Gourgou-Bourgade, et al DOI: /JCO

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1 Impact of FOLFIRINO compared with gemcitabine on Quality-of-Life in Patients with Metastatic Pancreatic Cancer: results from the PRODIGE 4/ACCORD 11 randomized trial Gourgou-Bourgade, et al DOI: /JCO The information provided may not reflect the complete protocol or any previous amendments or modifications. As described in the Information for Contributors ( only specific elements of the most recent version of the protocol are requested by JCO. The protocol information is not intended to replace good clinical judgment in selecting appropriate therapy and in determining drug doses, schedules, and dose modifications. The treating physician or other health care provider is responsible for determining the best treatment for the patient. ASCO and JCO assume no responsibility for any injury or damage to persons or property arising out of the use of these protocol materials or due to any errors or omissions. Individuals seeking additional information about the protocol are encouraged to consult with the corresponding author directly.

2 RANDOMIZED PHASE II / III STUDY COMPARING FOLFIRINO REGIMEN [OALIPLATIN / IRINOTECAN /LV5FU] WITH GEMCITABINE AS FIRST LINE CHEMOTHERAPY OF PATIENTS WITH METASTATIC CANCER OF THE PANCREAS TRIAL OBJECTIVES 2.1 Main objective of the phase II study To evaluate the efficacy of the oxaliplatin + irinotecan + 5 fluorouracil and folinic acid association (Folfirinox arm A) in the treatment of metastatic cancer of the pancreas; compared with the reference treatment with gemcitabine (arm B). The criterion will be the comparison of the objective response rate between the 2 arms. 2.2 Secondary objectives of the phase II study To compare the treatment tolerance between the two arms, especially grade 3 and 4 toxicities. 2.3 Main objective of the phase III study The main objective is to compare overall survival between the two therapeutic arms : the Folfirinox regimen (arm A) and the reference treatment with gemcitabine (arm B). 2.4 Secondary objectives of the phase III study To compare the progression-free survival between the 2 arms To compare the quality of life between the 2 arms. To compare the response rate between the 2 arms To compare the toxicity between the 2 arms PATIENTS SELECTION INCLUSION CRITERIA 1. Histological or cytological diagnosis of adenocarcinoma of the pancreas 2. Metastatic disease 3. Measurable disease excluding irradiated lesions; lesions are considered measurable if they can be accurately measured in at least one dimension, with the largest reported diameter >20 mm by conventional CT scan or >10 mm with a spiral CT scan 4. No prior chemotherapy 5. No prior abdominal radiotherapy (except for palliative radiotherapy on non-target lesions)

3 6. Age from 18 to 75 years 7. WHO/ECOG performance status Adequate hematological function (neutrophil count 1500/mm 3, platelets /mm 3 ) 9. Adequate hepatic function (bilirubin 1.5 x upper normal limit [ULN]; biliary drainage is permitted 10. Adequate renal function (creatinine <120 µmol/l or 13.6 mg/l) 11. Absence of cardiac insufficiency, chest pain (not medically controlled) and myocardial infarction in the 12 months preceding study entry 12. Signed informed consent ECLUSION CRITERIA 1. Presence of other kind of pancreatic tumors, specifically endocrine and acinar cell carcinomas 2. Presence of cerebral or meningeal metastases 3. Contraindication to any of the planned treatments 4. History of chronic diarrhea or colorectal inflammatory conditions, or of unresolved occlusion or sub-occlusion for which symptomatic treatment is being administered 5. Active infection or other serious underlying conditions which may prevent the patient from receiving the planned treatment 6. Other concomitant cancer or history of another malignancy with the exception of basal cell carcinoma or cervical cancer in situ. 7. Inclusion in another investigational clinical trial 8. Women who are pregnant, breast-feeding or not using adequate contraceptive measures 9. Individuals under correctional supervision or guardianship 10. Geographical, sociological or psychological reasons preventing medical follow-up TREATMENTS 6.1 Description of the study treatments Patients will be randomly allocated to receive either treatment A (FOLFIRINO) or treatment B (gemcitabine): The following treatments were to be administered on Day 1 of a 14-day cycle: Oxaliplatin (Eloxatin ), 85 mg/m² as a 2-hour IV infusion, immediately followed by

4 Folinic acid*, 400 mg/m² as a 2-hour IV infusion through a Y-tubing device Irinotecan (Campto ), 180 mg/ m² as a 90-min IV infusion (initiated 30 minutes after the folinic acid infusion), immediately followed by 5-FU, 400 mg/m² as a 5-min IV bolus followed by a 46-hour continuous IV infusion of 2.4 g/m² total (ie 1.2 g/m² on Day 1 and 1.2 g/m² on Day 2). *Folinic acid could be replaced by calcium levofolinate at a dose of 200 mg/m². Treatment was administered in an outpatient setting for a maximum of 12 cycles. Treatment B: gemcitabine Gemcitabine (Gemzar ) 1000 mg/m 2, 30-min IV infusion, weekly for 7 weeks (Day 1 to 43), then weekly from D57 for 3 weeks every 4 weeks. No intramuscular injection is permitted. For coherence with Arm A, a cycle was also defined as 14 days. A maximum of 12 cycles (ie ~6 months) was recommended. Further treatment was administered according to the investigator s decision. The experimental products will be prepared according to the Good Clinical Practices and according to modalities described in appendix 1. Irinotecan and oxaliplatin will be supplied by the study sponsor and the other drugs will be supplied by the pharmacy stock of the investigational center. Oxaliplatin and irinotécan are supplied by the sponsor: -these products will be labeled in conformity with the article R.5123 du Code de la Santé Publique and the recommendations of the European good fabrication practices (Appendix 1). -the products will be dispatched in the different pharmacies of the participating centers according to the Bonnes Pratiques de Distribution (BPD). All products will be traceable within the framework of the clinical study. Traceability will be mandatory throughout the overall duration of the study.

5 6. TREATMENT SCHEDULE

6 Efficacy and Safety Variables Efficacy and Safety Measurements Assessed and Flow Chart Flow chart of assessments Assessments on study (ie up to Cycle 12) are presented for Arm A in Table 1 and for Arm B in Table 2. Table 1: Schedule of assessments on-study Arm A (FOLFIRINO) Inclusion On study follow up 8 week On study follow up Cycles 1 to 4 exam Cycles 5 to 12 Informed consent Inclusion/exclusion criteria Randomisation Clinical exam Day D0 D1 D15 D29 D43 ~D50 D57 D71 D n Cycle C1 C2 C3 C4 C5 C6 Weight Height Performance status Concomitant treatments Adverse events 1 Laboratory exam 2 CBC PT, PTT Albumin, LDH Electrolytes, Ca, serum protein, glucose Hepatic enzymes q2 months Creatinine q2 months CEA, CA q2 months 4 Pregnancy test 5 CT scan (abdom/thorac/pelv) 6 q2 months ECG QoL questionnaire 1. SAEs occurring up to 30 days after the last chemotherapy injection were to be declared to the Sponsor within 48 hours after which, only related SAEs were to be declared. 2. Laboratory parameters were to be evaluated within 1 week prior to inclusion. 3. Bilirubin, ALT/AST, alkaline phosphatase, GGT. Analysis of total, free and conjugated bilirubin must be performed at least monthly. 4. Only the marker with the highest value relative to normal was evaluated subsequent to the first evaluation. 5. For women of child-bearing potential without adequate contraceptive means. 6. Imaging could be performed up to 3 weeks prior to inclusion.

7 Table 2: Schedule of assessments Arm B (Gemcitabine) Inclusion On study follow up to Cycle 4 8 week exam On study follow up Cycles 5 to 12 Informed consent Inclusion/exclusion criteria Randomization Clinical exam Day D0 D1 D8 D15 D22 D29 D36 D43 ~D50 D57 D64 D71 D n Cycle C1 C2 C3 C4 C5 C6 C7 Weight Height Performance status Concomitant treatments Adverse events 1 Laboratory exam 2 CBC PT, PTT Albumin, LDH Electrolytes, Ca, serum protein, glucose Hepatic enzymes q2 months Creatinine q2 months Glucose CEA, Ca q2 months 3 Pregnancy test 4 CT scan (abdom/thoracic/pelv) 5 q2 months ECG QoL questionnaire 1. SAEs occurring up to 30 days after the last chemotherapy injection were to be declared to the Sponsor within 48 hours after which, only related SAEs were to be declared. 2. Laboratory parameters were to be evaluated within 1 week prior to inclusion. 3. Only the marker with the highest value relative to normal was evaluated subsequent to the first evaluation. 4. For women of child-bearing potential without adequate contraceptive means. 5. Imaging could be performed up to 3 weeks prior to inclusion.

8 A) Inclusion Description of assessments by time period Eligible patients with signed informed consent were screened within 8 days prior to treatment initiation. CT scan and ECG could be performed up to 3 weeks prior to treatment initiation, and the QoL questionnaire was to be completed at the hospital the day of informed consent signature (ie on the day of randomization or in the 15 days prior). Physical exam including weight, height and ECOG performance status Concomitant treatment Laboratory exams Hematology and coagulation: complete blood count (CBC), prothrombin time (PT), partial thromboplastin time (PTT) Electrolytes, calcium Protein, albumin, glucose Bilirubin (total, free and conjugated), alkaline phosphatase, AST/ALT, lactate dehydrogenase (LDH) Creatinine CA 19 9 and CEA Pregnancy test (in women of child bearing age, not using adequate contraception) Thoracic abdominopelvic CT scan Electrocardiogram (ECG) Quality of Life questionnaire (EORTC QLQ C30) B) On study follow up for Cycles 1 4 Patients were to be followed up every 2 weeks in Arm A (FOLFIRINO) and every week in Arm B (gemcitabine), as summarized below. Additional visits were made as required. Arm A FOLFIRINO Day 1, Cycle 1 CBC and creatinine Day 8, Cycle 1 CBC, creatinine, calcium Every 2 weeks (Cycles 2 4), prior to treatment administration Physical exam, including weight and performance status Adverse events, including recovery of any toxicity to initial level, grade 1 or stability Laboratory exams (plasma) CBC Electrolytes, calcium, protein, glucose Bilirubin (total, free and conjugated) at least monthly, alkaline phosphatase, AST/ALT, GGT Creatinine CA 19 9 or CEA, for whichever had the highest value at baseline relative to normal

9 QoL questionnaire EORTC QLQ C30 Arm B gemcitabine Weekly, prior to treatment administration CBC Adverse events, including recovery of any toxicity to initial level or grade 1 Every 2 weeks (Cycles 2 4), prior to treatment administration Physical exam, including weight and performance status Laboratory exams (plasma) Electrolytes, calcium, protein, glucose Bilirubin (total, free and conjugated), alkaline phosphatase, AST/ALT, GGT Creatinine CA 19 9 or CEA, for whichever had the highest value at baseline relative to normal QoL questionnaire EORTC QLQ C30 C) On study follow up for Cycles 5 12 Patients were to be followed up as for Cycles 1 to 4 as appropriate for the treatment arm as described above, with the following exceptions for all patients (both treatment arms): Every 2 months from Week 8 (~D50), prior to treatment administration Thoracic abdominopelvic CT scan (including baseline lesions) Laboratory exams Total, free and conjugated bilirubin, ALT/AST, alkaline phosphatase, GGT Creatinine CEA or CA 19 9, for whichever had the highest value at baseline relative to normal D) Post treatment follow up Patients without progression at 6 months were to be followed up every 2 months for: Performance status, weight QoL questionnaire EORTC QLQ C30 Thoracic abdominopelvic CT scan (including baseline lesions) All patients with progression were to be followed up every 6 months until death for Long term toxicity Survival status Any other treatments for their disease.

10 6.2.3 Treatment duration In the two arms, it is recommended to pursue the per protocol chemotherapy for 6 months. Beyond this period, the therapeutic management of the patient is left to the investigator s discretion. In case of disease progression, the therapeutic management of the patient is left to the investigator s discretion. DOSE ADAPTATION In case of dose reduction the reduced dosage will be maintained in the remaining cycles. Any recurrent grade 4 toxicity after dose reduction will lead to treatment stop. PATIENTS WILL NEVER EIT THE STUDY. THEY WILL BE FOLLOWED UNTIL THEIR DEATH Hematological toxicity Dosage adjustment guidelines for toxicities in the FOLFIRINO arm The dose of leucovorin will not be modified for toxicity, but will be omitted if fluorouracil is omitted. Once a dose is decreased, re-escalation is not permitted. Patients are off study if they develop the same grade 4 toxicity despite a first dose reduction. 1. Hematologic toxicity Do not retreat until the granulocyte count is 1.5 x 10 9 /L and the platelet count is 75 x 10 9 /L.

11 1a. Doses according to the blood counts at the beginning of a cycle (Day 1) Blood counts at Day 1 DELAY OF CYCLE DOSES REDUCTION Irinotecan Oxaliplatin Fluorouracil Granulocytes Hold treatment 1 st occurrence: 1 st occurrence : 1 st occurrence: < 1.5 x 10 9 /L until reduction of no reduction of delete bolus 5FU granulocytes dose to 150 dose 1.5 x 10 9 /L mg/m² (one or two weeks if 2 nd occurrence: 2 nd occurrence: necessary). maintain the reduce the dose dose at 150 to 60 mg/m2 mg/m² In case of non 3 rd occurrence: 3 rd occurrence: recovery after treatment treatment 2 weeks delay, discontinuation discontinuation stop treatment* Platelets < 75 Hold the 1st occurrence : 1 st occurrence: 1 st occurrence: x 10 9 /L treatment until no reduction of reduce the dose reduce both the recovery dose to 60 mg/m² bolus and the

12 (platelets 75 x continuous 10 9 /L). 2 nd occurrence: 2 nd occurrence: infusion to 75% reduce the dose maintenance of of the original In case of non to 150 mg/m² the reduced doses recovery after dose 2 weeks delay, stop treatment 3 rd occurrence: 3 rd occurrence: treatment treatment discontinuation discontinuation 1b. According to the low nadir blood counts or in case of infection ADVERSE EVENTS Febrile neutropenia REDUCTION OF DOSE FOR SUBSEQUENT CYCLES 1 st occurrence: reduce the dose of irinotecan to 150 mg/m² and delete the bolus 5FU dose Grade 4 neutropenia during more than 7 days 2nd occurrence: reduce also the dose of oxaliplatin to 60 mg/m² Infection with concomitant grade 3-4 neutropenia 3rd occurrence: treatment discontinuation

13 Grade 3-4 thrombocytopenia 1st occurrence: reduce the oxaliplatin dose to 60 mg/m² and the continuous 5-FU dose to 75 % of the original dose 2 nd occurrence: reduce also the dose of irinotecan to 150 mg/m 2 and the dose of continuous 5FU of additional 25 % 3 rd occurrence: treatment discontinuation Consider the use of Filgrastim for recurrent grade 3/4 neutropenia despite a first-dose reduction or after febrile neutropenia. 2. Gastrointestinal toxicities Patients must be instructed in the use of loperamide as treatment for diarrhea, and must have a supply of this drug upon starting FOLFIRINO. Patients should not be retreated with irinotecan until recovery from diarrhea (without loperamide for at least 24 h) has occurred. ADVERSE EVENTS Diarrhea grade 3-4 or Diarrhea + fever and/or REDUCTION OF DOSE FOR SUBSEQUENT CYCLES 1 st occurrence: reduce the irinotecan dose to 150 mg/m 2 and delete the bolus 5FU dose 2 nd occurrence: reduce also the oxaliplatin dose to 60 mg/m²

14 neutropenia grade 3-4 and reduce the dose of continuous 5FU to 75 % of the original dose 3rd occurrence: treatment discontinuation Diarrhea 48 h despite high doses loperamide No systematic reduction of the irinotecan, oxaliplatin or 5FU doses after complete recovery, unless grade 3-4 diarrhea, or diarrhea + fever, and/or concomitant neutropenia grade Mucositis or hand-foot syndrome In case of grade 3-4 toxicity, a reduction in dosages of 25% of both bolus 5FU and of continuous 5FU will be carried out for the subsequent cycles. 4. Cardiac toxicity In case of angina pectoris or of myocardial infarction, 5FU has to be stopped. 5. Increase of bilirubin In case of elevation of bilirubin, it is suggested to exclude an obstruction of the biliary stent or a progressive disease and to postpone chemotherapy. If bilirubin is >1.5xULN, irinotecan is not recommended. If chemotherapy is medically indicated, it is necessary to provide a dose adjustment of irinotecan. 6. Other toxicities

15 Any other toxicity grade 2, except anemia and alopecia, can justify a reduction of dose if medically indicated, for example reduction of irinotecan to 150 mg/m² and/or oxaliplatin to 60mg/m² and/or 5FU of 25% depending of the type of adverse event. II. Gemcitabine dosage adjustment guidelines for toxicities 1. Doses according to the blood counts prior to each dose Blood counts on the day of therapy Granulocytes > 1.0 x 10 9 /L and platelets > 100 x 10 9 /L 0.5 < Granulocytes 1.0 x 10 9 /L or 50.0 x 10 9 /L < platelets 100 x 10 9 /L Granulocytes 0.5 x 10 9 /L or platelets 50.0 x 10 9 /L DELAY OF CYCLE No delay No delay Hold treatment until granulocytes 0.5 x 10 9 /L and platelets > 50.0 x 10 9 /L DOSES REDUCTION No dose reduction Reduce the dose to 75% of the original dose No dose reduction 2. Other toxicities Any other toxicity grade 2, except anemia and alopecia, can justify a reduction of dose of 25% if medically indicated.

16 EVALUATION CRITERIA 9.1 Main evaluation criteria of the phase II study The best response recorded between the beginning of the treatment and the disease progression or last evaluation will be taken into account (optimal overall response). The response will be determined according to the RECIST criteria (appendix 4). Objective responses must be confirmed by a new examination 4 weeks after they have been observed. 9.2 Secondary criteria of the phase II study Toxicity To be evaluable for toxicity the patients must have received at least one chemotherapy perfusion. Toxicity will be evaluated according to the NCI toxicity scale (version 3.0) (appendix 5) 9.3 Main criteria of the phase III study Efficacy The main criterion of the phase III study will be the duration of overall survival. 9.4 Secondary criteria of the phase III study Progression-free survival The progression-free survival duration is calculated from the date of randomization to the date of the first documented progression, the date of death, or the date of latest news Response rate The best response recorded between the beginning of the treatment and the disease progression or the last evaluation (optimal overall response) will be taken into account. The response will be determined according to RECIST criteria (appendix 4). All objective responses must be confirmed by a new examination 4 weeks after they have been observed. An independent review committee with two expert radiologists will evaluate externally all responses Toxicity To be evaluable for toxicity the patients must have received at least one chemotherapy perfusion.

17 Toxicity will be evaluated according to the NCI toxicity scale (version 3.0) (appendix 5) Quality of life The quality of life will be measured with the EORTC QLQ-C30 questionnaire (39) (appendix 9), and analyzed in accordance with the EORTC Quality of life Group (43). The main analysis will focus on the quality of life components that are usually altered the most. The most deteriorated components are the overall state of health and the quality of life (questions 29 et 30) : fatigue, pain, physical condition, psychological state, daily activity (38). Changes in the overall state of health and quality of life will be considered the main objective and the other criteria as secondary objectives. Other QLQ-C30 items will be analyzed only on an exploratory basis (43). The EORTC-PAN 24 questionnaire, specific to the pancreatic cancer will not be used because it has not yet been adapted to French patients and validated. STATISTICAL ANALYSIS PLAN 11.1 Number of patients required for the phase II study It will be concluded that Folfirinox has efficacy if the objective response rate is greater than or equal to 24%. In case the objective response rate is less than or equal to 10%, it will be concluded that Folfirinox has no efficacy. The number of patients required is determined using a multi-stage Fleming plan (27). With a power of 92%, a bilateral test alpha = 5% and a 3 stages plan we need to include 44 patients in each arm (88 in total). Decision regarding the continuation of the study will be made with respect to the results recorded in the experimental arm (Folfirinox): At the end of the 1st stage (20 patients included): - if 2 or less objective responses (RO) are observed, then the trial will be stopped and it will be concluded that Folfirinox has no efficacy. - if 8 or more objective responses are observed, then the study is pursued as the planned phase III study. - between 3 and 7 objective responses observer then the phase II study will continue with the inclusion of 10 additional patients: At the end of the 2 nd stage (30 patients included): - if 4 or less objective responses are observed, then it will be concluded that Folfirinox has no efficacy. - if 11 or more objective responses are observed, then it will be concluded that Folfirinox has efficacy and the study will be pursued as the planned phase III study. - between 5 and 10objectives responses the phase II study will be continued with 10 additional patients included.

18 At the end of the 3rd stage (40 patients in total): - if 6 or less objective responses are observed, then it will be concluded that Folfirinox has insufficient efficacy and the phase III study will be cancelled. - with 12 objective responses the study will be pursued as the planned phase III study. - if after 40 patients included no conclusion can be reached, then the phase II will be terminated and the phase III will be launched with the scheduled number of patients (see next section). The power of the statistical plan is 0.92 which means that there are 92% of chances that the experimental treatment has efficacy if the objective response rate is 60%. The alpha risk is 0.05 (i.e. 5% of chances that the experimental treatment has efficacy if the rate of non progression is 35%) Number of patients required for the phase III study To demonstrate a difference of three months (from 7 to 10 months; HR =0.7) between the median survival values, it will be necessary to include 360 patients with an overall alpha risk of 5%, a beta risk of 20% and a trial power of 80%. The power of 80% will be reached after 250 events observed (East 5 software) Statistical analysis The final statistical analysis will be performed after 250 events have been observed. Data will be expressed as: 1. percentage values for the qualitative variables, 2. Mean value and standard deviation or median value and range for the quantitative variables, 3. Survival curves will be estimated with the Kaplan Meier method (27). The reference point will be the date of randomization. Results concerning the primary evaluation criterion and the secondary evaluation criteria will be presented within their 95% confidence interval (Rothman). Comparison will be made using: 1. the 2 test or Fisher test for the qualitative variables 2. the t test of Student or a non-parametric test (Wilcoxon) for the quantitative variables, 3. the log-rank test for the survival data. All comparisons will be adjusted for the stratification factors. Alll tests will be bilateral with a 5 % threshold. The statistical calculations will be realized with the Stata v10 software.

19 11.4 Protocol violation No protocol exclusion will be accepted. Patients wrongly included and patients who will not comply with the protocol will be taken into account in the statistical analysis according to their randomization group (intent-to-treat analysis). To limit the number of patients lost to follow-up, the investigator of each center will be responsible for sending renewed visit requests to the patients who did not attend for scheduled follow-up visit Interim analysis and trial monitoring An interim analysis of efficacy will be performed after 2/3 of the required numbers of events (including death) have been observed, i.e. 167 events. To maintain an overall alpha risk of 5% (p in the final analysis), the interim analysis will be considered as significant with a p-value The Data Monitoring Committee (IDMC) will propose the trial s early termination if it deems it necessary and if the all data available from the trial or from other sources are sufficiently convincing to influence the therapeutic practice of the majority of clinicians. EARLY TREATMENT STOP The patient treatment can be prematurely stopped in case of: - Toxicity, - Disease progression, - consent withdrawal, - lost to follow-up, - Major protocol violation. Within the limit of feasibility, the patients who have prematurely stopped treatment will be followed according to the same modalities as the other patients.