Clinical trial NCT03535727
Conditions: Adenocarcinoma Pancreatic Neoplasms Neoplasm, Glandular Neoplasms Neoplasms Pancreatic Digestive System Neoplasm Endocrine Gland Neoplasms Digestive System Disease Pancreatic Diseases Endocrine System Diseases
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Start date: 2018-06-21; Completion date: 2022-10-03
Enrollment: 48 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to evaluate the clinical activity of gemcitabine, nab-paclitaxel, capecitabine, cisplatin, and irinotecan (GAX-CI) in patients with metastatic pancreatic cancer.

Detailed description:
This was a two-part, single-institution, open-label, dose-escalation, phase 1/2 study to evaluate the clinical activity of gemcitabine, nab-paclitaxel, capecitabine, cisplatin, and irinotecan in patients with metastatic pancreatic cancer.

Part 1 of the study was a Phase 1 3 + 3 dose escalation study designed to evaluate the maximally tolerated dose (MTD) and safety of increasing doses of nab-paclitaxel in combination with gemcitabine, capecitabine, cisplatin, and irinotecan. There were two cohorts of dose escalations. The two cohorts differed based on the treatment cycle length (28 days for Cohort 1 and 21 days for Cohort 2). Dose escalation started with Cohort 1. Enrollment for Cohort 2 dose level 1 began once dose level 2 of Cohort 1 was shown to be safe and did not exceed MTD.

Part 2 was a Phase 2 expansion cohort study for the evaluation of efficacy once the MTD had been determined.

Arms: arm 1: Gemcitabine: 500 mg/m\^2, IV over 30 minutes; Days 1 and 15 of a 28 day cycle

Nab-paclitaxel: 40 mg/m\^2, IV over 30 minutes; Days 1 and 15 of a 28 day cycle

Capecitabine: 500 mg BID, PO twice daily (BID); Days 1-7, 15-21 of a 28 day cycle

Cisplatin: 20 mg/m\^2, IV over 60 minutes; Days 1 and 15 of a 28 day cycle

Irinotecan: 20 mg/m\^2, IV over 30 minutes; Days 1 and 15 of a 28 day cycle arm 2: Gemcitabine 500 mg/m\^2, IV over 30 minutes; Days 1 and 15 of a 28 day cycle

Nab-paclitaxel 60 mg/m\^2, IV over 30 minutes; Days 1 and 15 of a 28 day cycle

Capecitabine: 500 mg BID: PO twice daily (BID); Days 1-7, 15-21 of a 28 day cycle

Cisplatin: 20 mg/m\^2, IV over 60 minutes; Days 1 and 15 of a 28 day cycle

Irinotecan: 20 mg/m\^2, IV over 30 minutes; Days 1 and 15 of a 28 day cycle arm 3: Gemcitabine: 500 mg/m\^2, IV over 30 minutes; Days 1 and 15 of a 28 day cycle

Nab-paclitaxel: 80 mg/m\^2, IV over 30 minutes; Days 1 and 15 of a 28 day cycle

Capecitabine: 500 mg BID, PO twice daily (BID); Days 1-7, 15-21 of a 28 day cycle

Cisplatin 20 mg/m\^2, IV over 60 minutes; Days 1 and 15 of a 28 day cycle

Irinotecan:20 mg/m\^2, IV over 30 minutes; Days 1 and 15 of a 28 day cycle arm 4: Gemcitabine:500 mg/m\^2, IV over 30 minutes; Days 1 and 15 of a 28 day cycle

Nab-paclitaxel:100 mg/m\^2, IV over 30 minutes; Days 1 and 15 of a 28 day cycle

Capecitabine:500 PO twice daily (BID); Days 1-7, 15-21 of a 28 day cycle

Cisplatin:20 mg/m\^2, IV over 60 minutes; Days 1 and 15 of a 28 day cycle

Irinotecan:20 mg/m\^2, IV over 30 minutes; Days 1 and 15 of a 28 day cycle arm 5: Gemcitabine:500 mg/m\^2, IV over 30 minutes; Days 1 and 15 of a 28 day cycle

Nab-paclitaxel:125 mg/m\^2, IV over 30 minutes; Days 1 and 15 of a 28 day cycle

Capecitabine: 500 mg BID, PO twice daily (BID); Days 1-7, 15-21 of a 28 day cycle

Cisplatin:20 mg/m\^2, IV over 60 minutes; Days 1 and 15 of a 28 day cycle

Irinotecan: 20 mg/m\^2, IV over 30 minutes; Days 1 and 15 of a 28 day cycle arm 6: Gemcitabine: 500 mg/m\^2, IV over 30 minutes; Days 4 and 11 of a 21 day cycle

Nab-paclitaxel:40 mg/m\^2, IV over 30 minutes; Days 4 and 11 of a 21 day cycle

Capecitabine:500 mg BID, PO twice daily (BID); Days 1-14 of a 21 day cycle

Cisplatin:20 mg/m\^2, IV over 60 minutes; Days 4 and 11 of a 21 day cycle

Irinotecan: 20 mg/m\^2, IV over 30 minutes; Days 4 and 11 of a 21 day cycle arm 7: Gemcitabine: 500 mg/m\^2, IV over 30 minutes; Days 4 and 11 of a 21 day cycle

Nab-paclitaxel:60 mg/m\^2, IV over 30 minutes; Days 4 and 11 of a 21 day cycle

Capecitabine:500mg BID, PO twice daily (BID); Days 1-14 of a 21 day cycle

Cisplatin:20 mg/m\^2, IV over 60 minutes; Days 4 and 11 of a 21 day cycle

Irinotecan: 20 mg/m\^2, IV over 30 minutes; Days 4 and 11 of a 21 day cycle arm 8: Gemcitabine: 500 mg/m\^2, IV over 30 minutes; Days 4 and 11 of a 21 day cycle

Nab-paclitaxel:80 mg/m\^2, IV over 30 minutes; Days 4 and 11 of a 21 day cycle

Capecitabine:500mg BID, PO twice daily (BID); Days 1-14 of a 21 day cycle

Cisplatin:20 mg/m\^2, IV over 60 minutes; Days 4 and 11 of a 21 day cycle

Irinotecan: 20 mg/m\^2, IV over 30 minutes; Days 4 and 11 of a 21 day cycle arm 9: Gemcitabine:500 mg/m\^2, IV over 30 minutes; Days 1 and 15 of a 28 day cycle

Nab-paclitaxel:125 mg/m\^2, IV over 30 minutes; Days 1 and 15 of a 28 day cycle

Capecitabine: 500 mg BID, PO twice daily (BID); Days 1-7, 15-21 of a 28 day cycle

Cisplatin:20 mg/m\^2, IV over 60 minutes; Days 1 and 15 of a 28 day cycle

Irinotecan: 20 mg/m\^2, IV over 30 minutes; Days 1 and 15 of a 28 day cycle
Interventions: intervention 1: Nab-paclitaxel intervention 2: Gemcitabine intervention 3: Capecitabine intervention 4: Cisplatin intervention 5: Irinotecan intervention 6: Nab-paclitaxel intervention 7: Gemcitabine intervention 8: Capecitabine intervention 9: Cisplatin intervention 10: Irinotecan
Intervention descriptions: intervention 1: IV over 30 minutes; Days 1 and 15 intervention 2: IV over 30 minutes; Days 1 and 15 intervention 3: PO twice daily (BID); Days 1-7, 15-21 intervention 4: IV over 60 minutes; Days 1 and 15 intervention 5: IV over 30 minutes; Days 1 and 15 intervention 6: IV over 30 minutes; Days 4 and 11 intervention 7: IV over 30 minutes; Days 4 and 11 intervention 8: PO BID; Days 1- 14 intervention 9: IV over 60 minutes; Days 4 and 11 intervention 10: IV over 30 minutes; Days 4 and 11

Protocol documents:
Prot_SAP_000.pdf: 
Cover Page for Protocol – J1847 
NCT Number: 
NCT03535727 
Official title of study 
A Phase I/II Study of Gemcitabine, Nab-
paclitaxel, Capecitabine, Cisplatin, and 
Irinotecan (GAX-CI) in Combination in 
Metastatic Pancreatic Cancer   
 
Document Date: 
April 8, 2022 


TITLE:  A phase I/II study of gemcitabine, nab-paclitaxel, capecitabine, cisplatin, and 
irinotecan (GAX-CI) in combination in metastatic pancreatic cancer 
 
Protocol #: 
 
 
 
 
 
J1847, IRB00167664  
 
 
Principal Investigator: 
Dung Le, M.D. 
 
 
 
 
 
 
 
Commercial Agents:  
Gemcitabine  
Nab-paclitaxel  
Capecitabine  
Cisplatin  
Irinotecan  
 
Protocol Type / Version # / Version Date: Original/ Version 1/ March 27, 2018 
Original/ Version 1.1/ April 11, 2018 
Original/ Version 1.2/ April 19, 2018 
Amendment 1/ Version 2.0/ June 20, 2018 
Amendment 2/ Version 3.0/ October 2, 2018 
Amendment 3/ Version 4.0/ July 30, 2019 
Amendment 4/ Version 5.0/ September 26, 2019 
Amendment 5/ Version 6.0/ January 2, 2020 
Amendment 6/ Version 7.0/ June 17, 2020 
Amendment 7/ Version 8.0/ April 8, 2021 
Amendment 8/ Version 9.0/April 08, 2022 
 
 
 
 


 
 
 
ii
TABLE OF CONTENTS 
 
 
Page 
1. 
OBJECTIVES ....................................................................................................................1 
1.1. 
Primary Objectives...................................................................................................1 
1.2. 
Secondary Objectives...............................................................................................1 
1.3  
Exploratory Objectives ............................................................................................1 
1.4  
Study Design ............................................................................................................1 
2. 
BACKGROUND ................................................................................................................2 
2.1 
Study Disease ...........................................................................................................2 
2.2 
Rationale ..................................................................................................................2 
3. 
PATIENT SELECTION ...................................................................................................4 
3.1 
Eligibility Criteria ....................................................................................................4 
3.2 
Exclusion Criteria ....................................................................................................4 
3.3 
Inclusion of Women and Minorities ........................................................................5 
4. 
TREATMENT PLAN ........................................................................................................5 
4.1 
Agent Administration...............................................................................................5 
4.2 
Continuation of Therapy ..........................................................................................7 
4.3 
Definition of a Dose Limiting Toxicity (DLT) ........................................................8 
4.4 
General Concomitant Medication and Supportive Care Guidelines ......................10 
4.5 
Duration of Therapy ...............................................................................................10 
4.6 
Duration of Follow Up ...........................................................................................10 
4.7 
Criteria for Removal from Study ...........................................................................11 
5.  
DOSING DELAYS/DOSE MODIFICATIONS ............................................................11 
5.1  
Suggested Dose Modifications for Other Non-Hematologic Toxicity ..................13 
5.2  
Suggested Dose Modifications for Hematologic Toxicity.....................................14 
6. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ......................15 
6.1 
Definitions..............................................................................................................15 
6.2 
Relationship ...........................................................................................................16 
6.3 
Expectedness ..........................................................................................................17 
6.4  
Reporting................................................................................................................17 
7. 
PHARMACEUTICAL INFORMATION ......................................................................19 
7.1  
Nab-paclitaxel (Abraxane) .....................................................................................19 
7.2  
Gemcitabine ...........................................................................................................21 
7.3  
Capecitabine ...........................................................................................................22 
7.4 
Cisplatin .................................................................................................................23 
7.5  
Irinotecan ...............................................................................................................24 
8. 
CORRELATIVE/SPECIAL STUDIES .........................................................................25 
8.1 
Plasma Marker Studies ..........................................................................................25 
8.2 
Whole Blood Studies .............................................................................................26 
8.3 
Tumor Tissue Studies ............................................................................................26 
8.4  
Genomic Analysis ..................................................................................................26 


 
 
 
iii 
9. 
STUDY CALENDAR ......................................................................................................27 
9.1  
Cohort 1 .................................................................................................................28 
9.2  
Cohort 2 .................................................................................................................30 
10. 
MEASUREMENT OF EFFECT ....................................................................................32 
10.1 
Antitumor Effect – Solid Tumors ..........................................................................32 
11. 
DATA REPORTING / REGULATORY REQUIREMENTS .....................................37 
11.1 
Data Management ..................................................................................................37 
11.2 
Safety Meetings .....................................................................................................37 
11.3  Monitoring .............................................................................................................37 
12. 
STATISTICAL CONSIDERATIONS ...........................................................................38 
12.1 
Study Design/Endpoints.........................................................................................38 
12.2 
Reporting and Exclusions ......................................................................................40 
REFERENCES .............................................................................................................................41 
APPENDIX A: Performance Status Criteria ............................................................................42 
APPENDIX B: Cohort 1 Capecitabine Patient Pill Diary .......................................................43 
APPENDIX C: Cohort 2 Capecitabine Patient Pill Diary .......................................................45 
APPENDIX D: SAE Reporting Form ........................................................................................47 
 
 
 
 


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1. OBJECTIVES 
 
1.1. 
Primary Objectives 
 
Part 1: The primary objective of the phase I portion is to assess safety of the combination of 
gemcitabine, nab-paclitaxel, capecitabine, cisplatin, and irinotecan (GAX-CI) in patients with 
untreated metastatic pancreatic adenocarcinoma (PDA) and to determine the maximally tolerated 
dose (MTD) or the recommended dose for phase II of the combination.  
 
Part 2: The primary objective of the phase II portion is to assess the efficacy of the combination 
of gemcitabine, nab-paclitaxel, capecitabine, cisplatin, and irinotecan (GAX-CI) in patients with 
untreated metastatic PDA based on the progression free survival (PFS).   
 
1.2. 
Secondary Objectives 
 
1.2.1   Part 2: Continue to assess the safety of GAX-CI in patients with untreated 
metastatic PDA. 
 
1.3  
Exploratory Objectives 
 
1.3.1 Part 2: To estimate the response rate (RR), disease control rate (DCR), and overall 
survival (OS) of the combination of gemcitabine, nab-paclitaxel, capecitabine, 
cisplatin, and irinotecan (GAX-CI) in patients with untreated metastatic PDA.  
 
1.3.2 To assess tumor burden dynamics using both standard protein biomarkers such as 
CA19-9 and CEA and exploratory biomarkers such as circulating tumor DNA.  
 
1.3.3 To assess baseline characteristics of the patients enrolled and correlate these 
molecular and clinicopathologic criteria with treatment response and toxicity. 
 
1.3.4 To evaluate molecular determinants of response using next generation sequencing 
and other sequencing techniques. 
 
1.4  
Study Design   
 
This is a two-part, single-institution, open-label, dose-escalation, phase 1/2 study to evaluate the 
clinical activity of gemcitabine, nab-paclitaxel, capecitabine, cisplatin, and irinotecan (GAX-CI) 
in patients with metastatic pancreatic cancer.  
 
Part 1 of the study is a 3 + 3 dose escalation study designed to evaluate the maximally tolerated 
dose (MTD), dose limiting toxicities (DLTs), and safety of increasing doses of nab-paclitaxel 
(Abraxane®) in combination with GX-CI. There will be two cohorts of dose escalations. The two 
cohorts differ based on the treatment cycle length (28 days for Cohort 1 and 21 days for Cohort 2). 
Dose finding study will be conducted for the 2 cohorts separately. Dose escalation will start with 
Cohort 1. Enrollment for Cohort 2 dose level 1 may start once dose level 2 of Cohort 1 is shown 
to be safe and does not exceed MTD. Dose levels 3-5 (if MTD is not reached), or any dose levels 


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lower than MTD, may enroll a total of 6 patients with amendment 2, for preliminary assessment 
of tumor response per RECIST 1.1. The recommended dose for phase 2 portion may be a dose 
level at or lower than MTD, and will be determined based on the review of the safety and tumor 
response data. Criteria for DLTs and dose escalations are defined in Section 4.3. 
 
Part 2 is an expansion cohort study for the evaluation of efficacy once the MTD or RDP2 has been 
determined. A dose level from Cohort 1 and/or Cohort 2 may be chosen for expansion once safety 
and efficacy have been evaluated in the first 6 patients in that dose level. If enrollment in an 
expansion cohort occurs at the same time as dose escalation, enrollment into the dose escalation 
will take priority. Due to the COVID 19 situation, version 7 of the protocol is amended to hold 
enrollment into cohort 2 until cohort 1 is complete to decrease the number of in person visits 
required of the patients.  The primary endpoint of Part 2 will be PFS. The treatment regimen would 
be considered of insufficient activity for further study in this population if the PFS rate at 6 months 
is 44% or less, and the minimum required level of efficacy that would warrant further study with 
the proposed regimen is a 65% PFS rate at 6 months (Section 12). 
 
2. BACKGROUND 
 
2.1 
Study Disease 
 
In 2018, there was an estimated 55,440 new cases of pancreatic cancer diagnosed in the United 
States1. Generally, most new cases of pancreatic cancer are advanced with extensive tumor growth 
usually due to the lack of symptoms during the early stages of the disease. As a result, few patients 
are considered candidates for surgical resection. Patients with advanced pancreatic cancer are 
usually treated with chemotherapy in an effort to improve survival and alleviate symptoms. 
Median survival time ranges from 4 to 6 months in patients with metastatic disease. With 
treatment, survival has improved to 6 to 11 months2,3.  Overall, the 5-year survival rate is about 
8% for all stages combined and decreases to 3% for patients with metastatic pancreatic cancer1. 
Currently, there are a few standard therapy options for patients. Single agent gemcitabine was FDA 
approved based on a comparative study between gemcitabine and 5-FU.  Gemcitabine produced 
significant improvement in disease-related symptoms and prolonged survival (1-year survival: 
18% versus 2%, respectively)4.  Subsequently, the oral tyrosine kinase inhibitor, erlotinib, was 
approved in combination with gemcitabine based on a slight increase in median survival over 
gemcitabine alone (6.24 months compared to 5.91 months)5.  A randomized phase III study 
performed in France comparing FOLFIRINOX (5-FU/irinotecan/oxaliplatin) to gemcitabine 
resulted in an improvement in survival of 6.8 months versus 11.1 months2.  While this regimen is 
being used, there are still concerns about its potential toxicity in a North American population and 
is being reserved for the most fit patients. Nab-paclitaxel is approved in combination for 
gemcitabine with a median survival of 8.5 months compared to 6.7 months with gemcitabine 
alone6.  Therapies for patients with metastatic pancreatic cancer are urgently needed. 
 
2.2 
Rationale 
 
Combination chemotherapy is now extending the lives of those with metastatic pancreatic cancer, 
however, overall survival (OS) remains less than 1 year2,6. In most cases, responses and prolonged 
survival are limited by the emergence of resistance mutations that render even triplet chemotherapy 


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3
ineffective2,7,8. Increasing the number of agents in a therapeutic cocktail could, in theory, improve 
outcomes and create a scenario where the emergence of solitary resistance mutations would no 
longer result in loss of efficacy. This hypotheses is supported by mathematical modeling that 
evaluates the number of tumor cells at treatment onset and evolution of mutations to predict the 
response to single versus dual versus multi-agent therapy8,9.  These models predict that patients 
with high tumor burden and monotherapy are unlikely to have a prolonged response.  The converse 
is true as well. Patients with lower burden disease and multi-agent therapy are more likely to have 
durable responses.     
 
  


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3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
1. Subjects must have histologically or cytologically confirmed untreated metastatic pancreatic 
adenocarcinoma. Subjects with islet cell neoplasms are excluded. Subjects with mixed 
histology will be excluded. 
 
2. Subject has one or more tumors measurable by CT scan using RECIST 1.1 criteria.  MRI is 
acceptable if a CT scan is contraindicated. 
 
3. Male or non-pregnant and non-lactating female of age >18 years.   
 
4. ECOG performance status <1 (Appendix A). ECOG 0 indicates that the patient is fully active 
and able to carry on all pre-disease activities without restriction; and, ECOG 1 indicates that 
the patient is restricted in physically strenuous activity but is ambulatory and able to carry out 
work of a light or sedentary nature. 
 
5. Subjects must have adequate organ and marrow function as defined below: 
 
− Absolute Neutrophil Count 
>1,500/mcL 
− Platelets 
 
 
 
 
 
>100 x 109/L 
− Hemoglobin   
 
 
 
 8 g/dL 
− Total Bilirubin 
 
 
 
within normal institutional limits (<1.5 X ULN if 
resolving biliary obstruction) 
− Alkaline phosphatase   
 
 5 X ULN 
− AST(SGOT)/ALT(SGPT) 
 2.5 x ULN ( 5 X ULN for subjects with 
documented liver metastases) 
- 
Creatinine 
 
 
 
 
within normal limits (creatinine clearance >60 
mL/min/1.73 m2 for subjects with creatinine 
levels above institutional normal.) 
 
6. Women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the 
duration of study participation.  Should a woman become pregnant or suspect she is pregnant 
while she or her partner is participating in this study, she should inform her treating physician 
immediately. 
 
7. Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
1. Patients who will be considered for surgery are ineligible.  
 
2. Subjects who have had any prior chemotherapy for pancreatic cancer or prior chemotherapy 


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5
within 5 years of enrollment for other cancer diagnoses. 
 
3. Subjects who have had radiotherapy for pancreatic cancer. 
 
4. Age > 76 years 
 
5. Subjects who are receiving or have received any other investigational agents within 28 days 
prior to Day 1 of treatment in this study. 
 
6. Subject has undergone major surgery, other than diagnostic surgery (i.e. surgery done to obtain 
a biopsy for diagnosis or an aborted Whipple), within 28 days prior to Day 1 of treatment in 
this study. 
 
7. Subject has known brain metastases. 
 
8. History of hypersensitivity or allergic reactions attributed to compounds of similar chemical 
or biologic composition to gemcitabine, nab-paclitaxel, capecitabine, cisplatin, or irinotecan. 
 
9. Uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
10. Subject has serious medical risk factors involving any of the major organ systems such that the 
Investigator considers it unsafe for the subject to receive an experimental research drug. 
 
11. Subject has a known history of infection with HIV, hepatitis B, or hepatitis C. 
 
12. Subject is pregnant or breast feeding. 
 
13. Subject is unwilling or unable to comply with study procedures. 
 
14. Subject with clinically significant wound. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial.   
 
4. TREATMENT PLAN 
 
4.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis. The description of the regimen is further 
described in Table 2. Reported adverse events and potential risks are described in Section 6.  
Appropriate dose modifications are described in Section 5. No investigational or commercial 
agents or therapies other than those described below may be administered with the intent to treat 
the subject's malignancy. The phase I portion of this study will evaluate up to 6 dose levels and 2 


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dosing schedules of the regimen to determine the MTD or the recommended dose for the Phase 2 
portion of the study. The recommended dose for the Phase 2 portion of the trial will be determined 
according to toxicity and efficacy based on objective response per Section 4.3.  
 
Table 1: Dose Levels 
 
Dose Escalation Schedule 
Cohort 
Dose 
Level 
Dose* 
Gemcitabine 
(mg/m2) 
Nab-
paclitaxel 
(mg/m2)** 
Capecitabine 
(mg BID) 
Cisplatin 
(mg/m2) 
Irinotecan 
(mg/m2) 
Cycle 
Length 
(Days) 
Cohort 
1 
Level -1 
(N=3-6) 
500 
20 
500 
20 
20 
28 
Level 1 
(N=3-6) 
500 
40 
500 
20 
20 
28 
Level 2 
(N=3-6) 
500 
60 
500 
20 
20 
28 
Level 3 
(N=6) 
500 
80 
500 
20 
20 
28 
Level 4 
(N=6) 
500 
100 
500 
20 
20 
28 
Level 5 
(N=6)*** 
500 
125 
500 
20 
20 
28 
Cohort 
2 
Level -1 
(N=3-6) 
500 
20 
500 
20 
20 
21 
Level 1 
(N=3-6) 
500 
40 
500 
20 
20 
21 
Level 2 
(N=3-6) 
500 
60 
500 
20 
20 
21 
Level 3 
(N=6) 
500 
80 
500 
20 
20 
21 
*Doses are stated as exact dose in units (e.g., mg/m2, mcg/kg, etc.) rather than as a percentage. 
**Doses may be rounded to the nearest whole and half-vial size (50 and 100 mg) and within 10% 
of the patient's ordered dose. 
*** Dose Level 5 will only be initiated if 4 out of 6 patients in Dose Level 4 do not have SD, PR, or 
CR by RECIST 1.1. 
 
 
 


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Table 2: Regimen Description 
 
Agent 
Suggested pre and/or post medications 
Route 
Schedule 
Cycle 
Length 
Nab-
paclitaxel  
5-HT3 antagonist IV + fosaprepitant IV 
+ 12mg decadron IV.  
Post IV meds:  8 mg oral BID decadron 
and 5-HT3 antagonist for 1-3 days. 
IV over 30 minutes* 
 
Cohort 1:  
Days 1 and 15 
Cohort 2:  
Days 4 and 11 
Cohort 1:  
28 days 
 
Cohort 2:  
21 days 
Gemcitabine 
See nab-paclitaxel 
IV over 30 minutes* 
Cohort 1:  
Days 1 and 15 
Cohort 2:  
Days 4 and 11 
Capecitabine 
5-HT3 antagonist oral or 
prochlorperazine oral prn 
PO BID 
Cohort 1:  
Days 1-7, 15-21 
Cohort 2: 
Days 1-14 
Cisplatin 
Normal saline 500cc IV pre and post 
IV over 60 minutes* 
Cohort 1:  
Days 1 and 15 
Cohort 2:  
Days 4 and 11 
Irinotecan 
Atropine should be immediately 
available for anti-cholinergic reactions 
IV over 30 minutes* 
Cohort 1:  
Days 1 and 15 
Cohort 2:  
Days 4 and 11 
*Infusion times are approximate (+/- 15 minutes) and may need to be adjusted based on patient tolerability 
 
The subject will be requested to maintain a medication diary of each dose of capecitabine 
(Appendix B and C).  The medication diary will be returned to the study team at the end of each 
cycle. 
 
4.1.1 Other Considerations 
 
The order of administration of the IV chemotherapeutic agents is nab-paclitaxel followed 
by gemcitabine followed by cisplatin followed by irinotecan. The hydration for cisplatin 
should occur pre and post infusion as standard of care for 30-60 minutes.  
 
Capecitabine tablets should be swallowed with water within 30 minutes after eating.  
Capecitabine can have an effect on warfarin or coumadin and phenytoin metabolism. 
 
4.2 
Continuation of Therapy 
 
Subjects will be evaluated during the treatment period to determine if continued treatment is 
appropriate. If, at any time during treatment the evaluation criteria are not met, GAX–CI can be 
held or the dose adjusted. Suggested dose modification criteria are in Section 5.   
 
To continue therapy, subjects must meet the following criteria (exceptions should be approved by 
the principal investigator): 


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8
 
Cohort 1 
• Absolute Neutrophil Count  
 
 
 
>1000/mcL 
 
 
• Platelets  
 
 
 
 
 
 
 
>70 x 109/L 
 
• Hemoglobin  
 
 
 
 
 
 
 
> 7 g/dL 
• Total Bilirubin 
 
 
 
 
 
 
< 2 x ULN 
• AST(SGOT)/ALT(SGPT)  
 
 
 
 5 X ULN 
• Creatinine 
  
 
 
 
 
 
 
< 1.5 x ULN   
(creatinine clearance >50 mL/min/1.73 m2 for subjects with creatinine levels > 1.5 x 
ULN.) 
 
Cohort 2 
• Absolute Neutrophil Count   
 
 
 
Day 4 of cycle: >1000/mcL 
   
 
 
 
 
 
 
 
 
Day 11 of cycle: >900/mcL 
• Platelets  
 
 
 
 
 
 
 
Day 4 of cycle: >80 x 109/L 
   
 
 
 
 
 
 
 
 
Day 11 of cycle: >70 x 109/L 
• Hemoglobin  
 
 
 
 
 
 
 
> 7 g/dL 
• Total Bilirubin 
 
 
 
 
 
 
< 2 x ULN 
• AST(SGOT)/ALT(SGPT)  
 
 
 
 5 X ULN 
• Creatinine 
  
 
 
 
 
 
 
< 1.5 x ULN   
(creatinine clearance >50 mL/min/1.73 m2 for subjects with creatinine levels > 1.5 x 
ULN) 
 
4.3 
Definition of a Dose Limiting Toxicity (DLT) 
 
The dose-limiting toxicity (DLT) for the combination in this study will be defined as one or more 
of the following possibly or probably related toxicities within the first cycle of treatment according 
to the NCI Common Toxicity Criteria for Adverse Events (CTCAE), Version 5: 
 
• Any Grade 3 or higher toxicity possibly or probably related to the study drug, with the 
exception of: 
 
• Grade 3 anemia that resolves to <grade 2 within 7 days.  Subjects should have 
repeat labs within 7 days to document resolution. 
 
• Grade 3 thrombocytopenia without clinically significant bleeding that resolves to 
<grade 2 within 7 days.  Subjects should have repeat labs within 7 days to 
document resolution. 
 
• Grade 3 or 4 neutropenia that resolves to <grade 2 within 7 days.  Subjects should 
have repeat labs within 7 days to document resolution. 
 
• Grade 3 or 4 leucopenia/lymphopenia. 
 
• Grade 3 nausea, vomiting, or diarrhea that resolves to <grade 2 within 72 hours. 


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9
 
• Grade 3 or 4 asymptomatic laboratory values that resolve to < grade 2 within 7 
days.  Subjects should have repeat labs within 7 days to document resolution. 
 
• Grade 3 dermatologic AEs that are considered mild in severity but only considered 
grade 3 because of >30% body surface involvement.  
 
• Grade 3 fatigue lasting less than 72 hours. 
 
DLTs will be evaluated for 28 days in Cohort 1 and 21 days in Cohort 2 (1 cycle length). 
Management and dose modifications are outlined in Section 5. Dose escalation will proceed within 
each dose level using a 3+3 design according to Table 3 to determine the MTD of GAX-CI. MTD 
is defined as the dose level in which 0 or 1 of 6 patients experiences a dose limiting toxicity with 
the next higher dose having at least 2 of 3 or 2 of 6 patients experiencing a DLT. Dose levels 3-5 
(if MTD is not reached), or any dose levels lower than MTD, may enroll a total of 6 patients to 
assess tumor response per RECIST 1.1, in order to determine the recommended dose for Phase 2 
expansion. The recommended dose for phase 2 portion may be a dose level at or lower than MTD, 
and will be determined based on the safety and tumor response data. If, however, the MTD is not 
chosen for expansion, then the PI will formally review the toxicity data with the other treating 
physicians before moving forward. 
 
Table 3: DLT Criteria 
 
Number of Patients 
with DLT at a Give 
Dose Level 
Dose Escalation Decision Rule 
0 out of 3 
• Enter 3 patients at the next higher dose level 
1 out of 3 
Enter 3 more patients at this dose level 
•  If ≤ 1 of 6 subjects in this cohort experience a DLT, proceed to the 
next higher dose level  
• If ≥ 2 of 6 subjects in this cohort experience a DLT, this dose level 
exceeded the MTD and dose escalation will be stopped. 3 subjects 
will be entered at the next lower dose level. 
≥ 2 out of 3 or 6 
This dose level exceeded the MTD and dose escalation will be 
stopped.  3 additional patients will be entered at the next lower dose 
level. 
≤ 1 of 6 (and the 
next higher level has 
exceeded the MTD) 
This is the MTD.  At least 6 patients must be entered at the MTD level 
to determine the dose to be used in Part 2 of this study. 
 
 
Note: The PI has the discretion to expand at the current dose level or move to other dose levels to 
complete and expand that level if there are no safety concerns. 
 


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Dose escalation will be conducted for the 2 cohorts separately. Dose escalation will start with 
Cohort 1. Enrollment for Cohort 2 dose level 1 may start once dose level 2 of Cohort 1 is shown 
to be safe and does not exceed MTD. 
 
Dose escalation to Dose Level 5 will only be initiated if 4 out of 6 patients in Dose Level 4 do not 
have  SD, PR, or CR by RECIST 1.1. 
 
Any dose level lower than MTD, or the highest dose level tested if MTD is not reached, may enroll 
a total of 6 patients to assess tumor response per RECIST 1.1. 
 
4.4 
General Concomitant Medication and Supportive Care Guidelines 
 
The concurrent use of all other drugs, over-the-counter medications, or alternative therapies must 
be documented.  The Principal Investigator should be alerted if the subject is taking warfarin, 
coumadin, or phenytoin. These drugs are not contra-indicated but should be monitored closely 
while on capecitabine. 
 
Subjects may not enroll in any other therapeutic clinical protocol or therapeutic investigational 
trial while enrolled in this study. Irradiation may be allowed during the study. Administration of 
other chemotherapy, immunotherapy, or anti-tumor hormonal therapy during the study is not 
allowed. 
 
Supportive care, including but not limited to anti-emetic medications, may be administered at the 
discretion of the Principal Investigator or Co-Investigators. Concurrent treatment with 
bisphosphonates is allowed. All concomitant treatments, including blood and blood products, must 
be reported on the case report form (CRF). Erythropoietin, G-CSF, or Neulasta may be 
administered at the discretion of the Principal Investigator or Co-Investigators. 
 
4.5 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue indefinitely or 
until one of the following criteria applies: 
 
• 
Disease progression: Subjects may be allowed to continue treatment if the Principal 
Investigator feels that the subject is receiving benefit (e.g. a mixed response).  
However, subjects who continue on study with progressive disease by RECIST should 
be taken off study after determination of continued disease progression on the next 
study scan. 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Unacceptable adverse event(s), 
• 
Subject decides to withdraw from the study, or 
• 
General or specific changes in the subject's condition render the subject unacceptable 
for further treatment in the judgment of the investigator. 
 
4.6 
Duration of Follow Up 
 


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Subjects will be followed for adverse events for a minimum of 28 days after the last dose of study 
drug or death, whichever occurs first. Survival status will be collected every 3 months (+/- 3 
weeks). Subsequent therapies and responses may be collected. Subjects removed from study for 
unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse event 
or death. 
 
Subjects who discontinued study treatment without documented disease progression should 
continue to be monitored for disease status by radiologic imaging.  Standard of care scans will be 
collected until: 1) start of a new antineoplastic therapy (information of the new cancer therapy will 
be collected), 2) disease progression, 3) death, 4) withdrawal of consent, or 5) study closure, 
whichever occurs first. 
 
4.7 
Criteria for Removal from Study 
 
Subjects will be removed from study when any of the criteria listed in Section 4.5 applies.  The 
reason for study removal and the date the subject was removed must be documented in the Case 
Report Form. 
 
5.  DOSING DELAYS/DOSE MODIFICATIONS 
 
Allowance of chemotherapy breaks of greater than 2 weeks will be decided on a case-by-case basis 
by the principal investigator. When the delay is due to toxicity, then the next cycle may begin with 
a dose reduction. 
 
If the delay is due to personal reasons, there will be no dose reductions. Any treatment delays 
beyond the protocol allowed window must be approved by the principal investigator. 
 
Some discretion is left up to the investigators to account for patients who may be doing 
exceptionally well and request a longer break from therapy or may need a little extra time for 
clinical and laboratory status to recover. Dose reductions will be managed based on Table 4. 
Additional dose reductions (depending on starting dose) are up to the discretion of the principal 
investigator. Given that there are certain toxicities that are typically associated with capecitabine 
(for example palmar-plantar erythrodysesthesia syndrome), investigators may choose to hold the 
capecitabine and decrease within a cycle  (300mg po bid and 150mg po bid). In subsequent cycles, 
the capecitabine will continue at the lower dose but the other agents do not need to be decreased 
to a lower dose level unless deemed necessary due to another adverse event. For example, if a 
subject on DL1 (Level 0) develops grade 2 palmar-plantar erythrodysesthesia syndrome during 
cycle 1, the capecitabine can be held until < grade 1 and restarted at a lower dose. The capecitabine 
period, however, should not be more than the original 7 or 14 day period. The subject should 
receive the next cycle at DL1 (Level 0) except for the capecitabine would remain at the lower dose 
unless deemed necessary to use DL-1 due to another adverse event. Capecitabine dose reductions 
can be done independently of the dose reductions for the IV chemotherapy agents.  
 
If patients experience bone marrow toxicity at dose level 3 in Cohort 2, patients may change the 
treatment schedule to the Cohort 1 schedule with a cycle length of 28 days after Cycle 6.  
 


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Table 4: Dose Reduction 
 
Dose Level 
Gemcitabine 
(mg/m2) 
Nab-
paclitaxel 
(mg/m2) 
Capecitabine 
(mg po bid) 
Cisplatin 
(mg/m2) 
Irinotecan 
(mg/m2) 
DL-1 
Level 0 
500 
20 
500 
20 
20 
DL1 
Level 0 
500 
40 
500 
20 
20 
Level -1 
500 
40 
500 
20 
0 
Level -2 
500 
40 
500 
0 
0 
Level -3 
500 
0 
500 
0 
0 
Level -4 
500 
0 
0 
0 
0 
DL2 
Level 0 
500 
60 
500 
20 
20 
Level -1 
500 
40 
500 
20 
20 
Level -2 
500 
40 
500 
20 
0 
Level -3 
500 
40 
500 
0 
0 
Level -4 
500 
0 
500 
0 
0 
Level -5 
500 
0 
0 
0 
0 
DL3 
Level 0 
500 
80 
500 
20 
20 
Level -1 
500 
60 
500 
20 
20 
Level -2 
500 
40 
500 
20 
20 
Level -3 
500 
40 
500 
20 
0 
Level -4 
500 
40 
500 
0 
0 
Level -5 
500 
0 
500 
0 
0 
Level -6 
500 
0 
0 
0 
0 
DL4 
Level 0 
500 
100 
500 
20 
20 
Level -1 
500 
80 
500 
20 
20 
Level -2 
500 
60 
500 
20 
20 
Level -3 
500 
40 
500 
20 
20 
Level -4 
500 
40 
500 
20 
0 
Level -5 
500 
40 
500 
0 
0 
Level -6 
500 
0 
500 
0 
0 
Level -7 
500 
0 
0 
0 
0 
DL 5 
Level 0 
500 
125 
500 
20 
20 
Level -1 
500 
100 
500 
20 
20 
Level -2 
500 
80 
500 
20 
20 
Level -3 
500 
60 
500 
20 
20 
Level -4 
500 
40 
500 
20 
20 
Level -5 
500 
40 
500 
20 
0 
Level -6 
500 
40 
500 
0 
0 
Level -7 
500 
0 
500 
0 
0 
Level -8 
500 
0 
0 
0 
0 
 
 
 


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5.1  
Suggested Dose Modifications for Other Non-Hematologic Toxicity 
 
Dose modifications are suggestions, but the final decision is left to the discretion of the Principal 
Investigator or Co-Investigator. 
 
Event Name 
Nausea 
Grade of Event 
Management/Next Dose 
≤ Grade 1 
No change in dose 
Grade 2 
No change in dose 
Grade 3 
Hold until < Grade 2.  Resume at one dose level lower, if indicated. 
Recommended management:  antiemetics. 
 
Event Name 
Vomiting 
Grade of Event 
Management/Next Dose 
≤ Grade 1 
No change in dose 
Grade 2 
No change in dose 
Grade 3-4 
Hold until < Grade 2.  Resume at one dose level lower, if indicated. 
Recommended management:  antiemetics. 
 
Event Name 
Diarrhea 
Grade of Event 
Management/Next Dose 
≤ Grade 1 
No change in dose 
Grade 2 
No change in dose 
Grade 3-4 
Hold until < Grade 2.  Resume at one dose level lower, if indicated. 
Recommended management:  Loperamide anti-diarrheal therapy 
Dosage schedule:  4 mg at first onset, followed by 2 mg with each loose motion until 
diarrhea-free for 12 hours (maximum dosage:  16 mg/24 hours) 
Adjunct anti-diarrheal therapy is permitted and should be recorded when used. 
 
Event Name 
Peripheral Neuropathy 
Grade of Event 
Management/Next Dose 
≤ Grade 1 
No change in dose 
Grade 2 
No change in dose 
Grade 3-4 
Hold until < Grade 2.  Resume at one dose level lower, if indicated. 
Recommended management: consider medications for neuropathy. 
 
Event Name 
Fatigue 
Grade of Event 
Management/Next Dose 
≤ Grade 1 
No change in dose 
Grade 2 
No change in dose 
Grade 3 
Hold until < Grade 2.  Resume at one dose level lower, if indicated. 
 
 
 


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Event Name 
Palmar-plantar erythrodysesthesia syndrome 
Grade of Event 
Management/Next Dose 
≤ Grade 1 
No change in dose 
Grade 2 
Hold capecitabine until ≤ Grade 1.  Resume at capecitabine 300mg 
po bid.  For 2nd occurrence, resume at 150mg po bid. 
Grade 3 
Hold capecitabine until ≤ Grade 1.  Resume at capecitabine 300mg 
po bid.  For 2nd occurrence, resume at 150mg po bid. 
Recommended management:  moisturizers to intact skin. 
 
5.2  
Suggested Dose Modifications for Hematologic Toxicity  
 
Cohort 1 
 
Event Name 
Neutropenia 
Laboratory Value  
Management/Next Dose 
Day 1 and 15 of cycle: 
<1000/mcL 
Hold until > 1000, no change in dose. Resume at one 
dose level lower, if indicated. Transient grade 3 
neutropenia may occur during days 15-28 of a cycle. 
The use of growth factors is permitted. 
 
Event Name 
Thrombocytopenia 
Laboratory Value  
Management/Next Dose 
Day 1 and 15 of cycle: <70 x 
109/L 
Hold until >70, no change in dose 
Grade 3-4 
Hold until >70.  Resume at one dose level lower, if 
indicated. 
A platelet goal of 50K should be considered for those on anticoagulation. 
 
Cohort 2 
 
Event Name 
Neutropenia 
Laboratory Value  
Management/Next Dose 
Day 4 of cycle: <1000/mcL 
Hold until > 1000, no change in dose 
Day 11 of cycle: <900/mcL 
Hold until >900.  Resume at one dose level lower, if 
indicated. Transient grade 3 neutropenia may occur 
during days 15-21 of a cycle. 
The use of growth factors is permitted. 
 
Event Name 
Thrombocytopenia 
Laboratory Value  
Management/Next Dose 
Day 4 of cycle: <80 x 109/L 
Hold until > 80, no change in dose 
Day 11 of cycle: <70 x 109/L Hold until >70, no change in dose 
Grade 3-4 
Hold until >70.  Resume at one dose level lower, if 
indicated. 
A platelet goal of 50K should be considered for those on anticoagulation. 


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6. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
This study will use the descriptions and grading scales found in the revised National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 for adverse 
event reporting. 
 
6.1 
Definitions 
 
6.1.1 Adverse Event (AE) 
 
Adverse event is defined as any undesirable sign, symptom or medical condition occurring 
after starting the study drug (or therapy) even if the event is not considered to be related to 
the study. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), 
signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., 
laboratory findings, electrocardiogram). Medical conditions/diseases present before 
starting the study treatment are only considered adverse events if they worsen after starting 
the study treatment (any procedures specified in the protocol). Adverse events occurring 
before starting the study treatment but after signing the informed consent form will not be 
recorded. Abnormal laboratory values or test results constitute adverse events only if they 
induce clinical signs or symptoms or require therapy. 
 
6.1.2 Serious Adverse Event (SAE) 
 
A serious adverse event is an undesirable sign, symptom or medical condition which:  
• Results in death  
• Is life threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe)  
• Requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see note below for exceptions) > 24 hours 
• Results in persistent or significant disability/incapacity  
• Is a congenital anomaly/birth defect (note: reports of congenital anomalies/birth 
defects must also be reported on the Pregnancy Supplemental Form)  
• Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention [e.g., medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above.). Examples of such events include, but are 
not limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization.) 
• Is a new cancer (that is not a condition of the study) 
• Is associated with an overdose 
 
Events not considered to be serious adverse events are hospitalizations for the:  


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• Admissions as per protocol for a planned medical/surgical procedure or to facilitate a 
procedure 
• Routine health assessment requiring admission for baseline/trending of health status 
(e.g., routine colonoscopy)  
• Medical/surgical admission for purpose other than remedying ill health state and was 
planned prior to entry into the study. Appropriate documentation is required in these 
cases  
• Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g., lack of housing, economic 
inadequacy, care-giver respite, family circumstances, administrative). 
• Admissions for monitoring of treatment-related infusion reactions that do not 
otherwise meet the criteria for a SAE. 
 
6.2 
Relationship 
 
The relationship of an AE to the administration of the study drug is to be assessed by the 
investigator according to the following definitions: 
 
• No (unrelated, not related, no relation): The time course between the administration of 
study drug and the occurrence or worsening of the adverse event rules out a causal 
relationship and another cause (concomitant drugs, therapies, complications, etc.) is 
suspected. 
• Yes (related): The time course between the administration of study drug and the 
occurrence or worsening of the adverse event is consistent with a causal relationship 
and no other cause (concomitant drugs, therapies, complications, etc.) can be identified. 
 
The following factors should also be considered: 
 
• The temporal sequence from study drug administration - The event should occur after 
the study drug is given. The length of time from study drug exposure to event should 
be evaluated in the clinical context of the event. 
• Underlying, concomitant, intercurrent diseases - Each report should be evaluated in the 
context of the natural history and course of the disease being treated and any other 
disease the subject may have. 
• Concomitant medication - The other medications the subject is taking or the treatment 
the subject receives should be examined to determine whether any of them might be 
recognized to cause the event in question. 
• Known response pattern for this class of study drug - Clinical and/or preclinical data 
may indicate whether a particular response is likely to be a class effect. 
• Exposure to physical and/or mental stresses - The exposure to stress might induce 
adverse changes in the recipient and provide a logical and better explanation for the 
event. 
• The pharmacology and pharmacokinetics of the study drug - The known pharmacologic 
properties (absorption, distribution, metabolism, and excretion) of the study drug 
should be considered. 
 


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6.3 
Expectedness 
 
Unexpected adverse event: An adverse event, which varies in nature, intensity or frequency from 
information on the investigational drug/agent provided in the Investigator’s Brochure, package 
insert or safety reports. Any adverse event that is not included in the informed consent is 
considered “unexpected”.  
 
Expected (known) adverse event: An adverse event, which has been reported in the Investigator’s 
Brochure. An adverse event is considered “expected”, only if it is included in the informed consent 
document as a risk. 
 
6.4  
Reporting 
 
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other means, 
will be collected, recorded, and followed as appropriate.  
 
All adverse events experienced by subjects will be collected and reported from the first dose of the 
investigational combination (GAX-CI), throughout the study, and will only be followed for 30 
days unless related to the investigational agent.   
 
Subjects who have an ongoing adverse event related to the study procedures and/or medication(s) 
may continue to be periodically contacted by a member of the study staff until the event is resolved 
or determined to be irreversible by the investigator. 
 
6.4.1 Routine Adverse Event Reporting 
 
If an ongoing AE changes in its intensity or in its perceived relationship to investigational 
product, a new AE entry for the event should be completed. Adverse events should be 
followed to resolution or stabilization, or reported as SAEs if they become serious. Follow-
up is also required for AEs that cause interruption or discontinuation of investigational 
product, or those that are present at the end of study participation. Subjects with AEs at 
study completion should receive post-treatment follow-up as appropriate.  
 
All identified non-serious AEs must be recorded and described on the appropriate Adverse 
Event Case Report Form (CRF). 
 
6.4.2 Laboratory Test Abnormalities 
 
Laboratory abnormalities present at the screening visit will be recorded as pre-treatment 
signs and symptoms. After study treatment administration, all grade 3 and 4 clinical 
laboratory results that represent an increase in severity from baseline will be reported as 
adverse events. A grade 1 or 2 clinical laboratory abnormality should be reported as an 
adverse event only if it is considered clinically significant by the investigator. 
 
In addition, the following laboratory abnormalities should also be captured on the AE CRF 


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page or SAE Reporting Form (Appendix D) as appropriate: 
 
▪ Any laboratory test result that is clinically significant or meets the definition of 
an SAE 
▪ Any laboratory abnormality that required the subject to have the investigational 
product discontinued or interrupted 
▪ Any laboratory abnormality that required the subject to receive specific 
corrective therapy 
 
It is expected that wherever possible, the clinical, rather than the laboratory term would be 
used by the reporting investigator (e.g., anemia versus low hemoglobin value). 
 
6.4.3 Serious Adverse Event Reporting 
 
All SAEs (including deaths) occurring from the first dose of the study drug through 30 
days after the last dose of study drug will be collected and recorded on the Adverse Event 
Case Report Form (CRF) and SAE Reporting Form (Appendix D).  
 
SAEs will be reported to the Johns Hopkins Medicine IRB per institutional guidelines.  
 
Adverse events that are serious, unexpected, and assessed by the investigator to be related 
to the study drug will be reported within 24 hours of becoming aware of the event 
occurrence to the post-marketing departments of the drug manufacturers (contact pharmacy 
to verify the manufacturer). 
 
After the initial SAE report, the investigator is required to proactively follow each subject 
and provide further information in regards to the subject’s condition. 
 
All AE(s) and SAE(s) will be followed until: 
 
• Resolution 
• The condition stabilizes 
• The event is otherwise explained 
• The subject is lost to follow-up 
• Death 
 
6.4.4  Overdose 
 
An overdose is defined as the accidental or intentional ingestion of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose 
must be reported as an SAE. 
 
6.4.5 Pregnancy 
 
Sexually active women of child bearing potential (WOCBP) must use an effective method 
of birth control during the course of the study, in a manner such that risk of failure is 
minimized. 


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Prior to study enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during study participation and the potential risk factors for an unintentional 
pregnancy. The subject must sign an informed consent form documenting this discussion. 
 
ALL WOCBP MUST HAVE A NEGATIVE SERUM PREGNANCY TEST 7 DAYS 
PRIOR TO RECEIVING INVESTIGATIONAL PRODUCT. All WOCBP should be 
instructed to contact the investigator immediately if they suspect they may be pregnant 
(e.g., missed or late menstrual period) at any time during study participation. 
 
If, following initiation of the investigational product, it is subsequently discovered that a 
study subject is pregnant or may have been pregnant at the time of the investigational 
product exposure, including during at least 6 half-lives after product administration, the 
investigational product will be permanently discontinued in an appropriate manner. 
Exceptions to the investigational product discontinuation may be considered for life-
threatening conditions only after consultation with the sponsor or as otherwise specified in 
this protocol. The investigator must immediately notify the sponsor of this event, record 
the pregnancy on the SAE form. Initial information on a pregnancy must be reported 
immediately to the sponsor and the outcome information provided once the outcome is 
known. Forward these forms to the sponsor according to SAE reporting procedures. 
 
Protocol-required procedures for study discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (e.g., x-rays studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated. Follow-up information 
regarding the course of the pregnancy, including perinatal and neonatal outcome must be 
reported. Infants should be followed for a minimum of 8 weeks. 
 
6.4.6 Other Safety Considerations 
 
Any significant changes noted during interim or final physical examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not 
these procedures are required by protocol, should also be recorded on the appropriate non-
serious AE or SAE page of the CRF. 
 
7. PHARMACEUTICAL INFORMATION 
 
 
7.1  
Nab-paclitaxel (Abraxane) 
 
For complete details on drug administration, storage, clinical pharmacology, and the human 
pharmacokinetics of nab-paclitaxel please see the nab-paclitaxel prescribing information. 
 
Description, Formulation, and Storage 
 
Nab-paclitaxel (albumin-bound form of paclitaxel) a microtubule inhibitor that promotes the 
assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing 
depolymerization.  This stability results in the inhibition of the normal dynamic reorganization of 


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the microtubule network that is essential for vital interphase and mitotic cellular functions. 
Paclitaxel induces abnormal arrays or “bundles” of microtubules throughout the cell cycle and 
multiple asters of microtubules during mitosis. 
 
Nab-paclitaxel is a white to yellow, sterile, lyophilized powder for reconstitution with 20 mL of 
0.9% Sodium Chloride Injection, USP prior to intravenous infusion. Each single-use vial contains 
100 mg of paclitaxel (bound to human albumin) and approximately 900 mg of human albumin 
(containing sodium caprylate and sodium acetyltryptophanate).  Each milliliter (mL) of 
reconstituted suspension contains 5 mg paclitaxel.  Nab-paclitaxel is free of solvents. 
 
Nab-paclitaxel should be stored between 20 and 25°C (68°F-77°F) in a secure and dry place. 
Retain in the original package to protect from bright light.  Neither freezing nor refrigeration 
adversely affects the stability of the product. 
 
Preparation and Administration 
 
Nab-paclitaxel reconstitution, preparation, and administration should be completed according to 
the manufacturer’s recommendation. 
 
Nab-paclitaxel may be administered on an outpatient basis. Nab-paclitaxel should be administered 
on day 1 and 15 for patients in Cohort 1 and day 4 and 11 for patients in Cohort 2 of each cycle by 
intravenous infusion over 30 minutes. Infusion times are approximate and may need to be adjusted 
based on patient tolerability. 
 
Nab-paclitaxel doses may be rounded to the nearest whole and half-vial size (50 and 100 mg) and 
within 10% of the patient's ordered dose. 
 
Reconstituted nab-paclitaxel in the vial should be used immediately, but may be refrigerated at 
2ºC to 8ºC (36ºF to 46ºF) for a maximum of 8 hours if necessary.  If not used immediately, each 
vial of reconstituted suspension should be replaced in the original carton to protect it from bright 
light.  Discard any unused portion.  
 
The suspension for infusion when prepared as recommended in an infusion bag should be used 
immediately but may be stored at ambient temperature (approximately 25ºC) and lighting 
conditions for up to 4 hours.  Discard any unused portion. 
 
Toxicities of Nab-paclitaxel 
 
Please see the nab-paclitaxel prescription information for more details on the known precautions, 
warnings, and adverse reactions of nab-paclitaxel. The most common adverse reactions (≥ 20%) 
in metastatic pancreas cancer patients are neutropenia, fatigue, peripheral neuropathy, nausea, 
alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration. 
Fetal harm can occur when administered to a pregnant woman. Women of childbearing potential 
should be advised not to become pregnant when receiving nab-paclitaxel. 
 
Subject Care Implications  


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21
 
The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal 
clinical drug interaction studies, caution should be exercised when administering nab-paclitaxel 
concomitantly with medicines known to inhibit (e.g., ketoconazole and other imidazole 
antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and 
nelfinavir) or induce (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either 
CYP2C8 or CYP3A4. 
 
7.2  
Gemcitabine 
 
For complete details on preparation instructions, storage, clinical pharmacology, a comprehensive 
list of adverse events and the human pharmacokinetics of Gemcitabine, please see the Gemcitabine 
prescribing information. 
 
Description, Formulation, and Storage 
 
Gemcitabine (difluorodeoxycytidine) is a pyrimidine antimetabolite, which is an analogue of 
deoxycytidine. It was initially synthesized as a potential antiviral drug but selected for anticancer 
development because of its activity in in-vivo and in vitro tumors. Gemcitabine is approved for the 
treatment of patients with pancreatic cancer and will be obtained commercially. Gemcitabine is 
commercially supplied as a powder for reconstitution in 200 mg and 1 gm vials. 
 
Intact vials containing sterile powder are stored at room temperature (20° to 25°C) (68° to 77°F). 
Gemcitabine solutions are stable for 24 hours at controlled room temperature of 20° to 25°C (68° 
to 77°F). Do not refrigerate as crystallization can occur. The diluted solution should be clear and 
colorless to light straw-colored solution 
 
Preparation and Administration 
 
Reconstitute the 200 mg vial with 5 mL 0.9% NaCl and the 1 g vial with 25 mL 0.9%NaCl. The 
resulting solution is approximately 38 mg/mL, but the concentration varies. It is suggested that 
when the desired dose is less than the entire vial, the entire volume be drawn up into a syringe in 
order to determine the actual concentration. Then the desired amount should be measured and 
diluted in 0.9%NaCl for infusion. Reconstituted solution should be further diluted in 100 ml NS 
for intravenous infusion. 
 
In this study, Gemcitabine may be administered on an outpatient basis. Gemcitabine should be 
administered on day 1 and 15 for patients in Cohort 1 and day 4 and 11 for patients in Cohort 2  of 
each cycle by intravenous infusion over 30 minutes following the nab-paclitaxel infusion. Infusion 
times are approximate and may need to be adjusted based on patient tolerability. 
 
Toxicities of Gemcitabine 
 
Please see the Gemcitabine prescribing information for more details on the known precautions, 
warnings, and adverse reactions of Gemcitabine. Gemcitabine can suppress bone marrow function 
as manifested by leukopenia, thrombocytopenia and anemia, and myelosuppression is usually the 
dose-limiting toxicity. Subjects should be monitored for myelosuppression during therapy. 


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22
Hemolytic-Uremic Syndrome (HUS) has been reported rarely with the use of Gemcitabine. 
Gemcitabine is a Pregnancy Category D drug. Gemcitabine can cause fetal harm when 
administered to a pregnant woman. Gemcitabine is embryotoxic causing fetal malformations (cleft 
palate, incomplete ossification) at doses of 1.5 mg/kg/day in mice (about 1/200 the recommended 
human dose on a mg/m2 basis). Gemcitabine is fetotoxic causing fetal malformations (fused 
pulmonary artery, absence of gall bladder) at doses of 0.1 mg/kg/day in rabbits (about 1/600 the 
recommended human dose on a mg/m2 basis). Embryotoxicity was characterized by decreased 
fetal viability, reduced live litter sizes, and developmental delays. There are no studies of 
Gemcitabine in pregnant women. If Gemcitabine is used during pregnancy, or if the subject 
becomes pregnant while taking Gemcitabine, the subject should be apprised of the potential hazard 
to the fetus. 
 
7.3  
Capecitabine 
 
For complete details on drug administration, storage, clinical pharmacology, and the human 
pharmacokinetics of capecitabine, please see the capecitabine prescribing information.  
 
Description, Formulation, and Storage 
 
Capecitabine is a fluoropyrimidinecarbamate with antineoplastic activity. It is an orally 
administered systemic prodrug of 5’-deoxy-5-fluorouridine (5’-DFUR) which is converted to 5-
fluorouracil. Normal cells, as well as tumor cells metabolize 5- Fluorouracil into 5-fluoro-2’-
deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). Both are 
metabolites that cause cell injury by two different mechanisms.  FdUMP and the folate factor, N5-
10-methylenetetrahydrofolate, bind to thymidylate synthase (TS) to inhibit the formation of 
thymidylate. This deficiency of thymidylate causes cell cycle division to halt. This is because 
thymidalate is necessary for thymidine triphosphate production, which is essential for DNA 
synthesis. FUTP works by incorporating itself into transcription in place of uridine triphosphate 
therefore interfering with RNA transcription and protein synthesis. 
 
Capecitabine is supplied as either 150 mg or 500 mg peach to light peach, oblong, film-coated, 
biconvex tablets for oral administration.  
 
Capecitabine will be provided as an outpatient prescription. Capecitabine should be stored at 25oC 
(77oF); excursions permitted to 15° to 30°C (59° to 86°F). Keep tightly closed. 
 
Dosing and Administration of Capecitabine 
 
Capecitabine will be administered on an outpatient basis. Capecitabine will be given by oral 
administration twice daily on days 1-7 and 15-21 for patient in Cohort 1 and on days 1-14 for 
patient in Cohort 2 of each cycle. Capecitabine tablets should be taken within 30 minutes after the 
end of a meal and swallowed with water.   
 
Toxicities of Capecitabine 
 
Please see the capecitabine prescribing information for more details on the known precautions, 


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23
warnings, and adverse reactions of capecitabine. The most common side effects of capecitabine 
are diarrhea, nausea, vomiting, stomatitis, abdominal pain, upset stomach, constipation, loss of 
appetite, dehydration, hand-and-foot syndrome (palms of the hands or soles of the feet tingle, 
become numb, painful, swollen or red), rash, dry, itchy or discolored skin, nail problems, hair loss, 
tiredness, weakness, dizziness, headache, fever, pain (including chest, back, joint, and muscle 
pain), trouble sleeping, and taste problems. Capecitabine is a Pregnancy Category D drug. Women 
of childbearing potential should be advised to avoid becoming pregnant while receiving treatment 
with capecitabine. If capecitabine is used during pregnancy, or if the subject becomes pregnant 
while taking capecitabine, the subject should be apprised of the potential hazard to the fetus. 
 
7.4 
Cisplatin 
 
For complete details on drug administration, storage, clinical pharmacology, and the human 
pharmacokinetics of Cisplatin, please see the Cisplatin prescribing information. 
 
Description, Formulation, and Storage 
 
Cisplatin (cis-diamminedichloroplatinum) is a heavy metal complex containing a central atom of 
platinum surrounded by two chloride atoms and two ammonia molecules in the cis position. 
Cisplatin inhibits DNA synthesis by forming inter- and intra-strand crosslinks. Other possible 
mechanisms include chelation of DNA and binding to cell membranes thereby stimulating immune 
mechanisms. 
 
Cisplatin Injection is a sterile aqueous solution, available commercially in 50, 100 and 200 mL 
multiple dose vials, each mL containing 1 mg of cisplatin and 9 mg sodium chloride in water for 
injection. HCl and/or sodium hydroxide added to adjust pH to 3.5 to 4.5. 
 
Intact vials should be stored at room temperature and be protected from light. Solutions diluted in 
0.9% or 0.45% NaCl to a concentration of 0.05-2mg/mL are stable for up to 72 hours at room 
temperature and protected from light. 
 
Preparation and Administration 
 
Unopened vials of dry powder are stable for the lot life indicated on the package when stored at 
room temperature (25° C, 77° F). The reconstituted solution is stable for 20 hours at room 
temperature (25° C, 77° F). Solution removed from the amber vial should be protected from light 
if it is not to be used within six hours. Once reconstituted, the solution should be kept at room 
temperature (25° C, 77° F). If the reconstituted solution is refrigerated a precipitate will form. 
 
Cisplatin may be administered on an outpatient basis. Cisplatin should be administered on day 1 
and 15 for patients in Cohort 1 and day 4 and 11 for patients in Cohort 2 of each cycle by 
intravenous infusion over 60 minutes following the gemcitabine infusion. Infusion times are 
approximate and may need to be adjusted based on patient tolerability. Cisplatin should be 
administered in 250 mL NaCl, following intravenous hydration with at least 500 ml of normal 
saline. 500ml of normal saline may also be administered after cisplatin.  Needles, syringes, 


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24
catheters, or IV administration sets containing aluminum parts should not be used, as contact with 
cisplatin yields a black precipitate. 
 
Toxicities of Cisplatin 
 
Please see the Cisplatin prescribing information for more details on the known precautions, 
warnings, and adverse reactions of Cisplatin. Common side effects include myelosuppression, 
nausea, vomiting, anorexia, elevation of BUN and creatinine, hyperuricemia, renal tubular 
damage, rare cardiac abnormalities, taste alteration, peripheral neuropathy, seizures, anaphylactoid 
and urticarial reactions (acute), rash, fatigue, otoxicity including hearing loss or tinnitus, and loss 
of muscle function. Cisplatin can cause fetal harm when administered to a pregnant woman. 
Cisplatin is mutagenic in bacteria and produces chromosome aberrations in animal cells in tissue 
culture. In mice, cisplatin is teratogenic and embryotoxic. If this drug is used during pregnancy or 
if the subject becomes pregnant while taking this drug, the subject should be apprised of the 
potential hazard to the fetus. Subjects should be advised to avoid becoming pregnant. 
 
7.5  
Irinotecan 
 
For complete details on drug administration, storage, clinical pharmacology, and the human 
pharmacokinetics of Irinotecan, please see the Irinotecan prescribing information. 
 
Description, Formulation, and Storage 
 
Irinotecan is a derivative of camptothecin. Camptothecins interact specifically with the enzyme 
topoisomerase I, which relieves torsional strain in DNA by inducing reversible single-strand 
breaks. Irinotecan and its active metabolite SN-38 bind to the topoisomerase IDNA 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. Mammalian cells cannot efficiently repair these double-strand breaks. 
 
Irinotecan is a sterile, pale yellow, clear, aqueous solution. It is available in three single-dose sizes 
in brown glass vials: 2 mL-fill vials contain 40 mg irinotecan hydrochloride, 5 mL-fill vials contain 
100 mg irinotecan hydrochloride, and 15 mL-fill vials contain 300 mg irinotecan hydrochloride. 
Each milliliter of solution contains 20 mg of irinotecan hydrochloride (on the basis of the trihydrate 
salt), 45 mg of sorbitol, NF, and 0.9 mg of lactic acid, USP. The pH of the solution has been 
adjusted to 3.5 (range, 3.0 to 3.8) with sodium hydroxide or hydrochloric acid. 
 
Store at controlled room temperature 15° to 30°C (59° to 86°F). Protect from light. It is 
recommended that the vial should remain in the carton until the time of use.  
 
Preparation and Administration 
 
Dilute irinotecan with 5% Dextrose Injection, USP (D5W), or 0.9% Sodium Chloride Injection, 
USP, prior to intravenous infusion. The solution is physically and chemically stable for up to 24 
hours at room temperature and in ambient fluorescent lighting. Solutions diluted in 5% dextrose 


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25
Injection, USP, and stored at refrigerated temperatures (approximately 2° to 8°C, 36° to 46°F), and 
protected from light are physically and chemically stable for 48 hours. Refrigeration of admixtures 
using 0.9% Sodium Chloride Injection, USP, is not recommended due to a low and sporadic 
incidence of visible particulates. Freezing irinotecan and admixtures of irinotecan may result in 
precipitation of the drug and should be avoided. 
 
The irinotecan injection solution should be used immediately after reconstitution as it contains no 
antibacterial preservative. Irinotecan may be administered on an outpatient basis and should be 
administered on day 1 and 15 for patients in Cohort 1 and day 4 and 11 for patients in Cohort 2 of 
each cycle by intravenous infusion over 30 minutes following the Cisplatin infusion. Infusion 
times are approximate and may need to be adjusted based on patient tolerability. 
 
Toxicities of Irinotecan 
 
Please see the Irinotecan prescribing information for more details on the known precautions, 
warnings, and adverse reactions of Irinotecan. Common adverse reactions (≥30%) observed in 
combination therapy clinical studies are: nausea, vomiting, abdominal pain, diarrhea, constipation, 
anorexia, 
mucositis, 
neutropenia, 
leukopenia 
(including 
lymphocytopenia), 
anemia, 
thrombocytopenia, asthenia, pain, fever, infection, abnormal bilirubin, alopecia. Common adverse 
reactions (≥30%) observed in single agent therapy clinical studies are: nausea, vomiting, 
abdominal pain, diarrhea, constipation, anorexia, neutropenia, leukopenia (including 
lymphocytopenia), anemia, asthenia, fever, body weight decreasing, alopecia.  
 
Subject Care Implications  
 
Irinotecan and its active metabolite, SN-38, are metabolized via the human cytochrome P450 3A4 
isoenzyme (CYP3A4) and uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1), 
respectively. Patients receiving concomitant ketoconazole, a CYP3A4 and UGT1A1 inhibitor, 
have increased exposure to irinotecan and its active metabolite SN-38.  Co-administration of 
Irinotecan with other inhibitors of CYP3A4 (e.g., clarithromycin, indinavir, itraconazole, 
lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole) or UGT1A1 (e.g., 
atazanavir, gemfibrozil, indinavir) may increase systemic exposure to irinotecan or SN-38.  
Discontinue strong CYP3A4 inhibitors at least 1 week prior to starting Irinotecan therapy.  Do not 
administer strong CYP3A4 or UGT1A1 inhibitors with Irinotecan unless there are no therapeutic 
alternatives. 
 
8. CORRELATIVE/SPECIAL STUDIES 
 
Research samples will be collected at the discretion of the PI based on availability of supplies and 
safety of patient and staff. 
 
8.1 
Plasma Marker Studies 
 
To assess tumor burden dynamics over the course of this study we will collect plasma at baseline 
and with the second on study follow-up scan.  An optional off study plasma sample may be 
collected. Whole blood will be collected in two 10 milliliter plasma preparation tubes with EDTA 


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26
(PPT, BD Vacutainer, Franklin Lakes, NJ) at the designated time points and processed using 
standard laboratory procedures within one hour of collection.  Using a pipette, plasma will be 
transferred to sterile 15 mL conical tube and stored at -80oC.  Stored samples will be used to 
measure circulating tumor DNA10. 
 
8.2 
Whole Blood Studies 
 
To assess the baseline characteristic of the subjects enrolled and to correlate these molecular and 
clinicopathologic criteria with treatment response and toxicity, whole blood will be collected in a 
10 milliliter plasma preparation tube with EDTA (PPT, BD Vacutainer, Franklin Lakes, NJ).   
Within two hours of collection, aliquots of 1 mL of whole blood will be transferred into 2 mL 
tubes and stored at -80oC.  This will be collected at baseline only. 
 
DNA may be extracted from whole blood and used to evaluate for any germline mutations that 
may correlate with response or toxicity.  These may include, but are not limited to FANC GENES, 
PALB2, BRCA1 and BRCA2.   
 
8.3 
Tumor Tissue Studies 
 
Tumor tissue specific somatic genetic changes and aberrations in protein expression may be 
explored in archived tumor tissue obtained prior to treatment on this protocol if blocks or slides 
are readily available.    
 
8.4  
Genomic Analysis 
 
Genomic sequencing library construction, whole genome/exome sequencing, whole transcriptome 
sequencing, microbial sequencing, neoepitope prediction, mutation burden, and bioinformatic 
analysis will be performed either at an on-campus laboratory or at an off-campus sequencing 
service. All the samples will be de-identified before sending to any laboratory for sequencing.  The 
FASTQ files, BAM files and VCF files will be generated and analyzed.  
 
Genomic sequencing data will be stored and computations conducted using a JH IT managed 
subscription of Azure. 
 
Clinical analysis   
 
Several CLIA-certified laboratories now offer molecular profiling of cancer specimens in 
commercial and noncommercial settings and provide these results to patients and their physicians 
(e.g. Foundation Medicine, PGDx, Michigan Center for Translational Pathology, or JHU CLIA 
Laboratories). It is possible, therefore, that some of our research analyses will be conducted in 
these CLIA-certified environments.  If tissue or cells are evaluated with next generation 
sequencing strategies to provide a molecular profile of individual cancer specimens in a CLIA-
certified facility, these results will be made available to the patient and their physician.  Patient 
confidentiality will be maintained, and the patient’s identity will not be publicly linked to any 
study results.  Researchers may use the data set generated in the CLIA assay setting to study 
genetic alterations across a large number of genes important in cancer. Germline mutations are 


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27
only identified in punitive cancer genes. Researchers will use the data set for exploratory research 
to study cancer cell heterogeneity. Some of the sequencing data obtained from the NGS strategies 
will be uploaded to government sponsored databases, such as GEO and dbGAP.  The results of the 
research studies may be published but subjects will not be identified in any publication. 
 
If a germline alteration of clinical importance (as judged by the Investigator) to the subject and his 
or her family members is identified by a CLIA-certified test in the course of this analysis, attempts 
will be made in writing to contact the subject and/or family members for genetic counseling 
referral. 
 
9. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 28 days prior to start of protocol therapy.  Scans 
and x-rays must be done < 21 days prior to the start of therapy.  In the event that the subject’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy. If a patient in Cohort 2 starts capecitabine on days 1-3 and 
becomes ineligible for the intravenous chemotherapy, then this course would not be considered a 
cycle.   
 
 


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28
9.1  
Cohort 1 
 
 
Cycle (28 days) 
Off 
Study 
 
Consent 
Pre-Study 
(baseline) 
Day 1 Days 
2-7 
Days 
8-14 
Day 
15 
Days 
16-21 
Days 
22-28 
Visit Windows (days)1 
 
-28 to 0 
± 4 
 
 
± 4 
 
 
± 28 
Nab-paclitaxel 
 
 
A 
 
 
A 
 
 
 
Gemcitabine 
 
 
B 
 
 
B 
 
 
 
Capecitabine 
 
 
C 
 
C 
 
 
Cisplatin 
 
 
D 
 
 
D 
 
 
 
Irinotecan 
 
 
E 
 
 
E 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Demographics (ethnicity 
and religion)2 
 
X 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
Family history of cancer 
 
X 
 
 
 
 
 
 
 
Concurrent meds 
 
X 
X 
 
 
X 
 
 
X 
Physical exam 
 
X 
X 
 
 
X 
 
 
X 
Vital signs3 
 
X 
X 
 
 
X 
 
 
X 
Height4 
 
X 
 
 
 
 
 
 
 
Weight 
 
X 
X 
 
 
X 
 
 
X 
Performance status 
 
X 
X 
 
 
X 
 
 
X 
CBC w/diff, plts5 
 
X 
X 
 
 
X 
 
 
X 
Serum chemistry5,6 
 
X 
X 
 
 
X 
 
 
X 
CA19-9/CEA7 
 
X 
X 
 
 
 
 
 
 
C-reactive protein 
 
X 
 
 
 
 
 
 
 
AE evaluation 
 
 
X 
 
 
X 
 
 
X 
Radiologic evaluation/ 
RECIST8 
 
X 
X 
 
 
 
 
 
 
B-HCG9 
 
X 
 
 
 
 
 
 
 
Plasma Sample10, 13 
 
X 
X 
 
 
 
 
 
X 
Whole Blood Sample11, 13 
 
X 
 
 
 
 
 
 
 
Archived Tumor Sample12, 
13 
 
X 
 
 


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29
In order to minimize the need for research-only in-person visits, telemedicine visits may be 
substituted for in person clinical trial visits or portions of clinical trial visits where determined to 
be appropriate and where determined by the investigator not to increase the participants risks. 
Prior to initiating telemedicine for study visits the study team will explain to the participant, what 
a telemedicine visit entails and confirm that the study participant is in agreement and able to 
proceed with this method. Telemedicine acknowledgement will be obtained in accordance with the 
Guidance for Use of Telemedicine in Research. In the event telemedicine is not deemed feasible, 
the study visit will proceed as an in-person visit. Telemedicine visits will be conducted using 
HIPAA compliant method approved by the Health System and within licensing restrictions. 
 
A: Nab-paclitaxel:  Dose as assigned; administration schedule 
B: Gemcitabine:  Dose as assigned; administration schedule 
C:  Capecitabine:  Dose as assigned; administration schedule 
D:  Cisplatin:  Dose as assigned; administration schedule 
E: Irinotecan: Dose as assigned; administration schedule 
 
1:   Longer delays to be approved by the Principal Investigator. 
2: Specifically, Ashkenazi Jewish decent 
3: Temperature, blood pressure, and heart rate.  
4:  Height collected prior to study entry may be used. 
5: Repeat labs within 7 days to follow and document the resolution of a dose limiting toxicity 
(Section 4.3) 
6: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, 
creatinine, glucose, phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium, 
magnesium. 
7: Tumor markers may be discontinued by the PI, if they are consistently in the normal range 
starting with the baseline values. 
8:  CT scan (chest/abdomen/pelvis) or MRI (if patient has contrast allergy); to be assessed at 
baseline (baseline scan must be within 21 days of the first dose) and every two cycles. On 
study CT scans/MRIs may be done within 7 days prior to the scheduled visit. If a scan is 
performed early for clinical reasons, the investigator can re-start the 2 cycle count as to not 
overuse imaging.  
9: Urine pregnancy test (women of childbearing potential). 
10: Plasma collection (approximately 20 cc) will occur at baseline and with the second on study 
follow-up scan (about week 16). An optional off study plasma sample may be collected. 
11: Whole blood collection (approximately 10 cc) will occur at baseline only. 
12: Attempts to obtain archival tumor samples will be made for every patient until the sample is 
obtained or documentation that the sample cannot be obtained.  
13: Research samples will be collected at the discretion of the PI based on availability of supplies 
and safety of patient and staff. 
 
 
 


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30
9.2  
Cohort 2 
 
 
Cycle (21 Days) 
Off 
Study 
 
Consent 
Pre-
Study 
(baseline) 
Days 
1-3 
Day 4 Days 
5-6 
Days 
7-10 
Day 
11 
Days 
12-14 
Days 
15-21 
Visit Windows (days)1 
 
-28 to 0 
± 4 
± 4 
 
 
± 4 
 
 
± 28 
Nab-paclitaxel 
 
 
 
A 
 
 
A 
 
 
 
Gemcitabine 
 
 
 
B 
 
 
B 
 
 
 
Capecitabine 
 
 
C 
 
 
Cisplatin 
 
 
 
D 
 
 
D 
 
 
 
Irinotecan 
 
 
 
E 
 
 
E 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Demographics (ethnicity 
and religion)2 
 
X 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
Family history of cancer 
 
X 
 
 
 
 
 
 
 
 
Concurrent meds 
 
X 
 
X 
 
 
X 
 
 
X 
Physical exam 
 
X 
 
X 
 
 
X 
 
 
X 
Vital signs3 
 
X 
 
X 
 
 
X 
 
 
X 
Height4 
 
X 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
X 
 
 
X 
 
 
X 
Performance status 
 
X 
 
X 
 
 
X 
 
 
X 
CBC w/diff, plts5 
 
X 
 
X 
 
 
X 
 
 
X 
Serum chemistry5,6 
 
X 
 
X 
 
 
X 
 
 
X 
CA19-9/CEA7 
 
X 
 
X 
 
 
 
 
 
 
C-reactive protein 
 
X 
 
 
 
 
 
 
 
 
AE evaluation 
 
 
 
X 
 
 
X 
 
 
X 
Radiologic evaluation/ 
RECIST8 
 
X 
 
X 
 
 
 
 
 
 
B-HCG9 
 
X 
 
 
 
 
 
 
 
 
Plasma Sample10, 13 
 
X 
 
X 
 
 
 
 
 
X 
Whole Blood Sample11, 13 
 
X 
 
 
 
 
 
 
 
 
Archived Tumor Sample12, 
13 
 
X 
 
 


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31
In order to minimize the need for research-only in-person visits, telemedicine visits may be 
substituted for in person clinical trial visits or portions of clinical trial visits where determined to 
be appropriate and where determined by the investigator not to increase the participants risks. 
Prior to initiating telemedicine for study visits the study team will explain to the participant, what 
a telemedicine visit entails and confirm that the study participant is in agreement and able to 
proceed with this method. Telemedicine acknowledgement will be obtained in accordance with the 
Guidance for Use of Telemedicine in Research. In the event telemedicine is not deemed feasible, 
the study visit will proceed as an in-person visit. Telemedicine visits will be conducted using 
HIPAA compliant method approved by the Health System and within licensing restrictions. 
 
A: Nab-paclitaxel:  Dose as assigned; administration schedule 
B: Gemcitabine:  Dose as assigned; administration schedule 
C:  Capecitabine:  Dose as assigned; administration schedule 
D:  Cisplatin:  Dose as assigned; administration schedule 
E: Irinotecan: Dose as assigned; administration schedule 
 
1:   Longer delays to be approved by the Principal Investigator. 
2: Specifically, Ashkenazi Jewish decent 
3: Temperature, blood pressure, and heart rate.  
4:  Height collected prior to study entry may be used. 
5: Repeat labs within 7 days to follow and document the resolution of a dose limiting toxicity 
(Section 4.3) 
6: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, 
creatinine, glucose, phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium, 
magnesium. 
7: Tumor markers may be discontinued by the PI, if they are consistently in the normal range 
starting with the baseline values. 
8:  CT scan (chest/abdomen/pelvis) or MRI (if patient has contrast allergy); to be assessed at 
baseline (baseline scan must be within 21 days of the first dose) and every three cycles. On 
study CT scans/MRIs may be done within 7 days prior to the scheduled visit. If a scan is 
performed early for clinical reasons, the investigator can re-start the 3 cycle count as to not 
overuse imaging. 
9: Urine pregnancy test (women of childbearing potential). 
10: Plasma collection (approximately 20 cc) will occur at baseline and with the second on study 
follow-up scan (about week 18). An optional off study plasma sample may be collected. 
11: Whole blood collection (approximately 10 cc) will occur at baseline only. 
12: Attempts to obtain archival tumor samples will be made for every patient until the sample is 
obtained or documentation that the sample cannot be obtained.  
13: Research samples will be collected at the discretion of the PI based on availability of supplies 
and safety of patient and staff. 
 
 
 
 
 
 


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10. MEASUREMENT OF EFFECT 
 
Although response is not the primary endpoint of this trial, patients with measurable disease will 
be assessed by standard criteria. For the purposes of this study, patients should be re-evaluated 
every 2-3 cycles.  
 
10.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks. 
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)11.  Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria. 
 
10.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with GAX-CI. 
 
Evaluable for objective response.  Only those patients who have measurable 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.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
10.1.2 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, as >10 mm with CT scan, or >10 mm with calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the protocol. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 


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33
the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline.  Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but 
in addition should be those that lend themselves to reproducible repeated measurements.  
It may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
10.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 


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34
 
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.  
 
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. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published [JNCI 
96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  
In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria 
which are to be integrated with objective tumor assessment for use in first-line trials in 
ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
10.1.4 Response Criteria 
 
10.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have 
reduction in short axis to <10 mm. 
 
Partial Response (PR): 
 
At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum 
diameters. 
 
Progressive Disease (PD):  
At least a 20% increase in the sum of the diameters of 


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35
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. 
 
10.1.4.2 
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). 
 
10.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
    
For Patients with Measurable Disease (i.e., Target Disease) 
 


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36
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 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 
 
10.1.5 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). 
 


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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.  
 
10.1.6 Progression-Free Survival (PFS)  
 
PFS is defined as the duration of time from start of treatment to time of first documented 
progression or death, whichever occurs first. 
 
10.1.7 Overall Survival (OS) 
 
OS is defined as the duration of time from start of treatment to time of death. 
 
11. DATA REPORTING / REGULATORY REQUIREMENTS 
 
11.1 
Data Management 
 
All information will be collected on study-specific case report forms (CRFs) by study staff. These 
data will be reviewed for completeness and accuracy by the Principal Investigator.  
 
11.2 
Safety Meetings 
 
Scheduled meetings will take place weekly and will include the protocol principal investigator, 
study coordinator(s), data manager(s), sub-investigators (as appropriate), collaborators (as 
appropriate), and biostatisticians (as appropriate) involved with the conduct of the protocol. During 
these meetings matters related to the following will be discussed: safety of protocol participants, 
validity and integrity of the data, enrollment rate relative to expectation, characteristics of 
participants, retention of participants, adherence to protocol (potential or real protocol violations), 
data completeness, and progress of data for objectives. 
 
11.3  Monitoring 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
The SKCCC Compliance Monitoring Program will provide external monitoring for JHU-affiliated 
sites in accordance with SKCCC DSMP (Version 6.0, 02/21/2019).  The SMC Subcommittee will 
determine the level of patient safety risk and level/frequency of monitoring.  
 
The PI is responsible for monitoring the study.  Data must be reviewed to assure the validity of 
data, as well as, the safety of the subjects.  The PI will also monitor the progress of the trial, review 
safety reports, and clinical trial efficacy endpoints, and confirm that the safety outcomes favor 
continuation of the study. 


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38
 
12. STATISTICAL CONSIDERATIONS 
 
12.1 
Study Design/Endpoints 
 
The phase I portion will evaluate up to 4 dose levels and 2 dosing schedules of the regimen to 
determine the MTD or recommended dose for Phase 2. The dose escalation will commence using 
a 3+3 design within each dosing schedule. The MTD will be defined as the dose level in which 0 
or 1 of 6 patients experiences a dose limiting toxicity (DLT) with the next higher dose having at 
least 2 of 3 or 2 of up to 6 patients experiencing a DLT. The recommended dose for the Phase 2 
portion of the trial will be determined according to toxicity and efficacy based on objective 
response. If, however, the MTD is not chosen for expansion, then the PI will formally review the 
toxicity data with the other treating physicians before moving forward. A total of 6 – 77 patients 
will be enrolled, and the actual number will vary depending on the number of DLTs. 
 
The phase II portion will evaluate the efficacy of the regimen.  The PI has discretion on selection 
of the dose level for expansion based on considerations of general tolerability and efficacy if the 
dose level is deemed safe. A dose level from cohort 1 and/or cohort 2 may be chosen for expansion. 
If both cohorts move to expansion, patients will be accrued into expansion cohort 2 and expansion 
Cohort 1 alternately. A block of 4 patients will be enrolled in one cohort and the next 4 patients 
into another cohort.   The primary endpoint of the expansion cohorts will be the PFS. The treatment 
regimen would be considered of insufficient activity for further study in these population if the 
PFS at 6 months is 44% or less (corresponding to median PFS 5.1 months under the assumption 
of exponential distribution), and the minimum required level of efficacy that would warrant further 
study with the proposed regimen is a 65% PFS at 6 months (corresponding to median PFS 9.7 
months).  
 
A total of 22 patients are needed for each expansion cohort selected in the phase II portion, 
including the 6 patients who are treated at the same dose level as phase II dose in phase I portion. 
We expect that 22 subjects are accrued in 24 months and will be followed for additional 12 months 
after the last patient is enrolled. A sample size 22 provides 90% power to detect a 6-month PFS of 
65% compared to the historical rate of 44%, based on a one-sided log-rank test at a 0.1 significance 
level. The calculation assumes an exponential distribution of the PFS time. To account for 10% 
loss of follow-up, we may enroll up to a total of 25 patients (including the 6 patients from phase 1 
portion) per expansion cohort in phase II portion.  
 
Genomic sequencing library construction, whole genome/exome sequencing, whole transcriptome 
sequencing, microbial sequencing, neoepitope prediction, mutation burden, and bioinformatic 
analysis will be performed either at an on-campus laboratory or at an off-campus sequencing 
service. All the samples will be de-identified before sending to any laboratory for sequencing.  The 
FASTQ files, BAM files and VCF files will be generated and analyzed. 
 
Genomic sequencing data will be stored and computations conducted using a JH IT managed 
subscription of Azure. 
 
Safety monitoring 


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39
The study will be continuously monitored for adverse events after the dose escalation phase. If the 
limiting toxicity events appear to be higher than 33%, we will temporarily halt the study pending 
dose modification. Specifically, we will apply a Bayesian toxicity monitoring rule that suspends 
the enrollment if the posterior probability of risk being larger than 0.33 is 70% or higher. The 
monitoring rule uses beta (1.5, 5.5) as prior distribution. This means that our prior guess at the 
proportion of toxicity is 21%, and there is 90% probability that this proportion is between 3% and 
49%.  Starting from the 1st patient enrolled in the phase II portion (after the 6 patients treated at 
phase II dose in phase I portion), the decision rule for safety stopping is as follows: 
 
Stop if: 
# of 
patients 
with AE 
3 
4 
5 
6 
7 
8 
9 
Out of  
3 
4 
7 
10 
13 
15 
18 
 
 
5 
8 
11 
14 
16 
19 
 
 
6 
9 
12 
 
17 
 
 
For example, starting with the 1st patients, if three out of the next 3 patients have limiting toxicity 
events, we will stop the accrual. If four or more out of the first 4-6 patients have limiting toxicity 
events, we will stop.  
 
The operating characteristics of the stopping rule are shown below and are based on 5000 
simulations: 
 
True AE rate 
% simulated trials 
declaring unsafe 
Average sample size 
(out of 19) 
0.10 
0.3 
19 
0.25 
10.0 
17.9 
0.3 
20.6 
17 
0.33 
27.9 
16.2 
0.40 
49.7 
14.1 
0.45 
66.3 
12.4 
0.50 
78.8 
10.8 
 
Data analysis  
The primary objective of Part 2 (expansion) of the study is to evaluate the efficacy of GAX-CI in 
metastatic pancreatic cancer patients. PFS is used as a primary outcome of efficacy. PFS is defined 
as the time from the date of initial dose to the date of disease progression or to death due to any 
cause, whichever occurs first. PFS will be censored on the date of the last evaluable tumor 
assessment documenting absence of progressive disease for patients who are alive and progression 
free. PFS will be summarized by the Kaplan-Meier method. Median PFS and 6-month PFS will be 
estimated from the Kaplan-Meier curve with corresponding 95% confidence interval (CI).  PFS 
will be compared with the historical data of 44% 6-month PFS using one-sample log-rank test. 
 
The secondary outcomes include toxicity, OR, DCR, and OS. We will characterize toxicity as 


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40
percentage by grade. DCR is defined as percentage of patients who achieved complete response 
(CR), partial response (PR), or stable disease (SD) among all evaluable patients. 95% CIs will be 
computed. OS is defined as the time from the date of initial dose to death due to any cause. For 
patients who still alive at the time of analysis, the OS time will be censored on the last date the 
patients are known to be alive. OS will be summarized by the Kaplan-Meier method.  
 
As exploratory analysis, the correlations between baseline characteristics of subjects and treatment 
response and toxicity will be examined using two-sample t-tests or fisher exact test depending on 
the variable type. To evaluate the correlations between tumor tissue specific somatic mutations 
and treatment response and toxicity, fisher exact test will be performed. In addition, regression 
analysis will be used to include other covariates. P-value less than 0.05 will be considered as 
statistically significant. We will not adjust for multiplicity in the hypothesis testing for these 
exploratory analyses. 
 
12.2 
Reporting and Exclusions 
 
12.2.1 Evaluation of toxicity – All patients will be evaluable for toxicity from the time of 
their first treatment with GAX-CI. 
 
12.2.2 Evaluation of response – All patients who start treatment must be assessed for 
response to treatment, even if there are major protocol treatment deviations or if 
they are ineligible.  Each patient will be assigned one of the following categories:  
1) complete response, 2) partial response, 3) stable disease, 4) progressive disease, 
5) early death from malignant disease, 6) early death from toxicity, 7) early death 
because of other cause unless accidental, or 8) unknown (not assessable, 
insufficient data).   
 
All of the patients who met the eligibility criteria (with the possible exception of 
those who received no study medication) should be included in the main analysis 
of the response rate.  Patients in response categories 4-8 should be considered to 
have a treatment failure (disease progression).  Thus, an incorrect treatment 
schedule or drug administration does not result in exclusion from the analysis of 
the response rate.   
 
All conclusions should be based on all eligible and treated patients.  Subanalyses 
may then be performed on the basis of a subset of patients, excluding those for 
whom major protocol deviations have been identified (e.g., early death due to other 
reasons, early discontinuation of treatment, major protocol violations, etc.).  
However, these subanalyses may not serve as the basis for drawing conclusions 
concerning treatment efficacy, and the reasons for excluding patients from the 
analysis should be clearly reported.  The 95% confidence intervals should also be 
provided.  


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41
REFERENCES 
 
1. 
American Cancer Society. Cancer Facts & Figures 2018. Atlanta: American Cancer 
Society; 2018. 
2. 
Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic 
pancreatic cancer. The New England journal of medicine 2011;364:1817-25. 
3. 
Fine RL, Fogelman DR, Schreibman SM, et al. The gemcitabine, docetaxel, and 
capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis. 
Cancer chemotherapy and pharmacology 2008;61:167-75. 
4. 
Burris HA, 3rd, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit 
with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a 
randomized trial. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology 1997;15:2403-13. 
5. 
Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with 
gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the 
National Cancer Institute of Canada Clinical Trials Group. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology 2007;25:1960-6. 
6. 
Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-
paclitaxel plus gemcitabine. The New England journal of medicine 2013;369:1691-703. 
7. 
De Jesus-Acosta A, Oliver GR, Blackford A, et al. A multicenter analysis of GTX 
chemotherapy in patients with locally advanced and metastatic pancreatic adenocarcinoma. 
Cancer chemotherapy and pharmacology 2012;69:415-24. 
8. 
Diaz LA, Jr., Williams RT, Wu J, et al. The molecular evolution of acquired resistance to 
targeted EGFR blockade in colorectal cancers. Nature 2012;486:537-40. 
9. 
Bozic I, Reiter JG, Allen B, et al. Evolutionary dynamics of cancer in response to targeted 
combination therapy. Elife 2013;2:e00747. 
10. 
Wang Q, Chaerkady R, Wu J, et al. Mutant proteins as cancer-specific biomarkers. 
Proceedings of the National Academy of Sciences of the United States of America 
2011;108:2444-9. 
11. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47. 
 
 
 
 


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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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43
APPENDIX B: Cohort 1 Capecitabine Patient Pill Diary 


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44
 COHORT 1 PATIENT DIARY FOR J1847 
 
 
       Name: _____________History #______________   Cycle #: ____   
 
 
• Take capecitabine tablet twice each day within 30 minutes after the end of a meal and 
swallowed with water. 
• Capecitabine should be taken each morning and night at the same time on designated days.  
If you forget a dose, take it as soon as you remember and then resume the next dose at the 
scheduled time.  If it is within 2 hours of your next dose, omit the missed dose. If you vomit 
within 30 minutes of taking your daily dose and you can see the pill, you may repeat the 
dose. 
• The use of any natural/herbal products or other “folk remedies” is discouraged 
• Bring your diary and pill supply with you to each clinic visit. 
 
 
 
Day 
Date 
Time Taken 
# of 
Pills 
Time Taken 
# of 
Pills 
Comments 
1 
 
                    AM     
PM 
       
 
2 
 
                    AM     
PM  
 
3 
 
                    AM     
PM       
 
4 
 
                    AM     
PM        
 
5 
 
                    AM     
PM        
 
6 
 
                    AM     
PM      
 
7 
 
                    AM     
PM     
 
capecitabine should not be taken on days 8-14 
15 
 
                    AM 
 
PM       
 
16 
 
                    AM     
PM 
 
 
17 
 
                    AM     
PM 
        
 
18 
 
                    AM     
PM 
    
 
19 
 
                    AM 
 
PM 
      
 
20 
 
                    AM     
PM 
 
 
21 
 
                    AM     
PM 
        
 
 
 
 
Completed By ____________________________     Date: ___________________ 
 
 
 
 
 
 
 
 
 
 
 
       
                                                                                                                                  
Study Staff Review _______________________________    Date: ___________________ 
 
 


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45
 
APPENDIX C: Cohort 2 Capecitabine Patient Pill Diary 
 
 


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46
COHORT 2 PATIENT DIARY FOR J1847 
 
 
       Name: _____________History #______________   Cycle #: ____   
 
 
• Take capecitabine tablet twice each day within 30 minutes after the end of a meal and 
swallowed with water. 
• Capecitabine should be taken each morning and night at the same time on designated days.  
If you forget a dose, take it as soon as you remember and then resume the next dose at the 
scheduled time.  If it is within 2 hours of your next dose, omit the missed dose. If you vomit 
within 30 minutes of taking your daily dose and you can see the pill, you may repeat the 
dose. 
• The use of any natural/herbal products or other “folk remedies” is discouraged 
• Bring your diary and pill supply with you to each clinic visit. 
 
 
 
 
Day 
Date 
Time Taken 
# of 
Pills 
Time Taken 
# of 
Pills 
Comments 
1 
 
                    AM     
PM 
       
 
2 
 
                    AM     
PM  
 
3 
 
                    AM     
PM       
 
4 
 
                    AM     
PM        
 
5 
 
                    AM     
PM        
 
6 
 
                    AM     
PM      
 
7 
 
                    AM     
PM     
 
8 
 
                    AM 
 
PM       
 
9 
 
                    AM     
PM 
 
 
10 
 
                    AM     
PM 
        
 
11 
 
                    AM     
PM 
    
 
12 
 
                    AM 
 
PM 
      
 
13 
 
                    AM     
PM 
 
 
14 
 
                    AM     
PM 
        
 
 
 
 
Completed By ____________________________     Date: ___________________ 
 
 
       
                                                                                                                                  
Study Staff Review _______________________________    Date: ___________________ 
 
 


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47
APPENDIX D: SAE Reporting Form 
 
 
 


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48
Serious Adverse Event Reporting Form  
 
 
 
Protocol Title: 
 
 
A phase I/II study of gemcitabine, nab-paclitaxel, capecitabine, cisplatin, and 
irinotecan (GAX-CI) in combination in metastatic pancreatic cancer 
Protocol 
Number: 
 
J1847 
Signature of PI: 
 
 
 
Principal Investigator: 
 
Dr. Dung Le 
Date: 
 
 
 
Report Type: 
Initial    
Follow-up 
Final Follow-up 
Death 
Addendum to: 
 
Serious Criteria (check all 
that apply): 
Death    
Life-threatening 
 Hospitalization or Elongation of 
Existing Hospitalization 
 Other Important Medical Event 
 Cancer 
 Overdose 
 Other:______________________ 
Hospital Admission 
Date: 
 
 
Hospital Discharge 
Date:   
Date Event 
Discovered: 
Section A: Subject Information 
Subject ID: 
Subject Gender: 
Male 
Female 
 
Section B: Event Information 
Event diagnosis or 
symptoms: 
 
Date of First Dose: 
 
Action taken with the study drug: 
 
None 
Interrupted 
Discontinued 
Delayed 
 
Date of Last Dose prior to 
Event: 
 
Number of Total Cycles: 
 
Event Onset Date: 
 
 
 
 
 
 
 
Event End Date: 


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49
Relationship to: 
Gemcitabine 
Nab-
paclitaxel 
Capecitabine 
Cisplatin 
Irinotecan 
Underlying 
Disease 
Unrelated 
 
 
 
 
 
 
Related 
 
 
 
 
 
 
Section C: Brief Description of the Event: 
 
Section D: Relevant Medical History 
 
Section E: Concomitant Drug (Not related to SAE) 
Name of the Drug 
Start Date 
Stop Date 
Route 
Dose 
Frequency 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section F: Comments 
 
Additional Documents: 
 Please specify