Metastatic Pancreatic Cancer
Conditions
Keywords
cancer, pancreatic cancer, metastatic pancreatic cancer
Brief summary
The pancreas cancer is the 4th cause of death. All stage confused, the survival at 5 years is note over 5 %. At metastatic stage, the pancreatic adenocarcinoma is an incurable disease with the survival median of 2-4 months without chemotherapy. Up to 2011, gemcitabine was the only reference treatment of this type of cancer. But until, the FOLFIRINOX could permitted to improve significantly the overall survival (6,8 months with gemcitabine vs 11,1 months with FOLFIRINOX) and the progression free survival (3,3 months with gemcitabine vs 6,4 months with FOLFIRINOX) for patients under 76 years. Main toxicities of this treatment are hematological, gastrointestinal and neuropathy with apparition of sensitive neuropathy, reversible, related to oxaliplatin. These results are on a population under 76 years old. In this study, the median age of patients at inclusion was 61 years old and FOLFIRINOX was still beneficial for patients more than 65 years old. Given the increase of proportion of patients than more of 65 years old with pancreatic cancer and given the increase of life expected, it is important to know the effectiveness and tolerance of such treatment for patient older than 65 years and 76 years. FIRGEM is an original strategic sequential treatment witch alternates, every 2 month, 4 cycles of FOLFIRI.3 and 2 cycles of 3 injections of gemcitabine. There is no cross resistance known between this 2 treatments witch limit toxicities and preserve quality of life of patients. A Phase II trial testing this treatment regimen to classical regimen of gemecitabine, showed an overall survival of 11 months in the FIRGEM regimen and an overall survival of 8,2 months in the gemcitabine regimen. The rate of progression was 45% near of progression rate with FOLFIRINOX. Tolerance is close to that FOLFIRINOX regimen but this strategic doesn't induce limiting neurotoxicities and allow to use oxaliplatin in 2de line of treatment. The trial propose to evaluate the effectiveness and tolerance of FOLFIRINOX regimen (8 cycles) with LV5FU2 in maintenance (that could increase the FOLFIRINOX tolerable without decrease efficiency), to FIRGEM regimen and to FOLFIRINOX (12 cycles) which is the reference regimen.
Interventions
Sponsors
Federation Francophone de Cancerologie Digestive
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Metastatic disease * At least one mesurable lesion according to RECIST V1.1 criteria * No prior chemotherapy (excepted if there is at least on lestion out of the irradition area) * Age \> 18 years. A favorable adviced by an onco geriatrician would be mandatory for inclusion of patients older than 75 older * Performance statut (WHO) 0-1 * Polynyclear ≥ 1500/mm3 * Bilirubine ≤ 1,5 fois la LSN, creatinin \< 120μmol / L * Signed informed consent form
Exclusion criteria
* Another type of pancreas tumor, as endocrine tumor ou with acinous cells * Ampulloma * Cerebral or meningeal metastasis * Gilbert disease * Neuropathie \> or = grade 1 * Study treatments contraindication * Uncontrolled diarrhoea or inflamatory disease of colon or rectum, or bowel obstruction or bowel sub-obstruction no resolved with specific treatment * Serious uncontrolled intercurrent infections or other serious uncontrolled concomitant disease prevent patient to receive study Cancer within the 5 years before inclusion, except for int situ cancer of the neck of the uterus or basal cell skin cancer * Significant previous cardiac and respiratory disease * Patient included in an other therapeutic study with experimental treatment * Pregnancy or breast feeding * Patient depreved of freedom or under gardianship * Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Alive and Without Radiological and/or Clinical Progression 6 Months After the Randomization. | 6 months after randomization | Progression was defined as radiological progression according to RECIST v1.1 criteria and/or clinical progression according to the investigator. Progression or death (for any reason) was considered if the event occured within the first 6 months since randomization. 6 month scans were 6 month scans with a +/- 1 month window. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to 3 years after the treatment start | Overall survival was defined as the time from the date of randomization to the patient's death (all causes). For alive patients, the date of last news was taken into account. The analysis was done on the ITT population meaning the patients who have been randomized. Numbers of patients correspond the number of patients randomized in the study. |
| Progression-free Survival (PFS) | up to 12 months after randomization | It was defined as the time between t randomization and the date of the first radiological progression (RECIST 1.1 criteria) and/or clinical progression according to the investigator or death (whatever the cause is); Patients alive without progression were censored at date of last news . |
Countries
France
Participant flow
Recruitment details
276 patients were randomized by 53 centers in France between 12 January 2015 and 28 November 2016. 3 patients withdrew their consent so they were never part on analyses populations.
Participants by arm
| Arm | Count |
|---|---|
| FOLFIRINOX Every two weeks (maximum of 12 cycles) : Oxaliplatin 85 mg / m2 Day1 in 2 hours - then Irinotecan 180 mg / m2 Day1 in 90 minutes - Folinic acid 400 mg / m2 Day1 in 2 h (during the irinotecan infusion) - 5-FU bolus 400 mg / m² Day1 followed by continuous 5-FU 2400 mg / m2 total over 46 hours
FOLFIRINOX: Perfusion :oxaliplatine, Irinotecan ,folinic acid, 5FU bolus and continue | 91 |
| FOLFIRINOX + LV5FU2 in Maintenance Folfirinox during 4 months followed by LV5FU2 maintenance until progression:
Folfirinox (as described in arm FOLFIRINOX) LV5FU2 : Folinic acid 400 mg/m² (200 mg/m² if Elvorine), in perfusion over 2 hours the 5FU 400 mg/m² in bolus over 10 mn followed by 5FU 2400 mg/m² in perfusion over 46 hours.
FOLFIRINOX: Perfusion :oxaliplatine, Irinotecan ,folinic acid, 5FU bolus and continue
LV5FU2: Perfusion: Folinic Acid,5FU Bolus,5FU continue | 92 |
| FIRGEM Alternance of 2 months of FOLFIRI.3 with 2 months of GEMCITABINE:
Folfiri.3: Irinotécan 90 mg/m² at day 1 in perfusion over 60 minutes in parralel of folinic acid Folinic acid 400 mg/m² (or 200 mg/m² Elvorine) at day 1 in perfusion over 2 hours 5FU continue 2000 mg/m² over 46 heures then irinotécan at 90 mg/m² (1h) at day 3 when 5U perfusion is over
Gemcitabine: 1000 mg/m² in perfusion over 30 mn at day 1,8,15,29,36 and 43 over (1 injection per week during 3 weeks followed with 7 days of rest )
FOLFIRI.3: Perfusion :Irinotecan,Acide folinique ,5FU continue
Gemcitabine: Gemcitabine perfusion | 90 |
| Total | 273 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Patients never treated | 4 | 1 | 2 |
Baseline characteristics
| Characteristic | FOLFIRINOX + LV5FU2 in Maintenance | FIRGEM | Total | FOLFIRINOX |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 41 Participants | 49 Participants | 135 Participants | 45 Participants |
| Age, Categorical Between 18 and 65 years | 51 Participants | 41 Participants | 138 Participants | 46 Participants |
| Age, Continuous | 64.18 years | 65.88 years | 64.81 years | 64.55 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 92 Participants | 90 Participants | 273 Participants | 91 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment France | 92 participants | 90 participants | 273 participants | 91 participants |
| Sex: Female, Male Female | 34 Participants | 43 Participants | 112 Participants | 35 Participants |
| Sex: Female, Male Male | 58 Participants | 47 Participants | 161 Participants | 56 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 82 / 91 | 80 / 92 | 83 / 90 |
| other Total, other adverse events | 88 / 88 | 91 / 91 | 87 / 87 |
| serious Total, serious adverse events | 31 / 88 | 53 / 91 | 57 / 87 |
Outcome results
Primary
Percentage of Patients Alive and Without Radiological and/or Clinical Progression 6 Months After the Randomization.
Progression was defined as radiological progression according to RECIST v1.1 criteria and/or clinical progression according to the investigator. Progression or death (for any reason) was considered if the event occured within the first 6 months since randomization. 6 month scans were 6 month scans with a +/- 1 month window.
Time frame: 6 months after randomization
Population: The primary endpoint was analysed on the mITT population meaning all the randomized patients with at least one dose of study drug taken
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| FOLFIRINOX | Percentage of Patients Alive and Without Radiological and/or Clinical Progression 6 Months After the Randomization. | 41 Participants |
| FOLFIRINOX + LV5FU2 in Maintenance | Percentage of Patients Alive and Without Radiological and/or Clinical Progression 6 Months After the Randomization. | 39 Participants |
| FIRGEM | Percentage of Patients Alive and Without Radiological and/or Clinical Progression 6 Months After the Randomization. | 30 Participants |
Secondary
Overall Survival (OS)
Overall survival was defined as the time from the date of randomization to the patient's death (all causes). For alive patients, the date of last news was taken into account. The analysis was done on the ITT population meaning the patients who have been randomized. Numbers of patients correspond the number of patients randomized in the study.
Time frame: Up to 3 years after the treatment start
Population: Endpoint was analyzed on the ITT population meaning the patients randomized in the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FOLFIRINOX | Overall Survival (OS) | 10.09 months |
| FOLFIRINOX + LV5FU2 in Maintenance | Overall Survival (OS) | 11.20 months |
| FIRGEM | Overall Survival (OS) | 7.34 months |
Secondary
Progression-free Survival (PFS)
It was defined as the time between t randomization and the date of the first radiological progression (RECIST 1.1 criteria) and/or clinical progression according to the investigator or death (whatever the cause is); Patients alive without progression were censored at date of last news .
Time frame: up to 12 months after randomization
Population: The analysis was done on the ITT population meaning the patients who have been randomized into the study
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FOLFIRINOX | Progression-free Survival (PFS) | 6.28 months |
| FOLFIRINOX + LV5FU2 in Maintenance | Progression-free Survival (PFS) | 5.73 months |
| FIRGEM | Progression-free Survival (PFS) | 4.50 months |