Colorectal Neoplasms
Conditions
Keywords
cancer, colorectal,
Brief summary
This is what the FFCD 11-01 - PRODIGE 25 trial proposes to study, as a preliminary for strategic studies evaluating the usefulness of including targeted therapeutics from the first line with aflibercept +/- LV5FU2.
Detailed description
The aflibercept-5-FU combination has never been evaluated as yet. Aflibercept, at a dose of 4 mg/kg, has already been used in combination with 5-FU at the doses used in the simplified LV5FU2 regimen (folinic acid 400 mg/m2 IV in 90 min, then 5-FU 400 mg/m2 IV bolus on D1, followed by continuous perfusion of 5-FU 2,400 mg/m2 in 46h) (23) as part of the above-mentioned VELOUR trial, evaluating its combination with FOLFIRI (= simplified LV5FU2 + irinotecan). This trial was preceded by a phase I trial validating the doses used (24). It is therefore not necessary to perform a phase I trial if you use the same doses of 5-FU without irinotecan, within the context of a strategy for reducing toxicity in patients to be treated over a long period, and not search for the maximum tolerated dose of the combination. The aflibercept-LV5FU2 combination can be useful for patients who will never be resectable or operable, and for whom 5-FU monotherapy can be suggested to delay the toxicities of combined chemotherapies. Within this context, it is possible for aflibercept to provide a survival benefit. The previous VELOUR trial (18) did not indicate that toxicity would have a major effect on quality of life and increase the hope of prolonged progression-free survival in the arm with aflibercept. This is what the FFCD 11-01 - PRODIGE 25 trial proposes to study, as a preliminary for strategic studies evaluating the usefulness of including targeted therapeutics from the first line. This trial will evaluate the efficacy of the combination and its tolerance by studying toxicities and quality of life. Quality of life will be studied via the EORTC questionnaire QLQ-C30. The thymidylate synthase polymorphism type 2R2R-2R3R versus 3R3R seems to predict greater efficacy of 5-FU monotherapy. Stratification in this criterion will confirm or negate the prognostic or predictive nature of 5-FU efficacy linked to these polymorphisms. The draft version of this trial has been studied and evaluated by the scientific council of the Fédération Francophone de Cancérologie Digestive (FFCD) then the Digestive Group of the Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) within the framework of their Partnership for Research in Digestive Oncology (PRODIGE cooperation).
Interventions
DRUGaflibercept
DRUGLV5FU2
Sponsors
Federation Francophone de Cancerologie Digestive
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥ 65 years * General condition WHO ≤ 2 * Metastatic rectal or colonic adenocarcinoma, histologically proved on the primary tumour or a metastasis * Metastases non-resectable and/or patient inoperable * patients where a single agent chemotherapy combined with an anti-angiogenic agent is an appropriate approach * At least one measurable target according to RECIST v1.1 criteria, no previously irradiated * No previous treatment of the metastatic disease. Previous chemotherapy in an adjuvant situation completed 6 months or more before diagnosis of the metastasis is authorized. * Adequate biological examination: Hb \> or = 9 g/dl, polynuclear neutrophils \> or = 1,500/mm3, platelets \> or =100,000/mm3, total bilirubin \< or = 1.5 x UNL, creatinine clearance, calculated according to Cockroft-Gault formula, \> 50 ml/min creatininemia \< 1.5 x UNL, ALP \< 5 x UNL, transaminases \< 5 x ULN, GGT\< 5 x UNL * Proteinuria (strip) \< 2+; if \> or = 2+, test proteinuria over 24 hours which must be ≤ 1 g. * Central genotyping of thymidylate synthase (TS) in blood DNA * Patients treated with anticoagulants (coumadin, warfarin) can be included if the INR can be closely monitored. A change in anticoagulant treatment for low molecular weight heparin is preferable in order to respect indications * Signed written informed consent obtained prior to inclusion
Exclusion criteria
* Patients with a primary tumour in place and presenting clinical symptoms (occlusion, haemorrhage) * History of brain metastases, uncontrolled spinal cord compression, or carcinomatous meningitis or new evidence of brain or leptomeningeal disease. * Uncontrolled hypercalcemia * Uncontrolled hypertension (SBP \> 150 mmHg and DBP \> 100 mmHg) or history of hypertensive attacks or hypertensive encephalopathy * Any progressive pathology not balanced over the past 6 months: hepatic insufficiency, renal insufficiency, respiratory insufficiency, * Any of the following within 6 months prior to inclusion: myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, NYHA class III or IV congestive heart failure, stroke or transient ischemic attack. * Any of the following within 3 months prior to inclusion: Grade 3-4 gastrointestinal bleeding/hemorrhage, treatment resistant peptic ulcer disease, erosive oesophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, pulmonary embolism or other uncontrolled thromboembolic event, wound or fractured bone * Major surgery during the 28 days preceding the start of treatment * Known acquired immunodeficiency syndrome (AIDS-related illnesses) or known HIV disease requiring antiretroviral treatment. * Treatment with concomitant anticonvulsivant agents that are CYP3A4 inducers (phenytoin, phenobarbital, carbamazepine), unless discontinued \>7 days. * Anti-tumoral treatments other than the trial treatments (chemotherapy, targeted therapy, immunotherapy) * Macronodular peritoneal carcinosis (risk of perforation) * Known DPD deficit * Prior history of malignant haemopathy or cancer except those treated more than 5 years ago and considered to be cured, in situ cervical carcinomas and treated skin cancers (excluding melanoma) * Patients on new oral anticoagulant therapy (rivaroxaban XARELTOR, apixaban ELIQUIS, dagigatran PRADAXA except if relay by vitamine K antagonist therapy) * Any contraindication to the treatments used in the trial * Impossibility of undergoing medical monitoring during the trial for geographic, social or psychological reasons
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Primary Objective Was the Percentage of Patients Alive and Without Progression 6 Months After the Randomization. | At 6 months after randomization | Progression was assessed by the investigator according to RECIST 1.1 criteria based on imaging studies performed every 8 weeks, even in case of deferred treatments. Clinical progressions, not confirmed on imaging, were not be counted in the primary endpoint |
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 the latest news was taken into account |
| Progression-free Survival (PPFS) | 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) according to the investigator or death; Patients alive without progression were censored at the date of last news |
Countries
France
Participant flow
Recruitment details
Between May 2015 and September 2020, 117 patients were randomized in France
Participants by arm
| Arm | Count |
|---|---|
| Aflibercept + LV5FU2 LV5FU2: LV5FU2 simplified every 2 weeks: folinic acid 400 mg/m2 IV over 90 min, then 5FU 400 mg/m2 IV bolus at D1, followed by continuous infusion of 5FU 2400 mg/m2 over 46 h.
Aflibercept : Preceded or not by an IV infusion of aflibercept 4 mg/kg over 1 hour | 56 |
| LV5FU2 LV5FU2 simplified every 2 weeks: folinic acid 400 mg/m2 IV over 90 min, then 5FU 400 mg/m2 IV bolus at D1, followed by continuous infusion of 5FU 2400 mg/m2 over 46 h. | 56 |
| Total | 112 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Patients not treated | 3 | 2 |
Baseline characteristics
| Characteristic | LV5FU2 | Total | Aflibercept + LV5FU2 |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 56 Participants | 112 Participants | 56 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 80.23 years STANDARD_DEVIATION 5.4 | 80.25 years STANDARD_DEVIATION 5.39 | 80.27 years STANDARD_DEVIATION 5.43 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 56 Participants | 112 Participants | 56 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment France | 56 participants | 112 participants | 56 participants |
| Sex: Female, Male Female | 23 Participants | 44 Participants | 21 Participants |
| Sex: Female, Male Male | 33 Participants | 68 Participants | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 37 / 56 | 36 / 56 |
| other Total, other adverse events | 55 / 56 | 56 / 56 |
| serious Total, serious adverse events | 26 / 56 | 13 / 56 |
Outcome results
Primary
The Primary Objective Was the Percentage of Patients Alive and Without Progression 6 Months After the Randomization.
Progression was assessed by the investigator according to RECIST 1.1 criteria based on imaging studies performed every 8 weeks, even in case of deferred treatments. Clinical progressions, not confirmed on imaging, were not be counted in the primary endpoint
Time frame: At 6 months after randomization
Population: Analysis population is the mITT population defined as all the patients randomized having received at least one dose of study treatment
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Aflibercept + LV5FU2 | The Primary Objective Was the Percentage of Patients Alive and Without Progression 6 Months After the Randomization. | Percentage of patients alive without progression at 6 months | 30 Participants |
| Aflibercept + LV5FU2 | The Primary Objective Was the Percentage of Patients Alive and Without Progression 6 Months After the Randomization. | Percentage of patients with progression or death at 6 months | 26 Participants |
| LV5FU2 | The Primary Objective Was the Percentage of Patients Alive and Without Progression 6 Months After the Randomization. | Percentage of patients alive without progression at 6 months | 30 Participants |
| LV5FU2 | The Primary Objective Was the Percentage of Patients Alive and Without Progression 6 Months After the Randomization. | Percentage of patients with progression or death at 6 months | 26 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 the latest news was taken into account
Time frame: Up to 3 years after the treatment start
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aflibercept + LV5FU2 | Overall Survival (OS) | 21.85 months |
| LV5FU2 | Overall Survival (OS) | 25.07 months |
Secondary
Progression-free Survival (PPFS)
It was defined as the time between t randomization and the date of the first radiological progression (RECIST 1.1 criteria) according to the investigator or death; Patients alive without progression were censored at the date of last news
Time frame: up to 12 months after randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aflibercept + LV5FU2 | Progression-free Survival (PPFS) | 7.28 months |
| LV5FU2 | Progression-free Survival (PPFS) | 7.23 months |