A Phase I/II Study of Eribulin in Combination With Oral Irinotecan for Adolescent and Young Adult Patients With Relapsed or Refractory Solid Tumors
Phase: PHASE1
Conditions: Relapsed Solid Tumors, Refractory Solid Tumors
Sponsor: University of Colorado, Denver

1 
COMIRB #15-0659 
 
TITLE:  A Phase I/Ib Study of Eribulin in Combination with Oral Irinotecan for 
Adolescent and Young Adult Patients with Relapsed or Refractory Solid Tumors 
 
Coordinating Center: 
 
 
Children’s Hospital Colorado 
 
*Principal Investigators:  
Carrye Cost, MD 
 
Center for Cancer and Blood Disorders 
 
Children's Hospital Colorado 
 
Office: 720-777-6775 
 
Email: carrye.cost@childrenscolorado.org 
 
 
 
Tom C. Badgett, MD, PhD 
 
Division of Pediatric Hematology/Oncology 
 
University of Kentucky 
 
Phone: 859-218-0332 
 
Email: tom.badgett@uky.edu  
 
 
Theodore Laetsch, MD 
 
Pediatric Oncology 
 
Children’s Health 
 
University of Texas Southwestern Medical Center 
 
Phone: 214-456-6405 
 
Email: ted.laetsch@utsouthwestern.edu 
 
 
Co-Investigators:  
 
 
Lia Gore, MD 
 
 
 
 
Margaret Macy, MD 
 
 
Center for Cancer and Blood Disorders  
 
Center for Cancer and Blood Disorders 
Children's Hospital Colorado 
 
 
 
 
Children’s Hospital Colorado 
Office: 720-777-6772 
 
 
 
 
Office: 720-777-8856 
Email: lia.gore@ucdenver.edu 
 
 
 
 
Email: margaret.macy@childrenscolorado.org 
 
 
Kelly Maloney, MD 
 
 
 
 
Melissa Widener, PA-C  
 
 
Center for Cancer and Blood Disorders  
 
Center for Cancer and Blood Disorders 
Children's Hospital Colorado 
 
 
 
 
Children’s Hospital Colorado 
Office: 720-777-6673 
 
 
 
 
Office: 720-777-4349 
Email: kelly.maloney@childrenscolorado.org 
Email: melissa.widener@childrenscolorado.org 
 
 
 
 
 
 
 
 
 
 
COMIRB
APPROVED
21-Apr-2017

Protocol # 15-0659 
Version Date: March 22, 2017 
 
2 
 
Lars Wagner, MD 
 
 
 
 
Markos Leggas, PhD 
Division of Pediatric Hematology/Oncology  
Department of Pharmaceutical Sciences 
University of Kentucky 
 
 
 
 
University of Kentucky 
Office: 859-218-0931 
 
 
 
 
Office: 859-257-2633 
Email: lars.wagner@uky.edu  
 
 
 
 
Email: mark.leggas@uky.edu 
 
 
 
Kenneth Chen, MD 
 
 
 
 
Andrew Martin, MD 
Division of Hematology/Oncology 
 
 
 
Division of Hematology/Oncology 
Department of Pediatrics 
 
 
 
 
Department of Pediatrics 
UT Southwestern Medical Center 
 
 
 
UT Southwestern Medical Center 
Office: 214-648-4920 
 
 
 
 
Office: 214-648-3896 
Email: kenneth.chen@utsouthwestern.edu   
Email: andrew.martin@utsouthwestern.edu 
 
 
 
 
Patrick Leavey, MD 
 
 
 
 
Kathleen Ludwig, MD 
Division of Hematology/Oncology 
 
 
 
Division of Hematology/Oncology 
Department of Pediatrics 
 
 
 
 
Department of Pediatrics 
UT Southwestern Medical Center 
 
 
 
UT Southwestern Medical Center 
Office: 214-648-3122 
 
 
 
 
Office: 214-456-6927 
Email: patrick.leavey@utsouthwestern.edu   
Email: kathleen.wiertel@utsouthwestern.edu 
 
 
Tamra Slone, MD 
 
 
 
 
Martha Stegner, MD 
Division of Hematology/Oncology 
 
 
 
Division of Hematology/Oncology 
Department of Pediatrics 
 
 
 
 
Department of Pediatrics 
UT Southwestern Medical Center 
 
 
 
UT Southwestern Medical Center 
Office: 214-648-3150 
 
 
 
 
Office: 214-648-3896 
Email: tamra.slone@utsouthwestern.edu  
 
Email: martha.stegner@childrens.com 
 
 
  
Tanya Watt, MD 
 
 
 
 
Jonathan Wickiser, MD 
Division of Hematology/Oncology 
 
 
 
Division of Hematology/Oncology 
Department of Pediatrics 
 
 
 
 
Department of Pediatrics 
UT Southwestern Medical Center 
 
 
 
UT Southwestern Medical Center 
Office: 214-456-6363 
 
 
 
 
Office: 214-648-3896 
Email: tanya.watt@utsouthwestern.edu   
 
Email: wickiser@utsouthwestern.edu  
 
 
Naomi Winick, MD 
 
 
 
 
 
Division of Hematology/Oncology 
 
 
 
 
Department of Pediatrics 
 
 
 
 
 
UT Southwestern Medical Center 
 
 
 
 
Office: 214-456-2382 
 
 
 
 
 
Email: naomi.winick@utsouthwestern.edu   
 
 
 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
3 
Statistician: 
 
 
 
 
 
Study Coordinator: 
Stacey A. Slone, MS 
Debra Schissel, RN, CPON, CCRP 
800 Rose Street, CC440 
Children’s Hospital Colorado  
Lexington, KY 40536 
13123 E. 16th Ave, B115 
Telephone: 859-323-1732 
Telephone: 720-777-2879 
Email: stacey.slone@uky.edu 
E-mail: debra.schissel@childrenscolorado.org 
 
 
 
 
 
Responsible Research Nurse: 
 
Responsible Data Manager: 
Debra Schissel, RN, CPON, CCRP 
Seda Carlton, BS 
Children's Hospital Colorado 
Children's Hospital Colorado 
13123 E. 16th Ave, B115 
13123 E. 16th Ave, B115 
Telephone: 720-777-2879 
Telephone: 720-777-6692 
Email: debra.schissel@childrenscolorado.org 
E-mail: seda.carlton@childrenscolorado.org  
 
 
 
 
Commercially Available Agents:  
Eribulin (Halaven®, Eisai Inc., Woodcliff Lake, NJ) 
Irinotecan (Camptosar®, Pfizer, New York City, NY) 
 
 
 
IND Sponsor: Exempt from IND requirement 
 
 
 
Protocol Version # / Version Date:  Version 3.0 / March 22, 2017 
 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
4 
SUMMARY 
 
This Phase I trial will establish the recommended phase II dose of eribulin in combination with 
fixed doses of oral irinotecan in adolescents and young adults with relapsed or refractory solid 
tumors.  Eribulin will be administered intravenously on days 1 and 8 of a 21-day cycle, while 
irinotecan will be administered orally on days 1-5.  The oral antibiotic cefixime will be used to 
reduce irinotecan-associated diarrhea, starting two days prior to each cycle and continuing 
through day 8. Patients will be assigned an eribulin dose level at the time of enrollment using a 3 
+ 3 Phase I design, and there will be no intrapatient dose escalation. Once the RP2D is defined, 
there will be 10 patients enrolled in a dose expansion cohort.   
 
 
Treatment Schema 
Day 
Cefixime 
Eribulin 
Oral Irinotecan 
-1 
X 
 
 
0 
X 
 
 
1 
X 
X 
X 
2 
X 
-- 
X 
3 
X 
-- 
X 
4 
X 
-- 
X 
5 
X 
-- 
X 
6 
X 
-- 
-- 
7 
X 
-- 
-- 
8 
X 
X 
-- 
9-19 
-- 
-- 
-- 
20 
X 
-- 
-- 
21 
X 
-- 
-- 
NEXT CYCLE 
 
 
 
 
 
 
Dose Escalation Schedule 
Dose Level 
Dose 
Oral Irinotecan 
(mg/m2/day x 5)  
Eribulin 
(mg/m2/dose) 
Level 0 
90 
0.8 
STARTING DOSE: Level 1 
90 
1.1 
Level 2 
90 
1.4 
 
 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
5 
TABLE OF CONTENTS 
 
COMIRB #15-0659 .........................................................................................................................1 
SUMMARY .....................................................................................................................................4 
1. 
OBJECTIVES ......................................................................................................................7 
1.1 
Primary Objectives ...................................................................................................7 
1.2 
Secondary Objectives ...............................................................................................7 
2. 
BACKGROUND .................................................................................................................7 
2.1 
Introduction ..............................................................................................................7 
2.2 
Eribulin ....................................................................................................................7 
2.3 
Irinotecan .................................................................................................................9 
2.4 
Rationale for Combining Eribulin and Irinotecan .................................................11 
2.5 
Correlative Studies Background ............................................................................11 
3. 
PATIENT SELECTION ....................................................................................................12 
3.1 
Eligibility Criteria ..................................................................................................12 
3.2 
Exclusion Criteria ..................................................................................................13 
3.3 
Inclusion of Women and Minorities ......................................................................14 
4. 
REGISTRATION PROCEDURES ...................................................................................15 
4.1 
Enrollment Guidelines ...........................................................................................15 
4.2 
Compliance with Laws and Regulations................................................................15 
5. 
TREATMENT PLAN ........................................................................................................16 
5.1 
Enrollment and Screening Process .........................................................................16 
5.2 
Agent Administration .............................................................................................16 
5.3 
Supportive Care .....................................................................................................18 
5.4 
Criteria for Starting Subsequent Cycles of Therapy ..............................................19 
5.5 
Definition of Dose-Limiting Toxicity ....................................................................20 
5.6 
Dose Escalating Criteria ........................................................................................21 
5.7 
Duration of Therapy ...............................................................................................21 
5.8 
Duration of Follow-Up ..........................................................................................22 
5.9 
Criteria for Removal from Protocol Therapy .........................................................22 
5.10 
Off-Study Criteria ..................................................................................................22 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................22 
6.1 
Dose Modifications for Hematological Toxicity ...................................................23 
6.2 
Dose Modifications for Non-Hematological Toxicity ...........................................23 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................24 
7.2 
Expected Toxicities ................................................................................................25 
7.3 
Adverse Event Characteristics ...............................................................................26 
7.4 
Expedited Adverse Event Reporting ......................................................................26 
7.5 
Routine Adverse Event Reporting .........................................................................27 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
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8. 
PHARMACEUTICAL INFORMATION ..........................................................................27 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................31 
9.1 
Laboratory Correlative Studies ..............................................................................31 
10. 
STUDY CALENDAR .......................................................................................................31 
11. 
MEASUREMENT OF EFFECT........................................................................................33 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................33 
12. 
REGULATORY REQUIREMENTS/DATA COLLECTION ..........................................39 
12.1 
Data Reporting .......................................................................................................39 
12.2 
Compliance with Laws and Regulations................................................................39 
12.3 
Protocol Review and Amendments ........................................................................39 
This protocol, the proposed informed consent and assent forms along with any 
documents given to participants (e.g., drug diaries) must be submitted, 
reviewed and approved by a properly constituted IRB governing each 
study location.  This process will occur following approval by the 
Coordinating Center IRB (COMIRB). ...................................................................39 
12.4 
Informed Consent...................................................................................................39 
12.5 
Study Documentation.............................................................................................40 
12.6 
DATA AND SAFETY MONITORING ................................................................40 
12.7 
Data and Safety Monitoring Committee (DSMC) .................................................40 
12.8 
Data Collection ......................................................................................................41 
13. 
STATISTICAL CONSIDERATIONS...............................................................................41 
13.1 
Study Design/Endpoints.........................................................................................41 
13.2 
Sample Size/Accrual Rate ......................................................................................42 
13.3 
Stratification Factors ..............................................................................................42 
13.4 
Analysis of Primary and Secondary Endpoints .....................................................42 
13.5 
Data Management ..................................................................................................43 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................44 
APPENDIX B 
INFORMATION ON POSSIBLE DRUG INTERACTIONS ...................45 
APPENDIX D 
ORAL IRINOTECAN ADMINISTRATION GUIDELINES ...................48 
APPENDIX E 
PATIENT INSTRUCTIONS FOR TREATING DIARRHEA..................49 
APPENDIX F 
ORAL IRINOTECAN ADMINISTRATION DIARY ..............................50 
APPENDIX G 
PHARMACOKINETIC STUDY FORM ..................................................51 
REFERENCES ..............................................................................................................................53 
 
 
 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
7 
 
1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 To estimate the recommended phase II dose (RP2D) of eribulin in combination 
with fixed-dose oral irinotecan in adolescents and young adults with 
relapsed/refractory solid tumors 
 
1.2 
Secondary Objectives 
 
1.2.1 To evaluate the toxicity profile of this combination and define the dose-limiting 
toxicities 
1.2.2 To characterize the pharmacokinetics of eribulin in patients receiving oral 
irinotecan 
1.2.3 To determine the antitumor activity of this drug combination within the confines 
of a Phase I/Ib trial 
 
2. BACKGROUND 
 
2.1 
Introduction 
 
New therapies are desperately needed for adolescents and young adults with metastatic or 
recurrent solid tumors. For example, less than one-fourth of patients with osteosarcoma, Ewing 
sarcoma, or rhabdomyosarcoma whose tumor recurs after initial frontline therapy are expected to 
have long-term survival. Outcomes are also poor for patients who have metastatic disease 
identified at the time of initial diagnosis. These tumor types are commonly seen not only in 
teenagers but also in young adults, and new therapeutic strategies will be necessary to improve 
their outcomes. Particularly attractive approaches include those in which robust preclinical 
activity has been seen in relevant in vivo models, and for which combination with other active 
agents is rational. With these ideas in mind, we will perform the first study assessing the 
combination of eribulin and irinotecan. Eribulin is a novel microtubule inhibitor with dramatic 
preclinical activity against pediatric sarcoma xenograft models, while irinotecan is a 
camptothecin commonly used in the treatment of a wide variety of solid tumors. Irinotecan has 
been successfully combined with microtubule inhibitors to treat pediatric sarcoma patients, and 
the two drugs have distinct and generally non-overlapping toxicity profiles. This study will 
provide necessary information for the design of a Phase II trial to better estimate the activity of 
this combination in specific tumor types. 
 
2.2 
Eribulin 
 
Eribulin (Halaven; Eisai Inc.) is a synthetic analogue of halichondrin B, a potent compound 
found in the marine sponge, Halichondria okadai.  Eribulin is a microtubule inhibitor which 
inhibits polymerization of tubulin subunits and prevents microtubule growth. This mechanism of 
action is distinct both from taxanes and epothilones, which disrupts microtubule dynamics by 
stabilizing microtubules [1] as well as vincristine, which shortens microtubules [2].  This 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
8 
dysregulation of microtubule dynamics caused by eribulin results in globular aggregates of 
unstable tubulin polymers, creating a G2-M blockade [3] that leads to apoptosis of treated cells 
[2, 4, 5]. 
 
Preclinical activity: Studies using both adult and pediatric cell lines have demonstrated that 
eribulin has activity against a wide variety of cancers at subnanomolar levels [4, 6].  
Additionally, growth of taxane-resistant human tumor cell lines harboring known β-tubulin 
mutations was also inhibited by eribulin [7], presumably due to its unique mechanism and unique 
binding site.  Eribulin has broad in vivo activity as demonstrated by its effects in xenografts 
models of adult breast, colon, melanoma and ovarian cancers [4].  In particular, compelling in 
vivo activity was seen in mouse xenograft experiments conducted by the Pediatric Preclinical 
Testing Program (PPTP), a NCI funded system used by CTEP to comprehensively and 
systematically evaluate new agents for pediatric cancer with the purpose of deciding which drugs 
move forward in NCI-sponsored national clinical trials. For example, treatment with single-agent 
eribulin resulted in complete responses of established xenografts in four different tumor types, 
including some responses which were maintained throughout the entire 12-week observation 
period. Particularly encouraging findings include the fact that systemic drug exposures in these 
experiments were similar to those seen in in patients receiving the recommended Phase II dose of 
eribulin, and that in many models, eribulin was more active than vincristine, which is used for a 
broad variety of pediatric cancers [6].   
 
Clinical Activity: In addition to the robust preclinical data describing eribulin’s activity against 
a wide variety of tumor cell lines and xenografts, there has also been extensive clinical 
evaluation of this drug, with 21 trials actively recruiting patients with a wide variety of cancers 
as of September 2013 (clinicaltrials.gov).  Results have been published from thirteen phase II or 
phase III clinical trials evaluating eribulin in patients with a wide variety of cancers [8-18].  In 
these studies, eribulin was considered by the investigators to be active  in non-small cell lung 
cancer [13], breast [8, 10, 11, 18], leiomyosarcoma [16], adipocytic sarcoma [16], ovarian [14] 
and prostate cancers [12].   
 
The greatest clinical benefit of eribulin to date has been in the treatment of metastatic breast 
cancer, leading to eribulin being approved by the US Food and Drug Administration (FDA) in 
2010 for the treatment of late stage metastatic breast cancer in patients who have received two or 
more prior therapies including an anthracycline and a taxane [19]. FDA approval was based on 
the encouraging results of a Phase III (EMBRACE) trial comparing eribulin monotherapy versus 
physician’s choice [10].  
 
Pharmacokinetic Data:  Eribulin demonstrates linear kinetics, with a rapid distribution phase 
and slow elimination phase, resulting in a prolonged plasma half-life of 34 -73 hours in phase I 
studies of patients with solid tumors [20, 21].  The primary route of elimination of eribulin is in 
feces (82%), with only a small fraction eliminated in the urine (9%). Importantly, approximately 
90% of eribulin is excreted unaltered [22], and so does not undergo significant metabolism. In 
fact, the in vivo metabolism of eribulin is quite minimal, with metabolites accounting for <0.6% 
of unchanged eribulin in the plasma [22].   
 
 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
9 
Since only a small percentage of the drug is metabolized, the potential for drug-drug interactions 
with eribulin is negligible.  No clinically significant change in exposure, measured by AUC0-∞ 
and Cmax, of eribulin when given in combination with ketoconazole, a CYP3A4 and P-gp 
inhibitor [23].  Additionally, the exposure of eribulin was not clinically significantly altered 
when given in combination with rifampin, an inducer of CPY3A4 [24]. 
 
Toxicity:  In the Phase III EMBRACE trial, the most common grade 3 and 4 toxicities that 
occurred more frequently in the eribulin treatment when compared with the Treatment of 
Physician’s Choice (TPC) arm were neutropenia, leukopenia and peripheral neuropathy.  
Neutropenia occurred in 52% of patients, with 24% experiencing grade 4.  Neutropenia was 
easily managed with dose-reductions, delays or granulocyte colony stimulating factor, and 
resulted in low incidence of febrile neutropenia (5%). The incidence of grade 3 or 4 peripheral 
neuropathy was <9% similar to patients treated with taxanes on the TPC arm (5%) [10].  In 
several other phase I and II trials in patients with advanced solid tumors, prostate cancer, 
squamous cell carcinoma of the head and neck, and breast cancer, the only grade 3 or 4 toxicities 
reported with an incidence of greater than 10% were leucopenia, lymphopenia and neutropenia 
[8, 9, 12, 20].  
 
Importantly, the toxicity profile of eribulin is distinct from protracted administration of 
irinotecan, in which the most common toxicities are diarrhea, abdominal pain, weight loss and 
electrolyte disturbances.  Less than 10% of patients treated with eribulin in the EMBRACE trial 
developed either abdominal pain or hypokalemia of any grade, and no other electrolyte 
abnormalities were reported.  While 18% of patients treated with eribulin developed diarrhea, 
this percentage was equal to those patients on the control arm, and so may relate more to the 
specific patient population. Of note, no patient receiving eribulin on the EMBRACE trial 
developed grade 3 or higher diarrhea.  Mild to moderate weight loss was slightly more common 
in the eribulin-treated arm, occurring in 21% of the patients treated with eribulin while on 14% 
of patients in the control arm were noted to have decreased weight.  Only 1% of patients treated 
with eribulin developed grade 3 or higher weight loss [10].  
 
2.3 
Irinotecan 
 
Irinotecan is a camptothecin agent which is metabolized into SN-38, a topoisomerase I inhibitor.  
SN-38 functions by stabilizing the DNA-topoisomerase I complex during DNA replication, 
resulting in DNA damage in the form of single strand breaks and leading to arrest of the cell 
cycle and cellular death [25]. 
 
Preclinical activity: Several preclinical studies have confirmed the activity of irinotecan in a 
variety of pediatric tumors including xenografts models of neuroblastoma [26, 27], 
rhabdomyosarcoma [28], Ewing’s sarcoma [26], and CNS tumors [29, 30]. 
 
Clinical Activity: Irinotecan has been extensively studied in adults both alone in combination 
with various agents, and is FDA approved for the treatment of metastatic carcinoma of the colon 
or rectum. In children, irinotecan has demonstrated activity in wide variety of solid tumors 
including Ewing sarcoma [31, 32], rhabdomyosarcoma [33-35], hepatoblastoma [36-38] and 
neuroblastoma [39, 40]. Although single-agent activity of irinotecan has been modest [41], the 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
10 
lack of significant myelosuppression when given on a protracted schedule makes it an attractive 
partner for combination studies. Currently, irinotecan is being studied by the Children’s 
Oncology Group (COG) in Phase II or III trials in combination with either vincristine or 
temozolomide in six different tumor types. Importantly, the combination of vincristine and 
protracted irinotecan will be part of the standard treatment arm in the next national COG Phase 
III trial for patients with newly-diagnosed rhabdomyosarcoma. 
 
Rationale for oral administration of irinotecan: When irinotecan is used to treat adults with 
colorectal cancer, the drug is typically administered once every 1-3 weeks in single large doses. 
However, the greatest activity in pediatric tumor types has been observed with more protracted 
scheduling in which smaller dosages are given daily for 5 consecutive days for either one or two 
weeks [42]. This protracted dosing schedule allows for greater exposure of this S-phase-specific 
agent over a three-week cycle, and also changes the toxicity profile. For example, while 
neutropenia and thrombocytopenia may be dose-limiting when irinotecan is given on the adult 
schedule, protracted administration of irinotecan results in only modest myelosuppression, with 
grade 4 neutropenia occurring in only 6% of treatment cycles on a large national Phase II trial, 
and grade 3-4 thrombocytopenia occurring in only 2% [41]. However, protracted administration 
does increase the likelihood of diarrhea, which is the dose-limiting toxicity when irinotecan is 
given in a protracted fashion [42]. 
 
Although protracted intravenous administration appears to be more efficacious against pediatric 
tumors compared to less frequent dosing, it is more costly and inconvenient. To circumvent these 
issues, several investigators have studied the administration of irinotecan given orally on a 
protracted schedule in both children and adults [40, 43-45]. Oral administration of irinotecan 
provides a convenient and cost-effective method for the protracted administration schedules 
which have shown greatest activity against pediatric tumors [46].  Due to irinotecan poor oral 
bioavailability, higher doses are required to reach similar levels of systemic exposure compared 
with intravenous administration.  Combining oral irinotecan with prophylactic cephalosporins as 
described below has allowed for escalation of the MTD by 50% to 90 mg/m2/dose x 5 days [44, 
47] translating into similar levels of the active metabolite SN-38 when compared with 
intravenous administration.  The tolerability, cost savings and convenience of administration 
make oral irinotecan an appropriate and attractive agent for use in the relapsed and refractory 
setting. 
 
Pharmacokinetic data: Irinotecan is converted into its active metabolite SN-38 in the liver by 
carboxylesterase enzymes [48].  SN-38 is subsequently converted to SN-38 glucuronide by 
uridine diphosphate glucuronosyltranferases (UDG).  Although the majority of irinotecan is 
metabolized into SN-38 under normal circumstances, a small minority is converted into two 
minor metabolites by cytochrome P450 isoenzyme CYP3A4. Predictably, inducers of the 
CYP3A4 isoenzyme have been shown to lead to increased clearance of irinotecan and reduced 
levels of SN-38 [49, 50].  Use of CYP3A4 inducers should be avoided due to concerns for 
decreased efficacy of irinotecan. 
 
Toxicity data: The dose limiting toxicities of irinotecan administered intravenously on adult 
schedules of once every 1-3 weeks are myelosuppression and diarrhea.  When irinotecan is 
administered on a protracted schedule as done in pediatrics, myelosuppression is substantially 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
11 
reduced while diarrhea remains the dose-limiting toxicity [51-53].  The addition of cephalosporin 
prophylaxis to various treatment regimens of irinotecan has increased the tolerability of 
protracted irinotecan by significantly decreasing the incidence of diarrhea, allowing for the 
escalation of the maximum tolerated dose (MTD) [44, 45, 54].  The active metabolite SN-38 is 
thought to act locally in the gastrointestinal tract, directly injuring the intestinal mucosa and 
leading to a secretory diarrhea [55]. Cephalosporins ameliorate irinotecan-associate diarrhea by 
limiting conversion of the inactive glucuronidated SN-38 to active SN-38 by glucuronidase 
producing enteric bacteria. Pediatric regimens using cephalosporins have shown significant 
reduction in severe diarrhea when antibiotics are started a few days prior to irinotecan, and 
continued for three days past the fifth chemotherapy day. [44, 45, 54] 
 
2.4 
Rationale for Combining Eribulin and Irinotecan 
 
While the planned testing of eribulin as a single agent in the pediatric population is necessary, 
nearly all pediatric cancers are treated with drug combinations, and searching for a suitable 
therapeutic partner for eribulin is the next logical step in development of this drug.   We propose 
testing the combination of eribulin and oral irinotecan in a phase I trial designed to determine the 
recommended phase II dose of eribulin when combined with a previously established, well-
tolerated regimen of oral irinotecan in adolescent and young adult cancer patients 13-30 years 
old.  This age range was chosen because the likely clinical application for this drug pair will be 
in the treatment of pediatric-type sarcomas (e.g., Ewing sarcoma, osteosarcoma), which more 
often occur in adolescents and young adults. Further, the age and size of these patients will 
preclude the need for additional dose-finding studies for eribulin, as would be necessary if small 
children were included. 
 
In adults, combination trials using eribulin with agents like carboplatin and cyclophosphamide 
are underway in non-small cell lung cancer, ovarian carcinoma, and breast cancer.  These drug 
partners all are myelosuppressive.  A more attractive partner may be one with non-overlapping 
dose-limiting toxicities like irinotecan.  When given on a protracted 5-day schedule, irinotecan 
does not cause severe myelosuppression, making it attractive for combination with eribulin.  Oral 
administration of irinotecan used alone and in combination therapy has been extensively tested in 
pediatrics in 5 clinical trials involving 158 patients, and provides a convenient and cost-effective 
method for the protracted administration schedules which have shown greatest activity against 
pediatric tumors. Importantly, the dose-limiting toxicity of protracted irinotecan is diarrhea, with 
only minimal myelosuppression. In addition, the combination of microtubule inhibitors and 
camptothecins is supra-additive, and is routinely used in COG studies which administer 
vincristine with 5-day cycles of irinotecan. Thus, this combination is attractive for study because 
of the potential for therapeutic synergy and the likelihood that both agents may be able to be 
administered at full dosage. 
 
2.5 
Correlative Studies Background 
 
The pharmacokinetics of eribulin and irinotecan are well characterized. Our objective in this 
study is to collect pharmacokinetic data to understand exposure-toxicity and potentially 
exposure-efficacy relationships that can manifest in these patients. Notably, the 
pharmacokinetics of eribulin has not been determined in younger patients and may potentially be 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
12 
different than in adults. Such differences have been observed with other anticancer drugs 
including topotecan, which is metabolized minimally and irinotecan, which is extensively 
metabolized [40, 56-61]. Comparatively, pediatric patients had similar irinotecan 
pharmacokinetics as adults but greater interpatient variability, which could be attributed to age. 
Such clearance differences would lead to higher exposure in pediatric populations and thus an 
overall lower dosage required for treatment. As the proposed population is likely to include 
patients with potentially high and low clearance characteristics, it is important to obtain 
pharmacokinetic evidence that may potentially provide evidence for differential dosing 
requirements based on age. 
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria 
 
3.1.1 Patients must >13 and <30 years of age at the time of study entry. 
3.1.2 Patients must have a histologically confirmed solid tumor malignancy at either original 
diagnosis or relapse for which no curative therapy exists, and which has either recurred or 
progressed after at least one prior systemic therapy. Patients with primary brain tumors, 
or those with brain metastases at time of potential enrollment, are excluded.  
Additionally, patients with GIST, alveolar soft part sarcoma, or dematofibrosarcoma 
protuberans are excluded.  
3.1.3 Patients must have either measurable or evaluable disease, as defined in Section 11.1.2. 
3.1.4 Performance Level: ECOG performance status ≤ 2 (Karnofsky ≥60%, see Appendix A).  
Note:  Patients who are unable to walk because of paralysis, but who are up in a 
wheelchair, will be considered ambulatory for the purposes of assessing the performance 
score. 
3.1.5 Prior Therapy:  No limit is placed on the number of prior therapies.  Prior treatment with 
irinotecan or eribulin is allowed, although patients must not have received co-
administration of eribulin and irinotecan and must not have had disease progression while 
receiving either eribulin or irinotecan. 
Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, 
immunotherapy, or radiotherapy prior to entering this study. 
a. Myelosuppressive chemotherapy:  Must not have received within three weeks of 
start date of this protocol chemotherapy; six weeks is required after administration 
of nitrosourea agents. 
b. Hematopoietic growth factors: At least 7 days since the completion of therapy 
with a growth factor or at least 14 days for a long-acting growth factor (e.g. 
pegfilgrastim) 
c. Biologic (anti-neoplastic agent): At least 7 days or 3 half-lives since the 
completion of therapy with a biologic agent, whichever is longer. For agents that 
have known adverse events occurring beyond 7 days after administration, this 
period must be extended beyond the time during which adverse events are 
expected to occur. The duration of this interval must be discussed with the PI of 
the study. 
d. Immunotherapy: At least 6 weeks since the completion of any type of 
immunotherapy (e.g. tumor vaccines). 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
13 
e. Monoclonal antibodies: At least 3 half-lives must have elapsed since prior therapy 
that included a monoclonal antibody. 
f. Radiotherapy: ≥ 2 weeks for local palliative XRT (small port); ≥ 6 months must 
have elapsed if prior TBI, craniospinal XRT; ≥ 3 months must have elapsed if ≥ 
50% radiation of pelvis; ≥ 6 weeks must have elapsed if therapeutic doses of 
MIBG or other substantial BM irradiation was given. 
g. Stem Cell Transplant or Rescue without TBI: Allogeneic and autologous HSCT 
will be allowed, if there is no evidence of active graft vs. host disease and ≥ 2 
months must have elapsed since infusion. Patients must not be on systemic 
immunosuppression.   
 
3.1.6 Organ Function Requirements: Patients must have normal organ and marrow function as 
defined below. 
 
Absolute neutrophil count 
≥ 1,000/mcL 
 
Platelets 
≥ 100,000/mcL (transfusion independent, defined as not  
 
 
receiving platelet transfusions within a 7-day period  
 
 
 
prior to enrollment) 
 
Hemoglobin  
≥ 8.0 g/dl (may receive RBC transfusions). 
 
Total bilirubin 
≤ 1.5 × institutional upper limit of normal for age 
 
AST(SGOT)/ALT(SGPT) 
≤ 2.5 × institutional upper limit of normal 
 
Albumin  
 
 
 
 
≥ 2 g/dl 
 
Creatinine 
within normal institutional limits for age 
OR 
                                                                    creatinine clearance ≥ 70 mL/min/1.73 m2 for patients      
with creatinine levels above institutional normal 
- 
EKG  
 
 
 
QTc < 480 msec (CTCAE Grade 2) 
 
3.1.7 Contraception:  Because chemotherapeutic agents may be teratogenic, males and females 
of child-bearing potential must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) prior to study entry and for the duration of study 
participation and for 4 months after the last dose of study chemotherapy.  
3.1.8 Informed Consent: All patients > 18 years must sign a written informed consent. Patients 
< 18 years old must provide assent, and the parent or legal guardian must sign the written 
informed consent. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Pregnancy or Breast-Feeding: Patients who are pregnant or breast-feeding are not 
eligible for this study due to the potential for fetal or teratogenic toxicities. 
Negative pregnancy tests must be obtained in female patients who are post-
menarchal. 
3.2.2 Major surgery within 14 days prior to start of treatment. No time limitations after 
minor surgery (eg: core biopsy or central line placement)  
 
 

Protocol # 15-0659 
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14 
3.2.3 Current evidence of GIST, alveolar soft part sarcoma, or dermatofibrosarcoma 
3.2.4 Concomitant Medications: 
a. Growth factor(s): Growth factors that support platelet or white cell number or 
function must not have been administered within the 7 days prior to enrollment 
(14 days if pegfilgrastim). 
 
b. Corticosteroids: Patients receiving corticosteroids who have not been on a stable 
or decreasing dose of corticosteroid for the 7 days prior to enrollment are not 
eligible. 
c. Investigational Drugs: Patients who are currently receiving another investigational 
drug are not eligible. 
d. Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents 
are not eligible.  
e. Enzyme-inducing anticonvulsants or other medications: Patients who are 
currently receiving the enzyme inducing anticonvulsants: phenytoin, 
phenobarbital, carbamazepine, oxcarbazepine are not eligible.  Patients who are 
currently taking rifampin, voriconazole, itraconazole, ketoconazole, aprepitant, or 
St. John’s Wort are not eligible. See Appendix B for more details 
f. Anticoagulants: Use of warfarin is not allowed while on study. Patients already on 
warfarin should use alternative anticoagulants while on this study. Warfarin must 
not have been administered within 7 days of starting protocol therapy. 
g. Medications that prolong the QTc: Patients receiving medications listed in 
Appendix C are not eligible. 
3.2.5 Infection: Patients who have an uncontrolled infection, or who are currently 
receiving treatment for C difficile infection. 
3.2.6 Patients with a history of allergic reactions attributed to eribulin or irinotecan. 
3.2.7 Patients with documented allergy to cephalosporins. 
3.2.8 Patients with CNS tumors or known brain metastases. 
3.2.9 Patients with known metastatic tumor in the bone marrow. 
3.2.10 Patients who in the opinion of the investigator may not be able to comply with the 
safety monitoring requirements of the study. 
3.2.11 Uncontrolled intercurrent illness that would limit compliance with study 
requirements. 
3.2.12 HIV-positive patients on combination antiretroviral therapy are ineligible because 
of the potential for pharmacokinetic interactions with eribulin and irinotecan. In 
addition, these patients are at increased risk of lethal infections when treated with 
marrow-suppressive therapy.   
 
 
3.3 
Inclusion of Women and Minorities 
 
Both males and females of all races and ethnic groups are eligible for this trial. 
 
 
 
 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
15 
4. REGISTRATION PROCEDURES 
 
4.1 
Enrollment Guidelines 
 
Eligible patients will be identified by the principal investigator and co-investigators of this study. 
Potentially eligible patients will be pre-screened by the investigators, study personnel, or the 
Principal Investigator by conducting a brief medical chart review to determine key eligibility 
criteria. 
 
Registration of all participants must occur before any study-related procedures.  Staff will be 
available to register participants Monday thru Friday, from 8:00 AM to 5:00 PM Mountain 
Standard Time.  In emergency situations, where a patient must be registered during holidays or 
off-hours, you may call the research coordinator at 303-358-2638.  You may not register a 
participant if a slot has not been reserved.   
 
Please follow these steps to register a participant:  
1. Obtain written informed consent/assent prior to any study related procedures.  
2. Complete the eligibility checklist.  The local investigator must sign the checklist 
confirming that eligibility has been reviewed.  
3. Send the signed eligibility checklist along with supporting source documents, including 
the consent/assent, to the research coordinator at Children’s Hospital Colorado (CHCO).  
You may send all the documents via fax or email.  Please fax to 720-777-7289 or email 
the CHCO coordinator listed in the front of the protocol.  
4. An investigator at CHCO will review and confirm eligibility.  The eligibility will be 
signed by the investigator and returned to the site.  An email or registration confirmation 
will be sent to the overall study PI, local investigator and local study coordinator.  
Patients will receive eribulin at the assigned dose level throughout their treatment unless 
dose modifications occur as outlined in Section 6.0. 
5. The participant will be assigned a participant number that includes the site number 
followed by the sequential order of participants enrolled local; site #_sequential number 
(e.g., 01_01, then 01_02 for site number 01) 
 
4.2 
Compliance with Laws and Regulations 
 
The study will be conducted in accordance with U.S. Food and Drug Administration (FDA) and 
International Conference on Harmonization (ICH) Guidelines for Good Clinical Practice (GCP), 
the Declaration of Helsinki, any applicable local health authority, and Institutional Review Board 
(IRB) requirements.  The PI or designee will be responsible for obtaining continuing and not less 
than annual IRB re-approval throughout the duration of the study.  Copies of the Investigator’s 
annual report to the IRB and copies of the IRB continuance of approval must maintained by the 
the appropriate participating site and the University of Colorado.  The PI or designee is also 
responsible for notifying the Data and Safety Monitoring Committee (DSMC) and the 
participating sites IRB of record of any significant adverse events that are serious and/or 
unexpected, as per standard operating procedure for those entities. In addition, the DSMC will 
review all adverse events at routine intervals as per standard operating procedures 
 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
16 
5. TREATMENT PLAN 
 
5.1 
Enrollment and Screening Process  
 
Any testing done specifically for research purposes related to this study should be performed 
only after written informed consent is obtained. 
 
 
5.2 
Agent Administration 
 
Treatment may be administered either in the inpatient or outpatient setting. Reported adverse 
events and potential 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. 
 
There will be no intra-patient dose escalations. 
 
Dose Escalation Schedule 
Dose Level 
Dose 
Irinotecan 
(mg/m2/day)  
Eribulin 
(mg/m2/dose) 
Level 0 
90 
0.8 
STARTING DOSE: Level 1 
90 
1.1 
Level 2 
90 
1.4 
 
 
 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
17 
 
Therapy Delivery Map – Cycle # ____ 
 
_______________________        ___________ 
               Patient name                       DOB 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
Observations 
Eribulin 
IV over 2-5 min 
See dose escalation 
scheme 
1, 8 
a. 
History 
b. Physical Exam 
(Ht/Wt/VS/ 
performance status) 
c. 
CMP 
d. CBC 
e. Pharmacokinetics1 
Irinotecan 
PO 
90 mg/m2/dose 
1-5 (On day 1, 
irinotecan is 
given at least 
15 minutes 
after eribulin) 
Cefixime 
PO 
400 mg/day 
-1 through 8 
 
Ht _____ Wt _____ BSA ______ 
Dose level = ______ 
 
Assigned Eribulin dose is ____ mg/m2 = _____ mg 
  
Date 
Due 
Date 
Given 
Day 
Eribulin 
Irinotecan 
 
Cefixime 
Studies 
 
 
-1 (20*) 
 
 
______mg 
 
 
 
0 (21*) 
 
 
______mg 
 
 
 
1 
_______mg 
______mg 
______mg 
a, b, c, d, e1 
 
 
2 
 
______mg 
______mg 
 
 
 
3 
 
______mg 
______mg 
 
 
 
4 
 
______mg 
______mg 
e (optional)2 
 
 
5 
 
______mg 
______mg 
 
 
 
6 
 
 
______mg 
 
 
 
7 
 
 
______mg 
 
 
 
8 
_______mg 
 
______mg 
b, c3, d4, e1 
 
 
15 
 
 
 
c3, d4 
 
 
20 
 
 
______mg 
 
 
 
21 
 
 
______mg 
 
1Blood samples for pharmacokinetic testing will be obtained pre-dose, 0.25, 1, 1.5, 2, 4, and 5 hours after the 
administration of eribulin on day 1 and prior to day 8 dose with regularly obtained labs (see Appendix g for 
Pharmacokinetic Study Form).  These samples will only be collected in the first treatment cycle.   
2 An optional single pharmacokinetic sample may be collected anytime between 24-96 hours if labs are being 
obtained at UK for other purposes.  
3CMP must be drawn weekly during cycle 1, and then may be drawn only at the start of subsequent cycles 
4CBC with differential should be drawn twice weekly during the first cycle, and then must be drawn at least 
weekly during subsequent cycles 
 
On day 1 in which eribulin and oral irinotecan are administered concurrently, the eribulin should 
precede irinotecan by at least 15 minutes. 
 
Subsequent cycles should start after day 21 as soon as the ANC ≥ 1,000/µL and platelets≥ 
100,000/µL, and eligibility criteria are met for renal and hepatic function (Section 3.1). 
This start date could vary by 3 days. 
 
 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
18 
5.2.1 Administration of Eribulin 
 
Aseptically withdraw the required amount of eribulin mesylate from the single-use vial and 
administer undiluted or diluted in 0.9% Sodium Chloride Injection, USP intravenously over 2 to 
5 minutes. 
 
5.2.2 Administration of Oral Irinotecan 
 
For oral use, the appropriate volume of irinotecan solution (20 mg/ml) is drawn up undiluted into 
a plastic oral syringe. Each dose is to be mixed with juice (crangrape, cranapple, cranberry, or 
other “cran” juice) immediately before administration. The oral syringes containing undiluted 
irinotecan are stable for 21days when stored in a refrigerator. Irinotecan has a very unpleasant 
flavor, and so the juice will be used to mask the drug taste (Appendix D). See protocol for 
premedication and supportive care measures. 
 
 
If emesis occurs within 20 minutes of taking a dose of irinotecan, then the dose may be repeated 
once. If emesis occurs after 20 minutes, the dose should not be repeated. Instructions for 
administration of oral irinotecan are included in Appendix D and a copy of Appendix B, 
outlining potential drug interactions with irinotecan, should be given to the patient. 
 
5.3 
Supportive Care 
 
5.3.1 Antiemetics 
 
Premedication with a 5-HT3 antagonist is recommended 30 minutes prior to daily irinotecan 
doses. Aprepitant and/or steroids should not be used as antiemetics on this study due to effects 
on CYP3A4 and potential interference with irinotecan metabolism. 
 
5.3.2 Growth Factors 
 
Patients should not receive growth factors, including GMCSF, GCSF, or pegylated GCSF unless 
indicated in the Dose Modification section, 6.1.  
 
5.3.3 Concomitant Medications 
 
Eribulin has been associated with prolonged QTc, so medications that prolong QTc should be 
avoided when possible. A list of medications that prolong QTc is provided in Appendix C. 
 
5.3.4 Supportive Care 
 
Appropriate antibiotics, blood products, antiemetics, fluids, and general supportive case are to be 
used as necessary.  
 
 
 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
19 
5.3.5 Prophylaxis for Irinotecan-Associated Diarrhea 
 
Cefixime or an available equivalent antibiotic will be used to reduce irinotecan-associated 
diarrhea as previously mentioned [44, 45]. Antibiotic treatment should start at least two days 
prior to the start of irinotecan. This antibiotic therapy should continue until 3 days after the last 
dose of irinotecan. 
 
 
5.3.6 Concomitant Medications for Diarrhea and Abdominal Cramping 
 
Patients and their families will be instructed to contact their physician if diarrhea occurs. Any 
patient who develops diarrhea or abdominal cramping within the first 4 hours after oral 
administration of irinotecan should receive atropine intravenously at a dose of 0.01 mg/kg 
(maximum 0.4 mg). This so-called “early onset diarrhea” is often presaged by cholinergic 
manifestations such as diaphoresis and abdominal cramping. Because patients are treated with 
irinotecan over multiple days, it may be difficult to distinguish immediate from delayed diarrhea. 
Patients with presumed immediate diarrhea who do not improve with atropine, or patients who 
develop diarrhea more than 4 hours after receiving irinotecan, should be given treatment with 
oral loperamide for late onset diarrhea as outlined below. 
 
All patients will receive a copy of instructions for the use of loperamide if/when diarrhea occurs 
(Appendix D). Each family will be provided with this antidiarrheal medicine with instructions to 
start at the first episode of poorly formed or loose stools, or at the earliest onset of bowel 
movements more frequent than normally expected for the patient. 
 
Loperamide (1 mg/5 ml or 1 caplet = 2 mg) dosing guidelines for diarrhea: 
Weight ≥ 43 kg (≥ 95 pounds): Take 4 teaspoonfuls or 2 caplets after the first loose stool, 
followed by two teaspoonfuls or one caplet every two hours as needed. 
Weight 20 kg to 43 kg (<94 pounds): Take 2 teaspoonfuls or 1 caplet after the first loose stool, 
followed by one teaspoonful or one-half caplet every 2 hours as needed. 
 
Because patients will be receiving prolonged exposure to antibiotics (i.e., cefixime), patients 
having significant diarrhea should have stool samples evaluated for C difficile toxin, as this is a 
potentially treatable cause of diarrhea. If patients have fever with diarrhea, or bloody diarrhea, 
evaluation of stools for bacterial culture should also be performed.  
 
If there is failure of loperamide to control diarrhea after 24 hours of use, patients may receive 
octreotide (Sandostatin™) at the dose of 10 micrograms/kg/dose subcutaneously every 12 hours 
x 3 days. 
 
5.4 
Criteria for Starting Subsequent Cycles of Therapy 
 
A cycle may be repeated if: 
 The patient has no evidence of disease progression as assessed clinically and/or with 
imaging studies 
 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
20 
 The patient meets eligibility criteria for hematopoietic, renal, and liver function (Section 
3.1) 
 The patient has not met any criteria for removal from protocol therapy as described in 
Section 5.9 
 
Patients who experience dose-limiting toxicity but do not have evidence of progressive disease 
may be eligible for additional protocol therapy as described in Section 6.0. 
 
5.5 
Definition of Dose-Limiting Toxicity 
 
Dose-limiting toxicity (DLT) will be defined as any of the following events, detailed in Sections 
5.5.2 and 5.5.3 that are possibly, probably or definitely attributable to protocol therapy. 
Decisions regarding the estimation of the recommended phase II dose and assigning treatment 
dosages to subsequent patients will be made on observations occurring in the first cycle of 
therapy. 
 
5.5.1 Grading of Adverse Events 
 
Adverse events (toxicities) will be graded according to the NCI Common Terminology Criteria 
for Adverse Events v4.02 (CTCAE) http://ctep.cancer.gov/reporting/ctc.html. 
 
Any suspected or confirmed dose-limiting toxicity should be reported within 24 hours to the 
coordinating center and Principal Investigators at both centers.  
 
5.5.2 Non-Hematological Dose-Limiting Toxicity 
 
Non-hematological dose-limiting toxicity is defined as any Grade 3 or Grade 4 non-
hematological toxicity that is possibly, probably or definitely attributable to the investigational 
drugs with the specific exclusion of: 
 
 Grade 3 nausea, vomiting or dehydration 
 Grade 3 diarrhea < 3 days 
 Grade 3 diarrhea regardless of duration if patient did not receive appropriate supportive 
care (cefixime, loperamide, or atropine as outlined in Section 5.3) 
 Grade 3 transaminase (AST/ALT) elevation that returns to grade ≤ 1 or baseline prior to 
the time for the next treatment cycle 
 Grade 3 GGT 
 Grade 3 fatigue < 3 days 
 Grade 3 fever, febrile neutropenia, or infection 
 Grade 3 electrolyte abnormalities (Na, K, Cl, CO2, Ca, Mg, Phosphate) that improve to ≤ 
grade 2 within 7 days, with or without supplements 
 
Allergic reactions that necessitate discontinuation of the study drugs will not be considered a 
dose-limiting toxicity. 
 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
21 
Patients who develop > Grade 3 QTc prolongation (> 501 msec) at any time must be removed 
from protocol therapy. 
 
5.5.3 Hematological Dose-Limiting Toxicity 
 
Hematologic DLT will be defined as any of the following: 
 Greater than 7 days duration of either grade 4 neutropenia or grade 4 thrombocytopenia 
of > 7 days duration 
 Grade 3 or 4 thrombocytopenia that requires platelet transfusions on greater than 2 
occasions during a cycle. 
 Failure to recover blood counts to eligibility criteria that cause a delay of ≥ 14 days 
between treatment cycles.  
 
5.6 
Dose Escalating Criteria 
 
A 3 + 3 design will be used to determine dose assignment for patients, as described in Section 
13.2. Specifically, the following rules will apply for dose escalation: 
 
A.   Evaluate 3 patients at dosek: 
1. If 0 of 3 patients have DLT, then  
i. If first cohort, increase dose to dosek+1 and go to A. 
ii. Otherwise, go to B. 
2. If 1 of 3 patients has DLT, then go to B. 
3. If more than 1 patient has DLT  
i. If lowest dose, then go to C.  
ii. Otherwise, decrease dose to dosek-1 and go to A. 
B.   Evaluate 3 additional patients at dosek : 
1. If 0 or 1 of 6 patients has DLT, then increase dose to dosek+1  and go to A. 
2. If 2 or more patients have DLT, then  
i. If lowest dose, then go to C. 
ii. Otherwise, decrease dose to dosek-1 and go to A. 
C.   Discontinue dose escalation/de-escalation. 
 
 
Accrual will continue until the recommended phase II dose for a Phase II study (RP2D) is 
established and at least 6 patients have been treated at this dose. The RP2D is the highest dose 
level at which no more than 1 of 6 patients experiences first-cycle DLT.  Doses higher than dose 
level 2 will not be studied in this trial. Once the RP2D is identified, an additional 10 patients will 
be enrolled at this dose level.  
 
5.7 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue for up to 17 
cycles until one of the following criteria applies: 
 
 Disease progression 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
22 
 Intercurrent illness that prevents further administration of treatment 
 Unacceptable adverse event(s) 
 Patient decides to withdraw from the study 
 General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
5.8 
Duration of Follow-Up 
 
Patients removed from study for unacceptable adverse event(s) will be followed until resolution 
or stabilization of the adverse event. All patients will be followed for at least 30 days after 
removal from study or until death, whichever occurs first.   
 
5.9 
Criteria for Removal from Protocol Therapy 
 
a. Clinical or radiographic progressive disease (See Section 11). 
b. Adverse events requiring removal from study (See Sections 6.1 and 6.2). 
c. Refusal of further protocol therapy by patient/parent/guardian. 
d. Non-compliance that in the opinion of the investigator does not allow for ongoing 
participation. 
e. Completion of 17 cycles of therapy.   
f. Determination that it is not in the patient’s best interest by the treating physician. 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off Study 
(see below). Ongoing adverse events, or adverse events that emerge after the patient is removed 
from protocol therapy, but within 30 days of the last dose of investigational agent, must be 
followed and reported. Follow-up data will be required unless consent is withdrawn. 
 
5.10 
Off-Study Criteria 
 
Patients will be considered off-study if any of the following events occur: 
 
a. Thirty days has expired after the last dose of protocol therapy. 
b. Death 
c. Lost to follow-up 
d. Withdrawal of consent for any further data submission. 
e. Entry onto another antineoplastic therapeutic study. 
f. Onset of new treatment regimen 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose modifications will involve eribulin but not irinotecan, given that the study question is to 
identify the recommended phase II dose of eribulin that can be safely administered with fixed-
dose irinotecan.  
 
Doses which have been reduced for toxicity will not be re-escalated. 
 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
23 
 
6.1 
Dose Modifications for Hematological Toxicity 
 
Patients who experience dose-limiting toxicity at dose levels 1 or 2 but do not have evidence 
of disease progression may continue to receive therapy modified as described below.  
 
Patients who experience Grade 3 febrile neutropenia may receive additional cycles of therapy at 
the same eribulin dose with the optional use of filgrastim/pegfilgrastim support. 
 
Patients who experience DLT at dose level 0 will not receive further therapy on study. 
 
6.1.1 Patients who have dose-limiting thrombocytopenia should receive subsequent 
cycles at the same dose of irinotecan with eribulin reduced to the next lowest dose 
level.  
6.1.2 Patients who have dose-limiting neutropenia (Grade 4 neutropenia of > 7 days 
duration or delay in the start of the next cycle for ≥ 14 days due to neutropenia) 
with no other dose-limiting toxicity should receive the same dose in the next cycle 
with filgrastim or pegfilgrastim support at standard doses. [Note: Patients MUST 
NOT receive prophylactic filgrastim or pegfilgrastim in the first cycle of therapy.] 
If dose-limiting neutropenia recurs after growth factor is added, then the eribulin 
dose should be decreased to the next lowest dose level and 
filgrastim/pegfilgrastim support used again.  
6.1.3 Patients who experience Grade 4 febrile neutropenia may receive additional 
cycles of therapy at the same eribulin dose with the use of filgrastim/pegfilgrastim 
support. 
 
6.2 
Dose Modifications for Non-Hematological Toxicity 
 
Patients who experience Grade 3 prolonged QTc (> 501 msec) will be removed from 
protocol therapy. 
 
Patients who experience dose-limiting toxicity at dose levels 1 or 2 but do not have evidence 
of disease progression may continue to receive therapy modified as described below.  
 
Patients who experience DLT at dose level 0 will not receive further therapy on study 
 
6.2.1 Patients who have any dose-limiting non-hematological toxicity (as defined in 
section 5.5.2) that returns to eligibility criteria within 7 days after the planned 
start of the next treatment cycle may continue on study but should receive 
subsequent doses at the next lower dose level of eribulin. If non-hematologic 
Grade 3 or 4 toxicities other than those listed in Section 5.5.2 recur at a reduced 
dose, the patient must be removed from protocol therapy.  
6.2.2 Patients who have any Grade 3 or 4 non-hematological toxicity that does not 
resolve to eligibility criteria by 7 days after the planned start of the next treatment 
cycle must be removed from protocol therapy. 
 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
24 
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
7.1 
Definitions 
 
Adverse Event: Any unfavorable and unintended sign (including abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medical treatment or procedure, 
regardless of whether it is considered related to the medical treatment or procedure (attribution of 
unrelated, unlikely, possible, probable or definite). 
 
Serious Adverse Event: An adverse event or suspected adverse reaction is considered “serious” 
if, in the view of the investigator, it results in any of the following outcomes: Death, a life-
threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or a congenital anomaly/birth defect. Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered serious when, based upon 
appropriate 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. 
 
Unanticipated Problems: Include adverse events which in the opinion of the principal 
investigator are both unexpected and probably or definitely related to the intervention / drug or 
device, any unforeseen development that potentially increases the likelihood of harm to 
participants or others in the future, information that indicates a change to the risks or potential 
benefits of the research or an actual unforeseen harmful or unfavorable occurrence to participants 
or others that relates to the research protocol (injuries, psychological events, drug errors). 
 
Other Reportable Adverse Events: Include death unrelated to study treatment if occurring 
within 30 days of the last study treatment, death at least possibly related to study treatment at any 
time point, secondary malignancy, pregnancy, fetal death, and neonatal death. 
 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.2) and the characteristics of an observed AE (Section 7.3) will 
determine whether the event requires expedited reporting (via Medwatch Forms) in addition to 
routine reporting. 
 
 
 
 
 
 
 
 
 
 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
25 
7.2 
Expected Toxicities 
 
7.2.1 
Adverse Events List for Eribulin 
 
Onset 
Common:  
>20% of patients 
Occasional:  
<20% of patients 
Rare:   
<10% of patients 
Immediate: hours to 
days 
Nausea, vomiting 
anaphylaxis 
Prompt: days to 
weeks 
Anorexia, weight loss, 
constipation, fatigue, 
pain, 
myelosuppression, 
increased LFTs, 
neuropathy,  
Diarrhea, headache, 
increased creatinine, 
cough, dyspnea 
Vertigo, hypertension, QT 
prolongation, venous 
thromboembolism, hand-
foot syndrome, rash, 
abdominal pain, mucositis, 
edema, pancreatitis, 
electrolyte abnormality, 
hyperglycemia, anxiety, 
depression, insomnia, 
dizziness, dysgeusia , 
pharyngolargyngeal pain, 
conjunctivitis,  
Delayed: weeks to 
months 
Alopecia 
 
 
 
7.2.2 Adverse Events List for Irinotecan 
 
Onset 
Common:  
>20% of patients 
Occasional:  
<20% of patients 
Rare:  
 <5% of patients 
Immediate: hours to 
days 
Nausea, vomiting, 
anorexia, fever, 
asthenia, cholinergic 
symptoms: (rhinitis, 
increased salivation, 
miosis, lacrimation, 
diaphoresis, flushing 
and intestinal 
hyperperistalsis that can 
cause abdominal 
cramping and early 
diarrhea) 
Constipation, headache, 
diarrhea  
Anaphylaxis, dehydration 
with dizziness and 
hypotension, bradycardia, 
dyspnea and cough, 
disorientation/confusion, 
somnolence, pain at infusion 
site 
Prompt: days to 
weeks 
Diarrhea, neutropenia, 
alopecia, eosinophilia, 
elevations in 
transaminases, alkaline 
phosphatase, bilirubin, 
mucositis, infection 
Anemia, rash, 
dyspepsia, 
thrombocytopenia 
Colitis, renal failure 
(secondary to severe 
dehydration), 
thromboembolic events, 
ileus 
Delayed: weeks to 
months 
 
 
Pneumonitis 
Unknown frequency 
and timing 
Fetal toxicities and teratogenic effects of irinotecan have been noted in animals at 
doses similar or less than those used in humans.  Toxicities include: decreased 
skeletal ossification, multiple anomalies, low birth weight and increased fetal 
mortality. It is not known if irinotecan is excreted into breast milk but it is 
excreted into rat milk. 
 
For a comprehensive list of adverse events please refer to the package insert. 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
26 
 
7.3 Adverse Event Characteristics  
 
 CTCAE term (AE description) and grade:  Adverse events that occur while the patient 
is on study will need to be recorded.  Please see below for specific reporting 
requirements.  Each investigative site will be responsible for maintaining an AE log that 
captures all AEs and SAEs.  All Adverse Events will be recorded as “related” or “not 
related” in the AE log.  Each site will also need to report all SAEs that occur at that 
institution to their respective IRB as per their IRB policy in addition to the protocol 
requirements. 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. 
 
 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. 
 
 
7.4 Expedited Adverse Event Reporting 
 
7.4.1 Investigators must report to the study PI’s and coordinating center 
(CHCO) any serious adverse event (SAE) that occurs after the initial dose of 
study treatment, during treatment, or within 30 days of the last dose of treatment 
on the standardized SAE form.  
 
Note: If subject is in Long Term Follow Up, death is reported at continuing review.  
 
Note: Abnormal laboratory values are not considered medical events, unless determined 
to be causative of SAE by the investigator or grade 5. 
 
 
 
7.4.2 The following table outlines the required forms and reporting structure for clinical 
trials. 
Expedited reporting 
to DSMC 
Expedited 
reporting to FDA 
Non-
expedited AE 
Form 
IRB 
 
All SAEs (severity 
of adverse event is 
Grade 3, 4 or 5) 
 
Suspected AE that 
is serious and 
unanticipated (not 
listed in IB or 
consent) 
 
CRF and 
DSMC 
reporting 
only 
 
Voluntary 
Medwatch 3500 
for serious and 
unanticipated 
 
CRF for all AEs, 
including SAEs 
 
 
Yes if it meets the IRB 
reporting 
requirements: If 
reportable event, 
please send copy of 
IRB report to CHCO 
 
 
 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
27 
7.5 Routine Adverse Event Reporting 
 
All Adverse Events (Grades 1-5) must be recorded on case report forms and reported to the 
overall PI in routine study data submissions.  AEs reported through expedited processes (e.g., 
reported to the IRB, FDA, etc.) must also be reported in routine study data submissions. 
All Adverse Events will be recorded as “related” or “not related” in the AE log.  Depending on 
the grade of each AE, it will need to be reported to CHCO within 5 calendar days or 24 hours.  
Please refer to the table below for AE reporting time lines. 
 
 
 
 
 
Attribution 
When to report AEs to CHCO
  Gr. 1 and 2 AE  
Expected and 
Unexpected 
Gr. 3 AE
Expected and 
Unexpected 
Gr. 4 AE 
Expected and 
Unexpected 
Gr. 5 AE 
Expected and 
Unexpected
Unrelated 
Unlikely 
  Record in AE 
Log 
5 calendar days 
5 calendar days 
24 hours
Possible 
Probable 
Definite 
  
 
Record in AE 
Log 
 
5 calendar days 
 
5 calendar days 
 
24 hours 
 
 
 
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. 
 
8.1 
Eribulin mesylate [11,15:18,21:24,28-Triepoxy-7,9-ethano-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), HalavanTM®] 
 
8.1.1 Dosage and Route of Delivery: Since this a Phase I study, dosage will be defined 
by the dose escalation scheme.  To administer the drug, it will be aseptically 
withdrawn from the single-use vial and administer undiluted or diluted in 0.9% 
Sodium Chloride Injection, USP intravenously over 2 to 5 minutes.  
8.1.2 Adjustment of Dosing: This is defined in section 6.1 and 6.2 of the protocol 
8.1.3 Source and pharmacology: Eribulin mesylate is a non-taxane microtubule 
dynamics inhibitor.  Eribulin mesylate is a synthetic analogue of halichondrin B, a 
product isolated from the marine sponge Halichondria okadai. 
 
Eribulin inhibits the growth phase of microtubules without affecting the 
shortening phase and sequesters tubulin into nonproductive aggregates. Eribulin 
exerts its effects via a tubulin-based antimitotic mechanism leading to G2/M cell-
cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death 
after prolonged mitotic blockage.  

Protocol # 15-0659 
Version Date: March 22, 2017 
 
28 
 
The pharmacokinetics (PK) of eribulin is linear with a mean elimination half-life 
of approximately 40 hours, a mean volume of distribution of 43 L/m2 to 114 L/m2 
and mean clearance of 1.16 L/hr/m2 to 2.42 L/hr/m2 over the dose range of 0.25 
mg/m2 to 4.0 mg/m2. The human plasma protein binding of eribulin at 
concentrations of 100 ng/mL to 1,000 ng/mL ranges from 49% to 65%. Eribulin 
exposure after multiple dosing is comparable to that following a single dose. No 
accumulation of eribulin is observed with weekly administration.  
 
Unchanged eribulin was the major circulating species in plasma following 
administration of 14C-eribulin to patients. Metabolite concentrations represented 
< 0.6% of parent compound, confirming that there are no major human 
metabolites of eribulin. Cytochrome P450 3A4 (CYP3A4) negligibly metabolizes 
eribulin in vitro. 
 
Eribulin is eliminated primarily in feces unchanged. After administration of 14C-
eribulin to patients, approximately 82% of the dose was eliminated in feces and 
9% in urine. Unchanged eribulin accounted for approximately 88% and 91% of 
the dose in feces and urine, respectively. 
 
8.1.4 Formulation & Stability: Eribulin mesylate injection, 1 mg/2 mL, in a single-use 
vial. One vial per carton. Store at 25°C (77°F); excursions permitted to 15°-30°C 
(59°-86°F). Do not freeze. Store the vials in their original cartons. 
 
8.1.5 Guidelines for Administration: See Treatment and Dose Modifications sections of 
the protocol. The FDA-approved dose of Eribulin as a single agent in adults is 1.4 
mg/m2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-
day cycle. 
 
8.1.6 Toxicity: In Phase 3 studies, the most common treatment-emergent adverse events 
noted are described. Over half of patients experienced neutropenia or leukopenia, 
and 20% had anemia. One third of patients complained of asthenia or fatigue. 
Nausea was observed in 22% and diarrhea in only 14%. Peripheral neuropathy 
was observed in 27%.  One third of patients experienced alopecia. Of the almost 
2000 patients exposed in completed clinical studies as of May 2013, 367 patients 
had related serious adverse events. The most frequent treatment-related SAEs 
were febrile neutropenia (3.3%), neutropenia (1.9%), and pyrexia (1.2%).   
 
 
8.1.7 Supplier: Eribulin is commercially available by Eisai. See package insert or IB for 
more detailed information.   
 
8.2 
Irinotecan [CPT-11,Camptothecin-11,7-ethyl-10-(4-[1-piperidino]-1-piperidino)-
carbonyloxy-camptothecin), Camptosar®], NSC #616348 
8.2.1 Dosage and Route of delivery: Irinotecan will be given orally daily for days 1-5 of 
each 21 day cycle.  The dose will be 90 mg/m2/dose. On day 1 of each cycle, it 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
29 
will be given at least 15 minutes after the eribulin.  For oral use, the appropriate 
volume of irinotecan solution (20 mg/ml) is drawn up undiluted into a plastic oral 
syringe. Each dose is to be mixed with juice (crangrape, cranapple, cranberry, or 
other “cran” juice) immediately before administration. The oral syringes 
containing undiluted irinotecan are stable for 21days when stored in a refrigerator. 
Irinotecan has a very unpleasant flavor, and so the juice will be used to mask the 
drug taste (Appendix D). See protocol for premedication and supportive care 
measures. 
 
If emesis occurs within 20 minutes of taking a dose of irinotecan, then the dose 
may be repeated once. If emesis occurs after 20 minutes, the dose should not be 
repeated. Instructions for administration of oral irinotecan are included in 
Appendix D and a copy of Appendix B, outlining potential drug interactions with 
irinotecan, should be given to the patient. 
 
8.2.2 Adjustment of Dosing: This is defined in section 6.1 and 6.2 of the protocol 
 
8.2.3 Source and pharmacology: Irinotecan is a semisynthetic water-soluble analog of 
camptothecin (a plant alkaloid isolated from Camptotheca acuminata). Irinotecan 
is a prodrug that requires conversion, by the carboxylesterase enzyme to the 
topoisomerase-I inhibitor, SN-38 in order to exert anti-tumor activity. SN-38 is 
approximately 1000 times more potent than irinotecan. Camptothecins interact 
specifically with the enzyme topoisomerase I which relieves torsional strain in 
DNA by inducing reversible single-strand breaks. Irinotecan and its active 
metabolite SN-38 bind to the topoisomerase I-DNA complex and prevent re-
ligation of these single-strand breaks. Current research suggests that the 
cytotoxicity of irinotecan is due to double-strand DNA damage produced during 
DNA synthesis when replication enzymes interact with the ternary complex 
formed by topoisomerase I, DNA, and either irinotecan or SN-38. Renal excretion 
is a minor route of elimination of irinotecan. The majority of the drug is 
metabolized in the liver. SN- 38 is conjugated to glucuronic acid and this 
metabolite has no anti-tumor activity. The extent of conversion of SN-38 to its 
glucuronide has been inversely correlated with the risk of severe diarrhea, because 
the other major route of SN-38 excretion is biliary excretion by canalicular 
multispecific organic anion transporter (cMOAT) which presumably leads to 
mucosal injury. In addition, APC and NPC are oxidative metabolites of irinotecan 
dependent on the CYP3A4 isoenzyme. After intravenous infusion of irinotecan in 
humans, irinotecan plasma concentrations decline in a multiexponential manner, 
with a mean terminal elimination half-life of about 6 to 12 hours. The mean 
terminal elimination half-life of the active metabolite SN-38 is about 10 to 20 
hours. Irinotecan is 30% to 68% bound to albumin and SN-38 is approximately 
95% bound to albumin. 
 
8.2.4 Formulation & Stability: Each mL of irinotecan injection contains 20 mg 
irinotecan (on the basis of the trihydrate salt); 45 mg sorbitol; and 0.9 mg lactic 
acid. When necessary, pH has been adjusted to 3.5 (range, 3.0 to 3.8) with sodium 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
30 
hydroxide or hydrochloric acid. Irinotecan is available in single-dose amber glass 
vials in 40mg (2ml) and 100mg (5ml). Store at controlled room temperature 15° 
to 30°C (59° to 86°F). Protect from light. It is recommended that the vial (and 
backing/plastic blister) should remain in the carton until the time of use. 
 
8.2.5 Guidelines for Administration: See Treatment and Dose Modifications sections of 
the protocol. 
 
For oral use, the appropriate volume of irinotecan solution (20 mg/ml) is drawn 
up undiluted into a plastic oral syringe. Each dose is to be mixed with juice 
(crangrape, cranapple, cranberry, or other “cran” juice) immediately before 
administration. The oral syringes containing undiluted irinotecan are stable for 
21days when stored in a refrigerator. Irinotecan has a very unpleasant flavor, and 
so the juice will be used to mask the drug taste (Appendix D). See protocol for 
premedication and supportive care measures. 
 
Cefixime or an available equivalent antibiotic will be used as diarrheal 
prophylaxis. Initiation of antibiotic treatment at least two days prior to the start of 
irinotecan is recommended. This antibiotic therapy should continue until 2 days 
after the last dose of irinotecan. 
 
Premedication with a 5-HT3 antagonist, like ondansetron is recommended 30 
minutes prior to daily irinotecan doses. Aprepitant is an inducer, a moderate 
inhibitor, and substrate of CYP3A4 and should not be used as an anti-emetic. 
 
If emesis occurs within 20 minutes of taking a dose of irinotecan, then the dose 
may be repeated once. If emesis occurs after 20 minutes, the dose should not be 
repeated. Instructions for administration of oral irinotecan are included in 
Appendix C. 
 
8.2.6 Supplier: Irinotecan is commercially available. See package insert for more 
detailed information. 
 
8.3 
Cefixime [Suprax®]  
 
8.3.1 Source and pharmacology: Cefixime is a third generation cephalosporin antibiotic 
for oral administration that inhibits bacterial cell wall synthesis by binding to one 
or more of the penicillin-binding proteins and interfering with the final 
transpeptidation step of peptidoglycan synthesis. Its spectrum of activity is similar 
to other third generation agents, including Enterobacteriaceae, and β-lactamase 
producing H. influenzae and N. gonorreae, and Staph. aureus. It is excreted 
primarily by the kidney. It has a serum half-life of approximately 3-4 hours. 
 
8.3.2 Formulation & Stability: Cefixime is available in scored 200 mg and 400 mg film 
coated tablets, and in a powder for oral suspension, which when reconstituted, 
provides 100mg/5ml. The powder for oral suspension is strawberry flavored and 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
31 
contains sodium benzoate, sucrose, and xanthan gum. 
 
8.3.3 Guidelines for Administration: Given orally at 400 mg daily. 
 
8.3.4 Supplier: Commercially available. 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Laboratory Correlative Studies 
 
The plasma concentrations of eribulin as well as irinotecan, SN-38 and SN-38 glucuronide will 
be measured to assess drug disposition and pharmacokinetic parameters in each patient. 
9.1.1 Pharmacokinetics 
9.1.1.1 
Collection of Specimen(s). Blood plasma samples for pharmacokinetics will be 
collected during cycle 1 on day 1 at pre-dose and at 15 minutes, 1 hour, 1.5 hours, 2 
hours, 4 hours, and 5 hours after the start of the eribulin infusion and a pre-dose 
sample on day 8. These samples will be required for all patients. An optional sample 
between 24-96 hours may also be collected after the start of the eribulin infusion, 
from patients that are available for blood draw. Whole blood samples will be 
collected from the central line or a peripheral IV provided a flush of at least 10 ml of 
normal saline has been administered.  At each time point, 7 ml of venous blood will 
be withdrawn into sodium heparinized collection tube. Please refer to 
Pharmacokinetic Study Form in Appendix G 
9.1.1.2 
Handling of Specimens(s). After collection, blood and anti-coagulant will be mixed 
by inverting the tube 8–10 times. Blood samples will be placed on ice immediately 
and centrifuged within 5 min at 7200 g at 4°C for 2 min. Plasma will be transferred 
into amber plastic tubes and stored on dry ice prior to transferring at −80°C until 
analysis. Plasma concentrations of free-base eribulin will be quantified using a 
validated liquid chromatography tandem mass spectrometry (LC/MS/MS) method as 
previously described [62]. Irinotecan, SN-38 and SN-38 glucuronide concentrations 
will be quantified using a validated HPLC method with fluorescence detection as 
previously described [63, 64]. 
9.1.1.3 
Shipping of Specimen(s). Samples will be collected by study personnel in Dr. 
Leggas’ lab for storage, processing and analysis. Please see Appendix G for 
additional information. 
9.1.1.4       Site(s) Performing Correlative Study. University of Kentucky and Children’s Hospital       
Colorado 
 
 
10. STUDY CALENDAR 
 
Evaluations/Material and Data to be Collected 
Required Clinical, Laboratory and Disease Evaluation 
 
All clinical and laboratory studies to determine eligibility must be performed within 7 days prior 
to enrollment unless otherwise indicated. Laboratory values used to assess eligibility (see Section 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
32 
3.0) must be no older than seven (7) days at the start of chemotherapy. The start of chemotherapy 
is defined as the initiation of treatment with irinotecan and eribulin. The start of protocol therapy 
is defined as the initiation of cefixime. Laboratory tests need not be repeated if chemotherapy 
starts within seven (7) days of obtaining labs to assess eligibility. If a post-enrollment lab value 
is outside the limits of eligibility, or laboratory values are >7 days old, then the following 
laboratory evaluations must be re-checked within 48 hours prior to initiating chemotherapy: CBC 
with differential, bilirubin, ALT (SGPT) and serum creatinine. If the recheck is outside the limits 
of eligibility, the patient must be re-screened to receive protocol-prescribed chemotherapy.  
 
Imaging studies must be obtained within 14 days prior to start of chemotherapy (repeat the tumor 
imaging if necessary). For patients whose disease is evaluated with bone marrow studies, the 
bone marrow aspirates and biopsies are required within 14 days prior to start of chemotherapy. 
Studies to be obtained 
Pre-
Study 
During 
Cycle 1 
Prior to 
Subsequent 
Cycles^ 
Off Treatment 
Off study# 
History 
X 
X 
X 
X 
X 
Physical Exam with vital signs 
X 
Weekly 
X 
X 
X 
Height, Weight, BSA 
X 
X 
X 
 
X 
Performance Status 
X 
 
X 
 
X 
CBC, differential, platelets 
X 
Twice 
weekly 
Weekly 
X 
X 
Complete metabolic profile 
X  
Weekly 
X 
X 
X 
Pregnancy test (only females of 
childbearing potential) 
X 
 
X 
 
 
12-lead EKG 
X 
X** 
X** 
 
 
Disease Evaluation 
X 
End of 
cycle 2$ 
End of cycle 4 
then every 3 
cycles 
X 
 
Patient Diary* 
 
X 
X 
 
 
Pharmacokinetics (as per Section 
9.1 and Appendix G) 
 
X 
 
 
 
 
*Patients will be given the diary from Appendix F to fill out with each cycle of treatment. They 
will return this prior to starting the next cycle 
#Every effort will be made to follow patients for at least 30 days after the last dose of medication, 
in order to monitor patients for resolution or late development of adverse events 
^ Labs should be done within 48 hours of initiation of the subsequent cycle of chemotherapy 
$ Disease evaluation should be done between days 15-21 of cycle 2 
**EKG will be performed prior to Day 8 eribulin during cycle 1, and prior to day 1 eribulin of 
cycle 2 
 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
33 
11. MEASUREMENT OF EFFECT 
 
Although not the primary endpoint of this trial, tumor response will be assessed by standard 
criteria.  For the purposes of this study, patients should be re-evaluated after cycles 2 and 4, and 
then every third cycle as long as clinically stable.   
 
11.1 
Antitumor Effect – Solid Tumors 
 
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) [65].  Changes in the largest diameter (uni-dimensional 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 study medications. 
 
Evaluable for objective response.  Only those patients who have measurable or evaluable 
disease present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for response.  These patients will have 
their response classified according to the definitions stated below.  (Note:  Patients who 
exhibit objective disease progression prior to the end of cycle 1 will also be considered 
evaluable). 
 
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 may only be 
considered measurable if there is documentation of residual viable disease after 
irradiation, or if there is unequivocal progression at that site following irradiation. 
 
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 
the short axis will be measured and followed. 
 
Evaluable Disease (also termed “non-measurable” or “non-target” disease).  All other 
lesions (or sites of disease), including smaller pathologic lymph nodes are considered 
evaluable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
34 
masses (not followed by CT or MRI), are also considered as evaluable (non-measurable). 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor evaluable (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 evaluable (non-
measurable) and 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 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 
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.  

Protocol # 15-0659 
Version Date: March 22, 2017 
 
35 
 
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).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  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 it can be documented 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.   
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the cycle of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
 
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 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
36 
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 [66-
68]. 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 [69]. 
 
Cytology, Histology  These techniques can be used to differentiate between partial 
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.   
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. 
 

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37 
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 
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. 
 
 
 
 
 
 
 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
38 
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 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
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 Evaluable (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). 
 

Protocol # 15-0659 
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39 
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.  
 
 
12. REGULATORY REQUIREMENTS/DATA COLLECTION 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.2 
Compliance with Laws and Regulations 
 
The study will be conducted in accordance with U.S. Food and Drug Administration (FDA) and 
International Conference on Harmonization (ICH) Guidelines for Good Clinical Practice (GCP), 
the Declaration of Helsinki, any applicable local health authority, and Institutional Review Board 
(IRB) requirements.  The PI or designee will be responsible for obtaining continuing and not less 
than annual IRB re-approval throughout the duration of the study.  Copies of the Investigator’s 
annual report to the IRB and copies of the IRB continuance of approval must maintained by the 
appropriate participating site and the Coordinating Site (CHCO).  The PI or designee is also 
responsible for notifying the Data and Safety Monitoring Committee (DSMC) and the 
participating sites IRB of record of any significant adverse events that are serious and/or 
unexpected, as per standard operating procedure for those entities. In addition, the DSMC will 
review all adverse events at routine intervals as outlined below. 
 
12.3 
Protocol Review and Amendments 
This protocol, the proposed informed consent and assent forms along with any documents given 
to participants (e.g., drug diaries) must be submitted, reviewed and approved by a properly 
constituted IRB governing each study location.  This process will occur following approval by 
the Coordinating Center IRB (COMIRB).  
Any changes made to the protocol will be submitted as amendments and must be approved by 
the IRB that governs CHCO prior to implementation.  The overall study PI and/or study 
coordinator will then distribute all amendments to the participating sites for submission to their 
local IRB.  All sites must then send all approved documents to the overall study coordinator at 
CHCO. 
 
12.4 
Informed Consent 
All participants must be provided a consent and assent form (if applicable) describing the study.  
All participants must be provided sufficient information to make an informed decision about 
their participation in this study.  The formal consent of a participant, using the IRB approved 
consent form, must be obtained before the participant is involved in any study-related procedure.  
The consent form must be signed and dated by the participant or the participant’s legally 

Protocol # 15-0659 
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40 
authorized representative, and by the person obtaining the consent.  The participant must be 
given a copy of the signed and dated consent document.  The original signed copy of the consent 
document must be retained in the medical record or research file.  
 
12.5 
Study Documentation 
The investigator must prepare and maintain adequate and accurate source documents designed to 
record all observations and other data pertinent to the study for each research participant.  This 
information enables the study to be fully documented and the study data to be subsequently 
verified.  
 
12.6 
DATA AND SAFETY MONITORING 
The overall PI Coordinating Center (CHCO) will be responsible for monitoring the trial per the 
trial monitoring plan, in addition to overseeing the safety and efficacy of the trial, executing the 
DSM plan and complying with all reporting requirements to the local and federal authorities.  
This oversight will be accomplished through additional oversight from the Data and Safety 
Monitoring Committee (DSMC) at the University of Colorado Cancer Center (CU Cancer 
Center).   
 
12.4.1. 
Monitoring Plan 
As the lead investigator in this multi-site trial, the overall PI is responsible for organizing and 
conducting monthly teleconferences with all participating sites.  The overall PI will also be 
responsible for including data from all of the participating sites within the overall trials six-
month DSM report to the DSMC to include minutes from monthly PI teleconferences.  Each 
participating site will be responsible for submitting the results and recommendations from the 
DSMC’s six-month review to their local IRB of record at the time of continuing review.   
 
Teleconferences will take place with each participating site only when there are active patients.  
This call will include the local investigator, local research coordinator, and overall PI and CHCO 
coordinator.  
 
 
 
12.4.2 
Subject Data Monitoring: 
Monitoring and auditing of research subjects on study will be conducted remotely by the CHCO 
coordinator and overall study PI.  Documentation that will be monitored is listed in the following 
section.  Data will be monitored for completeness and adherence to protocol requirements. 
 
 
12.7 
Data and Safety Monitoring Committee (DSMC) 
The DSMC is responsible for ensuring data quality and patient safety for all clinical studies at 
the CU Cancer Center.  A summary of the DSMC’s activities is as follows:  
 Conduct internal audits 
 Ongoing review of all serious adverse events (SAEs), unanticipated problems 
(UAPs) and reportable adverse events (AEs) 
 Has the authority to close and/or suspend trials for safety or trial conduct 
issues 
 May submit recommendations for corrective actions to the CU Cancer 
Center’s Executive Committee 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
41 
 
All SAEs, UAPs and reportable AEs are to be reported to the DSMC within 5 business days of 
receiving notification of the occurrence.  For all sub sites, please adhere to the tables in Section 
7.4 for AE reporting timelines to CHCO.  Once the AE is reported to CHCO, the primary 
coordinator will report AEs, as required to the DSMC and IRB for review.  
 
The overall PI will provide a DSM report to the CU Cancer Center DSMC on a six monthly 
basis.  The DSM report will include a protocol summary; current numbers; summary of toxicity 
data to include specific SAEs, UAPs and AEs; any dose modifications; all protocol deviations; 
and protocol amendments.  Results and recommendations from the review of this six month 
report by the DSMC will then be submitted by CHCO to all participating sites so they may 
submit to their IRB of record at time of continuing review.   
 
12.8 
Data Collection 
Data will be collected for this study and sent to CHCO for review via email or fax.  Data will be 
collected by the CHCO coordinator and reviewed along with the overall PI. 
 
Form / Source Documentation (SD) 
Submission Timeline 
Eligiblity Checklist 
Complete prior to registration with CHCO 
All source documentation that is submitted with the eligibility checklist must be de-identified.  
The only documents that will not be de-identified are the consent/assent forms and Patient Data 
Sheet.  All other forms and source documents submitted will be identified only by the subject 
number. 
 
12.8.1 Method 
 
Instructions for submitting data are listed in Study-Specific Data Management Plans created by 
CRDM SRF staff. 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
A phase I, dose-escalation trial is proposed to determine the recommended phase II dose (RP2D) 
of escalating doses of eribulin in combination with standard-dose oral irinotecan. Cohorts of 3 
patients per dose level are proposed using a 3+3 design [70, 71].  The following rules will be 
incorporated for dose escalation/de-escalation and establishing the recommended Phase II dose 
using the occurrence of DLT during the first cycle of therapy that is possibly, probably, or 
definitely attributable to study therapy. 
 
A.   Evaluate 3 patients at dosek: 
1. If 0 of 3 patients have DLT, then  
i. If first cohort, increase dose to dosek+1 and go to A. 
ii. Otherwise, go to B. 
2. If 1 of 3 patients has DLT, then go to B. 
3. If more than 1 patient has DLT  

Protocol # 15-0659 
Version Date: March 22, 2017 
 
42 
i. If lowest dose, then go to C.  
ii. Otherwise, decrease dose to dosek-1 and go to A. 
B.   Evaluate 3 additional patients at dosek: 
1. If 0 or 1 of 6 patients has DLT, then increase dose to dosek+1 and go to A. 
2. If 2 or more patients have DLT, then  
i. If lowest dose, then go to C. 
ii. Otherwise, decrease dose to dosek-1 and go to A. 
C.   Discontinue dose escalation/de-escalation. 
 
 
The RP2D is defined as the highest dose level in which there is no more than 1 DLT in 6 
patients. Ten additional patients will be enrolled at the RP2D level. Similar dose modifications as 
specified in Section 6 would be applied to these patients. Doses higher than dose level 2 will not 
be studied in this trial. 
 
13.2 
Sample Size/Accrual Rate 
 
The primary goal of this Phase I trial is to determine the RP2D and assess safety of the 
combination regimen.  A total of 6 -22 adolescent and young adult subjects will be accrued into 
the trial 
 
It is anticipated that 0.5-1 subjects will be accrued per month so that study accrual will be 
completed within 36 months. 
 
13.3 
Stratification Factors 
 
Not applicable for this trial  
 
13.4 
Analysis of Primary and Secondary Endpoints 
 
All patients who received study drug will be included in the safety analysis of this combination 
regimen.  Dose-limiting toxicity rate, adverse event data and corresponding toxicity grades 
during the days of treatment will be summarized in each dose level and in the overall patient 
population.  Incidence tables will be generated to summarize incidence of patients reporting at 
least one episode of each specific adverse event, incidence of adverse events causing withdrawal 
and incidence of serious adverse events. The total number of episodes for each event reported 
(Frequency Table), and the severity and attribution to study therapy of each episode reported 
(Severity Table and Attribution Table) will also be displayed.    
 
Listings of adverse events by patients will include the time to onset, the duration of each event, 
the severity of each event, and the relationship of the event to study therapy, whether it was a 
serious event, and whether it caused withdrawal. Safety data will be summarized for the overall 
patient group and by dose levels.  Toxicities will be graded according to Common Toxicity 
Criteria (CTCAE) v4.02.   
 
Estimates of antitumor effect based on RECIST 1.1 criteria will be estimated.  Furthermore, 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
43 
specific PD parameters will be assessed including SN-38 and SN-38 glucuronide.  Descriptive 
statistics will be employed to summarize quantitative levels of PD parameters at each time point 
of follow-up while changes in PD from baseline will be calculated and compared using paired 
statistical tests.  Pharmacokinetic modeling (two-compartment or non-compartmental models) 
will be employed to estimate several PK parameters (area under the concentration versus time 
curve, AUC, half-life, clearance, Cmax, etc).  These analyses will be considered exploratory in 
this Phase I trial.  
 
13.5 
Data Management 
 
The study statistician and staff from the Biostatistics Shared Resource Facility (BSRF) of the 
Markey Cancer Center worked closely with the study investigators and the Clinical Research and 
Data Management (CRDM SRF) at Markey in the development of eCRFs for the study.  
Specifically, the statisticians attended several meetings including the Protocol Initiation Meeting 
(PIM) to address all statistical considerations for this protocol including incorporation of dose-
escalation plans for this Phase I trial, appropriate and accurate collection of primary and 
secondary study endpoints and inclusion of valid values and range checks for data fields.  Red 
Cap, managed by staff at CHCO, will be the primary database repository of clinical data from all 
patients enrolled into this trial.  Data will be accessed by the study statistician on a regularly-
scheduled basis to perform statistical programming for conduct of data quality control, data 
management, generation of interim reports and statistical analysis.  The BSRF has developed an 
automated mechanism for generating a trigger for assessment of dose limiting toxicities based on 
the dose escalation rules in sections section 5.0 above.  In collaboration with the study team, 
procedures will be developed for timelines for data quality control, resolution of data queries, 
interim reporting and final data analysis.  
 
 
 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
44 
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. 
 
 
 
 
 
 
 
 
 
 

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Version Date: March 22, 2017 
 
45 
APPENDIX B 
INFORMATION ON POSSIBLE DRUG INTERACTIONS 
 
Information on Possible Interactions with Other Agents for Patients and Their Caregivers 
and Non-Study Healthcare Team 
 
Irinotecan interacts with many drugs that are processed by your liver.  Because of this, it is very 
important to tell your study doctors about all of your medicine before you start this study.  It is 
also very important to tell them if you stop taking any regular medicine, or if you start taking a 
new medicine while you take part in this study.  When you talk about your medicine with your 
study doctor, include medicine you buy without a prescription at the drug store (over-the-counter 
remedy), or herbal supplements such as St. John’s wort.  
 
Many health care prescribers can write prescriptions.  You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you and keep the attached information card in your wallet.  These are 
the things that you and they need to know:  
 
Irinotecan interacts with (a) certain specific enzyme(s) in your liver.  
 The enzyme(s) in question is CYP isoenzyme 3A4.  Irinotecan is broken down by this 
enzyme in order to be cleared from your system. 
 Irinotecan must be used very carefully with other medicines that need these liver enzymes 
to be effective or to be cleared from your system.   
 Other medicines may also affect the activity of the enzyme.   
o Substances that increase the enzyme’s activity (“inducers”) could reduce the 
effectiveness of the drug, while substances that decrease the enzyme’s activity 
(“inhibitors”) could result in high levels of the active drug, increasing the chance 
of harmful side effects. 
o You should notify your study doctor if you are prescribed: phenytoin, 
phenobarbital, carbamazepine or ketoconazole since these drugs are known to 
affect the levels of irinotecan in your body. 
 You and healthcare providers who prescribe drugs for you must be careful about adding or 
removing any drug in this category.  
 Before you start the study, your study doctor will work with your regular prescriber to 
switch any medicines that are considered “strong inducers/inhibitors or substrates of CYP 
3A4.” 
 Your prescribers should look at this web site 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx or consult a medical reference to see 
if any medicine they want to prescribe is on a list of drugs to avoid.   
 Please be very careful!  Over-the-counter drugs have a brand name on the label—it’s 
usually big and catches your eye.  They also have a generic name—it’s usually small and 
located above or below the brand name, and printed in the ingredient list.  Find the 
generic name and determine, with the pharmacist’s help, whether there could be an 
adverse interaction.   
 Be careful:  
o If you take acetaminophen regularly:  You should not take more than 4 grams a 
day if you are an adult.  Read labels carefully!  Acetaminophen is an ingredient in 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
46 
many medicines for pain, flu, and cold. 
o If you drink grapefruit juice or eat grapefruit:  Avoid these until the study is over.  
o If you take herbal medicine regularly:  You should not take St. John’s wort while 
you are taking Irinotecan. 
 
Other medicines can be a problem with your study drugs.  
 
 You should check with your doctor or pharmacist whenever you need to 
use an over-the-counter medicine or herbal supplement.  
 
 Your regular prescriber should check a medical reference or call your 
study doctor before prescribing any new medicine for you.  Your study 
doctor’s name is  
 
 
_____________________________________  
 
and he or she can be contacted at  
 
_____________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INFORMATION ON POSSIBLE DRUG INTERACTIONS  
You are enrolled on a clinical trial using the agent irinotecan.  This 
clinical trial is sponsored by the NCI.  Irinotecan interacts with 
drugs that are processed by your liver.  Because of this, it is very 
important to: 
Tell your doctors if you stop taking regular medicine or if you 
start taking a new medicine. 
Tell all of your prescribers (doctor, physicians’ assistant, nurse 
practitioner, pharmacist) that you are taking part in a clinical trial. 
Check with your doctor or pharmacist whenever you need to 
use an over‐the‐counter medicine or herbal supplement. 
 
 
 
 
Irinotecan interacts with a specific liver enzyme called CYP 3A4, 
and must be used very carefully with other medicines that interact 
with this enzyme.  
Before you start the study, your study doctor will work with 
your regular prescriber to switch any medicines that are 
considered “strong inducers/inhibitors or substrates of CYP 
3A4” 
Before prescribing new medicines, your regular prescribers 
should go to 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx for a list 
of drugs to avoid, or contact your study doctor.   
Your study doctor’s name is _____________________________ 
and can be contacted at 
_________________________________.  

Protocol # 15-0659 
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47 
 
APPENDIX C 
MEDICATIONS THAT PROLONG QTc 
 
  
 
For the most current list of medications, please refer to the following website: www.torsades.org
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Generic name 
Brand name
Amiodarone 
Cordarone®
Arsenic trioxide 
Trisenox® 
Astemizole 
Hismanal® 
Azithromycin 
Zithromax® 
Bepridil 
Vascor® 
Chloroquine 
Aralen® 
Chlorpromazine 
Thorazine® 
Clarithromycin 
Biaxin® 
Disopyramide 
Norpace®
Dofetilide 
Tikosyn® 
Domperidone 
Motilium® 
Droperidol
Inapsine®
Erythromycin 
Erythrocin®
Flecainide 
Tambocor® 
Halofantrine 
Halfan® 
Generic name
Brand name 
Haloperidol
Haldol® 
Ibutilide 
Corvert® 
Mesoridazine 
Serentil® 
Methadone 
Dolophine® 
Moxifloxacin 
Avelox® 
Pentamidine 
Pentam® 
Pimozide 
Orap® 
Probucol 
Lorelco® 
Procainamide
Procan® 
Quinidine 
Quinaglute® 
Sotalol 
Betapace® 
Sparfloxacin
Zagam® 
Terfenadine
Seldane® 
Thioridazine 
Mellaril® 
Vandetanib 
Caprelsa® 

Protocol # 15-0659 
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48 
 
 
 
APPENDIX D 
ORAL IRINOTECAN ADMINISTRATION GUIDELINES 
 
 
The hospital pharmacist will provide you with 5 doses of irinotecan, each in an oral syringe. 
Because irinotecan has an unpleasant taste, it is usually mixed with a small amount of 
juice IMMEDIATELY BEFORE giving the medicine to your child. 
 
 The best juice to use is CranGrape Juice, although CranApple or cranberry juice is fine as 
well. 
 
 DO NOT mix the irinotecan in orange juice, apple juice, milk or soda. 
 
 Use a disposable cup to mix the irinotecan with juice. The amount of juice used is up to 
you. The more juice used, the more the flavor of the irinotecan will be masked. However, 
it is critical that your child drink ALL of the juice mixed with irinotecan. Most parents 
start by mixing the irinotecan in about one teaspoon (5 ml) of juice. Discard the cup when 
empty after the irinotecan + juice has been taken. 
 
 Irinotecan should be mixed with juice only on the day the dose is given. The other doses 
should be stored in a REFRIGERATOR. Irinotecan will last for 21 days at a time, 
provided it has not been mixed with juice. 
 
 Use of nausea medicines (Zofran, Kytril, or Anzemet) may be helpful, and these 
medicines are best given about 30-60 minutes before the irinotecan. Please discuss this 
with your doctor. 
 
If you are unable to take the medicine, or vomits within 30 minutes of taking the medicine, 
please call your doctor for further instructions. 
 
 
 
 
 
 
 
 
 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
49 
APPENDIX E 
PATIENT INSTRUCTIONS FOR TREATING DIARRHEA 
 
Dear Patient or Parent: 
 
You are receiving irinotecan. This drug can cause severe diarrhea. Before your FIRST 
chemotherapy treatment please be sure to: 
 
1. BUY IMODIUM A-D. Make sure you have this medication at home before your first 
chemotherapy treatment. Imodium A-D is also called LOPERAMIDE and comes in 2 mg caplets 
and in liquid form at a concentration of 0.2mg/ml. 
 
2. AFTER your chemotherapy has started, at the FIRST SIGN of diarrhea be sure to START 
taking Imodium A-D. DO NOT DELAY starting Immodium A-D if you notice your stools to be 
more loose, soft, or watery than usual. Do not skip doses. Give Immodium A-D as follows: 
• > 43 kg (95 pounds) and more: 4 teaspoonfuls or 2 caplets after first loose stool followed by 2 
teaspoonfuls or 1 caplet every two hours as needed. 
• 20-43 kg (44-94 pounds): take 2 teaspoonfuls or 1 caplet after the first loose stool followed by 
one teaspoonful or one-half caplet every 2 hours as needed. 
 
3. STOP taking IMODIUM when you HAVE NOT had any bowel movements for 12 hours. 
 
4. Call your doctor if you still have diarrhea after taking Imodium for 24 hours, or if there is 
fever or vomiting, or if you have any questions.   
 
5. Your diarrhea can also get a little better if you take the following steps IN ADDITION TO 
taking Imodium A-D: 
- Drink plenty of water or Gatorade 
- Drink broth or clear soup to replace salt 
- Stay away from milk, dairy products, alcohol, hot or cold beverages, coffee, tea and drinks with 
Caffeine 
 
6. Do not take medicines such as Miralax, Mylanta, Maalox, Senokot, or Colace 
 
7. Eat foods that are easy to tolerate such as bananas, rice, apple sauce, chicken (white meat), 
white toast, and canned fruits 
 
8. Please fill out the Irinotecan Administration Diary below during this treatment and give to 
your nurse or physician. 
 
 

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Version Date: March 22, 2017 
 
50 
APPENDIX F 
ORAL IRINOTECAN ADMINISTRATION DIARY 
 
Patient Name _____________________ 
Course #______ 
 
Day of 
course 
Date 
Time 
Irinotecan 
Given 
Time 
Cefixime 
Given 
Number of 
stools 
Consistency 
(F=Formed 
L=Loose 
W=watery) 
Mark when 
Imodium A-D was 
started 
-1* 
 
------ 
 
 
 
 
0* 
 
------ 
 
 
 
 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
------ 
 
 
 
 
7 
 
----- 
 
 
 
 
8 
 
----- 
 
 
 
 
9 
 
----- 
----- 
 
 
 
10 
 
----- 
----- 
 
 
 
11 
 
----- 
----- 
 
 
 
12 
 
------ 
----- 
 
 
 
13 
 
----- 
----- 
 
 
 
14 
 
----- 
----- 
 
 
 
15 
 
----- 
----- 
 
 
 
16 
 
----- 
----- 
 
 
 
17 
 
----- 
----- 
 
 
 
18 
 
----- 
----- 
 
 
 
19 
 
----- 
----- 
 
 
 
20 
 
----- 
 
 
 
 
21 
 
------ 
 
 
 
 
*Course 1 only 
 
 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
51 
APPENDIX G 
PHARMACOKINETIC STUDY FORM 
Study Date 
________ 
Patient ID 
________ 
DOB: 
________ 
*Gender  
________ 
*Race 
____________ 
*Ethnicity 
________ 
BSA (m2) 
________ 
Height  
(cm or ft:in) 
____________ 
Weight  
(lb or kg) 
________ 
 
*This information is requested on a voluntary basis to account/explore potential differences in 
pharmacokinetics 
 
Eribulin: 
Dose (mg/m2) 
__________ 
 
Start time:     _______________ Stop time:     _______________ 
Notes:_______________________ 
 
  
Irinotecan: 
Dose (mg/m2) 
___________ 
 
Administration time:     _________________  
 
 
Notes:_______________________ 
 
 
Each sample for the PK study is to be 7 ml of whole blood collected into a sodium heparinized 
collection tube.  All times listed in the table below are relative to the start of the eribulin IV dose. 
Each tube must be labeled with the patient’s study ID number, time and date the sample was 
drawn. Data should be recorded on this Pharmacokinetic Study Form. 
 
Blood sample collection  
 
Date of Collection 
Time of Collection 
Pre dose 
 
 
15 min after end of infusion 
 
 
1 hr after end of infusion  
 
 
1.5 hr after end of infusion  
 
 
2 hr after end of infusion  
 
 
4 hr after end of infusion  
 
 
5 hr after end of infusion 
 
 
24‐96 hr after end of infusion (optional) 
 
 
Pre dose (day 8) 
 
 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
52 
Processing and shipping instructions for plasma samples 
 
A sample processing and handling kit containing all the consumables, labels, and storage 
containers will be provided for a set of 5 patients. Upon receipt keep all materials including the 
shipping box. Refer to shipping instructions below. 
 
Whole blood samples will be collected from the central line or a peripheral IV provided a flush 
of at least 10 ml of normal saline has been administered.  At each time point, ~7 ml of venous 
blood will be withdrawn into two 4-mL sodium heparin collection tubes. 
 
PK sample processing:  
1) Immediately upon collection place blood sample (heparinized) tubes in wet ice and note 
the collection time on the sample collection timesheet.  
2) Transfer blood sample into 4 clear siliconized microcentrifuge tubes. Centrifuge the 
blood samples for 2 min at 7200 g to separate plasma (top layer) from red blood cells.  
3) Transfer plasma into two amber siliconized tubes, with a plastic transfer pipet. Discard 
red cells. Cap the tubes. 
4) Complete information on the labels and affix onto each tube. 
5) Store samples on dry ice and transfer into the provided storage container (81 or 100 slot 
box) before storing in the -80ºC freezer. 
Shipping instructions: 
1. Place the small storage box containing the plasma samples into the plastic biohazard 
specimen bag. Seal the bag and place it in the Styrofoam container with dry ice. Enclose 
the sample collection timesheets for each patient into a plastic Ziploc bag in the 
container. Place the Styrofoam container back in the shipping box. Seal the box with 
shipping tape. Affix 1) the biohazard, 2) the exempt human specimen and 3) the dry ice 
labels on the shipping box. Place the provided return-shipping label on the package for 
overnight delivery to the Leggas lab at the University of Kentucky.  
2. Samples should only be shipped on Monday-Wednesday for overnight delivery.  
3. Ship samples to: 
Dr. Mark Leggas 
College of Pharmacy 
University of Kentucky 
789 South Limestone, Room 323 
Lexington, KY 40536-0596 
E-mail: mark.leggas @uky.edu 
(859) 327-1341 
 
 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
53 
REFERENCES 
 
1. 
Smith, J.A., et al., Eribulin binds at microtubule ends to a single site on tubulin to 
suppress dynamic instability. Biochemistry, 2010. 49(6): p. 1331-7. 
2. 
Jordan, M.A., et al., The primary antimitotic mechanism of action of the synthetic 
halichondrin E7389 is suppression of microtubule growth. Molecular cancer therapeutics, 
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3. 
Kuznetsov, G., et al., Induction of morphological and biochemical apoptosis following 
prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389. Cancer 
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4. 
Towle, M.J., et al., In vitro and in vivo anticancer activities of synthetic macrocyclic 
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5. 
Okouneva, T., et al., Inhibition of centromere dynamics by eribulin (E7389) during 
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Kolb, E.A., et al., Initial testing (stage 1) of eribulin, a novel tubulin binding agent, by 
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32. 
7. 
Kuznetsov, G., et al., Antiproliferative effects of halichondrin B analog eribulin mesylate 
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8. 
Aogi, K., et al., A phase II study of eribulin in Japanese patients with heavily pretreated 
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9. 
Arnold, S.M., et al., Phase II evaluation of eribulin mesylate (E7389, NSC 707389) in 
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10. 
Cortes, J., et al., Eribulin monotherapy versus treatment of physician's choice in patients 
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11. 
Cortes, J., et al., Phase II study of the halichondrin B analog eribulin mesylate in patients 
with locally advanced or metastatic breast cancer previously treated with an 
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of the American Society of Clinical Oncology, 2010. 28(25): p. 3922-8. 
12. 
de Bono, J.S., et al., Phase II study of eribulin mesylate (E7389) in patients with 
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of oncology : official journal of the European Society for Medical Oncology / ESMO, 
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13. 
Gitlitz, B.J., et al., A phase II study of halichondrin B analog eribulin mesylate (E7389) 
in patients with advanced non-small cell lung cancer previously treated with a taxane: a 
California cancer consortium trial. Journal of thoracic oncology : official publication of 
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14. 
Hensley, M.L., et al., Eribulin mesylate (halichondrin B analog E7389) in platinum-
resistant and platinum-sensitive ovarian cancer: a 2-cohort, phase 2 study. Cancer, 2012. 
118(9): p. 2403-10. 
15. 
Renouf, D.J., et al., A phase II study of the halichondrin B analog eribulin mesylate in 
gemcitabine refractory advanced pancreatic cancer. Investigational new drugs, 2012. 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
54 
30(3): p. 1203-7. 
16. 
Schoffski, P., et al., Activity of eribulin mesylate in patients with soft-tissue sarcoma: a 
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17. 
Spira, A.I., et al., A phase II study of eribulin mesylate (E7389) in patients with 
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18. 
Vahdat, L.T., et al., Phase II study of eribulin mesylate, a halichondrin B analog, in 
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19. 
Preston, J.N. and M.V. Trivedi, Eribulin: a novel cytotoxic chemotherapy agent. The 
Annals of pharmacotherapy, 2012. 46(6): p. 802-11. 
20. 
Goel, S., et al., A phase I study of eribulin mesylate (E7389), a mechanistically novel 
inhibitor of microtubule dynamics, in patients with advanced solid malignancies. Clinical 
cancer research : an official journal of the American Association for Cancer Research, 
2009. 15(12): p. 4207-12. 
21. 
Tan, A.R., et al., Phase I study of eribulin mesylate administered once every 21 days in 
patients with advanced solid tumors. Clinical cancer research : an official journal of the 
American Association for Cancer Research, 2009. 15(12): p. 4213-9. 
22. 
Dubbelman, A.C., et al., Mass balance study of [(1)(4)C]eribulin in patients with 
advanced solid tumors. Drug metabolism and disposition: the biological fate of 
chemicals, 2012. 40(2): p. 313-21. 
23. 
Devriese, L.A., et al., Eribulin mesylate pharmacokinetics in patients with solid tumors 
receiving repeated oral ketoconazole. Investigational new drugs, 2013. 31(2): p. 381-9. 
24. 
Devriese, L.A., et al., Pharmacokinetics of eribulin mesylate in patients with solid 
tumours receiving repeated oral rifampicin. British journal of clinical pharmacology, 
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25. 
Masuda, N., S. Kudoh, and M. Fukuoka, Irinotecan (CPT-11): pharmacology and 
clinical applications. Critical reviews in oncology/hematology, 1996. 24(1): p. 3-26. 
26. 
Vassal, G., et al., Therapeutic activity of CPT-11, a DNA-topoisomerase I inhibitor, 
against peripheral primitive neuroectodermal tumour and neuroblastoma xenografts. 
British journal of cancer, 1996. 74(4): p. 537-45. 
27. 
Thompson, J., et al., Efficacy of oral irinotecan against neuroblastoma xenografts. Anti-
cancer drugs, 1997. 8(4): p. 313-22. 
28. 
Houghton, P.J., et al., Therapeutic efficacy of the topoisomerase I inhibitor 7-ethyl-10-(4-
[1-piperidino]-1-piperidino)-carbonyloxy-camptothecin against human tumor 
xenografts: lack of cross-resistance in vivo in tumors with acquired resistance to the 
topoisomerase I inhibitor 9-dimethylaminomethyl-10-hydroxycamptothecin. Cancer 
research, 1993. 53(12): p. 2823-9. 
29. 
Hare, C.B., et al., Therapeutic efficacy of the topoisomerase I inhibitor 7-ethyl-10-(4-[1-
piperidino]-1-piperidino)-carbonyloxy-camptothecin against pediatric and adult central 
nervous system tumor xenografts. Cancer chemotherapy and pharmacology, 1997. 39(3): 
p. 187-91. 
30. 
Vassal, G., et al., Potent therapeutic activity of irinotecan (CPT-11) and its schedule 
dependency in medulloblastoma xenografts in nude mice. International journal of cancer. 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
55 
Journal international du cancer, 1997. 73(1): p. 156-63. 
31. 
Casey, D.A., et al., Irinotecan and temozolomide for Ewing sarcoma: the Memorial 
Sloan-Kettering experience. Pediatric blood & cancer, 2009. 53(6): p. 1029-34. 
32. 
Raciborska, A., et al., Vincristine, irinotecan, and temozolomide in patients with relapsed 
and refractory Ewing sarcoma. Pediatric blood & cancer, 2013. 60(10): p. 1621-5. 
33. 
Mixon, B.A., et al., Vincristine, irinotecan, and temozolomide for treatment of relapsed 
alveolar rhabdomyosarcoma. Journal of pediatric hematology/oncology, 2013. 35(4): p. 
e163-6. 
34. 
Pappo, A.S., et al., Two consecutive phase II window trials of irinotecan alone or in 
combination with vincristine for the treatment of metastatic rhabdomyosarcoma: the 
Children's Oncology Group. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology, 2007. 25(4): p. 362-9. 
35. 
Vassal, G., et al., Phase II trial of irinotecan in children with relapsed or refractory 
rhabdomyosarcoma: a joint study of the French Society of Pediatric Oncology and the 
United Kingdom Children's Cancer Study Group. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology, 2007. 25(4): p. 356-61. 
36. 
Zsiros, J., et al., Efficacy of irinotecan single drug treatment in children with refractory 
or recurrent hepatoblastoma--a phase II trial of the childhood liver tumour strategy 
group (SIOPEL). European Journal of Cancer, 2012. 48(18): p. 3456-64. 
37. 
Ijichi, O., et al., Response of heavily treated and relapsed hepatoblastoma in the 
transplanted liver to single-agent therapy with irinotecan. Pediatric transplantation, 2006. 
10(5): p. 635-8. 
38. 
Palmer, R.D. and D.M. Williams, Dramatic response of multiply relapsed 
hepatoblastoma to irinotecan (CPT-11). Medical and pediatric oncology, 2003. 41(1): p. 
78-80. 
39. 
Bagatell, R., et al., Phase II study of irinotecan and temozolomide in children with 
relapsed or refractory neuroblastoma: a Children's Oncology Group study. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology, 2011. 
29(2): p. 208-13. 
40. 
Wagner, L.M., et al., Phase I trial of oral irinotecan and temozolomide for children with 
relapsed high-risk neuroblastoma: a new approach to neuroblastoma therapy consortium 
study. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology, 2009. 27(8): p. 1290-6. 
41. 
Bomgaars, L.R., et al., Phase II trial of irinotecan in children with refractory solid 
tumors: a Children's Oncology Group Study. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology, 2007. 25(29): p. 4622-7. 
42. 
Furman, W.L., et al., Direct translation of a protracted irinotecan schedule from a 
xenograft model to a phase I trial in children. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology, 1999. 17(6): p. 1815-24. 
43. 
Drengler, R.L., et al., Phase I and pharmacokinetic trial of oral irinotecan administered 
daily for 5 days every 3 weeks in patients with solid tumors. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology, 1999. 17(2): p. 685-96. 
44. 
Furman, W.L., et al., Cefixime allows greater dose escalation of oral irinotecan: a phase 
I study in pediatric patients with refractory solid tumors. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology, 2006. 24(4): p. 563-70. 
45. 
Wagner, L.M., et al., Phase I trial of two schedules of vincristine, oral irinotecan, and 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
56 
temozolomide (VOIT) for children with relapsed or refractory solid tumors: a Children's 
Oncology Group phase I consortium study. Pediatric blood & cancer, 2010. 54(4): p. 
538-45. 
46. 
Wagner, L.M., Oral irinotecan for treatment of pediatric solid tumors: ready for prime 
time? Pediatric blood & cancer, 2010. 54(5): p. 661-2. 
47. 
Wagner, L.M., et al., Reducing irinotecan-associated diarrhea in children. Pediatric 
blood & cancer, 2008. 50(2): p. 201-7. 
48. 
Slatter, J.G., et al., Bioactivation of the anticancer agent CPT-11 to SN-38 by human 
hepatic microsomal carboxylesterases and the in vitro assessment of potential drug 
interactions. Drug metabolism and disposition: the biological fate of chemicals, 1997. 
25(10): p. 1157-64. 
49. 
Murry, D.J., et al., Influence of phenytoin on the disposition of irinotecan: a case report. 
Journal of pediatric hematology/oncology, 2002. 24(2): p. 130-3. 
50. 
Friedman, H.S., et al., Irinotecan therapy in adults with recurrent or progressive 
malignant glioma. Journal of clinical oncology : official journal of the American Society 
of Clinical Oncology, 1999. 17(5): p. 1516-25. 
51. 
Cosetti, M., et al., Irinotecan for pediatric solid tumors: the Memorial Sloan-Kettering 
experience. Journal of pediatric hematology/oncology, 2002. 24(2): p. 101-5. 
52. 
Bisogno, G., et al., Phase II study of a protracted irinotecan schedule in children with 
refractory or recurrent soft tissue sarcoma. Cancer, 2006. 106(3): p. 703-7. 
53. 
Kushner, B.H., et al., Five-day courses of irinotecan as palliative therapy for patients 
with neuroblastoma. Cancer, 2005. 103(4): p. 858-62. 
54. 
Wagner, L., et al., Pilot study of vincristine, oral irinotecan, and temozolomide (VOIT 
regimen) combined with bevacizumab in pediatric patients with recurrent solid tumors or 
brain tumors. Pediatric blood & cancer, 2013. 60(9): p. 1447-51. 
55. 
Takasuna, K., et al., Involvement of beta-glucuronidase in intestinal microflora in the 
intestinal toxicity of the antitumor camptothecin derivative irinotecan hydrochloride 
(CPT-11) in rats. Cancer research, 1996. 56(16): p. 3752-7. 
56. 
Pratt, C.B., et al., Phase I study of topotecan for pediatric patients with malignant solid 
tumors. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology, 1994. 12(3): p. 539-43. 
57. 
Rowinsky, E.K., et al., Phase I and pharmacological study of the novel topoisomerase I 
inhibitor 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) 
administered as a ninety-minute infusion every 3 weeks. Cancer research, 1994. 54(2): p. 
427-36. 
58. 
van Warmerdam, L.J., et al., Pharmacokinetics and pharmacodynamics of topotecan 
administered daily for 5 days every 3 weeks. Cancer chemotherapy and pharmacology, 
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59. 
Abbruzzese, J.L., et al., Phase I clinical and plasma and cellular pharmacological study 
of topotecan without and with granulocyte colony-stimulating factor. Clinical cancer 
research : an official journal of the American Association for Cancer Research, 1996. 
2(9): p. 1489-97. 
60. 
Tubergen, D.G., et al., Phase I trial and pharmacokinetic (PK) and pharmacodynamics 
(PD) study of topotecan using a five-day course in children with refractory solid tumors: 
a pediatric oncology group study. Journal of pediatric hematology/oncology, 1996. 18(4): 
p. 352-61. 

Protocol # 15-0659 
Version Date: March 22, 2017 
 
57 
61. 
Stewart, C.F., et al., Disposition of irinotecan and SN-38 following oral and intravenous 
irinotecan dosing in mice. Cancer chemotherapy and pharmacology, 1997. 40(3): p. 259-
65. 
62. 
Dubbelman, A.C., et al., Validation of high-performance liquid chromatography-tandem 
mass spectrometry assays for the quantification of eribulin (E7389) in various biological 
matrices. Journal of chromatography. B, Analytical technologies in the biomedical and 
life sciences, 2011. 879(15-16): p. 1149-55. 
63. 
Horn, J., et al., Validation of an HPLC method for analysis of DB-67 and its water 
soluble prodrug in mouse plasma. Journal of chromatography. B, Analytical technologies 
in the biomedical and life sciences, 2006. 844(1): p. 15-22. 
64. 
Owens, T.S., et al., High-performance liquid chromatographic assay with fluorescence 
detection for the simultaneous measurement of carboxylate and lactone forms of 
irinotecan and three metabolites in human plasma. Journal of chromatography. B, 
Analytical technologies in the biomedical and life sciences, 2003. 788(1): p. 65-74. 
65. 
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47. 
66. 
Rustin, G.J., et al., Re: New guidelines to evaluate the response to treatment in solid 
tumors (ovarian cancer). J Natl Cancer Inst, 2004. 96(6): p. 487-8. 
67. 
Bubley, G.J., et al., Eligibility and response guidelines for phase II clinical trials in 
androgen-independent prostate cancer: recommendations from the Prostate-Specific 
Antigen Working Group. J Clin Oncol, 1999. 17(11): p. 3461-7. 
68. 
Scher, H.I., et al., Design and end points of clinical trials for patients with progressive 
prostate cancer and castrate levels of testosterone: recommendations of the Prostate 
Cancer Clinical Trials Working Group. J Clin Oncol, 2008. 26(7): p. 1148-59. 
69. 
Vergote, I., et al., Re: new guidelines to evaluate the response to treatment in solid 
tumors [ovarian cancer]. Gynecologic Cancer Intergroup. J Natl Cancer Inst, 2000. 
92(18): p. 1534-5. 
70. 
Crowley, J. and D.P. Ankerst, Handbook of statistics in clinical oncology. 2nd ed. 2006, 
Boca Raton: Chapman & Hall/CRC. 617 p. 
71. 
Storer, B.E., Small-sample confidence sets for the MTD in a phase I clinical trial. 
Biometrics, 1993. 49(4): p. 1117-25. 
 

Consent and Authorization Form Approval
Page 1 of 16
Initials______
COMIRB # 15-0659
Protocol Version Date: March 22, 2017
Study Title:
A Phase I/Ib Study of Eribulin in Combination with Oral Irinotecan for 
Adolescent and Young Adult Patients with Relapsed or Refractory 
Solid Tumors
Principal Investigator:
Carrye Cost, MD, Tom Badgett, MD, PhD, Theodore Laetsch, MD
COMIRB No: 
15-0659
Version Date:
March 22, 2017
You are being asked to be in a research study.  This form provides you with information about the 
study. A member of the research team will describe this study to you and answer all of your 
questions. Please read the information below and ask questions about anything you don’t 
understand before deciding whether or not to take part. 
The word “you” refers to you or your child if the patient is under age 18.  “We” means the doctors 
and other people on the research team. 
Why is this study being done?
Currently there is no known effective treatment for your type of cancer.  You are being asked to take 
part in this study because you have a solid tumor for which there is no known curative therapy.  Your 
cancer is recurrent or refractory.  Recurrent means that the cancer has come back after treatment.  
Refractory means that the cancer has not responded to standard treatment.  Standard treatment 
may have included chemotherapy, surgery, radiation therapy and/or high-dose chemotherapy with a 
stem cell transplant.
This study is designed to test the experimental combination of eribulin and oral irinotecan in the hope 
of finding a drug combination that is safe and effective against solid tumors that have come back or 
not responded to standard therapy. Both drugs have been approved to treat different types of 
cancer, although the drugs have not been studied together in combination. This is called a Phase I 
study because the main purpose is to evaluate the safety of the drug combination, and what dose of 
eribulin may be best to use for further studies. The purposes of this study are to find out what effects 
the combination of the investigational drug, eribulin and oral irinotecan has on your type of cancer 
and whether both drugs can be given safely together. 
There are two parts to this study: the dose-escalation part, and the dose expansion part.
The first part of this study is called dose-escalation. This part of the study will determine the 
recommended dose of eribulin.  The dose of oral Irinotecan will not change.  The main goal of this 
part of the study will be to measure the safety and side effects of the combination.  The dose of 
eribulin you receive is determined when you are enrolled in the study.  Participants enrolled early in 
the study will receive a lower dose.  Participants enrolled later in the study period may receive a 
COMIRB
APPROVED
For Use
21-Apr-2017
20-Apr-2018

Consent and Authorization Form Approval
Page 2 of 16
Initials______
COMIRB # 15-0659
Protocol Version Date: March 22, 2017
higher dose.  The dose of oral irinotecan is not increased during this study.  The irinotecan dose is 
typical for patients with your type of cancer.  For each dose group, called a cohort, a number of 
scientists and doctors will carefully look at labs and other tests to make sure it is safe to enroll 
adolescents and young adults in the next higher dose group.  The dose of eribulin will not be 
increased higher than the dose that has been proven safe in adults. During the study, blood samples 
will be taken to measure how much of the chemotherapy are in your blood at certain times. 
The second part of this study is called the dose expansion phase.  This phase will plan to enroll 
more adolescents and young adults with a fixed dose of study drug that has been determined from 
the dose-escalation part of the study.   You will be given the same amount of eribulin and Irinotecan 
as the other patients that join during the dose expansion part of this study. 
The goals of this study are:

To determine the best dose of eribulin that can be safely given together with oral  irinotecan 
to treat adolescents and young adults with relapsed or refractory solid tumors;

To learn about the side effects (good and/or bad) of giving eribulin with oral irinotecan;

To determine if tumors get smaller after treatment with eribulin and oral irinotecan; 

To measure the amount of eribulin in your blood after you receive these medications
Other people in this study
Between 6-22 patients will be enrolled on this study at Children's Hospital Colorado, the University of 
Kentucky, or the University of Texas Southwestern Medical Center. 
What happens if I join this study?
Before you begin the study:
If you decide to participate in this study, you will sign this consent document and you will be given a 
copy of your signed consent before any of the procedures listed below are performed.  Please refer 
to the Calendar of Events located at the back of this consent form for guidance while reviewing the 
procedures that will take place at the screening and at various times during participation in this 
study. 
You will need to have the following exams, tests, or procedures to find out if you can be in the study.  
These tests will also be done at various times throughout the study and at the end of the study.  The 
purpose of these tests is to see how well the treatment works and to measure the status of your 
cancer.  If you had some of them recently, they may not need to be repeated.  This will be up to your 
study doctor.  These exams, tests or procedures are part of regular cancer care and may be done 
even if you do not join the study.

Your medical history will be reviewed;

You will have a physical exam including a measurement of your height and weight;

Your vital signs will be recorded (blood pressure, heart rate and temperature);

Your ability to perform daily tasks will be assessed;

You will be asked about any medications that you are taking or have taken recently;

Consent and Authorization Form Approval
Page 3 of 16
Initials______
COMIRB # 15-0659
Protocol Version Date: March 22, 2017

Various scans that are done for diagnosis and checking the response of the tumor to 
treatment.  These may include CT, MRI, or PET scans.  

An electrocardiogram (ECG) will be done to test the function of your heart;

If you are able to become pregnant, you will be asked to provide a urine sample for a 
pregnancy test*. If you are pregnant, you will not be allowed to participate in this study.
*If there is ANY chance that you can get pregnant, you must either agree to practice abstinence from 
heterosexual intercourse or begin an effective method of birth control.  
During the study:
Treatment Plan
If the exams, tests and procedures show that you are eligible to participate in this study, eribulin will 
be given as a 5-minute intravenous infusion on Days 1 and 8 of each cycle.  Irinotecan will be given 
orally on Days 1 through 5 of each cycle.  A cycle lasts 3 weeks (21 days).  
You can receive up to 17 cycles of therapy (approximately 12 months or about 1 year) as long as 
you are benefitting from treatment, not having bad side effects and continue to meet the criteria to 
continue safely on this study.  Although other participating subjects may receive a different dose of 
eribulin, your assigned dose will not change during your participation in this study unless you 
develop certain side effects that require lowering your dose of eribulin. 
Eribulin is given in the clinic and does not require hospitalization, although treatment can be given in 
the hospital if necessary.  Oral irinotecan can be started in the clinic on the Day 1 and you will need 
to obtain the remaining days of oral irinotecan from an outside pharmacy.  You will be given specific 
instructions from the research team on how to take the oral Irinotecan.  You will also be given a 
medication diary to fill out at home each time this oral medication is taken and we will ask you to 
return this diary at the end of each course of treatment.  Your study doctor will also prescribe an oral 
antibiotic to help reduce diarrhea caused by Irinotecan.  This antibiotic should be taken 2 days 
before you receive the first dose of eribulin and Irinotecan and taken for 10 days with each cycle of 
chemotherapy.  The study treatment plan is summarized in the table below:
Treatment Schema:
Day
-1
0
1
2
3
4
5
6
7
8
9-19
20
21
Eribulin
●
●
Oral Irinotecan
●
●
●
●
●
Cefixime (antibiotic)
●
●
●
●
●
●
●
●
●
●
●
●
Because eribulin is given intravenously, your physician may recommend that you have a “port” or 
some type of central venous line placed, if this has not already been done. These are special types 
of intravenous lines that are placed into a large vein in the chest by a surgeon during a short 
operation. The “port” or central line is used to administer chemotherapy drugs and also to withdraw 
small amounts of blood for testing during treatment. The risks associated with placement of these 
devices will be explained to you and you will be given a separate informed consent document to 
review and sign if placement of this device is necessary. If you do not have a central line, you will 
need to have a peripheral IV placed. There is a small amount of pain from the IV and a very small 
risk of minimal bleeding. 

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The dose of eribulin for the first patients enrolled on the study will be 80% of the dose given when 
used alone. Irinotecan will be given at the standard oral dose. Between 2 and 6 patients will receive 
the combination of eribulin at the starting dose. If the side effects are not too severe, the next group 
of patients will receive a higher dose of eribulin, but the dose of irinotecan will remain the same. If 
the side effects are too severe, the next group of patients will receive a lower dose of eribulin, but the 
dose of irinotecan will remain the same. 
Your dose of eribulin and irinotecan will not be increased. If you have bad side effects, the dose of 
eribulin may be decreased. If you are a patient enrolled early in this study you may receive a lower 
dose of eribulin than those who are enrolled later. It is therefore possible that you may receive a 
dose that is less likely to have any effect on your tumor. If you are a patient enrolled in this study at a 
high dose level it is possible that you will receive a dose that is more likely to cause side effects. 
Dosing is done this way because we do not yet know the best doses of the two drugs in combination 
to use.
Pharmacokinetic Samples – REQUIRED
To see how much study drug is in your blood, about 7 ml of blood will be collected during the study 
at the following time points: 

Day 1: pre-dose;

Day 1: 30 minutes, and 1, 1 ½, 2, 4, and 5 hours after the end of the eribulin infusion

Day 8: pre-dose
If you want to participate in this study, you must agree to have these samples taken. The samples 
may be drawn from an existing IV or central line. They will be collected on days when you are 
already in clinic or the hospital having blood work done. 
Pharmacokinetic Samples – OPTIONAL
There is an additional single blood draw for pharmacokinetics between day 2 and 4. This extra test is 
optional.  If you do not agree to have this sample taken, you can still receive treatment as part of this 
study.  
Consent to Use Sample for Pharmacokinetic Research
 Yes, I agree my samples can be used for Pharmacokinetic testing.
 No, I do not want my samples used for Pharmacokinetic testing.
By signing below, you indicate that you have read the information about “Pharmacokinetic Samples - 
Optional” and have indicated your choice.
_____________________
______
 ________________________________
PRINT Participant’s Name
Date
 
 Participant’s Signature (Ages 13-17)
__________________
_______ 
________________________________
PRINT Parent’s Name 
Date 
Parent’s Signature
How long will I be on this study?
You can receive up to 17 course of treatment on this study.  Each course is 21 days.  It will take 
about 12 months to complete the 17 courses. 

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After you stop treatment, you will continue to have tests and scans done to measure how much 
tumor is left.  Your study doctor will tell you how often these tests will be done.  Researchers will 
continue to collect information about you for 30 days after the last dose of study drug.  
What are the possible discomforts or risks?
While receiving treatment with this drug combination, you may be at risk of side effects.  
This is a Phase I study.  A Phase I study looks at how common and serious side effects can be for 
each patient at a specific dose of a drug. In a Phase I study, some patients may have very serious 
side effects and could die as a result of these side effects.
Everyone taking part in the study will be monitored carefully for any side effects.  However, doctors 
don’t know all the side effects that may happen.  Side effects may be mild or very serious.  Your 
health care team may give you medications to help lessen side effects.  Many side effects go away 
soon after you stop taking the combination of eribulin and Irinotecan.  In some cases, side effects 
can be serious, long lasting, or may never go away.  There is also a risk of death.  We will tell you if 
we learn of any new information that may affect your health, welfare, or decision to stay in this study.
You should tell your study doctor immediately if you think you are developing any unusual side 
effects even if they are not listed here. Any delay in treating these side effects may prolong their 
course, make them more difficult to treat and in rare occasions may even be fatal. 
You should not take any other medications, including non-prescription treatments such as aspirin, 
without the approval of your study doctor.
Possible Risks and side effects related to Eribulin include:
Common
(in more than 20% of patients)
Less Common
(in more than 4-20% of patients)

Fewer red blood cells in the blood

Low numbers of white blood cells 
called lymphocytes and 
neutrophils/granulocytes that may 
make it easier to get infections which 
may be life threatening;

Nausea;

A feeling of extreme tiredness not 
relieved by sleep(fatigue);

Hair loss

Watery eyes;

Abdominal pain;

Constipation;

Diarrhea;

Heartburn;

Vomiting;

Dry mouth;

Sores in mouth or in GI tract;

Swelling caused by fluid build-up in the tissues of the arms and 
legs;

Fever;

Infection;

Swelling and redness of skin if you are receiving radiation;

Low blood platelet count;

Bruising, bleeding;

Weight loss, 

Loss of appetite (anorexia);

Dizziness;

Headache;

Changes in taste;

Feeling of “pins and needles” in arms and legs;

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Common
(in more than 20% of patients)
Less Common
(in more than 4-20% of patients)

Muscle weakness;

Numbness, tingling or pain of the arms and legs;

Cough, shortness of breath, sore throat;

Increased blood level of liver tests (ALT, AST) which may 
mean there is damage to the liver;

Low levels of salts in the body (potassium ) which may require 
you to take another medicine to correct salt level
Abnormal heartbeat and heart rhythm (such as QT prolongation, which can lead to heart rhythm 
disorder) were seen in the EKGs (heart tracing) in some subjects with heart disease or heart rhythm 
disorders during clinical trials.  You should avoid taking medications that can interact with eribulin 
and make this potential side effect worse.  Talk to your study doctor before starting any new 
medicine. 
Some drugs, food and supplements that may interact with eribulin include: 
Antibiotics:
Azithromycin, clarithromycin, erythromycin, moxifloxacin, sparfloxacin
Heart Medicines:
Amiodarone, diltiazem, disopyramide, dofetilide, dronedenarone, 
flecainide, procainamide, sotalol
Nausea Medicines:
Chlorpromazine, droperidol
Some Chemotherapies:
Be sure to talk to your study doctor about this
Many other drugs:
Chloroquine, halofantrine, haloperidol, ibutilide, methodone, 
pentamidine, pimozide, quinidine, terfenadine, thioridazine
The list above does not include everything that may interact with your chemotherapy.  Talk to you 
study doctor before starting any new medications, over-the-counter medicines, or herbal 
supplements and before making a significant change in your diet.
 
Possible risks and side effects related to Irinotecan include:
Likely
(happens to 21-100 children out of 
100)
Less Likely
(happens to 5 - 20 
children out of 100)
Rare but serious
(happens to < 5 children out of 100)

Diarrhea that can occur 
during the infusion of 
irinotecan or immediately after 
and may be associated with 
abdominal cramping, a runny 
nose, tearing, salivation, 
sweating, flushing (feeling of 
warmth and red cheeks), and 
difficulty adjusting your eyes 
to light

Loss of body water

Nausea and Vomiting

Inflammation and/or sores in 
the mouth

Loss of appetite

Stomach pain

Fewer red blood cells 
and platelets in the 
blood

Diarrhea that may 
occur later from 1 day 
to 2 weeks after 
irinotecan which can 
cause excessive loss 
of water and salts 
from the body

Constipation

Pain at the injection 
site

Blood clots which may 
be in rare cases life 
threatening*

Severe allergic reaction which can be 
life threatening with shortening of 
breath, low blood pressure and a rapid 
heart rate

Severe loss of water from the body 
(dehydration) which if untreated may 
cause low blood pressure and severe 
loss of salts such as sodium and 
potassium from the body and could lead 
to the kidneys failing which could be life 
threatening

Inflammation of the part of the intestine 
known as the colon which can lead to 
infection, blood in the stools and 
abdominal pain

Headache

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Likely
(happens to 21-100 children out of 
100)
Less Likely
(happens to 5 - 20 
children out of 100)
Rare but serious
(happens to < 5 children out of 100)

Fever

A feeling of weakness and 
tiredness

Temporary hair loss

Elevation of liver and bone 
enzymes in the blood and of 
bilirubin (yellow pigment 
formed in the liver)

An increase in a type of white 
blood cell called eosinophil.  
These are sometimes 
associated with allergic 
reactions

Decrease in number of red 
and white blood cells and 
platelets made in the bone 
marrow

Rash

Inflammation and/or 
sores in the mouth, 
throat and/or 
esophagus

Headache

An upset stomach

Increase in liver and 
kidney levels

Skin inflammation

Trembling

Blood in the urine

Mildly increased level of protein and 
glucose in the urine

Low amount of protein in the blood

Mouth sores

Sensation of warmth on face

Risk to the unborn child in pregnant 
patients**

Pain at infusion site

Disorientation/confusion

Dizziness and low blood pressure

A blockage of the bowel that prevents 
passage through the bowel

Slow heart beat
* This toxicity is seen more commonly when irinotecan is given in combination with fluorouracil and 
leucovorin. It may rarely be a life threatening event.
** Birth defects and other serious abnormalities in the unborn baby have been noted with irinotecan 
in animal studies at doses similar to or less than those used in humans. The timing and frequency of 
these effects is as yet unknown. These may include multiple birth defects and abnormalities of bone 
formation, small size of baby at birth and increased risk of death of the unborn baby. Irinotecan is 
excreted in rat milk but this is unknown for humans.
Possible risks and side effects related to Cefixime:
Likely
(happens to 21-100 
children out of 100)
Less Likely
(happens to 5-20 
children out of 100)
Rare
(happens to less than 5 children out of 100)

Diarrhea 

Belly pain 

Nausea

vomiting

Indigestion

Headache 

Dizziness

Seizures 

Allergic reactions which can be life threatening with 
shortness of breath , low blood pressure, rapid heart rate

Low number of white blood cells in the blood

Increase in the blood of a type of white blood cells called 
eosinophils , which are sometimes associated with 
allergic reactions

Decrease in platelets which may make you bruise or 
bleed easily.

Inflammation of the large intestine which can cause 
watery diarrhea with blood in stools and cramping 
abdominal pain,   

High blood tests of kidney and liver function

Hepatitis, yellowing of skin and whites of eyes

Rash with blistering of the skin and sometimes also 
lesions in the eyes, lips and mouth.  There can also be 

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Likely
(happens to 21-100 
children out of 100)
Less Likely
(happens to 5-20 
children out of 100)
Rare
(happens to less than 5 children out of 100)
breakdown of the skin
Serious Side Effects:
Any of the side effects listed in the tables above can become serious. 
Imaging Studies:
You will have one or more of the following imaging studies, depending on which your doctor thinks is 
best to evaluate your tumor. You may have an MRI, CT, or FDG-PET scan. There are different risks 
associated with each of these scans and you doctor will discuss these risks with you. 
CT scans:  
As part of this study we will perform a CT scan of the area of your body where your tumor is and any 
additional areas that your doctor thinks are important to scan. CT is a way of taking detailed pictures 
inside your body by using X-rays.  X-rays are a type of radiation.
You get some radiation from your environment.  You get radiation from bricks and concrete, from 
some foods, and from radon gas, which is an invisible gas that seeps out of the ground.  The amount 
of radiation that this CT scan will deliver to your body (give you) is about the same as you would get 
from living in your environment for up to 5 years, depending on the area where the scan is focused.
This is an estimate.  The amount of radiation you get could be higher or lower, depending on the 
machine, the power setting, and your body weight. Exposure to radiation at high levels increases a 
risk of developing cancer. The risk of this procedure is not equal for everyone.  The risk is much 
higher for unborn babies if the mother has this procedure.  The risk is also much higher for young 
children and teenagers.  The risk is much lower for people over the age of 30. 
MRI:  
In this study we will take Magnetic Resonance Images (MRI’s) of your body. The MRI machine uses 
powerful magnetic waves to take pictures inside the body.  The waves themselves are not harmful, 
but they can cause metal to heat up and electronics to stop working.  You should NOT have an MRI 
if you have metal or electronic devices inside your body.   Heart pacemakers and insulin pumps are 
examples of electronic devices.
The MRI machine is a small round tube.  It might make you uncomfortable if you do not like tight 
spaces.  The most common side effect of having an MRI is flashing lights in the eyes.  This is 
caused by the magnetic waves and is not harmful.  Some people also experience warmth and 
reddening of the skin.  This usually goes away after a few minutes. 
IV contrast:  
As part of a CT or MRI scan, you may be given an intravenous injection of dye in order to help see 
the organs on the radiology images.  You will feel a slight pin prick when the needle is inserted into 
your vein.  You may have a warm, flushed sensation during the injection of the contrast materials 
and a metallic taste in your mouth that lasts for a few minutes.  Some people may develop allergic 
symptoms (e.g., hives, itching, difficulty breathing), and in very rare cases, anaphylactic shock (low 
blood pressure, with loss of consciousness, severe loss of body fluid that can lead  to shock or 
death).  In addition, if you have low kidney function, this dye can temporarily or permanently 
decrease your kidney function.

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Risks of an FDG-PET scan:  
The risks with a PET scan are very minimal.  The amount of radiation is low and the FDG degrades 
quickly so that no detectable radioactivity is present after several hours.  Any remaining FDG in your 
body is removed from the body through urine.  Family members are not at risk for exposure since 
greater than 90% of the radioactivity has left the body or decomposed before you have left the 
cancer clinic. 
Electrocardiogram (ECG)
For an ECG, someone (study staff or clinic staff) will attach special stickers to your chest, legs and 
arms.  Wires will be connected to these stickers to read the electrical activity of your heart.  You will 
have to lie still for a few minutes.  Removing the stickers might be a little uncomfortable and you may 
experience mild irritation, slight redness, and itching in this area.
Reproductive Risks:
Patients who agree to participate in this study should not become pregnant while on this study.  This 
study and the drugs used in this study may be hazardous to an unborn child.  Patients and their 
sexual partners should avoid sex and /or use an effective method(s) of contraception that is 
medically appropriate based on your study doctor’s recommendation at that time.
If you become pregnant, you suspect pregnancy or if you have missed your period or it is late, or if 
you have a change in your usual menstrual cycle (e.g. heavy bleeding during your period or bleeding 
between periods), you should immediately contact your study doctor. In case of pregnancy, you or 
your partner’s pregnancy and its outcome will be reported to the study sponsor.
If you become pregnant during this study, the study drug will be discontinued and you will be referred 
for obstetric care. The sponsor has not set aside any funds to pay for any aspects of obstetrics, child 
or related care and does not plan to pay for them.
What are the possible benefits of the study?
This study is designed for the researcher to learn more about the treatment combination of eribulin 
and oral irinotecan for adolescent and young adult patients with recurrent or refractory solid tumors.   
However, there is no guarantee that your health will improve if you chose to participate in this study. 
Also, there could be risks to being in this study. If there are risks, these are listed above in the 
section describing the discomforts or risks. 
Are there alternative treatments? 
There may be other ways of treating your cancer. These other ways include:

Getting treatment or care for your cancer without being in a study, such as other 
chemotherapy treatments;

Being in another study with a different experimental medicine;

Getting no treatment;

Getting palliative care. This type of care helps reduce pain, tiredness, appetite problems, and 
other difficulties caused by the cancer. It does not treat the cancer directly, but instead tries 
to improve how you feel, and keep you as active and comfortable for as long as possible.
You should talk to your doctor about your choices.  Make sure you understand all of your choices 
before you decide to take part in this study.  You may leave this study and still have these other 
choices available to you. 

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Who is paying for this study? 
Private grants are sponsoring this research.  The Morgan Adams Foundation and a K12 grant 
through the University of Colorado Denver are providing financial support and/or material for this 
study. The sponsor will only pay for research procedures, as explained on the following page in the 
‘Will I have to pay for anything?’ section. They will not pay for treatment or procedures that are 
considered standard of care or part of your usual cancer care. 
Will I be paid for being in the study?  
You will not be paid to be in the study.
Will I have to pay for anything?
There are some medical treatments that you would have to get for your cancer whether you are in 
this study or not. You will have to pay for these. The health care costs during your participation in 
this study that are considered part of the standard treatment of your disease will be billed to your 
insurance or other third-party payer. This includes routine blood tests, hospitalizations, radiology 
scans, and other procedures that will be done in this study, including the medications. 
All the drugs being used on this study are commercially available agents.  You will pay for the 
amount of drugs needed to complete this study.  The cost is normally covered by your insurance 
company. 
You and/or your insurance company, Medicare or Medicaid will be responsible for the costs of all 
care and treatment you receive during this study that you would normally receive for your condition. 
These are costs that are considered medically reasonable and necessary and will be part of the care 
you receive if you do not take part in this study. A co-payment/deductible from you may be required 
by your insurer or Medicare/Medicaid even if your insurer or Medicare/Medicaid has agreed to pay 
the costs.  The amount of this co-payment/deductible may be substantial. We encourage you to 
meet with a Financial Counselor at Children’s Hospital Colorado to review this information and what 
your expenses might be before you decide to participate. Patient Financial Services can be reached 
at 720.777.6422.
The required and optional pharmacokinetic research samples will be obtained and processed at no 
cost to you. Private grants are sponsoring these research procedures. 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage .   
Is my participation voluntary?
Taking part in this study is voluntary.  You have the right to choose not to take part in this study.  If 
you choose to take part, you have the right to stop at any time.  If you refuse or decide to withdraw 
later, you will not lose any benefits or rights to which you are entitled.  

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Can I be removed from this study? 
The study doctor may decide to stop your participation in the study without your permission if he or 
she thinks that being in the study may cause you harm, or for any other reason. Also, the sponsor 
may stop the study at any time.
The study doctor may also withdraw you from the study and the study drug may be stopped without 
your consent for one or more of the following reasons:

Staying in the study could be harmful for you;

You need treatment not allowed by the study

You are not able to complete the study procedures as required

You become pregnant

The study is stopped by sponsor, for reasons not related to you.
All information and samples collected from you before you stop the study may still be used by the 
sponsor to understand more about the study drug and/or your type of cancer.
If you are taken out of the study, you will still receive your normal medical care.  The only medical 
care that you will lose is the medical care you are getting as part of this study.  
What happens if I am injured or hurt during the study?
Dr. Carrye Cost should be informed about any injury you experience while you take part in this study. 
Her phone number is 720.777.6775. A member of the research team can be paged 24 hours a day 
for emergencies.  Please call 720.777.6740 at night and on weekends to have someone paged. 
If you are hurt by this research, we will give you medical care. You will get medical treatment if 
you are injured as a result of taking part in this study. It is important for you to understand that the 
Children's Hospital Colorado does not have funds set aside to pay for the cost of any care or 
treatment that might be necessary because you get hurt or sick while taking part in this study. 
Instead, you and/or your health plan will be charged for this treatment. There are no plans for the 
study to pay for medical treatment for injuries. Also, Children's Hospital Colorado will not pay for any 
wages you may lose if you are harmed by this study. However, signing this form does not mean that 
you are giving up any legal rights to try to get compensation for injury.
What are my rights if I take part in this study?
Taking part in this study is your choice.  You may choose either to take part or not to take part in the 
study.  If you decide to be in this study, you may stop the study at any time.   No matter what 
decision you make, there will be no penalty to you and you will not lose any of your regular benefits.  
Leaving the study will not affect your medical care.  You can still get your medical care from us and 
this institution.   
We will tell you about new information or changes in the study that may affect your health or your 
willingness to continue in the study.

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Who do I call if I have questions?
The researcher carrying out this study is Dr. Carrye Cost at Children’s Hospital Colorado and Dr. 
Tom Badgett at the University of Kentucky. You may ask any questions you have now. If you have 
questions, concerns, or complaints later, you may call Dr. Cost at 720.777.6777. You will be given a 
copy of this form to keep.  You can also call the responsible Institutional Review Board (COMIRB).  
You can call them at 303-724-1055. 
A description of this clinical trial will be available on http://www.Clinical Trials.gov. This Web site will 
not include information that can identify you. At most, the Web site will include a summary of the 
results. You can search this Web site at any time.
Who will see my research information?
The University of Colorado Denver and the hospital(s) it works with have rules to protect information 
about you.  Federal and state laws including the Health Insurance Portability and Accountability Act 
(HIPAA) also protect your privacy.   This part of the consent form tells you what information about 
you may be collected in this study and who might see or use it.  
The institutions involved in this study include: 

University of Colorado Denver

Children’s Hospital Colorado (CHCO)
CHCO shares a medical record system with the Barbara Davis Center and PedsConnect; therefore it 
is also possible that our information could be viewed by healthcare professionals at these 
organizations.  
Because this study involves the treatment of a medical condition, a copy of this consent form will be 
placed in your medical record. This will allow the doctors that are caring for you to obtain information 
about what medications or procedures you are receiving in the study and treat you appropriately.
We cannot do this study without your permission to see, use, and give out your information.  You do 
not have to give us this permission.  If you do not, then you may not be in this study.  
We will see, use, and disclose your information only as described in this form and in our Notice of 
Privacy Practices; however, people outside the University of Colorado Denver and its affiliate 
hospitals may not be covered by this promise.
We will do everything we can to keep your records a secret.  It cannot be guaranteed. 
The use and disclosure of your information has no time limit.  You can cancel your permission to use 
and disclose your information at any time by writing to the study’s Primary Investigator, at the name 
and address listed below.  If you do cancel your permission to use and disclose your information, 
your part in this study will end and no further information about you will be collected.  Your 
cancellation would not affect information already collected in this study.  

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Dr. Carrye Cost
The Center for Cancer and Blood Disorders
Children’s Hospital Colorado, Box B115
13123 East 16th Avenue
Aurora, CO 80045
Both the research records that identify you and the consent form signed by you may be looked at by 
others who have a legal right to see that information.  By signing this form, you are also giving Dr. 
Cost permission to give your health information to these groups:

Federal offices such as the Food and Drug Administration (FDA) and Office of Human 
Research Protection (OHRP),that protect research subjects like you;

People at the Colorado Multiple Institutional Review Board (COMIRB)

The study doctor and the rest of the study team;

The laboratory that will store blood samples, University of Kentucky

The Clinical Trials Office at the University of Colorado Cancer Center;

Officials at the institution where the research is being conducted and officials at other 
institutions involved in this study who are in charge of making sure that we follow all the rules 
for research;

The National Cancer Institute, the National Institute of Health and/or the Department of 
Health and Human Services.
We might talk about this research study at meetings.  We might also print the results of this research 
study in medical and scientific journals.  We will always keep the names of research subjects, like 
you, private.  
You have the right to request access to your personal health information from the Investigator. To 
ensure proper evaluation of test results, your access to these study results may not be allowed until 
after the study has been completed.
The investigator (or staff acting on behalf of the investigator) will use your information for the 
research outlined in this consent form. They will also make all or some of the following health 
information about you collected in this study available to:  University of Kentucky, University of 
Texas Southwestern Medical Center.
Information about me that will be seen, collected, used and disclosed in this study:

Portions of my previous and current medical records that are relevant to this study, including 
but not limited to diagnosis(es), history and physical, laboratory or tissue studies, radiology 
studies, and procedure results.

Research visits and research test records.

Blood samples and the data with the samples. 
What happens to Data, Tissue, Blood and Specimens that are collected in this study? 
Scientists at the University of Colorado Denver, and the hospitals involved in this study work to find 
the causes and cures of disease.  The data, blood and specimens collected from you during this 
study are important to this study and to future research.  If you join this study:

Consent and Authorization Form Approval
Page 14 of 16
Initials______
COMIRB # 15-0659
Protocol Version Date: March 22, 2017

The data, blood, or other specimens are given by you to the investigators for this research 
and so no longer belong to you.  

Both the investigators and any sponsor of this research may study your data and tissue, 
blood, or other specimens collected from you.

If data, blood, or other specimens are in a form that identifies you, UCD or the hospitals 
involved in this study may use them for future research only with your consent or IRB 
approval.

Any product or idea created by the researchers working on this study will not belong to you.

There is no plan for you to receive any financial benefit from the creation, use or sale of 
such a product or idea. 
HIPAA Authorization for Optional Additional Study Procedures
In this form, you were given the option to agree to additional, optional research procedures.  You 
must also give us your permission, under HIPAA rules, to use and disclose the information collected 
from these optional procedures, as described above.  
If you decline to give us permission to use and disclose your information, you cannot take part in 
these optional procedures, but you can still participate in the main study.  Please initial next to your 
choice:
______ I give permission for my information, from the optional procedures I have agreed to above, to 
be used and disclosed as described in this section. 
______ I do not give permission for my information for any optional procedures to be used and 
disclosed; I understand that I will not participate in any optional procedures. 

Consent and Authorization Form Approval
Page 15 of 16
Initials______
COMIRB # 15-0659
Protocol Version Date: March 22, 2017
Agreement to be in this study and use my data
I have read this paper about the study or it was read to me.  I understand the possible risks and 
benefits of this study.  I understand and authorize the access, use and disclosure of my information 
as stated in this form.  I know that being in this study is voluntary.  I choose to be in this study: I will 
get a signed and dated copy of this consent form.
Signature:
Date: _________
                       Subject, (if over 18 years); OR Parent/Guardian
Print Name:
Relation to Subject: ____________________________________
Signature:
Date: _________
                    Subject (Ages 13-17) in addition to Parent Signature
Print Name:
Consent form reviewed by:
           
Date:
Print Name:
Investigator:
Date:
(Investigator must sign within 5 days)
Signature of Witness:  _________________________________
  Date_________
 (If applicable: required for subjects who are non-English speaking or with other limitations that 
require a witness signature)

Witness to Signature

Witness to consent process

Consent and Authorization Form Approval
Page 16 of 16
Initials______
COMIRB #15-0659
Protocol Version Date: March 22, 2017
Schedule and Description of Assessments
Studies to be obtained
Pre-
Study
During 
Cycle 1
Prior to 
Subsequent 
Cycles^
Off Treatment
Off study#
Complete History
X
X
X
X
X
Physical Exam with vital signs
X
Weekly
X
X
X
Height, Weight, BSA
X
X
X
X
Performance Status
X
X
X
CBC, differential, platelets
X
Twice 
weekly
Weekly
X
X
Complete metabolic profile
X 
Weekly
X
X
X
Pregnancy test (only females of 
childbearing potential)
X
X
12-lead EKG
X
X**
X**
Disease Evaluation
X
End of 
cycle 2$
End of cycle 4 
then every 3 
cycles
X
Patient Diary*
X
X
Pharmacokinetics (as per Section 9.1 and 
Appendix F)
X&
*Patients will be given the diary from Appendix F to fill out with each cycle of treatment. They will return this prior to starting the next cycle
#Every effort will be made to follow patients for at least 30 days after the last dose of medication, in order to monitor patients for resolution or late 
development of adverse events
^ Labs should be done within 48 hours of initiation of the subsequent cycle of chemotherapy
$ Disease evaluation should be done between days 15-21 of cycle 2
**EKG will be performed prior to Day 8 eribulin during cycle 1, and prior to day 1 eribulin of cycle 2
$Pharmacokinetics on Day 1 and 8 are required, whereas PKs on Day 4 are optional.
Areas shaded are research-related interventions.