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

NCT03231722 | Completed Phase 3 DMC

• 1 other identifier: TRIPLETE
• Study Type: interventional
• Target: 435
• Locations: 1 country
• Sites: 4

Brief Summary

• 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.

Conditions

Metastatic Colorectal Cancer

Keywords

mFOLFOXIRI + Panitumumab; RAS and BRAF wt

Outcome Measures

Primary Outcomes (1)

• Overall response rate

  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

  12 months

Secondary Outcomes (8)

• Overall Toxicity Rate

  24 months

• Toxicity Rate

  24 months

• Progression Free Survival

  24 months

• Overall Survival

  48 months

• Centrally assessed Overall response rate

  12 months

Study Arms (2)

mFOLFOX6 + Panitumab

ACTIVE COMPARATOR

* Panitumumab 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.

Drug: Panitumumab; Drug: Irinotecan; Drug: l-leucovorin; Drug: 5-fluorouracil

mFOLFOXIRI + Panitumumab

EXPERIMENTAL

* Panitumumab 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.

Drug: Panitumumab; Drug: Irinotecan; Drug: Oxaliplatin; Drug: l-leucovorin; Drug: 5-fluorouracil

Interventions

Panitumumab DRUG

6 mg/kg iv over 60 minutes, day 1

mFOLFOX6 + Panitumab; mFOLFOXIRI + Panitumumab

Irinotecan DRUG

150 mg/sqm iv over 60 minutes day 1

mFOLFOX6 + Panitumab; mFOLFOXIRI + Panitumumab

Oxaliplatin DRUG

85 mg/sqm iv over 2 hours day 1

mFOLFOXIRI + Panitumumab

l-leucovorin DRUG

200 mg/sqm iv over 2 hours

mFOLFOX6 + Panitumab; mFOLFOXIRI + Panitumumab

5-fluorouracil DRUG

400 mg/sqm iv bolus, day 1 followed by 2400 mg/sqm 48 h-continuous infusion, starting on day 1;

mFOLFOX6 + Panitumab; mFOLFOXIRI + Panitumumab

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Gruppo Oncologico del Nord-Ovest: lead

Study Sites (4)

Fondazione IRCCS Istituto Nazionale Tumori

Milan, 20133, Italy

Location

Fondazione IRCCS Istituto Oncologico Veneto

Padua, 35128, Italy

Location

A.O. Universitaria Pisana - Pisa (Pi) Oncologia Medica

Pisa, 56126, Italy

Location

Azienda Ospedaliera Universitaria Integrata Verona

Verona, 37126, Italy

Location

Related Publications (3)

• Sposito C, Pietrantonio F, Maspero M, Di Benedetto F, Vivarelli M, Tisone G, De Carlis L, Romagnoli R, Gruttadauria S, Colledan M, Agnes S, Ettorre G, Baccarani U, Torzilli G, Di Sandro S, Pinelli D, Caccamo L, Sartore Bianchi A, Spreafico C, Torri V, Mazzaferro V. Improving Outcome of Selected Patients With Non-Resectable Hepatic Metastases From Colorectal Cancer With Liver Transplantation: A Prospective Parallel Trial (COLT trial). Clin Colorectal Cancer. 2023 Jun;22(2):250-255. doi: 10.1016/j.clcc.2023.01.003. Epub 2023 Feb 3.

  PMID: 36822922 DERIVED

• Rossini D, Antoniotti C, Lonardi S, Pietrantonio F, Moretto R, Antonuzzo L, Boccaccino A, Morano F, Brugia M, Pozzo C, Marmorino F, Bergamo F, Tamburini E, Passardi A, Randon G, Murgioni S, Borelli B, Buonadonna A, Giordano M, Fontanini G, Conca V, Formica V, Aglietta M, Bordonaro R, Aprile G, Masi G, Boni L, Cremolini C. Upfront Modified Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan Plus Panitumumab Versus Fluorouracil, Leucovorin, and Oxaliplatin Plus Panitumumab for Patients With RAS/BRAF Wild-Type Metastatic Colorectal Cancer: The Phase III TRIPLETE Study by GONO. J Clin Oncol. 2022 Sep 1;40(25):2878-2888. doi: 10.1200/JCO.22.00839. Epub 2022 Jun 6.

  PMID: 35666229 DERIVED

• Borelli B, Moretto R, Lonardi S, Bonetti A, Antoniotti C, Pietrantonio F, Masi G, Burgio V, Marmorino F, Salvatore L, Rossini D, Zaniboni A, Zucchelli G, Martignetti A, Di Battista M, Pella N, Passardi A, Boccaccino A, Leone F, Colombo C, Granetto C, Vannini F, Marsico VA, Martinelli E, Antonuzzo L, Vitello S, Delliponti L, Boni L, Cremolini C, Falcone A. TRIPLETE: a randomised phase III study of modified FOLFOXIRI plus panitumumab versus mFOLFOX6 plus panitumumab as initial therapy for patients with unresectable RAS and BRAF wild-type metastatic colorectal cancer. ESMO Open. 2018 Jul 9;3(4):e000403. doi: 10.1136/esmoopen-2018-000403. eCollection 2018.

  PMID: 30018814 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Panitumumab; Irinotecan; Oxaliplatin; Leucovorin; Fluorouracil

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Camptothecin; Alkaloids; Heterocyclic Compounds; Coordination Complexes; Organic Chemicals; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring

Study Officials

• Chiara Cremolini, MD, PhD

  U.O. Oncologia Medica 2 Universitaria - Azienda Ospedaliero-Universitaria Pisana Dipartimento di Ricerca Traslazionale e Nuove Tecnologie - Università di Pisa Istituto Toscano Tumori

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: open label
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 3, 2017
• First Posted: July 27, 2017
• Study Start: September 13, 2017
• Primary Completion: June 15, 2022
• Study Completion: June 24, 2022
• Last Updated: January 5, 2023

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will not share

Locations

IT (4)