Dual Targeting of EGFR With Cetuximab and Afatinib to Treat Refractory wtKRAS Metastatic Colorectal Cancer

A Multicentric Randomized Phase II Trial Evaluating Dual Targeting of EGFR Using the Combination of Cetuximab and Afatinib Versus Cetuximab Alone in Patients With Chemotherapy Refractory wtKRAS Metastatic Colorectal Cancer

This is a multicentric, phase II and open label study.75 patients are expected to be randomized in 35 centers. The main objective is to assess the efficacy and safety of Afatinib -cetuximab combo versus cetuximab alone in treatment of patients with refractory wtKRAS metastatic colorectal cancer.

Study Overview

• Status: Completed
• Conditions: Metastatic Colorectal Cancer
• Intervention / Treatment: Drug: Cetuximab + Afatinib; Drug: Cetuximab

Detailed Description

Patients who will sign the inform consent will be enrolled into one of two groups. Group A will receive Afatinib ( 40mg per day) and Cetuximab (500mg/m2)every two weeks until progression. Group B will receive Cetuximab (500mg/m2) alone every two weeks until progression and after progression,patients from group B will receive afatinib (group A treatment) until progression. The criteria for evaluation will be tumor response and progression documented by CT scan and according to RECIST criteria version 1.1.

Patient will also sign a inform consent before participating in biological study. The aim of this translational study is to collect tumor and blood sample in order to determine, the biological factors which are predictive of the response to treatment.

• Study Type: Interventional
• Enrollment (Actual): 75
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Nantes, France, 44805
    • Institute de Cancerologie de la Loire

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:

1. Metastatic colorectal cancer expressing the wtKRAS status
2. No previous EGFR targeted therapy.
3. Must have failed a prior regimen containing irinotecan for metastatic disease and a prior regimen containing oxaliplatin for metastatic disease
4. Must have previously received a thymidylate synthase inhibitor (eg, fluorouracil, capecitabine, raltitrexed, or fluorouracil-uracil) at any point for treatment of colorectal cancer (CRC)
5. Life expectancy of at least 3 months.
6. Patient with ECOG ≤ 1
7. Patients aged ≥ 18.
8. Patient with measurable lesions according to RECIST criteria (version 1.1) with spiral CT scan and defined as ≥ 10 mm in longest diameter and 2X the slice thickness for extra nodal lesions and/or > 15 mm in short axis diameter for nodal lesions
9. Patient able to receive adequate oral nutrition of ≥ 1500 calories per day and free of significant nausea and vomiting

10. Patient with adequate organ function:

    • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
    • Haemoglobin ≥ 9 g/dL
    • Platelets (PTL) ≥ 100 x 109/L
    • AST/ALT ≤ 3 x ULN (≤ 5 x ULN in case of liver metastases)
    • GammaGT < 3 x ULN (< 5 x ULN in case of liver involvement)
    • Bilirubin ≤ 1.5 x ULN
    • Creatinine clearance ≥ 50 mL/min (Cockcroft and Gault formula)
11. Adequate contraception if applicable.
12. Ability to take oral medication in the opinion of the investigator
13. Patient able and willing to comply with study procedures as per protocol
14. Patient able to understand and willing to sign and date the written voluntary informed consent form at screening visit prior to any protocol-specific procedures
15. Patient affiliated to a social security regimen

Exclusion Criteria:

1. Previous EGFR targeted therapy.
2. Mutant KRAS status
3. Prior severe reaction to a monoclonal antibody
4. No heart failure or coronary heart disease symptoms Clinically relevant cardiovascular abnormalities, as judged by the investigator, such as, but not limited to, uncontrolled hypertension, congestive heart failure NYHA classification > III, unstable angina, myocardial infarction within six months prior to randomisation, or poorly controlled arrhythmia
5. Cardiac left ventricular dysfunction with resting ejection fraction of less than institutional lower limit of normal (if no lower limit of normal is defined in the institution, the lower limit is 50%)
6. Symptomatic brain metastases requiring treatment
7. Major surgery within 28 days or minor surgery within 14 days of the start of the study treatment
8. Radiotherapy less than two weeks prior to the start of the study treatment
9. Systemic chemotherapy, hormonal therapy, immunotherapy ≤ 21 days before study treatment
10. No major comorbidity that may preclude the delivery of treatment or active infection (HIV or chronic hepatitis B or C) or uncontrolled diabetes.
11. Concomitant occurrence of another cancer, or history of cancer within the past five years except in situ carcinoma of the cervix treated or basal cell carcinoma or squamous cell carcinoma.
12. Known pre-existing interstitial lung disease
13. Significant or recent acute gastrointestinal disorders with diarrhea as a major symptom e.g., Crohn's disease, malabsorption, or CTCAE grade >2 diarrhea of any etiology
14. Pregnant woman or lactating woman.
15. Persons deprived of liberty or under guardianship.
16. Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
17. Previous history of keratitis, ulcerative keratitis or severe dry eye.

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: Cetuximab + Afatinib; Afatinib 40 mg daily Cetuximab 500 mg/m2 every 2 weeks until progression	Drug: Cetuximab + Afatinib; Afatinib taken orally, cetuximab administered intravenously; Other Names: Erbitux
Active Comparator: Arm B : Cetuximab alone; Cetuximab 500mg/m2 every 2 weeks until progression After progression: Cetuximab 500mg/m2 + Afatinib 40 mg per day until progression	Drug: Cetuximab + Afatinib; Afatinib taken orally, cetuximab administered intravenously; Other Names: Erbitux; Drug: Cetuximab; Cetuximab administered intravenously; Other Names: Erbitux

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Non progression rate at 6 months	The progression rate is defined as percentage of patients without progression at 6 months after observation of all patients at 6 months	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (OR)	Overall response rate is defined as percentage of subjects with a confirmed complete or partial response as per RECIST V1.1 criteria	6 months
Progression free survival	It is define as the time of from randomization to date of first documented progression or any cause of death	until progression or death, expected average approximately 4 months
Overall and specific survival	Overall and specific survival is defined from time of randomization to the date of documented death	until death, on average approximately 14 months
Quality of life	EORTC QLQ-C30 and QLQ-CR29 are questionnaires developed to assess the quality of life of cancer patients	During treatment, on average approximately 4 months
Tolerance of the treatment	Safety of the study treatment will be assessed on occurrence of Adverse Events (AEs)	until progression, expected approximately 4 months

Collaborators and Investigators

• Sponsor: UNICANCER
• Investigators: Principal Investigator: Helene SENELLART, Dr, Centre René Gauducheau- Nantes Saint herbelain; Principal Investigator: Evelyne BOUCHER, Dr, Centre Eugène Marquis-Rennes; Principal Investigator: Emmanuelle SAMALIN SCALZI, Dr, Centre Val d'Aurel-Paul Lamarque-Montpellier; Principal Investigator: Meher BEN ABDELGHANI, Dr, Centre Paul Strauss-STRASBOURG; Principal Investigator: Antoine ADENIS, Pr, Centre Oscar Lambret_Lille; Principal Investigator: Christelle DE LA FOUCHARDIERE, Dr, Centre Léon Bérard-Lyon; Principal Investigator: François GHIRENGHELLI, Dr, Centre Georges Leclerc-Dijon; Principal Investigator: Olivier DUBROEUCQ, Dr, Centre Jean Godinot-Reims; Principal Investigator: Emmanuelle MITRY, Dr, Hopital Rene Huguenin_Intitut Curie_Paris; Principal Investigator: Christophe BORG, Pr, Hôpital Jean Minjoz-Besaçon; Principal Investigator: Yves BOUCARN, Dr, Institut Bergonié Bordeaux; Principal Investigator: Christophe BORG, Pr, Centre Hospitalier de Belfort-Montbelliard; Principal Investigator: Marion CHAUVENET, Dr, Centre hospitalier Lyon Sud-PIERRE BENITE

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2012
• Primary Completion (Actual): November 1, 2015
• Study Completion (Actual): December 1, 2017

Study Registration Dates

• First Submitted: March 1, 2013
• First Submitted That Met QC Criteria: August 6, 2013
• First Posted (Estimate): August 9, 2013

Study Record Updates

• Last Update Posted (Actual): May 8, 2018
• Last Update Submitted That Met QC Criteria: May 6, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: Chemotherapy refractory; wtKRAS metastatic colorectal cancer; cross over
• 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; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Cetuximab; Afatinib
• Other Study ID Numbers: UCGI 25

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No