Sorafenib in Combination With Irinotecan in Metastatic Colorectal Cancer Patients With KRAS Mutated Tumors (NEXIRI2)

A Randomized Phase II Trial Assessing Sorafenib in Combination With Irinotecan in Metastatic Colorectal Cancer Patients With KRAS Mutated Tumors After Failure of All Drugs Known to be Effective

The aim of this multicenter randomized phase II trial is to determine the efficacy of sorafenib and irinotecan combination versus irinotecan monotherapy or versus sorafenib monotherapy in metastatic colorectal cancer patients with KRAS mutated tumors after failure of all active drugs known to be effective.

Study Overview

• Status: Completed
• Conditions: Metastatic Colorectal Cancer Patients With KRAS Mutated Tumors
• Intervention / Treatment: Drug: Irinotecan monotherapy; Drug: Sorafenib monotherapy; Drug: Sorafenib and irinotecan combination

• Study Type: Interventional
• Enrollment (Actual): 173
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Bobigny, France, 93009
    • Hôpital Avicenne
  • Caen, France, 14076
    • Centre Francois Baclesse
  • Lille, France, 59020
    • Centre Oscar Lambret
  • Lyon, France, 69373
    • Centre Leon Berard
  • Marseille, France, 13365
    • Hôpital La Timone
  • Montpellier, France, 34298
    • CRLC Val d'Aurelle-Paul Lamarque
  • Reims, France, 51092
    • C.H.U. de REIMS
  • Rouen, France, 76038
    • CHU Charles Nicolle
  • St. Herblain, France, 44805
    • Institut de cancérologie de l'Ouest - René Gauducheau

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female ≥ 18 years old
• Histologically confirmed diagnosis of colorectal cancer
• Asymptomatic or resected primary tumor
• Metastatic colorectal cancer patient not eligible for curative surgery

• At least one target lesion:

  • Unidimensionally measurable on cross-sectional imaging
  • In an area not previously irradiated
• Disease progression after failure of active drugs (5-Fu or 5-Fu prodrugs, irinotecan, oxaliplatin, bevacizumab)
• Patients with bone metastases are eligible if they have other measurable lesions
• WHO performance status ≤ 2
• Confirmation of KRAS mutation in codons 12 or 13 in the primary tumor or metastases
• Total bilirubin ≤ 1.5 ULN, ALT or AST ≤ 2.5 ULN (or < 5 in case of liver impairment)
• Haemoglobin ≥ 10 g/dL, neutrophils ≥ 1,500/mm3, platelets ≥ 100,000/mm3
• Serum creatinine ≤ 1.5 ULN
• Negative pregnancy test in women of childbearing potential
• Use of an effective contraceptive method during the whole treatment and up to 3 months after the completion of treatment in males and females
• Life expectancy of at least 3 months
• Informed consent signed prior any study specific procedures
• Tumor evaluation should be performed within 3 weeks prior to starting treatment

Exclusion Criteria:

• History of Gilbert's syndrome
• Symptomatic brain metastases or carcinomatous meningitis
• Bone-only metastases
• History or presence of other cancers within the past 5 years (except curatively treated non-melanoma skin cancer and in situ cervical cancer)
• Prior surgery or radiotherapy within 4 weeks before entering the study
• Cardiac arrhythmia requiring treatment (except for beta-blockers and digoxin), unstable cardiac disease, myocardial infarction within the previous 6 months, > grade II NYHA heart failure, uncontrolled hypertension
• Kalemia lower than normal serum potassium value
• From ECG, QTc interval > 470 ms
• History of acute or chronic pancreatitis
• History of epileptic seizures requiring long-term anticonvulsant therapy
• History of organ transplantation with use of immunosuppression therapy
• Severe bacterial or fungal infection (Grade > 2 NCI-CTCAE v.4.0)
• Known HIV infection
• Long-term use of CYP 3A4 enzyme-inducing agents such as rifampicin, St. John's Wort (hypericum perforatum), phenytoin, carbamazepine, phenobarbital, dexamethasone, and ketoconazole
• Pregnant or breastfeeding women
• Bowel malabsorption or extended bowel resection that could affect the absorption of sorafenib, occlusive syndrome, inability to take oral medications
• Inflammatory bowel disease with chronic diarrhea (NCI-CTCAE v.4.0)
• Participation in another clinical trial 30 days prior to study entry
• Concurrent treatment with any other investigational product or anticancer therapy (except for irinotecan or sorafenib)
• Psychological, social, geographical disorders or any other condition that would preclude study compliance (treatment administration and study follow-up).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Irinotecan monotherapy; Intravenous infusion irinotecan 180 mg/m2 over 90 minutes (D1=D15) with cross over to irinotecan and sorafenib combination at progression.	Drug: Irinotecan monotherapy
Active Comparator: Sorafenib monotherapy; Oral sorafenib 400 mg twice daily (total dose 800 mg/day) with cross over to irinotecan and sorafenib combination at progression	Drug: Sorafenib monotherapy
Experimental: Sorafenib and irinotecan combination; Intravenous infusion irinotecan 120 mg/m2 over 90 minutes (D1=D15) at Cycle 1, 150 mg/m² at C2 if no diarrhea > grade 1 and no other toxicity > grade 2, and 180 mg/m² at C3 in the same conditions; Oral sorafenib 400 mg twice daily (total dose 800 mg/day) from C1. 1 cycle = 15 days and 1 course = 4 weeks.	Drug: Sorafenib and irinotecan combination

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Non-progression rate	To evaluate the non-progression rate at 2 months according to RECIST criteria (Version 1.1)	At 2 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease control rate	According to RECIST criteria (Version 1.1)	At 2 months
Treatment-related toxicity	According to NCI CTC V4.0	At 6 months
Overall survival	Overall survival is defined as the time from the date of inclusion to the date of death from any cause.	At 6 months
Quality of life questionnaire	Using the EORTC QLQ-C30 questionnaire	6 months
Progression Free Survival	Progression Free Survival is defined as the time from the date of inclusion to first documentation of objective tumor progression or to death due to progression.	At 6 months
Response rate	According to RECIST criteria (Version 1.1)	At 2 months

Other Outcome Measures

Outcome Measure	Time Frame
Cmax and Tmax of sorafenib and irinotecan	Up to 3 months

Collaborators and Investigators

• Sponsor: Institut du Cancer de Montpellier - Val d'Aurelle
• Investigators: Principal Investigator: Emmanuelle SAMALIN, MD, CRLC Val d'Aurelle-Paul Lamarque; Study Chair: Marc YCHOU, MD,, CRLC Val d'Aurelle

Publications and helpful links

General Publications

• Samalin E, Fouchardiere C, Thezenas S, Boige V, Senellart H, Guimbaud R, Taieb J, Francois E, Galais MP, Lievre A, Seitz JF, Metges JP, Bouche O, Boissiere-Michot F, Lopez-Crapez E, Bibeau F, Ho-Pun-Cheung A, Ychou M, Adenis A, Di Fiore F, Mazard T. Sorafenib Plus Irinotecan Combination in Patients With RAS-mutated Metastatic Colorectal Cancer Refractory To Standard Combined Chemotherapies: A Multicenter, Randomized Phase 2 Trial (NEXIRI-2/PRODIGE 27). Clin Colorectal Cancer. 2020 Dec;19(4):301-310.e1. doi: 10.1016/j.clcc.2020.04.008. Epub 2020 May 15.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2012
• Primary Completion (Actual): March 1, 2015
• Study Completion (Actual): September 1, 2015

Study Registration Dates

• First Submitted: October 19, 2012
• First Submitted That Met QC Criteria: October 24, 2012
• First Posted (Estimate): October 29, 2012

Study Record Updates

• Last Update Posted (Actual): August 22, 2019
• Last Update Submitted That Met QC Criteria: August 20, 2019
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Keywords: Sorafenib; KRAS mutation; Metastatic colorectal cancer patients
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase Inhibitors; Protein Kinase Inhibitors; Topoisomerase I Inhibitors; Sorafenib; Irinotecan
• Other Study ID Numbers: NEXIRI2; 2012-000644-94 (EudraCT Number)