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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01919879
Recruitment Status : Completed
First Posted : August 9, 2013
Last Update Posted : May 8, 2018
Sponsor:
Information provided by (Responsible Party):
UNICANCER

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.

Condition or disease Intervention/treatment Phase
Metastatic Colorectal Cancer Drug: Cetuximab + Afatinib Drug: Cetuximab Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 75 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : October 2012
Actual Primary Completion Date : November 2015
Actual Study Completion Date : December 2017


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 Name: 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 Name: Erbitux

Drug: Cetuximab
Cetuximab administered intravenously
Other Name: Erbitux




Primary Outcome Measures :
  1. Non progression rate at 6 months [ Time Frame: 6 months ]
    The progression rate is defined as percentage of patients without progression at 6 months after observation of all patients at 6 months


Secondary Outcome Measures :
  1. Overall response rate (OR) [ Time Frame: 6 months ]
    Overall response rate is defined as percentage of subjects with a confirmed complete or partial response as per RECIST V1.1 criteria

  2. Progression free survival [ Time Frame: until progression or death, expected average approximately 4 months ]
    It is define as the time of from randomization to date of first documented progression or any cause of death

  3. Overall and specific survival [ Time Frame: until death, on average approximately 14 months ]
    Overall and specific survival is defined from time of randomization to the date of documented death

  4. Quality of life [ Time Frame: During treatment, on average approximately 4 months ]
    EORTC QLQ-C30 and QLQ-CR29 are questionnaires developed to assess the quality of life of cancer patients

  5. Tolerance of the treatment [ Time Frame: until progression, expected approximately 4 months ]
    Safety of the study treatment will be assessed on occurrence of Adverse Events (AEs)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01919879


Locations
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France
Institute de Cancérologie de la Loire
Nantes, France, 44805
Sponsors and Collaborators
UNICANCER
Investigators
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Principal Investigator: Helene SENELLART, Dr Centre René Gauducheau- Nantes Saint herbelain
Principal Investigator: Evelyne BOUCHER, Dr Centre Eugène Marquis-Rennes
Principal Investigator: Eric FRANCOIS, Dr Centre Antoine Lacassagne-Nice
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
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Responsible Party: UNICANCER
ClinicalTrials.gov Identifier: NCT01919879    
Other Study ID Numbers: UCGI 25
First Posted: August 9, 2013    Key Record Dates
Last Update Posted: May 8, 2018
Last Verified: May 2018
Keywords provided by UNICANCER:
Chemotherapy refractory
wtKRAS metastatic colorectal cancer
cross over
Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Cetuximab
Afatinib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action