Clinical trial NCT01905150
Conditions: Pancreatic Cancer
Keywords: pancreatic Cancer G-FLIP, Gemcitabine 5FU Leucovorin Irinotecan Oxaliplatin G-FLIP-DM (G-FLIP + Low doses Docetaxel and Mitomycin C) Vitamin C (ascorbic acid)
Sponsor: Bruckner Oncology
Start date: 2014-08-13; Completion date: 2020-01-01
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Pancreatic cancer, especially at advanced metastatic stage, is a devastating disease. It is the fourth leading cause of cancer death. Its prognosis is grim - 5-year survival rate being 6%. The current therapies for advanced metastatic pancreatic cancer are very toxic and with limited efficacy. A safer and more effective therapy for this devastating disease is greatly needed.

G-FLIP regimen is a combination of low doses (doses lower than those approved by the FDA and used in the clinic) of several anti-cancer drugs, Gemcitabine, Fluorouracil, Leucovorin, Irinotecan and Oxaliplatin. The efficacy of G-FLIP against cancers (especially pancreatic cancer) is based on laboratory and clinical results, which indicates the synergistic efficacy of these anti-cancer drugs against cancer cells and overcoming tumor drug resistance that cancer cells frequently develop. Also, because of their low doses, this regimen is less toxic than when these drugs are used alone.

Meanwhile, intravenous infusion of high doses (doses significantly higher than the daily nutritional requirements) of Vitamin C (ascorbic acid) has been observed to have anti-cancer activities. This is especially true when Vitamin C is used in combination with other anti-cancer drugs.

Detailed description:
STUDY OBJECTIVE

The objective of this study is to evaluate the safety, tolerability and efficacy of G-FLIP (Low Doses of Gemcitabine, Fluorouracil \[5FU\], Leucovorin, Irinotecan, and Oxaliplatin), when used in combination with ascorbic acid (Vitamin C), as first-line therapy in patients with advanced pancreatic cancer. The objective of this study is also to evaluate the safety, tolerability and efficacy of G-FLIP-DM (G-FLIP + Low Doses of Docetaxel and Mitomycin C), when used in combination with ascorbic acid, in patients with advanced pancreatic cancer who develop Disease Progression (DP) with G-FLIP treatment. The primary endpoint is 12-month survival rate. The secondary endpoints include Overall Survival (OS), Quality of Life (QOL), Response Rate (RR), Progression-Free-Survival (PFS), and safety.

STUDY DRUGS

Study drugs include G-FLIP, G-FLIP-DM, and Vitamin C (Ascorbic Acid)

STUDY DESIGN

Sample Size:

There will be 34 "evaluable" study subjects in this study.

Treatments:

G-FLIP: All study subjects are treated with G-FLIP. Each treatment cycle of G-FLIP is 2 weeks, with G-FLIP given on Days 1 and 2 of each cycle. If study subjects exhibit Disease Progression (DP), treatment with G-FLIP will stop, and they will be treated with G-FLIP-DM.

G-FLIP-DM: Study subjects who exhibit DP with G-FLIP treatment will be treated with G-FLIP-DM. Each G-FLIP-DM treatment cycle is 2 weeks, with G-FLIP-DM given on Days 1 and 2 of each cycle.

Ascorbic Acid: Ascorbic acid will be administered twice weekly throughout the study, given on any 2 separate days of the week. Ascorbic acid will be administered throughout the study including during the follow-up period, even if treatment with G-FLIP or G-FLIP-DM has been terminated due to DP. Additionally, in 50% of the study subjects (i.e., 15 evaluable study subjects), treatment with ascorbic acid will begin on the same week when G-FLIP begins. In the other 50% of the study subjects (i.e., the other 15 evaluable study subjects), treatment with ascorbic acid will be delayed by 2 cycles. Results from these 2 groups of study subjects would allow comparison of potential acute safety of ascorbic acid, when used in combination with G-FLIP.

Open-Label: This is an open-label study, where investigators and study subjects are not blinded to the treatment.

Randomization: The assignment of study subjects will be randomized, as long as they meet eligibility criteria of the study.

DOSE DELAY AND DOSE MODIFICATION

In the event of adverse drug reactions, dose delay and dose modification will be dependent on the type of toxicities. The detailed dose modification scheme for G-FLIP, G-FLIP-DM and Ascorbic Acid are outlined in the protocol.

CONCOMITANT MEDICATIONS AND PROPHYLACTIC TREATMENT

Other than G-FLIP, G-FLIP-DM and ascorbic acid, patients cannot receive any other standard or investigational treatment for their cancer, or any study drugs for any non-cancer indications, while on this study. All concomitant medications (including names, dosage and schedule) must be recorded.

Prophylactic treatment for drug-related symptoms can be given according to Package Inserts of the study drugs and clinical practice. Supportive treatment may include anti-emetic, anti-diarrhea, anti-pyretic, anti-allergic, anti-hypertensive, analgesics, antibiotics, allopurinol, and others such as blood products and bone marrow growth factors. Patients may use erythropoietin for anemia. The investigator may utilize erythropoietic factors, or blood or platelet transfusions at their discretion.

DURATION OF TREATMENT AND FOLLOW-UP

At least six months of treatment is recommended for study subjects who have a response from G-FLIP or G-FLIP-DM, unless or until:

* Patients exhibit disease progression in the opinion of the principal investigator
* Unacceptable toxicity from the treatment
* Patient withdrawal of consent (Note: The investigator should make every effort to contact the subject to perform a final evaluation and to determine the reason(s) for withdrawal from the study.)
* Investigator's discretion to withdraw patients from the study because continued participation in the study is not in the patient's best interest.
* Underlying illness: a condition, injury, or disease unrelated to the intended disease which the study is investigating, that renders continuing treatment unsafe or regular follow-up impossible
* General or specific changes in the patient's condition that renders the patient ineligible for further investigational treatment
* Non-compliance with investigational treatment, protocol-required evaluations or follow-up visits

After treatment, study subjects should be followed so that information on survival and post study treatment are available for at least 1 year after the study subjects participate in the trial.

EFFICACY ASSESSMENTS

The efficacy of the study drugs will be assessed according to the following parameters:

Response Criteria of Complete Response (CR), Partial Response (PR), Stable Disease (SD), and Progressive Disease (Disease Progression or DP) will be derived from CT or MRI according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) (Eisenhauer et al. 2009).

Response Rate (RR) is the number of study subjects, expressed as a percentage of the total number of study subjects participated in the trial, who exhibit PR or CR that has been confirmed from 2 consecutive scans (CT or MRI).

Progression-Free-Survival (PFS) is the length of time when SD (or better) of a study subject is first documented until the time when DP, or death from any cause, occurs.

Overall Survival (OS) is the time from which the study subjects are first treated with G-FLIP to the time when death from any cause occurs. OS, which is the time from which the study subjects are first diagnosed with advanced pancreatic cancer to the time when death from any cause occurs, will also be recorded.

12-Month Survival Rate is the number of study subjects, expressed as a percentage of the total number of study subjects in the trial, who survive for 12 months starting from the time when the study subjects are accrued to the trial. The 12-Month Survival Rate for study subjects who survive for 12 months starting from the time when the study subjects are first diagnosed with advanced pancreatic cancer will also be recorded.

Safety Assessments

The efficacy of the study drugs will be assessed from the first dose to 1 month after last dose of the study drugs. The assessments will be based on the following parameters, performed at baselines and at various times during the study:

* physical exams
* evaluation of symptoms
* vital signs
* ECOG performance status and survival
* clinical pathology (clinical chemistry, renal function \[assessed utilizing the Cockcroft-Gault formula\], hematology, and coagulation)
* urinalysis
* QOL, assessed as described by Aaronson NK, et al. 1993.

Arms: arm 1: G-FLIP in combination with Vitamin C, then G-FLIP-DM in combination with Vitamin C arm 2: G-FLIP alone, then G-GLIP-DM alone
Interventions: intervention 1: G-FLIP intervention 2: G-FLIP-DM intervention 3: Vitamin C
Intervention descriptions: intervention 1: G-FLIP is a combination of Low Doses of Gemcitabine, Fluorouracil \[5FU\], Leucovorin, Irinotecan, and Oxaliplatin intervention 2: G-FLIP-DM is low doses of Gemcitabine, Fluorouracil \[5FU\], Leucovorin, Irinotecan, Oxaliplatin, Docetaxel and Mitomycin C intervention 3: High dose of Vitamin C, used in combination with G-FLIP and then G-FLIP-DM

Protocol documents:
Prot_000.pdf: 
Page 1 of 6 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
An Open Label Phase 2 Trial to Evaluate Safety, Tolerability, and Efficacy of G-FLIP 
(Low Doses of Gemcitabine, Fluorouracil [5FU], Leucovorin, Irinotecan, and Oxaliplatin), 
Followed by G-FLIP-DM (G-FLIP + Low Doses of Docetaxel and Mitomycin C), When 
Used in Combination with Vitamin C, in Patients with Advanced Pancreatic Cancer 
 
 
 
Protocol Number: 
G-FLIP-VitC-Ph2 
 
NCT Number:   
NCT01905150 
 
Study Drugs: 
G-FLIP, G-FLIP-DM, and Vitamin C (Ascorbic Acid) 
 
Current Version:  
January 6, 2015 
 
 
 


Study Drugs:  G-FLIP, G-FLIP-DM and Vitamin C 
Confidential and Proprietary 
Protocol#:  G-FLIP-VitC-Ph2 (Version: January 6, 2015) 
Page 2 of 6 
STUDY SYNOPSIS 
Study Title 
An Open Label Phase 2 Trial to Evaluate Safety, Tolerability, and Efficacy of G-FLIP (Low Doses of 
Gemcitabine, Fluorouracil [5FU], Leucovorin, Irinotecan, and Oxaliplatin), Followed by G-FLIP-DM 
(G-FLIP + Low Doses of Docetaxel and Mitomycin C), When Used in Combination with Vitamin C, in 
Patients with advanced Pancreatic Cancer 
Study No. 
G-FLIP-VitC-Ph2 
Study 
Objectives 
The objective of this study is to evaluate the safety, tolerability and efficacy of G-FLIP, when used in 
combination with ascorbic acid, in patients with advanced pancreatic cancer.  The objective of this 
study is also to evaluate the safety, tolerability and efficacy of G-FLIP-DM, when used in combination 
with ascorbic acid, in patients with advanced pancreatic cancer who develop DP with G-FLIP 
treatment.  The primary endpoint is 12-month survival rate.  The secondary endpoints include Overall 
Survival (OS), Quality of Life (QOL), Response Rate (RR), Progression-Free-Survival (PFS), and 
safety. 
Study Drugs G-FLIP, G-FLIP-DM, and Vitamin C (Ascorbic Acid) 
Study Design Sample Size:  There will be 30 “evaluable” study subjects in this study. 
 
Treatments: 
 
G-FLIP:  All study subjects are treated with G-FLIP.  Each treatment cycle of G-FLIP is 2 weeks, 
with G-FLIP given on Days 1 and 2 of each cycle.  If study subjects exhibit Disease Progression 
(DP), treatment with G-FLIP will stop, and they will be treated with G-FLIP-DM. 
 
G-FLIP-DM:  Study subjects who exhibit DP with G-FLIP treatment will be treated with G-FLIP-
DM.  Each G-FLIP-DM treatment cycle is 2 weeks, with G-FLIP-DM given on Days 1 and 2 of 
each cycle. 
 
Ascorbic Acid:  Ascorbic acid will be administered twice weekly throughout the study, given on any 
2 separate days of the week. 
  
In 50% of the study subjects (i.e., 15 evaluable study subjects), treatment with ascorbic acid will 
begin on the same week when G-FLIP begins.  In the other 50% of the study subjects (i.e., the other 
15 evaluable study subjects), treatment with ascorbic acid will be delayed by 2 cycles.  Results 
from these 2 groups of study subjects would allow comparison of potential acute safety of ascorbic 
acid, when used in combination with G-FLIP. 
 
Open-Label:  This is an open-label study, where investigators and study subjects are not blinded to the 
treatment. 
 
Randomization:  The assignment of study subjects will be randomized, as long as they meet eligibility 
criteria of the study. 
Dosing of G-
FLIP 
G-FLIP is administered on Days 1 and 2 of every 2-week cycle.  The dosing of G-FLIP is shown in 
Table A (below): 
 
Table A:  Administration of G-FLIP 
 
Drug (Dose) 
Administration 
Day 1 
Day 2 
Gemcitabine (500 mg/m2) 
Infused IV over 50 mins 
 
Leucovorin (200 mg/m2) 
Infused IV over 30 mins 
 
Irinotecan (80 mg/m2) 
Infused IV over 90 mins 
 
5-FU (1,500 mg/m2) 
Infused IV continuously over 20 hrs 
Oxaliplatin (40 mg/m2) 
 
IV infusion over 2 hrs 
IV = intravenous or intravenously 
 
 
- cont’d on the next page - 


Study Drugs:  G-FLIP, G-FLIP-DM and Vitamin C 
Confidential and Proprietary 
Protocol#:  G-FLIP-VitC-Ph2 (Version: January 6, 2015) 
Page 3 of 6 
- cont’d from the previous page - 
 
STUDY SYNOPSIS (cont’d) 
Dosing of G-
FLIP-DM 
G-FLIP-DM is administered to study subjects who exhibit DP with G-FLIP treatment.  The dosing of 
G-FLIP-DM is shown in Table B (below): 
 
Table B:  Administration of G-FLIP-DM 
 
Drug (Dose) 
Administration 
Day 1 
Day 2 
Gemcitabine (400 mg/m2) 
Infused IV over 50 mins 
 
Leucovorin (200 mg/m2) 
Infused IV over 30 mins 
 
Irinotecan (80 mg/m2) 
Infused IV over 90 mins 
 
5-FU (1,500 mg/m2) 
Infused IV continuously over 20 hrs 
Docetaxel (25 mg/m2) 
 
Infused IV over 1 hr 
Oxaliplatin (30 mg/m2) 
 
Infusion IV over 2 hrs 
Mitomycin C (5 mg/m2)a 
 
Infused IV over 15 mins 
IV = intravenous or intravenously 
a Given during the first 2 out of every 3 cycles. 
Dosing of 
Ascorbic 
Acid 
Ascorbic acid (100 g in 1 liter) is infused intravenously (IV) twice weekly, given on any 2 separate 
days of the week. 
 
Ascorbic acid administration is given throughout the study, including during the follow-up period 
when treatment with G-FLIP or G-FLIP-DM has been terminated due to DP.  If study subjects miss 
up to 4 infusions over 4 weeks, they are still eligible to remain in the study.  The times and dates of 
Ascorbic acid administration, and if study subjects miss intended administration, must be recorded. 
Dose Delay 
and Dose 
Modification 
In the event of adverse drug reactions related to G-FLIP and G-FLIP-DM, dose delay and dose 
modification will be dependent on the type of toxicities.  The dose modification scheme for G-FLIP 
is outlined in Appendix A, and that for G-FLIP-DM in Appendix B. 
 
For ascorbic acid related reactions including infusion reactions, hypersensitivity reactions, chills, etc., 
the dose of ascorbic acid can be reduced to 75 g and can further be reduced to 50 g if necessary. 
Concomitant 
Medications 
and 
Prophylactic 
Treatment 
Other than G-FLIP, G-FLIP-DM and ascorbic acid, patients cannot receive any other standard or 
investigational treatment for their cancer, or any study drugs for any non-cancer indications, while on 
this study.  All concomitant medications (including names, dosage and schedule) must be recorded. 
 
Prophylactic treatment for drug-related symptoms can be given according to Package Inserts of the 
study drugs and clinical practice.  Supportive treatment may include anti-emetic, anti-diarrhea, anti-
pyretic, anti-allergic, anti-hypertensive, analgesics, antibiotics, allopurinol, and others such as blood 
products and bone marrow growth factors.  Patients may use erythropoietin for anemia.  The 
investigator may utilize erythropoietic factors, or blood or platelet transfusions at their discretion. 
Duration of 
Treatment 
and Follow-
Up 
At least six months of treatment is recommended for study subjects who have a response from G-
FLIP or G-FLIP-DM, unless or until: 
 
- Patients exhibit disease progression in the opinion of the principal investigator 
- Unacceptable toxicity from the treatment 
- Patient withdrawal of consent (Note:  The investigator should make every effort to contact the 
subject to perform a final evaluation and to determine the reason(s) for withdrawal from the study.) 
- Investigator’s discretion to withdraw patients from the study because continued participation in the 
study is not in the patient’s best interest. 
- Underlying illness: a condition, injury, or disease unrelated to the intended disease which the study 
is investigating, that renders continuing treatment unsafe or regular follow-up impossible 
- General or specific changes in the patient's condition that renders the patient ineligible for further 
investigational treatment 
- Non-compliance with investigational treatment, protocol-required evaluations or follow-up visits 
 
After treatment, study subjects should be followed so that information on survival and post study 
treatment are available for at least 1 year after the study subjects participate in the trial. 
 
- cont’d on the next page - 


Study Drugs:  G-FLIP, G-FLIP-DM and Vitamin C 
Confidential and Proprietary 
Protocol#:  G-FLIP-VitC-Ph2 (Version: January 6, 2015) 
Page 4 of 6 
- cont’d from the previous page - 
 
STUDY SYNOPSIS (cont’d) 
Efficacy 
Assessments 
The efficacy of the study drugs will be assessed according to the following parameters: 
 
Response Criteria of Complete Response (CR), Partial Response (PR), Stable Disease (SD), and 
Progressive Disease (Disease Progression or DP) will be derived from CT or MRI according to 
Response Evaluation Criteria in Solid Tumors (RECIST 1.1) (Eisenhauer et al. 2009).  A summary 
of RECIST 1.1 is shown in Appendix C. 
 
Response Rate (RR) is the number of study subjects, expressed as a percentage of the total number of 
study subjects participated in the trial, who exhibit PR or CR that has been confirmed from 2 
consecutive scans (CT or MRI). 
 
Progression-Free-Survival (PFS) is the length of time when SD (or better) of a study subject is first 
documented until the time when DP, or death from any cause, occurs. 
 
Overall Survival (OStreatment) is the time from which the study subjects are first treated with G-FLIP to 
the time when death from any cause occurs.  OSdiagnosis, which is the time from which the study 
subjects are first diagnosed with advanced pancreatic cancer to the time when death from any cause 
occurs, will also be recorded.  
 
12-Month Survival Rate is the number of study subjects, expressed as a percentage of the total number 
of study subjects in the trial, who survive for 12 months starting from the time when the study 
subjects are accrued to the trial.  The 12-Month Survival Rate for study subjects who survive for 12 
months starting from the time when the study subjects are first diagnosed with advanced pancreatic 
cancer will also be recorded. 
Safety 
Assessments 
The efficacy of the study drugs will be assessed from the first dose to 1 month after last dose of the 
study drugs.  The assessments will be based on the following parameters, performed at baselines and at 
various times during the study: 
 
- physical exams 
- evaluation of symptoms 
- vital signs 
- ECOG performance status and survival 
- clinical pathology (clinical chemistry, renal function [assessed utilizing the Cockcroft-Gault 
formula], hematology, and coagulation) 
- urinalysis 
- QOL, assessed as described by Aaronson NK, et al. 1993. 
Inclusion 
Criteria 
Inclusion:  Patients must meet all inclusion criteria before enrollment: 
A. Patients must have histologically or cytologically confirmed metastatic (Stage IV), locally 
advanced unresectable (stage III), or locally recurrent pancreatic adenocarcinoma, and have never 
been treated with any chemotherapy or have received prior chemotherapy for their cancer. 
B. Eastern Cooperative Oncology Group (ECOG) performance status being 0-2. 
C. Expected survival >3 months. 
D. Patients 18 years of age and older of both genders. 
E. Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) 
must use accepted contraceptive methods (abstinence, intrauterine device [IUD], oral 
contraceptive or double barrier device) during the study, and must have a negative serum or urine 
pregnancy test within 2 weeks prior to treatment initiation. 
F. Fertile men must practice effective contraceptive methods during the study, unless documentation 
of infertility exists. 
G. At least 2 weeks must have elapsed from any prior surgery or hormonal therapy. 
 
- cont’d on the next page - 


Study Drugs:  G-FLIP, G-FLIP-DM and Vitamin C 
Confidential and Proprietary 
Protocol#:  G-FLIP-VitC-Ph2 (Version: January 6, 2015) 
Page 5 of 6 
- cont’d from the previous page - 
 
STUDY SYNOPSIS (cont’d) 
Inclusion 
Criteria 
(cont’d) 
H. Laboratory values ≤2 weeks must be: 
- Adequate hematologic (granulocyte count ≥1500/mm3; white blood cell [WBC] 3500 
cells/mm3 or 3.5 bil/L; platelet count 150,000 cells/mm3 or 150 bil/L; absolute neutrophil 
count [ANC] ≥1500 cells/mm3 or 1.5 bil/L; and hemoglobin ≥9 g/dL or ≥90 g/L). 
- Adequate hepatic function (aspartate aminotransferase [AST/SGOT] 3x upper normal limit 
[UNL], alanine aminotransferase [ALT/SGPT] 3x UNL (≤5x UNL if liver metastases 
present), bilirubin 1.5x UNL). 
- Adequate renal function (serum creatinine 2.0 mg/dL).   
- Adequate coagulation (“International Normalized Ratio” or INR must be <1.5) unless on 
therapeutic anticoagulants. 
I. 
No evidence of active infection and no serious infections within the past month. 
J. 
Mentally competent, able to understand and willing to sign the informed consent form. 
Exclusion 
Criteria 
Exclusion:  Patients with any of the following characteristics are excluded: 
A.  Patients under the age of 18. 
B.  Locally advanced resectable disease from pancreatic cancer. 
C. Previous radiotherapy for cerebral metastases, central nervous system (CNS) or epidural tumor. 
D. Patients receiving any other standard or investigational treatment for their cancer, or any other 
investigational agent for any non-cancer indication within the past 4 weeks. 
E. Patients with any active uncontrolled bleeding, or a bleeding diathesis (e.g., active peptic ulcer 
disease). 
F. Pregnant women, or women of child-bearing potential not using reliable means of contraception. 
G. Lactating females.   
H. Fertile men unwilling to practice contraceptive methods during the study period. 
I. 
Life expectancy less than 3 months. 
J. 
Any condition or abnormality which may, in the opinion of the investigator, compromise the 
safety of patients. 
K. Unwilling or unable to follow protocol requirements. 
L. Active heart disease including but not limited to symptomatic congestive heart failure, 
symptomatic coronary artery disease, symptomatic angina pectoris, symptomatic myocardial 
infarction, or symptomatic congestive heart failure. 
M. Patients with a history of myocardial infarction that is <3 months prior to registration. 
N. Patients with any amount of clinically significant pericardial effusion. 
O. Evidence of active serious infection. 
P. Patients with known HIV infection. 
Q. Requirement for immediate palliative treatment of any kind including surgery and radiation. 
R. Patients that have received a chemotherapy regimen requiring stem cell support in the previous 6 
months. 
S. Patients with Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency; a history of oxalate renal 
calculi and/or hyperoxaluria; a history of systemic iron overload; and creatinine clearance <60 
cc/minute. 
T. Any condition or abnormality which may, in the opinion of the investigator, compromise the 
safety of the patient. 
 
- cont’d on the next page - 


Study Drugs:  G-FLIP, G-FLIP-DM and Vitamin C 
Confidential and Proprietary 
Protocol#:  G-FLIP-VitC-Ph2 (Version: January 6, 2015) 
Page 6 of 6 
- cont’d from the previous page - 
 
STUDY SYNOPSIS (cont’d) 
Study 
Procedures 
The study procedures outlined in Table C (below): 
 
Table C:  Study Procedures 
 
 
Assessments 
Pre-
Study 
Screen6 
Each 2-Week Cycle 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Days 
5-14 
Informed consent 
 
 
 
 
 
 
Medical history 
 
 
 
 
 
 
Pregnancy test for women of child-bearing 
potential 
 
 
 
 
 
 
G-FLIP or G-FLIP-DM1 
 
 
 
 
 
 
Ascorbic Acid 
 
Given twice weekly2 
Neupogen 
 
 
 
 
 
 
Evaluation of symptoms and vital signs 
5 
 
 
 
 
 
ECOG performance status, QOL, and survival 
(12-month survival rate and OS) 
 
 
 
 
 
 
Clinical chemistry4, hematology and coagulation 
 
3 
 
 
 
 
Urinalysis 
 
 
 
 
 
 
Efficacy assessments: 
 
 
- CT or MRI (for RR and PFS) 
 
Post Cycle 4, then every 6th cycle7 
- CA 19-9 
 
Every other cycle7 
Survival and post-trial cancer treatment 
Monitor bi-monthly via phone contact after 
patients are removed from study 
DP = Disease Progression; ECOG = Eastern Cooperative Oncology Group; G-FLIP = low doses of 
gemcitabine, fluorouracil (5FU), leucovorin, irinotecan, and oxaliplatin; G-FLIP-DM = G-FLIP + low doses of 
docetaxel and mitomycin C; hr = hour; IV = intravenous or intravenously; min = minute; OS = Overall 
Survival; PFS = Progression-Free-Survival; QOL = Quality of Life; RR = Response Rate. 
1 All study subjects are treated with G-FLIP.  If study subjects exhibit DP, treatment with G-FLIP will stop 
and they will be treated with G-FLIP-DM. 
2 Ascorbic acid (100 g in 1 liter) is infused IV twice weekly, given on 2 separate days of the week. 
3 These tests are performed on Day 1 of each treatment cycle, with CBC results available for review before 
administration of the anti-tumor agents and other results available for review on Day 2. 
4 Renal function will be assessed utilizing creatinine and/or Cockcroft-Gault formula. 
5 Other than evaluation of symptoms and vital signs, height and weight, physical exam, medications, and date 
of diagnosis of advanced pancreatic cancer are also determined during pre-study medical screening. 
6 Pre-study screening tests, which are also enrollment evaluations, must be performed according the following 
time frames: 
Within 4 weeks:  tumor assessment (imaging scans [CT or MRI] and CA 19-9) 
Within 2 weeks:  medical history, physical exam, vital signs, height, weight, ECOG, evaluation of 
symptoms and medications, QOL, date of diagnosis of advanced pancreatic cancer, clinical chemistry, 
hematology, coagulation, and urinalysis. 
Within 2 weeks:  pregnancy test for women of child-bearing potential. 
7 Additional scans and CA 19-9 tests can be performed during the study at the discretion of the investigator. 
 
 
 

SAP_001.pdf: 
Page 1 of 2 
 
 
 
 
STATISTICAL ANALYSIS PLAN (SAOP) 
 
FOR 
 
CLINICAL STUDY PROTOCOL 
 
 
 
An Open Label Phase 2 Trial to Evaluate Safety, Tolerability, and Efficacy of G-FLIP 
(Low Doses of Gemcitabine, Fluorouracil [5FU], Leucovorin, Irinotecan, and Oxaliplatin), 
Followed by G-FLIP-DM (G-FLIP + Low Doses of Docetaxel and Mitomycin C), When 
Used in Combination with Vitamin C, in Patients with Advanced Pancreatic Cancer 
 
 
 
Protocol Number: 
G-FLIP-VitC-Ph2 
 
NCT Number:   
NCT01905150 
 
Study Drugs: 
G-FLIP, G-FLIP-DM, and Vitamin C (Ascorbic Acid) 
 
Current Version:  
January 6, 2015 
 
 


Study Drugs:  G-FLIP, G-FLIP-DM and Vitamin C 
Confidential and Proprietary 
Protocol#:  G-FLIP-VitC-Ph2 (Version: January 6, 2015) 
Page 2 of 2 
STATISTICAL ANALYSIS PLAN 
 
This is a Phase II single-arm.  Therefore, results are not compared to any concurrent control 
group.  The primary endpoint is 12-month survival rate, and the secondary endpoints include 
QOL, RR, PFS, CA 19-9, and safety. 
 
Efficacy:  Distributions of the time-to-event endpoints (i.e., OS and PFS) will be estimated using 
Kaplan-Meier methodology.  The medians of these time-to-event endpoints, as well as the 
number of treatment cycles of G-FLIP and G-FLIP-DM, will be presented with the appropriate 
95% CIs.  Results derived from this trial will be cross-referenced with the recent Phase 3 trial 
of FOLFIRINOX in patients with metastatic pancreatic cancer (Thierry C, et al.  FOLFIRINOX 
versus Gemzar® for Metastatic Pancreatic Cancer.  NEJM 2011, 364:1817-1823.) for 
comparison purposes. 
 
QOL and CA 19-9 will be assessed at baseline, as well as at multiple time points during G-
FLIP and G-FLIP-DM treatments.  QOL and CA 19-9 results at baseline, during G-FLIP vs. G-
FLIP-DM treatments will be compared using Within-Subject Analysis of Variance (ANOVA). 
 
RR during G-FLIP treatment will be cross-referenced to the Phase 3 trial of FOLFIRINOX in 
patients with metastatic pancreatic cancer (Thierry C, et al. 2011), for comparison purposes.  
RR associated with G-FLIP vs. G-FLIP-DM treatments will be compared using Within-Subject 
ANOVA.  RR associated with G-FLIP-DM treatment is not expected to be as high as RR 
associated with G-FLIP treatment, since G-FLIP-DM is to be given to study subjects who 
exhibit DP with G-FLIP treatment.  However, a significant RR associated with G-FLIP-DM 
would suggest that G-FLIP-DM may be a viable “salvage” or “rescue” regimen for patients 
with advanced pancreatic cancer who have failed G-FLIP regimen. 
 
Safety:  Safety data (vital signs, laboratory parameters, and ADRs, etc.) will be tabulated for all 
subjects.  ADRs will be evaluated according to the latest version of National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE). 
 
Treatment of ascorbic acid will begin on the same week as G-FLIP in 50% of the study 
subjects, and in the other 50% of the study subjects, ascorbic acid treatment will be delayed by 
2 cycles.   The safety results collected during this 4-week period between the 2 groups of study 
subjects will be compared using between-subject ANOVA to assess the acute safety of 
ascorbic acid, when used in combination with G-FLIP.