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• Click on the Regulatory tab at the top of your screen 
• Click on the Site Registration tab 
• Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does 
not reflect compliance with protocol requirements for individuals participating on the 
protocol or the enrolling investigator’s status with the NCI or their affiliated networks. 
 
4.3 
Patient Registration 
 
4.3.1 OPEN / IWRS 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available to users on a 24/7 basis.  It 
is integrated with the CTSU Enterprise System for regulatory and roster data interchange 
and with the Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment.  Patient enrollment data entered by Registrars in 
OPEN / IWRS will automatically transfer to the NCI’s clinical data management system, 
Medidata Rave. 
 
For trials with slot reservation requirements, OPEN will connect to IWRS at enrollment 
initiation to check slot availability.  Registration staff should ensure that a slot is 
available and secured for the patient before completing an enrollment. 
 
• 
Site 
staff 
with 
the 
appropriate 
roles 
will 
reserve 
slots 
using 
IWRS 
(https://open.ctsu.org/).  
• City of Hope Cancer Center will receive notification via the IWRS when a slot has been 
reserved. An email will be sent from the City of Hope Cancer Center to the site 
requesting further information such as: the patient initials, tumor type and potential start 
date. The spot will show as ‘pending approval’ in the system until the site sends a 
REGISTRATION 
FORM/ELIGIBILITY 
CHECKLIST 
(see 
CTSU 
website) 
accompanied with the signed consent, baseline labs, pathology report, CT/x-ray reports to 
the City of Hope Cancer Center at ccc@coh.org for review and confirmation of 
eligibility.  
• Once the Registration has been reviewed, the City of Hope Cancer Center will either 
approve or disapprove the request depending on confirmation of patient eligibility. If 
approved, the City of Hope Cancer Centre will update the spot to ‘reserved’ in IWRS.  
• The site can now enroll the patient into the study in OPEN  
* At the time of registration the treatment arm will be randomly assigned  
 


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17 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
4.3.2 
OPEN/IWRS User Requirements 
 
OPEN/IWRS users must meet the following requirements: 
• Have a valid CTEP-IAM account (i.e., CTEP username and password). 
• To enroll patients or request slot reservations:  Be on an ETCTN Corresponding 
or Participating Organization roster with the role of Registrar. 
• To approve slot reservations or access cohort management:  Be identified to 
Theradex as the “Client Admin” for the study.  
• Have regulatory approval for the conduct of the study at their site. 
 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes. Site 
staff should use the registration forms provided on the CTSU web site as a tool to 
verify eligibility. 
• If applicable, all patients have signed an appropriate consent form and HIPAA 
authorization form. 
 
4.3.3 
OPEN/IWRS Questions 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which 
is available on the Theradex website:  http://theradex.com/CTMS/Downloads.aspx. This 
link to the Theradex website is also on the CTSU website OPEN tab. For questions about 
the use of IWRS for slot reservations, contact the Theradex Helpdesk: 609-619-7802 or 
Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 7 days.  Issues that would 
cause treatment delays should be discussed with the Principal Investigator.  If a patient does not 
receive protocol therapy following registration, the patient’s registration on the study may be 
canceled.  The Study Coordinator (cccp@coh.org) should be notified of cancellations as soon as 
possible. 
 
5. TREATMENT PLAN 
 
5.1 Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 


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18 
risks are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
5.1.1 Gemcitabine and Eribulin 
Gemcitabine should be administered before Eribulin. 
 
5.1.1.1 
Eribulin (E7389) Administration 
 
Eribulin will be administered on an outpatient basis after gemcitabine as an intravenous bolus 
over 2-5 minutes, once a week for two weeks in a row (on Days 1 and 8) of a 21 day cycle.   
The patient’s starting dose will be 1.4 mg/m2/week.  The dose may be reduced for individual 
patients in subsequent cycles depending on toxicity (Section 6.2); there will be no intra-
patient dose escalation.   
 
 
Reported adverse events (AEs) and potential risks of eribulin are described in Section 7.1. 
Appropriate dose modifications for eribulin are described in Section 6.2. No investigational 
or commercial agents or therapies other than those described in Section 5 (Treatment Plan) 
may be administered with the intent to treat the patient’s malignancy. 
 
5.1.1.2 
Gemcitabine Administration 
 
Gemcitabine at a dose of 1000mg/m2 will be administered intravenously over 30 minutes 
before eribulin once a week for two weeks in a row (on Day 1 and 8) of a 21 day cycle.  
 
The patient’s starting dose will be 1000 mg/m2/week.  The dose may be reduced for 
individual patients in subsequent cycles depending on toxicity (Section 6.2); there will be no 
intra-patient dose escalation.   
 
Reported adverse events (AEs) and potential risks of gemcitabine are described in Section 0. 
Appropriate dose modifications for gemcitabine are described in Section 6.2. No 
investigational or commercial agents or therapies other than those described in Section 5.0 
(Treatment Plan) may be administered with the intent to treat the patient’s malignancy. 
 
 
5.2 General Concomitant Medication and Supportive Care Guidelines 
 
Prophylactic antiemetic therapy will be given as per institutional policy. 
 
Erythropoietin may be administered for anemia/fatigue at the investigators’ discretion, however 
prophylactic use of granulocyte/platelet colony stimulating factors is not permitted. If the patient 
experiences febrile neutropenia as a documented toxicity on this study then granulocyte colony 
stimulating factors may be used in line with institutional and ASCO guidelines.  
 
Antidiarrheal medications, potentially including loperamide, along with supplemental fluids and 
other supportive measures are recommended at the discretion of the investigator. 


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19 
 
All supportive measures consistent with optimal patient care will be given throughout the study. 
Patients should be cautioned about the concomitant use of cimetidine, trimethoprim, or other 
agents that interfere with creatinine secretion or the creatinine assay.   
  
5.3 Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
 
• 
Disease progression, 
 
• 
Intercurrent illness that prevents further administration of treatment with a 14 day 
delay in protocol scheduled treatment, 
 
• 
Unacceptable adverse event(s), 
 
• 
Patient decides to withdraw from the study, or 
 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
Note: if a patient is to come off protocol apart from for disease progression then the 
treating physician should contact the study PI by email (sarmad.sadeghi@usc.edu). 
 
5.4 Duration of Follow Up 
 
Patients will be followed every 3 months for up to 36 months after end of treatment with 
gemcitabine and eribulin, until progression, start of a treatment with an agent other than 
gemcitabine or eribulin, of disease or death, whichever occurs first.  In addition, patients 
removed from study for unacceptable adverse event(s) will be followed until resolution or 
stabilization of the adverse event and will then be followed every 3 months, as above. 
 
5.5 Criteria for Removal from Study 
 
Patients will remain on-study for 36 months after going off treatment, progression of disease or 
initiation of new treatment, (whichever comes first) or at death or patient withdrawal of consent. 
The reason for study removal and the date the patient was removed must be documented in the 
Case Report Form. Every effort should be made to evaluate patients for a date and details of 
progression should they come off treatment for reasons other than progressive disease and in all 
cases for survival unless consent is specifically with drawn for that follow up.   
 
 
 
 


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20 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 
Retreatment criteria and dosing delays 
 
 
Prior to retreatment, patients must have recovered the following organ function: 
• 
absolute neutrophil count 
>1,000/mm3 (750/mm3 for day 8)  
• 
platelets 
 
 
>75,000/mm3 
• 
total bilirubin 
 
 1.5 institutional upper limit of normal 
(IULN) 
• 
AST(SGOT)/ALT(SGPT) 
 3 X IULN  
• 
Neuropathy  
Grade 0-1 
 
Management of anemia (RBC transfusion, erythropoietin, etc) need not delay treatment at the 
discretion of the treating physician.  
 
Fatigue and other laboratory and non-laboratory toxicities not listed above or under dose 
modifications (6.2, 6.3 and 6.4) may not require treatment delays and may be managed at the 
discretion of the treating physician. 
 
Laboratory evaluations must be repeated within 24 hours prior to initiation of each cycle of 
therapy. Patients not fulfilling these criteria should have treatment delayed by 1 week to allow 
for recovery of organ function. Patients who cannot be retreated within 2 weeks of the originally 
scheduled Day 1 or Day 8 treatment should be removed from study. 
 
Patients with grade 1 QTc elevation are monitored with ECG (EKG) examination after 
eribulin treatment between 10 to 40 minutes of completion of the eribulin on day 1 and day 
8 treatments for the first 3 cycles of treatment. The expectation for QTc prolongation to 
manifest after 6 treatments with eribulin is low, and therefore continuation of ECG (EKG) 
monitoring for eribulin beyond the third cycle is left to the discretion of the treating 
physician. Patients with prolongation of QTc to grade 2 or greater should have ECG 
(EKG) undertaken at intervals until this resolves and have their ongoing involvement 
discussed with the study PI by email (sarmad.sadeghi@usc.edu). 
 
6.2 
Dose modifications for eribulin 
 
If day 1 or day 8 dose of eribulin must be held for toxicities related to eribulin, day 1 or day 8 
treatment (both eribulin and gemcitabine) will be held until toxicities resolve to a grade that 
would allow treatment to proceed. If patient cannot be treated (retreated) within 2 weeks of the 
originally scheduled Day 1 or Day 8 treatment, then treatment with eribulin will be discontinued.  
 
• 
There will be no dose modifications for grade 1 or 2 toxicities that recover to a grade 
0 or 1 or otherwise meet laboratory re-treatment parameters in 6.1 prior to the 
next cycle of treatment. 
 
• 
If a patient experiences a grade 3 or 4 non-hematological toxicity attributable to 
eribulin, excluding:  


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21 
o alopecia,  
o hypersensitivity,  
o nausea and vomiting that have not been treated with maximal 
antiemetic therapy or  
o diarrhea that has not been treated with optimal antidiarrheal therapy 
 
 
  
which resolves to a grade 0 or 1 prior to the next cycle of treatment, or within 
a  2 week delay, the patient may be retreated with eribulin at one dose level 
lower. If a lower dose is not possible due to a prior dose reduction, then 
treatment with eribulin will be discontinued. 
 
• 
If a patient experiences a grade 3 or 4 hematological toxicity attributable to eribulin, 
excluding: 
o Leukopenia 
o Lymphopenia 
 
 
 
which resolves to a grade 0 or 1, prior to the next cycle of treatment, or 
within a ≤ 2 week delay, the patient may be retreated with eribulin one dose 
level lower or at the same level with G-CSF support based on the preference 
of the treating physician. If a lower dose is not possible due to a prior dose 
reduction, then treatment with eribulin will be discontinued. 
 
• 
Patients who cannot be retreated within 2 weeks of the originally scheduled Day 1 or 
Day 8 treatment, he or she should have eribulin discontinued. 
 
• 
No patient should have his/her eribulin dose re-escalated following dose reduction for 
toxicity. 
 
Dose Level 
Eribulin Dose 
Level  0 
1.4 mg/m2/week 
Level -1 
1.0 mg/m2/week 
Level -2 
0.7 mg/m2/week 
 
6.3 
Dose modifications for gemcitabine 
 
• If gemcitabine is discontinued for any reason other than disease progression, patients may 
continue to receive eribulin. In cases of disease progression, combination treatment will be 
discontinued. 
 
• Gemcitabine doses held on day 8 of a cycle where day 8 dose of eribulin is administered will 
not be made up at a later date.  
• If more than one dose reduction applies, then use the lowest. Doses that are reduced at any 
point in a cycle will not be subsequently increased. 
• If based on the criteria provided here a situation arises where because of toxicities 
gemcitabine dose is discontinued, treatment with eribulin alone shall be continued. 
 


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22 
 
 
The following dose levels of gemcitabine will be used: 
 
Dose Level 
Gemcitabine Dose 
Level  0 
1000 mg/m2/week 
Level -1 
750 mg/m2/week 
Level -2 
500 mg/m2/week 
 
If further dose reductions are required, gemcitabine will be discontinued. 
 
6.4 Dose Modifications for Eribulin and Gemcitabine for Nausea, Vomiting, Diarrhea, 
Neutropenia and Thrombocytopenia 
 
 
Nausea 
Management/Next Dose for 
Eribulin 
Management/Next Dose for 
Gemcitabine 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at 
same dose level. 
Hold until ≤ Grade 1.  Resume at 
same dose level. 
Grade 3 
Hold* until < Grade 2.  Resume at 
one dose level lower, if indicated.** 
Hold* until < Grade 2.  Resume at 
one dose level lower, if indicated.** 
Grade 4 
Off protocol therapy 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions for the same drug should go off protocol therapy. 
Recommended management:  antiemetics. 
 
 
Vomiting 
Management/Next Dose for 
Eribulin 
Management/Next Dose for 
Gemcitabine 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at 
same dose level. 
Hold until ≤ Grade 1.  Resume at 
same dose level. 
Grade 3 
Hold* until < Grade 2.  Resume at 
one dose level lower, if indicated.** 
Hold* until < Grade 2.  Resume at 
one dose level lower, if indicated.** 
Grade 4 
Off protocol therapy 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions for the same drug should go off protocol therapy. 
Recommended management:  antiemetics. 
 
 
Diarrhea 
Management/Next Dose for 
Eribulin 
Management/Next Dose for 
Gemcitabine 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at 
same dose level. 
Hold until ≤ Grade 1.  Resume at 
same dose level. 


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23 
Diarrhea 
Management/Next Dose for 
Eribulin 
Management/Next Dose for 
Gemcitabine 
Grade 3 
Hold* until < Grade 2.  Resume at 
one dose level lower, if indicated.** 
Hold* until < Grade 2.  Resume at 
one dose level lower, if indicated.** 
Grade 4 
Off protocol therapy 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions for the same drug should go off protocol therapy. 
Recommended management:  Loperamide antidiarrheal therapy 
Dosage schedule:  4 mg at first onset, followed by 2 mg with each loose motion until diarrhea-
free for 12 hours (maximum dosage:  16 mg/24 hours) 
Adjunct anti-diarrheal therapy is permitted and should be recorded when used. 
 
 
Neutropenia 
Management/Next Dose for 
Eribulin 
Management/Next Dose for 
Gemcitabine 
≤ Grade 1 (≥ 1500) 
No change in dose 
No change in dose 
Grade 2 (1000 to 
<1500) 
No change in dose 
No change in dose 
Grade 3 (500 to 
<1000) 
For Day 1: 
Hold* until neutrophil ≥ 1000.  
Resume at one dose level lower, if 
indicated.** 
 
For Day 8: 
Hold* until neutrophil ≥ 750.  
Resume at one dose level lower, if 
indicated.** 
 
For Day 1: 
Hold* until neutrophil ≥ 1000.  
Resume at one dose level lower, if 
indicated.** 
 
For Day 8: 
Hold* until neutrophil ≥ 750.  
Resume at one dose level lower, if 
indicated.** 
Grade 4 (<500) 
For Day 1: 
Hold* treatment for one week and 
add GCSF. When neutrophils 
recover to Grade <4 treatment may 
continue according to the grade of 
residual neutropenia. GCSF should 
be added to the future cycles on 
Day 9. 
If neutrophils are still at grade 4 
after one week of GCSF, patient 
will be removed from study. 
 
For Day 8: 
Hold* treatment for one week and 
add GCSF. When neutrophils 
recover to Grade <4 treatment may 
continue according to the grade of 
residual neutropenia. GCSF should 
For Day 1: 
Hold* treatment for one week and 
add GCSF. When neutrophils 
recover to Grade <4 treatment may 
continue according to the grade of 
residual neutropenia. GCSF should 
be added to the future cycles on 
Day 9. 
If neutrophils are still at grade 4 
after one week of GCSF, patient 
will be removed from study. 
 
For Day 8: 
Hold* treatment for one week and 
add GCSF. When neutrophils 
recover to Grade <4 treatment may 
continue according to the grade of 
residual neutropenia. GCSF should 


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24 
Neutropenia 
Management/Next Dose for 
Eribulin 
Management/Next Dose for 
Gemcitabine 
be added to the future cycles on 
Day 9. 
If neutrophils are still at grade 4 
after one week of GCSF, patient 
will be removed from study. 
be added to the future cycles on 
Day 9. 
If neutrophils are still at grade 4 
after one week of GCSF, patient 
will be removed from study. 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions for the same drug should go off protocol therapy. 
 
 
Thrombocytopenia 
Management/Next Dose for 
Eribulin (Dose reduction 
applicable only after Gemcitabine 
is discontinued§) 
Management/Next Dose for 
Gemcitabine 
≤ Grade 1 ≥75K) 
No change in dose 
No change in dose 
Grade 2 (50K to 
<75K) 
Hold until ≤ Grade 1.  Resume at 
same dose level. 
Hold until ≤ Grade 1.  Resume at 
same dose level. 
Grade 3 (25Kto 
<50K) 
Hold* until ≤ Grade 1.  Resume at 
one dose level lower, if indicated.** 
Hold* until ≤ Grade 1.  Resume at 
one dose level lower, if indicated.** 
Grade 4 (<25K) 
Hold* until ≤ Grade 1.  Resume at 
one dose level lower, if indicated.** 
Discontinue Gemcitabine 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions for the same drug should go off protocol therapy.  
§Thrombocytopenia is more likely to be a toxicity of gemcitabine and gemcitabine dose 
reduction should occur first, if indicated.  
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting (via CTEP-AERS) in addition to 
routine reporting. 
 
7.1 Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf  for 
further clarification. Frequency is provided based on 2318 patients. Below is the CAEPR for 


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25 
Eribulin Mesylate (E7389; Halichondrin B Analog). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades 
to determine if expedited reporting is required. 
 
 
7.1.1 CAEPR for E7389 (halichondrin B analog) 
 
Version 2.6, March 23, 20161 
 
 Adverse Events with Possible  
 Relationship to Eribulin Mesylate (E7389; Halichondrin B Analog) 
 (CTCAE 4.0 Term) 
[n= 2318] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 3) 
 
Febrile neutropenia 
 
 Febrile neutropenia (Gr 3) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
Anal mucositis 
 
 Anal mucositis (Gr 2) 
Constipation 
 
 
 Constipation (Gr 3) 
 
Diarrhea 
 
 Diarrhea (Gr 2) 
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
Nausea 
 
 
 Nausea (Gr 3) 
 
Rectal mucositis 
 
 Rectal mucositis (Gr 2) 
 
Small intestinal mucositis  
 Small intestinal mucositis (Gr 
2) 
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS   
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
INFECTIONS AND INFESTATIONS 
  
 
Infection2 
 
 Infection2 (Gr 3) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Dermatitis radiation 
 
 Dermatitis radiation (Gr 2) 
 
Radiation recall reaction 
(dermatologic) 
 
 Radiation recall reaction 
(dermatologic) (Gr 2) 
INVESTIGATIONS 
  


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26 
 
 Adverse Events with Possible  
 Relationship to Eribulin Mesylate (E7389; Halichondrin B Analog) 
 (CTCAE 4.0 Term) 
[n= 2318] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
 
 
Alanine aminotransferase 
increased 
 
  
 
Aspartate 
aminotransferase 
increased 
 
  
 
Lymphocyte count 
decreased 
 
  
Neutrophil count 
decreased 
 
 
 Neutrophil count decreased (Gr 
4) 
 
Platelet count decreased  
 Platelet count decreased (Gr 3) 
 
Weight loss 
 
  
White blood cell 
decreased 
 
 
 White blood cell decreased (Gr 
4) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 2) 
 
Hyperglycemia 
 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
 Back pain (Gr 2) 
 
Bone pain 
 
  
 
Myalgia 
 
 Myalgia (Gr 2) 
 
Pain in extremity 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 
 
Paresthesia 
 
  
 
Peripheral motor 
neuropathy 
 
 Peripheral motor neuropathy 
(Gr 2) 
 
Peripheral sensory 
neuropathy 
 
 Peripheral sensory neuropathy 
(Gr 3) 
PSYCHIATRIC DISORDERS 
  
 
Insomnia 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 


NCI Protocol #: 9653 
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27 
 
 Adverse Events with Possible  
 Relationship to Eribulin Mesylate (E7389; Halichondrin B Analog) 
 (CTCAE 4.0 Term) 
[n= 2318] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
 
 
Laryngeal mucositis 
 
 Laryngeal mucositis (Gr 2) 
 
Pharyngeal mucositis 
 
 Pharyngeal mucositis (Gr 2) 
 
Tracheal mucositis 
 
 Tracheal mucositis (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
Alopecia 
 
 
 Alopecia (Gr 2) 
 
Rash maculo-papular 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be 
distributed to all Principal Investigators at the time of revision. The current version can be 
obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
 
2Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS 
SOC. 
 
3Muscle weakness includes Generalized muscle weakness, Muscle weakness left-sided, Muscle 
weakness lower limb, Muscle weakness right-sided, Muscle weakness trunk, and Muscle 
weakness upper limb under the MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS SOC. 
 
 
Adverse events reported on Eribulin Mesylate (E7389; Halichondrin B Analog) trials, but 
for which there is insufficient evidence to suggest that there was a reasonable possibility 
that Eribulin Mesylate (E7389; Halichondrin B Analog) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system 
disorders - Other (bone marrow failure); Blood and lymphatic system disorders - Other (febrile 
bone marrow aplasia); Blood and lymphatic system disorders - Other (pancytopenia); Hemolysis; 
Leukocytosis; Spleen disorder 
CARDIAC DISORDERS - Acute coronary syndrome; Atrial fibrillation; Cardiac arrest; 
Cardiac disorders - Other (cardiogenic shock); Cardiac disorders - Other (edema); Heart failure; 
Myocardial infarction; Palpitations; Pericardial effusion; Pericardial tamponade; Pericarditis; 
Sinus bradycardia; Sinus tachycardia; Supraventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Vertigo 
EYE DISORDERS - Blurred vision; Cataract; Dry eye; Eye disorders - Other (visual 
impairment); Watering eyes 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Bloating; Colitis; 
Colonic obstruction; Dry mouth; Duodenal fistula; Dyspepsia; Dysphagia; Enterocolitis; 
Esophageal stenosis; Gastric hemorrhage; Gastritis; Gastrointestinal disorders - Other 


NCI Protocol #: 9653 
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28 
(abdominal hernia); Gastrointestinal disorders - Other (eructation); Gastrointestinal disorders - 
Other (gastric pneumatosis); Ileus; Lower gastrointestinal hemorrhage; Oral dysesthesia; Oral 
hemorrhage; Oral pain; Pancreatitis; Rectal hemorrhage; Retroperitoneal hemorrhage; Small 
intestinal obstruction; Stomach pain; Upper gastrointestinal hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema 
face; Flu like symptoms; Gait disturbance; General disorders and administration site conditions - 
Other (general physical health deterioration); Infusion site extravasation; Injection site reaction; 
Malaise; Multi-organ failure; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure; Hepatic hemorrhage; 
Hepatic pain; Hepatobiliary disorders - Other (hepatitis) 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Immune system disorders - Other 
(angioedema) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Fracture; 
Gastric anastomotic leak; Vascular access complication 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Alkaline phosphatase 
increased; Blood bilirubin increased; CPK increased; Cholesterol high; Creatinine increased; 
Electrocardiogram QT corrected interval prolonged; GGT increased; INR increased; 
Investigations - Other (blood chloride decreased); Investigations - Other (blood LDH increased); 
Investigations - Other (breath sounds abnormal); Investigations - Other (c-reactive protein 
increased); Investigations - Other (neutrophil count increased); Lipase increased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; 
Hyperkalemia; Hypoalbuminemia; Hypocalcemia; Hypoglycemia; Hypokalemia; 
Hypomagnesemia; Hyponatremia; Hypophosphatemia; Metabolism and nutrition disorders - 
Other (failure to thrive) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Flank pain; Muscle 
weakness3; Musculoskeletal and connective tissue disorder - Other (muscle spasms); 
Musculoskeletal and connective tissue disorder - Other (musculoskeletal stiffness) 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Leukemia secondary to oncology chemotherapy; Myelodysplastic syndrome; 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (tumor 
hemorrhage); Treatment related secondary malignancy; Tumor pain 
NERVOUS SYSTEM DISORDERS - Acoustic nerve disorder NOS; Ataxia; Depressed level 
of consciousness; Dysesthesia; Dysphasia; Edema cerebral; Encephalopathy; Hydrocephalus; 
Intracranial hemorrhage; Ischemia cerebrovascular; Lethargy; Memory impairment; Neuralgia; 
Recurrent laryngeal nerve palsy; Reversible posterior leukoencephalopathy syndrome; Seizure; 
Sinus pain; Somnolence; Syncope; Transient ischemic attacks; Tremor 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Psychiatric disorders - Other 
(mental status changes) 
RENAL AND URINARY DISORDERS - Acute kidney injury; Hematuria; Proteinuria; Renal 
and urinary disorders - Other (hemorrhage urinary tract); Renal calculi; Urinary retention; 
Urinary tract obstruction; Urinary tract pain; Urine discoloration 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Breast pain; Pelvic pain; 
Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory 
distress syndrome; Atelectasis; Bronchopulmonary hemorrhage; Epistaxis; Hiccups; Hypoxia; 
Pharyngolaryngeal pain; Pleural effusion; Pneumonitis; Pneumothorax; Postnasal drip; 


NCI Protocol #: 9653 
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29 
Productive cough; Pulmonary fibrosis; Respiratory failure; Respiratory, thoracic and mediastinal 
disorders - Other (asthma); Respiratory, thoracic and mediastinal disorders - Other (chronic 
obstructive pulmonary disease); Sore throat; Voice alteration; Wheezing 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Hyperhidrosis; Nail loss; 
Palmar-plantar erythrodysesthesia syndrome; Pruritus; Skin and subcutaneous tissue disorders - 
Other (skin exfoliation) 
VASCULAR DISORDERS - Capillary leak syndrome; Hypertension; Hypotension; 
Lymphocele; Phlebitis; Superior vena cava syndrome; Thromboembolic event 
 
 
Note: Eribulin Mesylate (E7389; Halichondrin B Analog) in combination with other agents 
could cause an exacerbation of any adverse event currently known to be caused by the other 
agent, or the combination may result in events never previously associated with either agent. 
 
Adverse Event List for Gemcitabine 
 
>10%: Cardiovascular: Peripheral edema (20%), edema (13%) Central nervous system: 
Pain (10% to 48%), fever (30% to 41%), somnolence (5% to 11%) Dermatologic: Rash 
(24% to 30%), alopecia (15% to 18%), pruritus (13%) Gastrointestinal: Nausea/vomiting 
(64% to 71%; grades 3/4: 1% to 13%), constipation (10% to 31%), diarrhea (19% to 
30%), stomatitis (10% to 14%) Hematologic: Anemia (65% to 73%; grade 4: 1% to 3%), 
leukopenia (62% to 71%; grade 4: ≤1%), neutropenia (61% to 63%; grade 4: 6% to 7%), 
thrombocytopenia (24% to 47%; grade 4: ≤1%), hemorrhage (4% to 17%; grades 3/4: 
<1% to 2%); myelosuppression is the dose-limiting toxicity Hepatic: Transaminases 
increased (67% to 78%; grades 3/4: 1% to 12%), alkaline phosphatase increased (55% to 
77%; grades 3/4: 2% to 16%), bilirubin increased (13% to 26%; grades 3/4: <1% to 6%) 
Renal: Proteinuria (10% to 45%; grades 3/4: <1%), hematuria (13% to 35%; grades 3/4: 
<1%), BUN increased (8% to 16%; grades 3/4: 0%) Respiratory: Dyspnea (6% to 23%) 
Miscellaneous: Flu-like syndrome (19%), infection (8% to 16%; grades 3/4: <1% to 2%)  
 
1% to 10%: Local: Injection site reactions (4%) Neuromuscular & skeletal: Paresthesia 
(2% to 10%) Renal: Creatinine increased (2% to 8%) Respiratory: Bronchospasm (<2%) 
 
<1% (Limited to important or life-threatening; reported with single-agent use or with 
combination therapy, all reported rarely): Adult respiratory distress syndrome, 
anaphylactoid reaction, anorexia, arrhythmias, bullous skin eruptions, cellulitis, 
cerebrovascular accident, CHF, chills, cough, desquamation, diaphoresis, gangrene, GGT 
increased, headache, hemolytic uremic syndrome (HUS), hepatotoxic reaction (rare), 
hypertension, insomnia, interstitial pneumonitis, liver failure, malaise, MI, peripheral 
vasculitis, petechiae, pulmonary edema, pulmonary fibrosis, radiation recall, renal failure, 
respiratory failure, rhinitis, sepsis, supraventricular arrhythmia, weakness 
 
Please refer the reader to the package insert(s) for the comprehensive list of adverse 
events 
 
7.2 Adverse Event Characteristics  
 


NCI Protocol #: 9653 
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30 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in 
section 7.3.4. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 Expedited Adverse Event Reporting 
 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP Web site (http://ctep.cancer.gov).  The 
reporting procedures to be followed are presented in the “NCI Guidelines for 
Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and 
DCP INDs and IDEs” which can be downloaded from the CTEP Web site 
(http://ctep.cancer.gov).  These requirements are briefly outlined in the tables below 
(Section 7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
 
7.3.2 CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Study Coordinator of the Lead Organization, Principal 
Investigator, and the local treating physician.  CTEP-AERS provides a copy feature for 
other e-mail recipients.  
 
7.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 


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31 
Note:  A death on study requires both routine and expedited reporting regardless of 
causality, unless as noted below.  Attribution to treatment or other cause must be 
provided. 
 
Death due to progressive disease should be reported as Grade 5 “Neoplasms benign, 
malignant and unspecified (incl cysts and polyps) - Other (Progressive Disease)” 
under the system organ class (SOC) of the same name.  Evidence that the death was a 
manifestation of underlying disease (e.g., radiological changes suggesting tumor growth 
or progression: clinical deterioration associated with a disease process) should be 
submitted.  
 
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via AdEERS 
within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via AdEERS within 24 hours of learning of 
the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 


NCI Protocol #: 9653 
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32 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
7.3.4 Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
N/A 
 
7.4 Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported through 
CTEP-AERS must also be reported in routine study data submissions. 
 
7.5 Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
7.6 Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting 
via CDUS unless otherwise specified.  
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 7.1. 


NCI Protocol #: 9653 
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33 
 
 
8.1 CTEP IND Agent(s) 
 
8.1.1 CTEP IND Agent -  Eribulin - E7389 (NSC #707389) 
 
Chemical Name: 
11,15:18,21:24,28-Triepoxy-7,9-ethanol-12,15-methano-9H,15H-furo[3,2-
i]furo[2’,3’:5,6]pyrano[4,3-b][1,4]dioxacyclopentacosin-5(4H)-one,2-[(2S)-3-
amino-2-hydroxypropyl]hexacosahydro-3-methoxy-26-methyl-20,27-
bis(methylene)-
,(2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS
)-methanesulfonate (salt) 
 
Other Names: 
Halichondrin B analog, ER-086526, B1939, eribulin mesylate 
 
Classification: 
Synthetic analog of the very rare marine sponge natural product, halichondrin B 
 
Molecular Formula: 
C40H59NO11 CH4O3S 
 
M.W.: 
826.00 
 
Approximate Solubility:   
o Freely soluble in water, methanol, ethanol, 1-octanol, benzyl alcohol, dimethylsufoxide, N-
methylpyrrolidone, dichloromethane and ethylacetate, and at pH 3-7. 
o Soluble in acetone and at pH 9, and sparingly soluble in acetonitrile. 
o Insoluble in tert-butylmethyl ether, n-heptane and n-pentane, but slightly soluble at pH 11 
 
Mode of Action: 
Tubulin-binding agent (inhibition of microtubule polymerization) 
 
How Supplied: 
E7389 is supplied by Eisai Medical Research Inc., and distributed by CTEP/NCI as 
1 mg/vial (0.5mg/mL- 2mL fill).  The clear, colorless, and sterile solution is 
packaged in 5 mL glass vial. 
 
Component 
Grade 
Quantity per viala 
E7389b 
Eisai Standard 
1 mg 
Ethanol 
USP 
0.1 mL 
Hydrochloric acid 
NF 
Adjusting pH if needed 
Sodium hydroxide 
NF 
Adjusting pH if needed 
Water for Injection 
USP 
Qs to 2 mL 
 
aContain an excess of 0.26 mL with total drug content of 1.13 mg 
 
bAnhydrous salt 
 
Preparation:   E7389 may be administered without further dilution or may be diluted in up to 100mL 0.9% 
Sodium Chloride Injection.   
   
Storage: 
Store the intact vials as directed by the product label.  Protection from light is not necessary. 
 
 
 
Stability: 
Shelf-life surveillance of the intact vials is on-going. 
• 
Undiluted E7389 solution (IV bolus) stored in a Polypropylene syringe is stable for 
4 hours at ambient temperature and 24 hours at refrigerated temperature. 
• 
E7389 diluted to a concentration between 0.02 mg/mL and 0.2 mg/mL in 0.9% 


NCI Protocol #: 9653 
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34 
NaCl should not be stored longer than 24 hours at 2 to 8°C.. 
 
Route of Administration:  
Intravenous over 2-5 minutes. 
Availability:   E7389 is an investigational agent supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI. 
 
E7389 is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.3). 
 
8.1.2 Agent Ordering and Agent Accountability 
 
8.1.2.1 
NCI-supplied agents may be requested by the Principal Investigator (or their 
authorized designee) at each participating institution.  Pharmaceutical Management 
Branch (PMB) policy requires that agent be shipped directly to the institution where 
the patient is to be treated.  PMB does not permit the transfer of agents between 
institutions (unless prior approval from PMB is obtained).  The CTEP-assigned 
protocol number must be used for ordering all CTEP-supplied investigational agents.  
The responsible investigator at each participating institution must be registered with 
CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), Curriculum Vitae, Supplemental Investigator Data Form (IDF), and 
Financial Disclosure Form (FDF).  If there are several participating investigators at 
one institution, CTEP-supplied investigational agents for the study should be ordered 
under the name of one lead investigator at that institution. 
 
Active CTEP-registered investigators and investigator-designated shipping designees 
and ordering designees can submit agent requests through the PMB Online Agent 
Order Processing (OAOP) application (https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx).  Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account 
(https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an “active” account 
status and a “current” password.  For questions about drug orders, transfers, returns, 
or accountability, call (240) 276-6575 Monday through Friday between 8:30 am and 
4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
 
8.1.2.2 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all 
agents received from DCTD using the NCI Drug Accountability Record Form 
(DARF).  (See the NCI Investigator’s Handbook for Procedures for Drug 
Accountability and Storage.) 
 
8.1.2.3 
Investigator Brochures - The current versions of the IBs for the agents will be 
accessible to site investigators and research staff through the PMB Online Agent 
Order Processing (OAOP) application.  Access to OAOP requires the establishment 
of a CTEP Identity and Access Management (IAM) account and the maintenance of 
an “active” account status and a “current” password.  Questions about IB access may 
be directed to the PMB IB coordinator via email. 
 


NCI Protocol #: 9653 
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35 
8.1.2.4 
Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  PMBRegPend@ctep.nci.nih.gov 
• PMB 
policies 
and 
guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx  
• CTEP Identity and Access Management (IAM) account: https://eapps-
ctep.nci.nih.gov/iam/ 
• CTEP 
Associate 
Registration 
and 
IAM 
account 
help:  
ctepreghelp@ctep.nci.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
• IB Coordinator: IBCoordinator@mail.nih.gov 
 
8.2 Gemcitabine 
 
Product description and storage: (Gemzar®, Lilly Oncology) The gemcitabine will not 
be provided by the PMB and should be obtained from commercial sources. Gemcitabine 
is commercially available in vials containing either 200 mg or 1 g of gemcitabine HCl 
(expressed as free base) formulated with mannitol (200 mg or 1 g, respectively) and 
sodium acetate (12.5 mg or 62.5 mg, respectively) as a sterile lyophilized powder. 
Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment. 
The recommended diluent for reconstitution of gemcitabine is 0.9% Sodium Chloride 
Injection without preservatives. Due to solubility considerations, the maximum 
concentration for gemcitabine upon reconstitution is 40 mg/mL. Reconstitution at 
concentrations greater than 40 mg/mL may result in incomplete dissolution, and should 
be avoided. When prepared as directed, gemcitabine solutions are stable for 24 hours at 
controlled room temperature 20° to 25°C (68° to 77°F). Solutions of reconstituted 
gemcitabine should not be refrigerated, as crystallization may occur. Please refer to the 
commercial package insert for complete drug information.  
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
While, for patients who consent, tissue from the diagnostic biopsy or prior TURBT or 
cystectomy will be collected and stored at a Biobank, no correlative studies are planned as part 
of this trial. However, patients can enroll in other non-therapeutic and biomarker clinical studies 
concurrently provided they do not require or suggest changes in therapy that are independent of 
progression criteria in this protocol. 
The Biobank is being run by UC Davis Comprehensive Cancer Center and supported by the 
National Cancer Institute. 
 
9.1 Collection of Specimens 
Tumor specimens from the diagnostic biopsy should be submitted for banking along with a 
completed specimen submission form and a copy of the corresponding pathology report.   


NCI Protocol #: 9653 
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36 
 
Ideally, 1-2 paraffin-embedded tissue blocks containing formalin-fixed tumor, processed 
according to standard institutional protocols, will be submitted.  If blocks are unavailable, 10-15 
unstained slides will be accepted as an alternative. Tissue should be cut at ~5 microns and 
mounted on positively charged (+) slides. 
 
9.2 Shipping of Specimens 
All archival paraffin block/slide specimens should be sent at ambient temperature.  For summer 
shipments, please include a room temperature cool pack to insulate the specimen and protect the 
paraffin from melting.  Specimens should be shipped to the following address: 
 
 
 
Philip C Mack, PhD / Leslie Snyder-Solis 
 
UCD Cancer Center  
 
4501 X Street, Suite 1009 
 
Sacramento, CA 95817 
 
Phone: 916-734-6447 
Email: ljsnyder@ucdavis.edu or pcmack@ucdavis.edu 
 
Please notify the bank at the time of shipping via email (ljsnyder@ucdavis.edu). 
 
 
 
 
9.3 Biomarker Studies 
 
No biomarker studies are planned as part of this protocol. However, patients can enroll in other 
non therapeutic clinical trials. 
 


NCI Protocol #: 9653 
Version Date: February 20, 2017 
 
37 
 
 
10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 7 days prior to start of protocol therapy.  Scans 
and x-rays must be done <4 weeks prior to the start of therapy.  In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy.  
 
Item 
Pre-
Stud
y 
Wk 
1 
Wk 
2 
Wk 
3 
 
Wk 
4 
Wk 
5 
Wk 
6 
 
Wk 
… 
Wk 
… 
Wk 
… 
Off 
Study 
 
 
Cycle 1 
 
Cycle 2 
 
Cycle … 
 
Eribulin 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
Gemcitabine 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent Medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
H&P 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Medication List 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Ht, Wt, BSA 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Vital Signs 
X 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
Performance Status 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
CBC-Diff 
X 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
CMP†, LDH 
X 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
Creatinine Clearance 
calculation 
X 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
ECG (EKG) § 
X 
* 
* 
 
 
* 
* 
 
 
 
 
 
 
Adverse Events 
Assessment 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Staging Imaging q 6wks** 
X 
Tumor measurements are repeated every 6 weeks.  
Documentation (radiologic) must be provided for patients 
removed from study for progressive disease. 
X 
Paraffin Embedded Tissue 
Collection 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine -HCG (pregnancy 
test) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
†CMP includes Na, K, Cl, CO2, BUN, Cr, Glu, AST, ALT, ALK Phos, Bili, Ca, Phos, Total Protein, Albumin. 
 
§ Baseline ECG (EKG) and in case of QTc prolongation, there will be follow up ECGs- see section 6.1. 
 
*Only if Pre-Study ECG (EKG) shows a grade I QTc prolongation. See section 6.1. 
 
**Staging will consist of cross sectional imaging with CT scan of chest, abdomen and pelvis or MRI of abdomen 
and pelvis with CT of the chest. The same imaging modality and technique should be used for each episode of re-
imaging. Bone scan will be done at study entry: if it is negative then it need not be repeated unless symptoms, signs 
or other imaging suggests bone metastases. If the bone scan is positive or equivocal for metastases then it should be 
repeated at each imaging episode. Note: If patient remains on study therapy beyond cycle 12 then imaging can be 
repeated every 12 weeks for the remainder of the study in the absence of symptoms or signs suggesting progression.  
 


NCI Protocol #: 9653 
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38 
 
11. MEASUREMENT OF EFFECT 
 
11.1 Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be evaluated for disease at baseline prior to 
treatment start and then re-evaluated for response every 6 weeks (i.e. after every 2 cycles).  For 
patients who achieve a CR or PR, the next set of scans will serve as confirmatory scans, provided 
that they are obtained at least 4 weeks following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1)45.  Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria. 
 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with eribulin and gemcitabine. 
 
Evaluable for objective response.  Eligible patients who have measurable disease present 
at baseline and have received any amount of protocol therapy, will be considered 
evaluable for response.  These patients will have their response classified according to the 
definitions stated below.  
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm by chest 
x-ray or as ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable.  If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the 
protocol. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 


NCI Protocol #: 9653 
Version Date: February 20, 2017 
 
39 
the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 


NCI Protocol #: 9653 
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40 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for body 
scans).   
 
Ideally, the same type of scanner should be used and the image acquisition protocol 
should be followed as closely as possible to prior scans.  Body scans should be performed 
with breath-hold scanning techniques, if possible. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 
2008].  In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria which are to be integrated with objective tumor assessment for use in 
first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology  These techniques can be used to differentiate between partial 


NCI Protocol #: 9653 
Version Date: February 20, 2017 
 
41 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both approaches 
may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 


NCI Protocol #: 9653 
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42 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
11.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>3 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>3 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 


NCI Protocol #: 9653 
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43 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >3 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 


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44 
11.1.6 Progression-Free Survival 
 
Progression-free survival (PFS) is defined as the duration of time from start of treatment 
to time of progression or death, whichever occurs first.  Patients who begin another 
cytoreductive therapy prior to prior to progressing will be censored at the time of their 
last disease evaluation prior to starting the new treatment.  Patients who have not yet 
progressed or died will be censored at the time of their last disease evaluation.  
Progression of disease (PD) will be defined as described above and as assessed at the 
local treating institution. 
 
12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Study Oversight 
 
See also Section 14 ‘CCCP POLICIES FOR MONITORING CONSORTIUM TRIALS,’ 
Subsection 14.1 ‘Oversight. 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.   
 
For the Phase 1 portion of this study, all decisions regarding dose escalation/expansion/de-
escalation require sign-off by the Protocol Principal Investigator through the CTMS/IWRS.  In 
addition, for the Phase 1 portion, the Protocol Principal Investigator will have at least monthly, 
or more frequently, conference calls with the Study Investigators and the CTEP Medical 
Officer(s) to review accrual, progress, and adverse events and unanticipated problems.   
 
During the Phase 2 portion of the study, the Protocol Principal Investigator will have, at a 
minimum, quarterly conference calls with the Study Investigators and the CTEP Medical 
Officer(s) to review accrual, progress, and pharmacovigilance.  Decisions to proceed to the 
second stage of a Phase 2 trial will require sign-off by the Protocol Principal Investigator and the 
Protocol Statistician through IWRS and Medidata Rave. 
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 


NCI Protocol #: 9653 
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45 
plan. 
 
12.2 
Data Reporting 
 
Data collection for this study will be done exclusively through Medidata Rave.  Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate 
roles assigned in the Regulatory Support System (RSS).  To access Rave via iMedidata, the site 
user must have an active CTEP IAM account (https://eapps-ctep.nci.nih.gov/iam) and the 
appropriate Rave role (Rave CRA, Read-Only, or Site Investigator) on either the Corresponding 
Organization or Participating Organization roster at the enrolling site.   
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page.  Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed.  Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the 
upper right pane of the iMedidata screen.   
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com. 
 
12.2.1 Method 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS). Data is 
to be submitted to CTMS at least once every two weeks via Medidata Rave (or other 
modality if approved by CTEP).  Information on CTMS reporting is available at:  
http://www.theradex.com/CTMS.  On-site audits will be conducted on a 18-36 month 
basis as part of routine cancer center site visits. More frequent audits may be conducted if 
warranted by accrual or due to concerns regarding data quality or timely submission.  For 
CTMS monitored studies, after users have activated their accounts, please contact the 
Theradex Help Desk at (609) 799-7580 or by email at ctms@theradex.com for additional 
support with Rave and completion of CRFs. 
 
12.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all 
investigators at the ETCTN Sites understand the procedures for data submission for each 
ETCTN protocol and that protocol specified data are submitted accurately and in a timely 
manner to the CTMS via the electronic data capture system, Medidata Rave.   


NCI Protocol #: 9653 
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46 
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less 
than once every 2 weeks.  The timeliness of data submissions and timeliness in resolving 
data queries will be tracked by CTMS.  Metrics for timeliness will be followed and 
assessed on a quarterly basis.  For the purpose of Institutional Performance Monitoring, 
data will be considered delinquent if it is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing 
basis as data is received.  Queries will be issued by CTMS directly within Rave.  The 
queries will appear on the Task Summary Tab within Rave for the CRA at the ETCTN to 
resolve.  Monthly web-based reports are posted for review by the Drug Monitors in the 
IDB, CTEP.  Onsite audits will be conducted by the CTMS to ensure compliance with 
regulatory requirements, GCP, and NCI policies and procedures with the overarching 
goal of ensuring the integrity of data generated from NCI-sponsored clinical trials, as 
described in the ETCTN Program Guidelines, which may be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
)  and CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include the recommended 
phase 2 dose (RP2D), and a description of any dose-limiting toxicities (DLTs).  CTMS 
will utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository 
(caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-
resources/interoperability-and-semantics/metadata-and-models).  Customized eCRFs will 
be included when appropriate to meet unique study requirements.  The PI is encouraged 
to review the eCRFs, working closely with CTMS to ensure prospectively that all 
required items are appropriately captured in the eCRFs prior to study activation.  CTMS 
will prepare the eCRFs with built-in edit checks to the extent possible to promote data 
integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried 
out by the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex 
on a monthly basis.  The trial’s lead institution is responsible for timely submission to 
CTMS via Rave, as above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
). 
 
 
12.3 Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 


NCI Protocol #: 9653 
Version Date: February 20, 2017 
 
47 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 


NCI Protocol #: 9653 
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48 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
13. STATISTICAL CONSIDERATIONS 
 
This is a Phase II/Screening trial.  Currently there is no highly effective “standard of care” for 
patients with advanced urothelial cancer who are not suitable candidates for receiving cisplatin-
based therapy; and in this setting, the gemcitabine-carboplatin combination (GC) is often used.  
Based on the results of this screening trial, if the activity of GE is sufficiently promising based 
on the overall response rate, then the next step would be to plan a randomized Phase II trial of 
GE vs. GC;  if GE demonstrates superiority in terms of progression-free survival (PFS), then a 
Phase III study would be considered.  After discussion with CTEP, it was determined that for GE 
to be considered sufficiently promising for further study in this population of patients with 
advanced urothelial cancer who are not suitable candidates for receiving cisplatin-based therapy, 
that GE should have  a response rate that was clearly greater than 20% and not significantly less 
than 50%. 
 
13.1 Study Design / Endpoints 
 
Primary Endpoint.  The primary endpoint in this trial is objective response rate defined as either 
a confirmed complete response (CR) or a confirmed partial response (PR) based on RECIST 
v1.1 (described in Section 11.1 above). 
 
Study Design.   This trial will use a Simon two-stage Optimum design, with a false-positive error 
rate of 9% when the true objective response rate is 20% and a false-negative error rate of 9% 
when the true response rate is 50%.  A total of 7 patients will be enrolled in the 1st stage.  The 
first-stage stopping rule is defined as observing only 1 or fewer responses among the first 7 


NCI Protocol #: 9653 
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49 
patients. If 2 or more responses are observed, the trial will continue to a total of 21 patients.   If 7 
or more patients of the 21 experience a CR or PR then this will be evidence that the true response 
rate of GE is greater than 20% and not significantly less than 50%. 
 
Study enrollment will be extended beyond 21 patients treated to 21 response-evaluable patients if 
the following 2 conditions hold:  (1) 7 or more patients of the 21 eligible patients experience a 
CR or PR, AND (2) there are patients who failed to receive 2 courses of treatment and undergo 
radiographic evaluation of tumor burden after the 2nd course for reasons be unrelated to disease 
progression.  Thus accrual will be extended to “replace” patients who terminated treatment early 
for reasons of adverse events or toxicity or decisions unrelated to disease progression; patients 
who fail to receive 2 courses because of early progression will not be “replaced”.  Although all 
eligible patients who begin treatment will be included in the primary analysis, this extension will 
permit an estimate of the response rate in those patients who could receive 2 courses of therapy.  
Accrual will be assessed on a quarterly basis. 
 
Secondary Endpoints.  The secondary endpoints are (1) progression free survival calculated from 
the date of start of GE treatment to the date of progression or death prior to progression (as 
defined in Section 11.1.6), and (2) toxicity as graded by the CTCAE v4. 
 
Monitoring Safety/Tolerability.  Safety and toxicity will be reviewed monthly at the CCCP Data 
Coordinating Meetings, in which all toxicities (especially Grade 3+) are assembled and 
reviewed.  The first 7 patients treated with the combination of gemcitabine and eribulin will be 
specifically monitored during these calls.  In addition, safety boundaries (using a modified 
sequential probability ratio test) will be used to flag an unexpected number of patients who 
experience unacceptable toxicity (TOX).    
 
In this Phase II/screening trial, unacceptable toxicity (TOX) will be defined as any toxicity 
related to treatment, that results in failure to complete two courses of GE, or treatment related 
death at any time on treatment.  Patients who have not yet completed the first 2 courses of GE, or 
who do not complete 2 courses of treatment and do not experience an unacceptable toxicity, will 
not be considered at risk for TOX (for purposes of applying these toxicity monitoring boundaries 
only).  
 
Criteria for flagging an excessive number of patients with TOX are based on the sequential 
probability ratio test with =0.15, =0.10, po=0.10 and pa=0.25. Every time a patient is classified 
as having had a TOX, the cumulative number of patients (X) who have experienced a TOX will 
be compared to the number of patients (N) who are at risk.  If the number of patients, N, is 
greater than NX, the number given in the bottom row of the Table below, then the boundary has 
not been crossed. If N is less than or equal to NX, then the boundary has been crossed and a 
careful review of all the toxicities and tolerability will be initiated. 
 
Table:  Boundary for Monitoring Toxicity  
X: # pts who experienced a TOX 
2 
3 
4 
5 
Nx:  Boundary crossed if # pts. At risk (N) is  Nx 
2 
8 
14 
20 
 
These rules were selected to ensure a small chance that the boundary would not be crossed if the 


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50 
true chance of TOX were less than 10% and a reasonable chance that the boundary would be 
crossed if the true chance were 25-30%. The Table below summarizes these probabilities. The 
values in the table below are based on 10,000 simulations and are accurate to 0.01 (based on a 
95% confidence interval). 
 
 
 
 
 
Table: Probability that the Toxicity Monitoring Boundary is Crossed Because Too Many Patients 
Experienced a TOX  
True Chance of an Unacceptable Toxicity (TOX) 
10% 
15% 
20% 
25% 
30% 
Probability of Suspending Accrual to Review Toxicities   
0.08 
0.24 
0.45 
0.64 
0.80 
 
13.2   Sample Size/Accrual Rate 
 
This trial will enroll a minimum of 7 eligible patients who begin treatment and a maximum of up 
to 25-29 patients, depending on how many patients will be replaced because they did not receive 
2 courses. 
 
This trial is expected to accrue patients at a rate of approximately 2 patients per month.  
 
This study is open to men and women and to all racial and ethnic categories.  Based on the 
accrual to our nearly completed trial of eribulin as a single agent in advanced bladder cancer 
(NCI # 7435), we would expect the following accrual to this trial. 
 
Accrual Targets (for n=21) 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
0 
+ 
2 
= 
2 
Not Hispanic or Latino 
6 
+ 
13 
= 
19 
Ethnic Category: Total of all subjects 
6 
+ 
15 
= 
21 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 
0 
= 
0 
Asian 
0 
+ 
2 
= 
2 
Black or African American 
0 
+ 
0 
= 
0 
Native Hawaiian or other Pacific Islander 
0 
+ 
0 
= 
0 
White 
6 
+ 
13 
= 
19 
Racial Category: Total of all subjects 
6 
+ 
15 
= 
21 
 
13.3  Stratification Factors 
 
Not applicable in this study. 
 
13.4   Analysis of Results  
 
The outcome status (in terms of toxicity, number of course begun, amount of eribulin and 
gemcitabine received (and percent of planned), reason off treatment, tumor response, and 


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51 
progression/survival) of all patients registered in this study, will be reported. All eligible patients 
who begin treatment will be included in the primary analysis of response and progression-free 
survival. All toxicities experienced by patients who begin treatment will be reported.   
 
Toxicity.  All observed toxicities will be summarized in terms of type (organ affected or 
laboratory determination such as absolute neutrophil count), severity (by the CTCAE v4.0), and 
time of onset (i.e. course of treatment).  Tables will be created to summarize these toxicities and 
side effects, overall, by course – possibly by the cause of the cisplatin ineligibility, if numbers 
permit. 
 
Clinical Outcome.  The overall response rate will be 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; 90% confidence intervals will be constructed.  
A secondary estimate (more conservative) of the overall response rate will count in the 
numerator, only those patients who experienced a confirmed CR or PR AND who received 2 or 
more doses of eribulin. PFS will be measured from the start of treatment on Day 1, until 
progression, death, or the start of another treatment; patients who have not progressed, but who 
begin another treatment, will be censored at that time, for the measure of PFS. This is a 
secondary endpoint, and will be summarized with a Kaplan-Meier plot and confidence intervals 
(at 3, 6, 9, and 12 months).  Overall survival will also be summarized in a manner similar to PFS. 
 
13.5   Reporting and Exclusions 
 
Evaluation of toxicity.  All toxicities experienced by patients who receive any treatment of 
eribulin or gemcitabine will be reported.  For purposes of applying the criteria to monitor 
toxicity/safety, only those patients who complete the first 2 courses of treatment or who 
experience a TOX will be evaluable.   
 
Evaluation of response.  All patients included in the study must be assessed for response to 
treatment, even if there are major protocol treatment deviations or if they are ineligible.  Each 
patient will be assigned one of the following categories:  1) complete response, 2) partial 
response, 3) stable disease, 4) progressive disease, 5) early death from malignant disease, 6) 
early death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).    
 
All patients who met the eligibility criteria (with the exception of those who never received any 
protocol treatment) will be included in the primary analysis of the response rate.  Patients in 
response categories 3-9 are considered to be non-responders.  Thus, an incorrect treatment 
schedule or drug administration does not result in exclusion from the analysis of the response 
rate.    
 
A secondary analysis of response will include only those patients who have received at least 2 
doses of eribulin and had disease reassessment after the 2nd course, or who had progressive 
disease prior to completing 2 courses.   
 


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52 
14. 
CCCP POLICIES FOR MONITORING CONSORTIUM TRIALS 
 
The protocol principal investigator (PI) is responsible for monitoring the conduct and progress of 
this Phase II trial, including the ongoing review of accrual, data and toxicities, as well as the 
accumulation of reported adverse events from other trials testing the same drug(s).  The 
participating clinicians and their designees are responsible for timely submission of adverse 
event reports (see Section 7.0) and case report forms.  The Data Coordinating Center for the 
CCCP Consortium is responsible for providing the PI with access to the submitted case report 
form data in summary and detail in a timely fashion.   Although the PI is responsible for 
evaluating the cumulative reported adverse events and the impact that these have on the 
continued conduct of the trial, it is the Data Coordinating Center of the CCCP that distributes all 
submitted SAE reports to the appropriate individuals, including the local protocol principal 
investigators, at each of the participating institutions.   
 
The Data Coordinating Center posts a summary (accrual, toxicities, and responses) of each 
CCCP initiated trial on the CCCP website.  In this way, each PI has access to up-to-date 
information on the status of his or her trial.  In consultation with the collaborating statistician, the 
PI is responsible for review of: 
 
(a) 
for Phase I trials, all dose limiting toxicities and decisions regarding dose escalation, 
expansion, as well as decisions to terminate escalation, and  
(b) 
for Phase II trials, the toxicities and therapeutic endpoints referred to in the statistical 
plan. 
 
The Data Coordinating Committee meets monthly to review data management and data quality 
issues – completeness of data submissions as well as accuracy in terms of built-in, computerized 
logic checks.  Any issues identified and the corrective plans are presented to the Internal 
Committee and at the next CCCP teleconference meeting for review and approval. 
 
14.1 Oversight 
Oversight of the conduct of CCCP trials occurs at several levels: 
 
1. 
The Data Coordinating Center for the CCCP flags all trials that are approaching a 
decision in terms of toxicity (for both Phase I and Phase II trials) or responses (for Phase 
II trials).  Decisions are made by the PI with input from the statistician and discussion 
with the principal investigator of the funding mechanism (U01 Cooperative Agreement or 
N01 Contract, as appropriate) or his or her designee, and are communicated to the 
participating centers by the CCCP Data Coordinating Center. At the monthly 
teleconferences, the accrual of each open protocol is reviewed. 
 
2. 
For CTEP sponsored Phase I trials, data are reported to the NCI-designated clinical 
trials monitoring service (CTMS) which will audit patients’ records on each protocol – at 
each CCCP institution; this audit is initiated by CTEP.   
 
3. 
An independent CCCP DSMC will review CCCP trials every 6 months. This DSMC 
will consist of 5 voting members (3 medical oncologists or hematologists involved in 


NCI Protocol #: 9653 
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53 
Phase I/II cancer clinical trials but not participating in CCCP studies, a patient 
representative and a statistician) and a non-voting CCCP statistician.   
 
a. 
DSMC meetings will take place twice a year.  Additional meetings will be 
convened if necessary.  
b. 
This DSMC will review each CCCP trial in terms of accrual, toxicity/safety, 
and adherence to trial design, audit results, and likelihood of successful completion.   
c. 
The DSMC will report to the CCCP leadership. 


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54 
 
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58 
 
APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead.