Ignite Creation Date:
2024-10-26 @ 3:35 PM
Last Modification Date:
2024-10-26 @ 3:35 PM
Study NCT ID:
NCT06509126
Status:
RECRUITING
Last Update Posted:
None
First Post:
2024-06-14
Brief Title:
Intermittent or Continuous Panitumumab Plus FOLFIRI for Left Sided RASB-RAF Wild-type Metastatic Colorectal Cancer
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Randomized Phase 3 Study of Intermittent or Continuous Panitumumab Plus FOLFIRI for First-line Treatment of Patients With Unresectable Left Sided RASB-RAF Wild-type Metastatic Colorectal Cancer IMPROVE-2 Trial
Status:
RECRUITING
Status Verified Date:
2024-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
IMPROVE-2
Brief Summary:
The investigators hypothesize that intermittent first-line Panitumumab plus FOLFIRI is effective in first line as the same regimen given continuously resulting in a Time to Treatment Failure TTF not inferior to that obtained with standard continuous regimen of Panitumumab plus FOLFIRI in the treatment of metastatic left sided RASB-RAF wild-type colorectal cancer patients
Correlative mechanistic studies on tissue and blood samples liquid biopsies could identify potential biomarkers of efficacy and help understanding the evolutionary dynamics of tumors in response to therapy thus optimizing the treatment approach with a personalized anti-EGFR treatment strategy
Correlative mechanistic studies on tissue and blood samples liquid biopsies could identify potential biomarkers of efficacy and help understanding the evolutionary dynamics of tumors in response to therapy thus optimizing the treatment approach with a personalized anti-EGFR treatment strategy
Detailed Description:
This study is a multicentric open label academic randomized phase-3 study The study population will include untreated and unresectable left sided RASBRAF wild-type metastatic colorectal cancer mCRC patients eligible for first-line treatment A total of 500 patients 250 for arm will be enrolled
All patients will receive an induction treatment with Panitumumab as 60 minutes or 90 minutes for doses over 1000 mg intravenous infusion at the dosage of 6 mgkg given every two weeks plus FOLFIRI chemotherapy as standard guidelines
Before starting FOLFIRI plus Panitumumab at the time of enrollment patients will be immediately randomized electronically 11 to one of the two arms standard continuous or exploratory intermittent treatment
Induction treatment with FOLFIRI plus panitumumab will continue until progressive disease unacceptable toxicity or informed consent withdrawal or for up to 8 cycles
At the end of induction treatment in presence of complete or partial response or stable disease non-progressing patients will be allocated to one of the two pre-assigned arms
A Standard CONTINUOUS ARM Panitumumab plus FOLFIRI until treatment failure as previous defined unacceptable toxicity or informed consent withdrawal ARM A Panitumumab will be administered as 60 minutes or 90 minutes for doses over 1000 mg intravenous infusion at the dosage of 6 mgkg followed by irinotecan 180 mgm2 over 60 minutes and folinic acid 200 mgm2 over 120 minutes before Fluorouracil bolus 400 mgm2 followed by Fluorouracil 2400 mgm2 continuous infusion over 46 hours FOLFIRI regimen Every cycle will be administered every two weeks - 3 days
B Experimental INTERMITTENT ARM treatment free interval until progressive disease when another treatment period of Panitumumab plus FOLFIRI up to 8 cycles will be restarted non-progressing patients will undergo again a treatment free interval until progressive disease This intermittent strategy will be continued until progression disease occurred on treatment ARM B Panitumumab will be administered at same dose and infusion with FOLFIRI
All measurable and non-measurable lesions must be documented at screening within 28 days prior to randomization and re-assessed at each subsequent tumor evaluation every 8 weeks while the patient is on study Tumor assessment by CT scan chest abdomen and pelvis or MRI abdomen and pelvis CEA CA 199 and any other tests resulted positive during baseline staging will be performed at week 8 and every 8 weeks during treatment until treatment failure in both arms Patients discontinuing study treatment without progressive disease will undergo tumor assessments every 8 weeks until progressive disease or study withdrawal Surgery on metastatic disease can be carried out in case of appropriate tumor shrinkage at response evaluation resectability will have to be evaluated by a multidisciplinary team In the standard arm the patients without disease recurrence at first tumor assessment performed 30 days after metastasis surgery will be treated with further 8 or 16 weeks of Panitumumab plus FOLFIRI to complete six months of treatment if the response was obtained after 16 or 8 weeks respectively If at the end of this further treatment no disease recurrence occurred the patient will only continue with tumor evaluation every 8 weeks When the surgery will be obtained after 24 weeks of treatment if no disease recurrence will be observed at first tumor assessment performed 30 days after surgery no further treatment will be carried out
On the contrary in the experimental arm the patients will have a treatment free interval until progressive disease when another additional treatment period of Panitumumab plus FOLFIRI to 8 cycles will be restarted non-progressing patients will undergo again a treatment free interval until progressive disease This intermittent strategy will be continued until progression disease occurred on treatment
Toxicities will be evaluated at each clinical visit throughout the study treatment and up to 4 weeks after last cycle of treatment accordingly to the Common Terminology Criteria for Adverse Events AEs of the National Cancer Institute CTCAE-NCI version 50
Quality of Life will be assessed by the EORTC QLQ-C30 v30 and QLQ-CR29 questionnaire that will be completed by patients at baseline prior to induction treatment start once eligibility is confirmed and every 8 weeks until disease progression treatment failure or death The time toxicity as the amount of time spent in pursuing cancer therapy can be substantial in cancer patients by hospital-free days a pragmatic and patient-centered outcome will be assessed too
Biomarkers will be evaluated on tumor tissues from primary tumors or metastases at baseline When available on the bases of a separate additional not mandatory for the inclusion in the study informed consent biomarkers will be evaluated on metastases tissue of resected metastasis when the patients will undergo metastasis surgery Blood samples will be collected at baseline during treatment and at progression Biomarkers will be correlated with clinical response patient outcome and toxicity
Study design is based on a non-inferiority comparison in terms of time to treatment failure TTF the primary end-point
Noninferiority is defined as a 130 upper limit of 95 CI of hazard ratio of TTF for the experimental arm corresponding to a lower limit of hazard ratio of TTF of 077 in favor of the control arm Based on previous trials expected median TTF in the control arm is 12 months The above reported non-inferiority limit means that the worst possible median TTF in the experimental arm will be 923 months With a statistical power of 80 a 1-sided probability of alpha error of 005 a random allocation of patients with a 11 ratio one interim and one final TTF analyses planned a priori 480 patients will be needed 240 patients for each arm and 360 events of treatment failure are required for the final analysis The interim analysis will be performed after the first 134 events will be observed
Considering 5 of drop-out a total of 500 patients is planned for accrual 250 for each arm
Randomization will be performed with a stratified procedure that will account for metastatic spread liver only vs not liver only previous adjuvant chemotherapy yes vs no and synchronous metastases yes vs no
All patients will receive an induction treatment with Panitumumab as 60 minutes or 90 minutes for doses over 1000 mg intravenous infusion at the dosage of 6 mgkg given every two weeks plus FOLFIRI chemotherapy as standard guidelines
Before starting FOLFIRI plus Panitumumab at the time of enrollment patients will be immediately randomized electronically 11 to one of the two arms standard continuous or exploratory intermittent treatment
Induction treatment with FOLFIRI plus panitumumab will continue until progressive disease unacceptable toxicity or informed consent withdrawal or for up to 8 cycles
At the end of induction treatment in presence of complete or partial response or stable disease non-progressing patients will be allocated to one of the two pre-assigned arms
A Standard CONTINUOUS ARM Panitumumab plus FOLFIRI until treatment failure as previous defined unacceptable toxicity or informed consent withdrawal ARM A Panitumumab will be administered as 60 minutes or 90 minutes for doses over 1000 mg intravenous infusion at the dosage of 6 mgkg followed by irinotecan 180 mgm2 over 60 minutes and folinic acid 200 mgm2 over 120 minutes before Fluorouracil bolus 400 mgm2 followed by Fluorouracil 2400 mgm2 continuous infusion over 46 hours FOLFIRI regimen Every cycle will be administered every two weeks - 3 days
B Experimental INTERMITTENT ARM treatment free interval until progressive disease when another treatment period of Panitumumab plus FOLFIRI up to 8 cycles will be restarted non-progressing patients will undergo again a treatment free interval until progressive disease This intermittent strategy will be continued until progression disease occurred on treatment ARM B Panitumumab will be administered at same dose and infusion with FOLFIRI
All measurable and non-measurable lesions must be documented at screening within 28 days prior to randomization and re-assessed at each subsequent tumor evaluation every 8 weeks while the patient is on study Tumor assessment by CT scan chest abdomen and pelvis or MRI abdomen and pelvis CEA CA 199 and any other tests resulted positive during baseline staging will be performed at week 8 and every 8 weeks during treatment until treatment failure in both arms Patients discontinuing study treatment without progressive disease will undergo tumor assessments every 8 weeks until progressive disease or study withdrawal Surgery on metastatic disease can be carried out in case of appropriate tumor shrinkage at response evaluation resectability will have to be evaluated by a multidisciplinary team In the standard arm the patients without disease recurrence at first tumor assessment performed 30 days after metastasis surgery will be treated with further 8 or 16 weeks of Panitumumab plus FOLFIRI to complete six months of treatment if the response was obtained after 16 or 8 weeks respectively If at the end of this further treatment no disease recurrence occurred the patient will only continue with tumor evaluation every 8 weeks When the surgery will be obtained after 24 weeks of treatment if no disease recurrence will be observed at first tumor assessment performed 30 days after surgery no further treatment will be carried out
On the contrary in the experimental arm the patients will have a treatment free interval until progressive disease when another additional treatment period of Panitumumab plus FOLFIRI to 8 cycles will be restarted non-progressing patients will undergo again a treatment free interval until progressive disease This intermittent strategy will be continued until progression disease occurred on treatment
Toxicities will be evaluated at each clinical visit throughout the study treatment and up to 4 weeks after last cycle of treatment accordingly to the Common Terminology Criteria for Adverse Events AEs of the National Cancer Institute CTCAE-NCI version 50
Quality of Life will be assessed by the EORTC QLQ-C30 v30 and QLQ-CR29 questionnaire that will be completed by patients at baseline prior to induction treatment start once eligibility is confirmed and every 8 weeks until disease progression treatment failure or death The time toxicity as the amount of time spent in pursuing cancer therapy can be substantial in cancer patients by hospital-free days a pragmatic and patient-centered outcome will be assessed too
Biomarkers will be evaluated on tumor tissues from primary tumors or metastases at baseline When available on the bases of a separate additional not mandatory for the inclusion in the study informed consent biomarkers will be evaluated on metastases tissue of resected metastasis when the patients will undergo metastasis surgery Blood samples will be collected at baseline during treatment and at progression Biomarkers will be correlated with clinical response patient outcome and toxicity
Study design is based on a non-inferiority comparison in terms of time to treatment failure TTF the primary end-point
Noninferiority is defined as a 130 upper limit of 95 CI of hazard ratio of TTF for the experimental arm corresponding to a lower limit of hazard ratio of TTF of 077 in favor of the control arm Based on previous trials expected median TTF in the control arm is 12 months The above reported non-inferiority limit means that the worst possible median TTF in the experimental arm will be 923 months With a statistical power of 80 a 1-sided probability of alpha error of 005 a random allocation of patients with a 11 ratio one interim and one final TTF analyses planned a priori 480 patients will be needed 240 patients for each arm and 360 events of treatment failure are required for the final analysis The interim analysis will be performed after the first 134 events will be observed
Considering 5 of drop-out a total of 500 patients is planned for accrual 250 for each arm
Randomization will be performed with a stratified procedure that will account for metastatic spread liver only vs not liver only previous adjuvant chemotherapy yes vs no and synchronous metastases yes vs no
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None