Colorectal Neoplasms
Conditions
Keywords
colorectal, cancer, metastasis
Brief summary
The intensity of tumour response appears to be correlated with the feasibility and the duration of a therapeutic pause or of a reduced maintenance therapy maintained until progression in patients initially controlled by so-called induction chemotherapy. Bevacizumab combined with cytotoxic chemotherapy (5-FU, irinotecan and/or oxaliplatin) has shown that it is possible to improve the tumour response rate and patient prognosis in 1st and 2nd lines. With a very favourable safety profile , it is an excellent candidate as induction treatment and also as maintenance treatment. Prospective data from recent trials have actually demonstrated improvement in PFS and/or overall survival with bevacizumab maintenance alone or in combination with 5FU (or capecitabine) after induction chemotherapy (FOLFIRI or FOLFOX + bevacizumab). At the same time, the maintenance of anti-angiogenic pressure after progression in 1st line metastatic has demonstrated its benefit in terms of PFS and overall survival. Bevacizumab maintenance in 2nd line metastatic, despite progression, thus appears to be a valid strategy.
Detailed description
Thus, the objective of this work is to combine continuous blocking of angiogenesis by bevacizumab given on the first 3 metastatic lines in a randomised phase II trial evaluating a descending strategy of immediate optimisation by 4 cycles of FOLFOXIRI-bevacizumab and 4 cycles of FOLFIRI-bevacizumab, followed by maintenance treatment with 5FU-bevacizumab until progression (re-introduction of induction in case of progression) and evaluate an ascending strategy with 5FU-bevacizumab immediately followed, at progression, by the introduction of irinotecan, then oxaliplatin, with maintenance of blocking of angiogenesis by bevacizumab.
Interventions
DRUG5 FLUOROURACYL
Folinic acid is administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as a 2 hr infusion. The 5FU bolus is administered in less than 10 minutes at 400 mg/m² (on D1). The continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hr (D1 and D2). The cycles will last 14 days. For this 1st line chemotherapy, the investigator has the choice of using capecitabine instead of LV5FU2; in this case the cycle lasts 21 days.
DRUGacide folinique
200 mg/m² if Elvorine
DRUGirinotecan
Irinotecan is administered IV at a dose of 180 mg/m² over 90 minutes. Folinic acid is administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as an infusion over 2 hours, to be given in Y along with irinotecan. The 5FU bolus is administered in less than 10 minutes at 400 mg/m² (on D1). The continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hr (D1 and D2). The cycles will last 14 days.
DRUGOxaliplatin
Oxaliplatin is administered IV at a dose of 85 mg/m² over 120 minutes. Folinic acid is administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as an infusion over 2 hours, to be given in Y along with oxaliplatin. The 5FU bolus is administered in less than 10 minutes at 400 mg/m² (on D1). The continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hr (D1 and D2). The cycles will last 14 days.
DRUGcapécitabine
For this 1st line chemotherapy, the investigator has the choice of using capecitabine instead of LV5FU2; in this case the cycle lasts 21 days.
DRUGbevacizumab
Bevacizumab is administered IV at a dose of 5 mg/kg over 90 min at cycle 1, then 60 min at cycle 2 and 30 min in subsequent cycles. Bevacizumab is administered every 2 weeks before the start of chemotherapy
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 colorectal cancer, histologically proven (on primary tumour and/or metastases) * Unresectable and non-pretreated metastases * BRAF wild-type * Patient considered able to receive 3 lines of chemotherapy * At least one measurable target lesion \> 1 cm according to RECIST 1.1 (Appendix 4) * Tumour assessment according to RECIST, performed 4 weeks or less prior to randomization * Age ≥ 18 years * WHO performance status ≤ 2 (Appendix 5) * No major surgery within 4 weeks prior to randomisation. Wound healing must be complete * Life expectancy greater than 3 months * Laboratory tests: Neutrophils ≥ 1500/mm3, platelets ≥ 100,000/mm3, haemoglobin \> 9 g/dL * Creatinine clearance \> 30 mL /min (capecitabine dose modification if the creatinine clearance \< 30-50 mL/min), serum creatinine \< 1.25 x ULN * Liver function tests: bilirubin \< 1.25 x ULN, AST/ALT \< 5 x ULN * Women of childbearing age and men (who have sexual relations with women of childbearing age) must agree to use effective contraception without interruption throughout the duration of treatment and for 6 months after the last administration * Signed informed consent
Exclusion criteria
* Patient with a potentially resectable colorectal cancer; i.e. for whom the goal of chemotherapy would be to make all metastases resectable * Patients with symptomatic metastases * Patient with aggressive disease and a large tumour volume * Active gastroduodenal ulcer, wound or bone fracture * At least one of the following laboratory values: Neutrophils \<1500/mm3, platelets \< 100,000/mm3, haemoglobin \< 9 g/dL, total bilirubin \> 1.5 N, alkaline phosphatase \> 2.5 N (or \> 5 N in case of hepatic involvement), serum creatinine \> 1.5 N, 24 hr proteinuria \> 1 g * Chronic inflammatory bowel disease, extensive resection of the small bowel * Clinically significant coronary artery disease or a history of myocardial infraction within the last 6 months. Uncontrolled hypertension while receiving chronic medication * Abdominal or major extra-abdominal surgical procedure (except diagnostic biopsy) or radiation within 4 weeks before starting treatment * Previous treatment with an anti-angiogenic or irinotecan * Known or suspected central nervous system metastasis CNS metastases, or suspected CNS metastases * Other previous malignancies within 5 years, except for basal cell carcinoma of the skin or pre-invasive carcinoma of the cervix - Peritoneal macro-nodular carcinomatosis * History of haemoptysis ≥ grade 2 (defined as ≥ 2.5 mL of bright red blood per episode) in the month prior to inclusion * Known hypersensitivity to any component of bevacizumab or to one of the study treatments * Active infection requiring intravenous antibiotics at start of treatment * History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or active gastrointestinal bleeding within 6 months prior to treatment start * Pregnant or breastfeeding women * Concomitant participation in another clinical study involving a drug during the treatment phase and 30 days before starting the study treatment * Patient unable to undergo medical treatment for geographical, social, psychological or legal reasons.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Primary Objective Was the Percentage of Patients Without Failure of the Strategy 16 Months After the Randomization. | 16 months after randomization | The failure of the strategy is defined by the following events: * Progression (under certain condition) using RECIST version 1.1 and defined as a 20% increase in the sum of the longest diameter of target lesions compared the little sum of diameters observed durin the study (NADIR), or a measurable increase in a nontarget lesion, or the appearance of new lesions * Death (all causes) * Toxicity leading to definitive stop of chemotherapy (oxaliplatine and/or irinotecan). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Response Rate (Using RECIST Version 1.1) | At 16 months | Best response derived from all the CT scans performed during treatment and based on RECIST 1.1 definition of response. |
| Overall Survival (OS) | Up to 3 years after the treatment start | Overall survival was defined as the time from the date of the patient's inclusion to the patient's death (all causes). For alive patients the date of the latest news was taken into account |
| Progression Free Survival (PFS) | up to 24 months after randomization | The progression-free survival is the time from inclusion to the first radiological progression or death (all causes). For patients alive without progression date of last news will be considered. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions compared the little sum of diameters observed durin the study (NADIR), or a measurable increase in a nontarget lesion, or the appearance of new lesions |
Countries
France
Participant flow
Recruitment details
Patients were randomized between 15 September 2016 and 10 April 2018 by 9 french centers
Participants by arm
| Arm | Count |
|---|---|
| Standard Arm (Escalation Strategy - Arm A) LV5FU2 +avastin then after progression: FOLFIRI + avastin and then after the 2nd progression:FOLFOX4 (eloxatine)+ avastin.
5 FLUOROURACYL: administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as a 2 hr infusion.
The 5FU bolus is administered in less than 10 minutes at 400 mg/m² (on D1). The continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hr (D1 and D2).
Irinotecan: administered IV at a dose of 180 mg/m² over 90 minutes. Folinic acid :administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as an infusion over 2 hours, to be given in Y along with irinotecan.
Oxaliplatin: administered IV at a dose of 85 mg/m² over 120 minutes.
bevacizumab: administered IV at a dose of 5 mg/kg over 90 min at cycle 1, then 60 min at cycle 2 and 30 min in subsequent cycles.
Bevacizumab is administered every 2 weeks before the start of chemotherapy | 11 |
| Experimental Arm (De-escalation Strategy -Arm B) (4 cycles of FOLFOXIRI (campto) + avastin and 4 cycles of FOLFIRI + avastin) is followed by maintenance with capecitabine
5 FLUOROURACYL: Folinic acid is administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as a 2 hr infusion.
The 5FU bolus is administered in less than 10 minutes at 400 mg/m² (on D1). The continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hr (D1 and D2).
acide folinique: 200 mg/m² if Elvorine
irinotecan: administered IV at a dose of 180 mg/m² over 90 minutes.
Oxaliplatin: administered IV at a dose of 85 mg/m² over 120 minutes.
capécitabine: For this 1st line chemotherapy, the investigator has the choice of using capecitabine instead of LV5FU2; in this case the cycle last 21 days.
bevacizumab: Bevacizumab is administered IV at a dose of 5 mg/kg over 90 min at cycle 1, then 60 min at cycle 2 and 30 min in subsequent cycles. Bevacizumab is administered every 2 weeks before the start of chemotherapy | 10 |
| Total | 21 |
Baseline characteristics
| Characteristic | Experimental Arm (De-escalation Strategy -Arm B) | Total | Standard Arm (Escalation Strategy - Arm A) |
|---|---|---|---|
| Age, Continuous | 66.32 years STANDARD_DEVIATION 10.2 | 65.99 years STANDARD_DEVIATION 9.38 | 65.70 years STANDARD_DEVIATION 9.14 |
| kRAS mutation status (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) Mutated | 7 Participants | 15 Participants | 8 Participants |
| kRAS mutation status (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) Non mutated | 3 Participants | 6 Participants | 3 Participants |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment France | 10 participants | 21 participants | 11 participants |
| Sex: Female, Male Female | 2 Participants | 6 Participants | 4 Participants |
| Sex: Female, Male Male | 8 Participants | 15 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 11 | 5 / 10 |
| other Total, other adverse events | 10 / 11 | 9 / 10 |
| serious Total, serious adverse events | 4 / 11 | 0 / 10 |
Outcome results
Primary
The Primary Objective Was the Percentage of Patients Without Failure of the Strategy 16 Months After the Randomization.
The failure of the strategy is defined by the following events: * Progression (under certain condition) using RECIST version 1.1 and defined as a 20% increase in the sum of the longest diameter of target lesions compared the little sum of diameters observed durin the study (NADIR), or a measurable increase in a nontarget lesion, or the appearance of new lesions * Death (all causes) * Toxicity leading to definitive stop of chemotherapy (oxaliplatine and/or irinotecan).
Time frame: 16 months after randomization
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Standard Arm (Escalation Strategy - Arm A) | The Primary Objective Was the Percentage of Patients Without Failure of the Strategy 16 Months After the Randomization. | No strategy failure | 7 Participants |
| Standard Arm (Escalation Strategy - Arm A) | The Primary Objective Was the Percentage of Patients Without Failure of the Strategy 16 Months After the Randomization. | Strategy failure | 4 Participants |
| Experimental Arm (De-escalation Strategy -Arm B) | The Primary Objective Was the Percentage of Patients Without Failure of the Strategy 16 Months After the Randomization. | No strategy failure | 4 Participants |
| Experimental Arm (De-escalation Strategy -Arm B) | The Primary Objective Was the Percentage of Patients Without Failure of the Strategy 16 Months After the Randomization. | Strategy failure | 6 Participants |
Secondary
Best Response Rate (Using RECIST Version 1.1)
Best response derived from all the CT scans performed during treatment and based on RECIST 1.1 definition of response.
Time frame: At 16 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Standard Arm (Escalation Strategy - Arm A) | Best Response Rate (Using RECIST Version 1.1) | Partial response | 3 Participants |
| Standard Arm (Escalation Strategy - Arm A) | Best Response Rate (Using RECIST Version 1.1) | Progression | 0 Participants |
| Standard Arm (Escalation Strategy - Arm A) | Best Response Rate (Using RECIST Version 1.1) | Stability | 7 Participants |
| Standard Arm (Escalation Strategy - Arm A) | Best Response Rate (Using RECIST Version 1.1) | Non evaluable | 1 Participants |
| Standard Arm (Escalation Strategy - Arm A) | Best Response Rate (Using RECIST Version 1.1) | Complete response | 0 Participants |
| Experimental Arm (De-escalation Strategy -Arm B) | Best Response Rate (Using RECIST Version 1.1) | Non evaluable | 0 Participants |
| Experimental Arm (De-escalation Strategy -Arm B) | Best Response Rate (Using RECIST Version 1.1) | Complete response | 1 Participants |
| Experimental Arm (De-escalation Strategy -Arm B) | Best Response Rate (Using RECIST Version 1.1) | Partial response | 6 Participants |
| Experimental Arm (De-escalation Strategy -Arm B) | Best Response Rate (Using RECIST Version 1.1) | Stability | 2 Participants |
| Experimental Arm (De-escalation Strategy -Arm B) | Best Response Rate (Using RECIST Version 1.1) | Progression | 1 Participants |
Secondary
Overall Survival (OS)
Overall survival was defined as the time from the date of the patient's inclusion 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) |
|---|---|---|
| Standard Arm (Escalation Strategy - Arm A) | Overall Survival (OS) | 31.08 months |
| Experimental Arm (De-escalation Strategy -Arm B) | Overall Survival (OS) | 33.80 months |
Secondary
Progression Free Survival (PFS)
The progression-free survival is the time from inclusion to the first radiological progression or death (all causes). For patients alive without progression date of last news will be considered. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions compared the little sum of diameters observed durin the study (NADIR), or a measurable increase in a nontarget lesion, or the appearance of new lesions
Time frame: up to 24 months after randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Standard Arm (Escalation Strategy - Arm A) | Progression Free Survival (PFS) | 8.24 months |
| Experimental Arm (De-escalation Strategy -Arm B) | Progression Free Survival (PFS) | 13.22 months |