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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
34
G-FLIP is a combination of Low Doses of Gemcitabine, Fluorouracil \[5FU\], Leucovorin, Irinotecan, and Oxaliplatin
G-FLIP-DM is low doses of Gemcitabine, Fluorouracil \[5FU\], Leucovorin, Irinotecan, Oxaliplatin, Docetaxel and Mitomycin C
High dose of Vitamin C, used in combination with G-FLIP and then G-FLIP-DM
Bruckner Oncology
The Bronx, New York, United States
Overall Survival
Mean months subjects survived.
Time frame: Survival was monitored from the first day of treatment until the date of death or last followed up.
Objective Response
Objective Response as a means of efficacy assessment was evaluated in terms of response rate. The response rate assessments included Complete Responses (CR), Partial Responses (PR), Overall Response Rate (ORR), Stable Disease (SD), and Disease Control Rate (DCR). The response rate was according to Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI. CR was disappearance of all target lesions. PR was \>=30% decrease in the sum of the longest diameter of target lesions. ORR was CR + PR. SD was a condition that was not PR or Progressive Disease (PD). Finally, DCR was ORR + SD.
Time frame: Performed before the start of treatment, at the beginning of each 2-week treatment cycle, at follow-up visit two weeks after completion of treatment, and for up to 3 years after the start of treatment.
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