Clinical trial NCT01919879: Dual Targeting of EGFR With Cetuximab and Afatinib to Treat Refractory wtKRAS Metastatic Colorectal Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Metastatic Colorectal Cancer
Keywords: Chemotherapy refractory
wtKRAS metastatic colorectal cancer
cross over
Lead sponsor: UNICANCER
Sponsor class: OTHER
First posted: 2013-08-09
Enrollment: 75
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Non progression rate at 6 months
timeFrame: 6 months
Secondary outcomes:
measure: Overall response rate (OR)
timeFrame: 6 months
measure: Progression free survival
timeFrame: until progression or death, expected average approximately 4 months
measure: Overall and specific survival
timeFrame: until death, on average approximately 14 months
measure: Quality of life
timeFrame: During treatment, on average approximately 4 months
measure: Tolerance of the treatment
timeFrame: until progression, expected approximately 4 months
Other outcomes:
Locations:
city: Nantes
country: France
facility: Institute de Cancérologie de la Loire
Study officials:
affiliation: Centre René Gauducheau- Nantes Saint herbelain
name: Helene SENELLART, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Eugène Marquis-Rennes
name: Evelyne BOUCHER, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Antoine Lacassagne-Nice
name: Eric FRANCOIS, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Val d'Aurel-Paul Lamarque-Montpellier
name: Emmanuelle SAMALIN SCALZI, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Paul Strauss-Strasbourg
name: Meher BEN ABDELGHANI, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Oscar Lambret_Lille
name: Antoine ADENIS, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Léon Bérard-Lyon
name: Christelle DE LA FOUCHARDIERE, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Georges Leclerc-Dijon
name: François GHIRENGHELLI, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Jean Godinot-Reims
name: Olivier DUBROEUCQ, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Hopital Rene Huguenin_Intitut Curie_Paris
name: Emmanuelle MITRY, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Jean Minjoz-Besaçon
name: Christophe BORG, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: Institut Bergonié Bordeaux
name: Yves BOUCARN, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Hospitalier de Belfort-Montbelliard
name: Christophe BORG, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Hospitalier Lyon Sud-Pierre Benite
name: Marion CHAUVENET, Dr
role: PRINCIPAL_INVESTIGATOR
References: