Clinical Trials /

First Line mFOLFOXIRI + PANITUMUMAB vs mFOLFOX + PANITUMUMAB IN RAS AND BRAF WT METASTATIC COLORECTAL CANCER PATIENTS

NCT03231722

Description:

- The association of FOLFOX (5-fluoruracil, folinic acid, and oxaliplatin) and pan is a standard option for the first-line treatment of unresectable RAS and BRAF wt mCRC patients. - The phase III TRIBE trial recently demonstrated that FOLFOXIRI (5-fluoruracil, folinic acid, oxaliplatin and irinotecan) plus bev significantly prolongs PFS and OS and increases RECIST response rate, ETS and DoR, as compared to FOLFIRI (5-fluoruracil folinic acid, and irinotecan) plus bev. The advantage provided by the intensification of the upfront chemotherapy backbone is independent of RAS and BRAF mutational status. - Some phase II trials recently assessed the safety and activity of the combination of three-drugs chemotherapy regimens with an anti-EGFR monoclonal antibody. Promising activity results in terms of RECIST response rate and R0 resection rate have been achieved, with some safety concerns with special regards to gastrointestinal toxicity. - In the phase II randomized MACBETH study the combination of a modified schedule of FOLFOXIRI with cetuximab determined remarkable activity results, with an acceptable and manageable safety profile. - The optimal duration of the upfront treatment with chemotherapy plus anti-EGFRs is not established. The phase II MACRO-2 trial suggested that interrupting FOLFOX after 4 months while continuing cet alone as maintenance, is a reasonable option. - Activity parameters (RECIST response rate, ETS, DoR) are clinically relevant endpoints, associated with longer survival, in particular with anti-EGFR moAb-based treatment. On the basis of these considerations, we designed the present phase III randomized trial of first-line mFOLFOXIRI plus pan versus mFOLFOX6 plus pan in RAS and BRAF wt unresectable mCRC patients.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: First Line mFOLFOXIRI + PANITUMUMAB vs mFOLFOX + PANITUMUMAB IN RAS AND BRAF WT METASTATIC COLORECTAL CANCER PATIENTS
  • Official Title: The TRIPLETE Study RANDOMIZED PHASE III STUDY OF TRIPLET mFOLFOXIRI PLUS PANITUMUMAB Versus mFOLFOX6 PLUS PANITUMUMAB AS INITIAL THERAPY FOR UNRESECTABLE RAS AND BRAF WILDTYPE METASTATIC COLORECTAL CANCER PATIENTS

Clinical Trial IDs

  • ORG STUDY ID: TRIPLETE
  • NCT ID: NCT03231722

Conditions

  • Metastatic Colorectal Cancer

Interventions

DrugSynonymsArms
PanitumumabmFOLFOX6 + Panitumab
IrinotecanmFOLFOX6 + Panitumab
OxaliplatinmFOLFOXIRI + Panitumumab
l-leucovorinmFOLFOX6 + Panitumab
5-fluorouracilmFOLFOX6 + Panitumab

Purpose

- The association of FOLFOX (5-fluoruracil, folinic acid, and oxaliplatin) and pan is a standard option for the first-line treatment of unresectable RAS and BRAF wt mCRC patients. - The phase III TRIBE trial recently demonstrated that FOLFOXIRI (5-fluoruracil, folinic acid, oxaliplatin and irinotecan) plus bev significantly prolongs PFS and OS and increases RECIST response rate, ETS and DoR, as compared to FOLFIRI (5-fluoruracil folinic acid, and irinotecan) plus bev. The advantage provided by the intensification of the upfront chemotherapy backbone is independent of RAS and BRAF mutational status. - Some phase II trials recently assessed the safety and activity of the combination of three-drugs chemotherapy regimens with an anti-EGFR monoclonal antibody. Promising activity results in terms of RECIST response rate and R0 resection rate have been achieved, with some safety concerns with special regards to gastrointestinal toxicity. - In the phase II randomized MACBETH study the combination of a modified schedule of FOLFOXIRI with cetuximab determined remarkable activity results, with an acceptable and manageable safety profile. - The optimal duration of the upfront treatment with chemotherapy plus anti-EGFRs is not established. The phase II MACRO-2 trial suggested that interrupting FOLFOX after 4 months while continuing cet alone as maintenance, is a reasonable option. - Activity parameters (RECIST response rate, ETS, DoR) are clinically relevant endpoints, associated with longer survival, in particular with anti-EGFR moAb-based treatment. On the basis of these considerations, we designed the present phase III randomized trial of first-line mFOLFOXIRI plus pan versus mFOLFOX6 plus pan in RAS and BRAF wt unresectable mCRC patients.

Trial Arms

NameTypeDescriptionInterventions
mFOLFOX6 + PanitumabActive ComparatorPanitumumab 6 mg/kg iv over 60 minutes, day 1 (if the first infusion is tolerated, then subsequent infusions may be administered over 30 to 60 minutes) followed by Oxaliplatin 85 mg/sqm iv over 2 hours, day 1 in two-way with L-Leucovorin 200 mg/sqm iv over 2 hours, day 1 followed by 5-fluorouracil 400 mg/sqm iv bolus, day 1 followed by 5-fluoruracil 2400 mg/sqm 48 h-continuous infusion, starting on day 1; to be repeated every 2 weeks for a maximum of 12 cycles. If no progression occurs, patients will receive maintenance with 5FU/LV plus pan at the same dose used at the last cycle of the induction treatment. 5FU/LV plus pan will be repeated biweekly until disease progression, unacceptable toxicity or patient's refusal. The prosecution of pan until disease progression is recommended also if 5-FU is interrupted because of adverse events, patient's refusal or investigator's choice.
  • Panitumumab
  • Irinotecan
  • l-leucovorin
  • 5-fluorouracil
mFOLFOXIRI + PanitumumabExperimentalPanitumumab 6 mg/kg iv over 60 minutes, day 1 (if the first infusion is tolerated, then subsequent infusions may be administered over 30 to 60 minutes) followed by Irinotecan 150 mg/sqm iv over 60 minutes day 1, followed by Oxaliplatin 85 mg/sqm iv over 2 hours day 1, in two-way with L-Leucovorin 200 mg/sqm iv over 2 hours, day 1 followed by 5-fluoruracil 2400 mg/sqm 48 h-continuous infusion, starting on day 1; to be repeated every 2 weeks for a maximum of 12 cycles. If no progression occurs, patients will receive maintenance with 5FU/LV plus pan at the same dose used at the last cycle of the induction treatment. 5FU/LV plus pan will be repeated biweekly until disease progression, unacceptable toxicity or patient's refusal. The prosecution of pan until disease progression is recommended also if 5-FU is interrupted because of adverse events, patient's refusal or investigator's choice.
  • Panitumumab
  • Irinotecan
  • Oxaliplatin
  • l-leucovorin
  • 5-fluorouracil

Eligibility Criteria

        Inclusion Criteria:

          -  Written informed consent to study procedures and to molecular analyses.

          -  Histologically proven diagnosis of colorectal cancer.

          -  Initially unresectable metastatic colorectal cancer not previously treated with
             chemotherapy for metastatic disease.

          -  At least one measurable lesion according to RECIST 1.1.

          -  Availability of a tumour tissue sample (primary tumour and/or metastatic sites).

          -  Male or female of 18-75 years of age

          -  ECOG PS ≤2 for patients aged ≤70 years; ECOG PS 0 for patients aged 71 to 75 years.

          -  Life expectancy of at least 12 weeks

          -  Previous adjuvant chemotherapy allowed only if with fluoropyrimidine monotherapy and
             more than 6 months elapsed between the end of adjuvant and first relapse.

          -  RAS (codons 12, 13, 59, 61, 117 and 146 of KRAS and NRAS genes) and BRAF (V600E
             mutation) wt status of primary colorectal cancer or related metastasis (local or
             central laboratory assessment).

          -  Neutrophils ≥1.5 x 109/L, Platelets ≥100 x 109/L, Hgb ≥9 g/dl.

          -  Total bilirubin ≤ 1.5 fold the upper-normal limits (UNL), ASAT (SGOT) and/or ALAT
             (SGPT) ≤ 2.5 x UNL (or <5 x UNL in the case of liver metastases), alkaline phosphatase
             ≤ 2.5 x UNL (or <5 x UNL in case of liver metastases).

          -  Creatinine clearance ≥50 mL/min or serum creatinine ≤1.5 x UNL.

          -  Male subjects with female partners of childbearing potential must be willing to use
             adequate contraception - Contraception, starting with the first dose of study therapy
             through 180 days after the last dose of treatment.

        Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception
        for the subject.

          -  Women of childbearing potential must have a negative blood pregnancy test at the
             baseline visit

          -  Female subjects of childbearing potential must be willing to use an adequate method of
             contraception - Contraception, for the course of the study starting with the first
             dose of study therapy through 180 days after the last dose of treatment.

        Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception
        for the subject.

          -  Will and ability to comply with the protocol.

        Exclusion Criteria:

          -  Previous treatment for metastatic disease.

          -  Radiotherapy to any site within 4 weeks before the study.

          -  Previous adjuvant oxaliplatin-containing chemotherapy.

          -  Previous treatment with EGFR inhibitors.

          -  Untreated brain metastases or spinal cord compression or primary brain tumours.

          -  History or evidence upon physical examination of CNS disease unless adequately
             treated.

          -  Symptomatic peripheral neuropathy > 1 grade NCIC-CTG criteria.

          -  Creatinine clearance < 50 mL/min or serum creatinine >1.5 x UNL.

          -  Clinical signs of malnutrition.

          -  Neutrophils <1.5 x 109/L, Platelets <100 x 109/L, Hgb <9 g/dl.

          -  Diagnosis of interstitial pneumonitis or pulmonary fibrosis.

          -  Active uncontrolled infections or other clinically relevant concomitant illness
             contraindicating chemotherapy administration.

          -  Clinically significant (e.g. active) cardiovascular disease for example
             cerebrovascular accidents (≤6 months), myocardial infarction (≤6 months), unstable
             angina, New York Heart Association (NYHA) grade II or greater congestive heart failure
             (CHF), serious cardiac arrhythmia requiring medication.

          -  Treatment with any investigational drug within 30 days prior to enrolment or 2
             investigational agent half-lives (whichever is longer)

          -  Other co-existing malignancies or malignancies diagnosed within the last 5 years with
             the exception of localized basal and squamous cell carcinoma or cervical cancer in
             situ.

          -  Lack of physical integrity of the upper gastrointestinal tract, malabsorption
             syndrome, or inability to take oral medication.

          -  Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)
             related illness, or hepatitis B or C.

          -  Definite contraindications for the use of corticosteroids and antihistamines as
             premedication.

          -  History of severe allergic reactions or hypersensitivity to trial drugs or any of
             their excipients.

          -  Any concomitant drugs contraindicated for use with the trial drugs according to the
             product information of the pharmaceutical companies.

          -  Pregnant or lactating women. Women of childbearing potential with either a positive or
             no pregnancy test at baseline. Postmenopausal women must have been amenorrheic for at
             least 12 months to be considered of non-childbearing potential. Sexually active males
             and females (of childbearing potential) unwilling to practice contraception during the
             study and until 180 days after the last trial treatment.
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate
Time Frame:12 months
Safety Issue:
Description:the percentage of patients, relative to the total of enrolled subjects, achieving a complete (CR) or partial (PR) response, according to RECIST 1.1 criteria

Secondary Outcome Measures

Measure:Overall Toxicity Rate
Time Frame:24 months
Safety Issue:
Description:the percentage of patients, relative to the total of enrolled subjects, experiencing any adverse event, according to National Cancer Institute Common Toxicity Criteria (version 4.0)
Measure:Toxicity Rate
Time Frame:24 months
Safety Issue:
Description:the percentage of patients, relative to the total of enrolled subjects, experiencing a specific adverse event of grade 3/4, according to National Cancer Institute Common Toxicity Criteria (version 4.0)
Measure:Progression Free Survival
Time Frame:24 months
Safety Issue:
Description:the time from randomization to the first documentation of objective disease progression or death due to any cause, whichever occurs first. Documentation of disease progressive disease is defined as per RECIST 1.1 criteria based on investigator assessment
Measure:Overall Survival
Time Frame:48 months
Safety Issue:
Description:the time from randomization to the date of death due to any cause
Measure:Centrally assessed Overall response rate
Time Frame:12 months
Safety Issue:
Description:the percentage of patients, relative to the total of enrolled subjects, achieving a complete (CR) or partial (PR) response, according to RECIST 1.1 criteria based on central re-evaluation of CT scan images.
Measure:Early Tumour Shrinkage Rate
Time Frame:up to 2 months from randomization
Safety Issue:
Description:the percentage of patients, relative to the total of the enrolled subjects, achieving a ≥20% decrease in the sum of diameters of RECIST target lesions at week 8 compared to baseline.
Measure:Deepness of Response
Time Frame:12 months
Safety Issue:
Description:the relative change in the sum of longest diameters of RECIST target lesions at the nadir, in the absence of new lesions or progression of non-target lesions, when compared with baseline.
Measure:R0 Resection Rate
Time Frame:12 months
Safety Issue:
Description:the percentage of patients, relative to the total of enrolled subjects, undergoing secondary R0 resection of metastases

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Gruppo Oncologico del Nord-Ovest

Trial Keywords

  • mFOLFOXIRI + Panitumumab
  • RAS and BRAF wt

Last Updated

May 9, 2019