Trial Title:
Intermittent or Continuous Panitumumab Plus FOLFIRI for Left Sided RAS/B-RAF Wild-type Metastatic Colorectal Cancer
NCT ID:
NCT06509126
Condition:
Colorectal Cancer Stage IV
Conditions: Official terms:
Colorectal Neoplasms
Leucovorin
Folic Acid
Fluorouracil
Irinotecan
Panitumumab
Levoleucovorin
Conditions: Keywords:
Metastatic colorectal cancer
Left sided
RAS and BRAF wild type
Intermittent therapy
Liquid biopsy
Panitumumab
Study type:
Interventional
Study phase:
Phase 3
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Panitumumab
Description:
Administered at the dosage of 6mg/kg as 60 minutes, or 90 minutes for doses over 1000 mg,
intravenous infusion
Arm group label:
CONTINUOUS ARM
Arm group label:
INTERMITTENT ARM
Other name:
Vectibix
Intervention type:
Drug
Intervention name:
Irinotecan
Description:
Administered at the dosage of 180 mg/m2 over 60 minutes intravenous infusion
Arm group label:
CONTINUOUS ARM
Arm group label:
INTERMITTENT ARM
Other name:
Campto
Intervention type:
Drug
Intervention name:
5-fluorouracil
Description:
Administered at the dosage of 400 mg/m2 (bolus intravenous infusion) followed by
continuous intravenous infusion over 46 hours at the dosage of 2400 mg/m2
Arm group label:
CONTINUOUS ARM
Arm group label:
INTERMITTENT ARM
Other name:
5-FU
Intervention type:
Drug
Intervention name:
L-folinic acid
Description:
Administered at the dosage of 200 mg/m2 over 120 minutes as intravenous infusion
Arm group label:
CONTINUOUS ARM
Arm group label:
INTERMITTENT ARM
Other name:
LFA
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 RAS/B-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.
Detailed description:
This study is a multicentric open label academic randomized phase-3 study. The study
population will include untreated and unresectable left sided RAS/BRAF 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 mg/kg, 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 1:1 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 mg/kg, followed by irinotecan 180 mg/m2 over 60 minutes and folinic
acid 200 mg/m2 over 120 minutes before Fluorouracil bolus 400 mg/m2 followed by
Fluorouracil 2400 mg/m2 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 19.9; 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 5.0.
Quality of Life will be assessed by the EORTC QLQ-C30 v.3.0 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 ≤ 1.30 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 0.77 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 9.23 months. With a statistical power of 80%,
a 1-sided probability of alpha error of 0.05, a random allocation of patients with a 1:1
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).
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Written informed consent to study procedures and to correlative studies.
2. Histologically proven left sided mCRC.
3. RAS/BRAF wild-type and pMMR and/or MSS status assessed at local centers according a
validated method defined by EMA
4. Disease judged unresectable by the local multidisciplinary team
5. Patient candidate to receive Induction treatment with FOLFIRI plus panitumumab as
per standard clinical practice
6. No prior treatments (chemotherapy, radiation or surgery) for mCRC. Surgery for
primary CRC tumor before starting treatment is allowed.
7. Either sex aged ≥ 18
8. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1 at study entry.
9. Imaging-documented measurable disease, according to RECIST 1.1 criteria.
10. Known dihydropyrimidine dehydrogenase (DPYD) activity is mandatory. Additional
analysis of polymorphisms uridine diphosphate-glycosyltransferase 1 (UGT1A1) enzyme
is recommended but not mandatory
11. Adequate bone marrow hematological function: absolute neutrophil count (ANC) ≥ 1.5 x
109/L and platelet count ≥ 100 x 109/L and hemoglobin ≥ 9 g/dL.
12. Adequate liver function: total bilirubin ≤ 1.5 x upper limit of normal (ULN) or ≤ 2
(in case of biliary stent) and aspartate aminotransferase (AST)/alanine
aminotransferase (ALT) ≤ 5 X ULN.
13. Adequate renal function: serum creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 60
mL/min in males and ≥50 mL/min in females (calculated according to Cockroft-Gault
formula).
14. Electrolytes (i.e. magnesium, calcium, sodium and potassium) within laboratory
normal range
Exclusion Criteria:
1. Prior malignancy within five years. Exceptions include basal cell carcinoma of the
skin or squamous cell carcinoma of the skin that has undergone potentially curative
therapy or in situ cervical cancer.
2. Prior chemotherapy or any other medical treatment for mCRC (previous adjuvant
chemotherapy is allowed if terminated > 6 months previously).
3. Major surgical intervention within 4 weeks prior to enrollment.
4. Pregnancy and breast-feeding.
5. Any brain metastases.
6. Complete deficiency of activity of dihydropyrimidine dehydrogenase (DPYD) or known
UGT1A1 homozygosity.
7. Required dose reduction of 5-fluorouracil in the past for toxicity.
8. Evidence of severe or uncontrolled systemic disease or any concurrent condition
which in the investigator's opinion makes it undesirable for the patient to
participate in the study, or which would jeopardize compliance with the protocol, or
would interfere with the results of the study.
9. History of poor co-operation, non-compliance with medical treatment, unreliability
or any condition that may impair the patient's understanding of the Informed consent
form.
10. Participation in any interventional drug or medical device study within 30 days
prior to treatment start.
11. Sexually active males and females (of childbearing potential) unwilling to practice
contraception (barrier contraceptive measure or oral contraception) during the study
and until 6 months after the last trial treatment.
12. History of interstitial pneumonitis or pulmonary fibrosis.
13. History of corneal perforation or ulceration keratitis
Gender:
All
Minimum age:
18 Years
Maximum age:
100 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Istituto Nazionale Tumori di Napoli - IRCCS - Fondazione G. Pascale
Address:
City:
Napoli
Zip:
80131
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Antonio Avallone, MD
Phone:
003908117770357
Email:
a.avallone@istitutotumori.na.it
Contact backup:
Last name:
Elena Di Gennaro, MS
Phone:
003908117770584
Email:
e.digennaro@istitutotumori.na.it
Start date:
June 12, 2024
Completion date:
June 2028
Lead sponsor:
Agency:
National Cancer Institute, Naples
Agency class:
Other
Source:
National Cancer Institute, Naples
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06509126
