Cetuximab in Refractory Colorectal Cancer With K-RAS Mutated and Favorable FcγRIIa (CD32) Genotype (MUTEX)

This study has been completed.
Sponsor:
Collaborator:
Merck, S.L., Spain
Information provided by (Responsible Party):
Merck KGaA
ClinicalTrials.gov Identifier:
NCT01450319
First received: October 7, 2011
Last updated: May 10, 2016
Last verified: May 2016
  Purpose
This national, multicenter, open-label phase 2 study without any control arm aims to evaluate the activity of cetuximab monotherapy in the treatment of refractory colorectal cancer in subjects with K-RAS mutated and FcγRIIa polymorphism tumors, in which there is no therapeutic alternative for treatment. Failure of the first and second line conventional therapeutic lines was documented.

Condition Intervention Phase
Colorectal Neoplasms
Drug: Cetuximab
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II Clinical Study of Cetuximab in Refractory Colorectal Cancer With K-RAS Mutated and Favourable FcγR IIa (CD32) Genotype

Resource links provided by NLM:


Further study details as provided by Merck KGaA:

Primary Outcome Measures:
  • Overall Survival (OS) Time [ Time Frame: From the date of informed consent signature until death, assessed up to 3 years ] [ Designated as safety issue: No ]
    Overall survival was defined as the time from date of informed consent signature until death.


Secondary Outcome Measures:
  • Percentage of Subjects With Disease Control Rate (DCR) [ Time Frame: From the date of informed consent signature until progressive disease, assessed up to 3 years ] [ Designated as safety issue: No ]
    DCR was defined as those subjects achieving complete response (CR), partial response (PR) or stable disease (SD), according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v.1.1). For target lesions (TLs), CR was defined as the disappearance of all TLs; PR was defined as at least a 30 percent (%) decrease in the sum of longest diameter (SLD) of the TLs, taking as a reference the baseline (BL) SLD; Stable disease (SD) was defined as neither sufficient decrease in SLD to qualify for PR nor sufficient increase in SLD to qualify for PD; and PD was defined as at least a 20% increase in the SLD of TLs, taking as reference the smallest SLD recorded since the treatment started. For non-target lesions (NTLs), CR was defined as the disappearance of all NTLs and normalization of tumor marker levels; SD was defined as the persistence of 1 or more NTLs and/or maintenance of tumor marker levels above normal limits; and progressive disease (PD) was defined as the appearance

  • Progression Free Survival (PFS) Time [ Time Frame: From the date of informed consent signature until progressive disease (PD) or death, assessed up to 3 years ] [ Designated as safety issue: No ]
    PFS was defined as the time from informed consent signature until PD or death, whatever occurred first. Subjects who did not have disease progression or were lost to follow-up, were censored at the date of last contact, known to be alive and progression free; moreover, those subjects who started a new treatment (different from cetuximab), were censored at the date of starting the new treatment. For TLs, PD was defined at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from BL or the appearance of one or more new lesions. For NTLs, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. Participants without second-line PD or death were censored at the date of last tumor assessment where non-progression was documented.

  • Number of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Leading to Discontinuation, AEs Leading to Death [ Time Frame: From the date of enrollment up to 30 days after the last dose of study drug administration, From the date of enrollment up to 30 days after the last dose of study drug administration, assessed up to 3 years ] [ Designated as safety issue: Yes ]
    An AE was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A SAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. Treatment-emergent are events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state.

  • Number of Subjects With Fcγ Receptors (FCγR) IIa/IIIa Polymorphisms [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    The antibody fragment C portion (FCy) of cetuximab interacts with Fc-gamma receptors (FCyRs) expressed by immune effector cells. Polymorphisms were described in genes coding for FCyRIIa and in FCyRIIIa. A histidine/arginine polymorphism at position 131 for FCyRIIa gene and valine ⁄ phenylalanine polymorphism at position 158 for the FCyRIIIa gene were reported to be functionally relevant in the ADCC mechanism. All subjects were analyzed and classified as carriers of every different polymorphism of FCy Receptors: for FCyRIIa (H/H, homozygous alleles with histidine and R/H, heterozygous alleles with arginine/histidine) and FCyRIIIa (V/V, homozygous alleles with valine, F/F, homozygous alleles with phenylalanine and F/V, heterozygous alleles with valine ⁄ phenylalanine) (units: subjects with every type of polymorphism) .The FCyR genotype was determined using a TaqMan Allelic Discrimination Assay.

  • Overall Survival (OS) Related to Codon G13D [ Time Frame: From the date of informed consent signature until death, lost-to-follow-up or end of study, whatever occurred first (maximal up to 3 years) ] [ Designated as safety issue: No ]
    OS was defined as the time from informed consent signature until death. Subjects without death were censored at the last date known alive (within the study).

  • Overall Survival (OS) Related to Killer Inhibitory Receptors 2DS4 (KIR2DS4) Functional Receptor (f/d) and Non-functional Receptor (NFR) [ Time Frame: From the date of informed consent signature until death, lost-to-follow-up or end of study, whatever occurred first (maximal assessed up to 3 years) ] [ Designated as safety issue: No ]
    OS was defined as the time from informed consent signature until death. Subjects without death were censored at the last date known alive (within the study).

  • Beta 2-microglobulin [ Time Frame: Baseline, Week 8 ] [ Designated as safety issue: No ]

Enrollment: 70
Study Start Date: December 2011
Study Completion Date: December 2014
Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cetuximab Drug: Cetuximab
Cetuximab will be administered intravenously at a dose of 500 milligram per square meter (mg/m^2) every 2 weeks until disease progression, death, or consent withdrawal.
Other Name: Erbitux

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Written informed consent form signed by the subject
  • Age greater than or equal to (>=) 18 years
  • Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to (=<) 2
  • Life expectancy of greater than (>) 2 months
  • Histological confirmed colorectal cancer (CRC) with mutated K-RAS and favorable genotypes (any H in FcγRIIa-131). Selection will be done only based on Cluster of differentiation (CD)32 polymorphisms
  • Epidermal growth factor receptor (EGFR) expression in his/her tumor sample
  • Stage 4 metastatic disease, with at least 1 measurable lesion according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) criteria, documented within 28 days prior to the study inclusion
  • Tumor tissue sample available for the assessment of K-RAS status and FcγRIIa (CD32) genotype
  • Subject who has received at least 2 prior therapeutic lines
  • Adequate bone marrow function, defined as:

    • haemoglobin > 9.0 gram per deciliter (g/dL)
    • platelet count >100*10^9 per liter
    • absolute neutrophil count (ANC) >=1.5*10^9/Liter
  • Adequate hepatic and renal function, defined as:

    • Serum bilirubin =<1.5 times the upper limit of normal (ULN)
    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =<2.5*ULN in absence of liver metastasis and ALT and AST =<5*ULN in the presence of liver metastasis
    • Alkaline phosphatase =<2.5*ULN or =<5 in the presence of liver metastasis or =<10 in the absence of liver metastasis
    • Creatinine clearance >= 50 milliliter per minute (mL/min) (according to Cockcroft and Gault formula) or serum creatinine <1.5*ULN
  • Adequate recovery after recent surgery, chemotherapy or radiotherapy. Prior major surgery, chemotherapy, treatment with an investigational product or radiotherapy must have occurred at least 4 weeks before study inclusion
  • Women of child-bearing potential must have a negative pregnancy test performed within 7 days prior to the study inclusion. Postmenopausal women must be amenorrheic for at least 12 months. If the risk of conception exists both male and female subjects must use effective contraception (for example, abstinence, intrauterine device (IUD), oral contraceptive, double barrier method or to be surgically sterile) since the signature of the consent form until at least 6 months after the end of treatment or end of last dose, whichever occurs first

Exclusion Criteria:

  • Previous treatment with monoclonal antibodies against EGFR
  • Toxicity, due to previous treatment, not resolved to Grade 1 before the subject's inclusion into the study
  • Clinically relevant coronary disease or myocardial infarction, unstable angina, Grade >=2 congestive cardiac insufficiency according to New York Heart Association (NYHA) within 6 months before starting the study treatment
  • Clinically significant vascular disease (for example, aortic aneurysm which requires surgery, pulmonary embolism, recent peripheral arterial thrombosis) within 12 months prior to starting the study treatment
  • Evidence of uncontrolled brain metastases
  • History of active neurological disease
  • History of uncontrolled seizures
  • History of lung fibrosis, acute pulmonary damage or interstitial pneumonia
  • Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C infection, or presence of severe, uncontrolled intercurrent infections or other severe uncontrolled concomitant diseases
  • Current Grade >=2 (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE]) infection
  • History of uncontrolled diabetes, uncontrolled hypertension or hepatic involvement
  • Known or suspected allergy or hypersensitivity to cetuximab
  • History of previous malignancy other than CRC occurring within 5 years before starting the study treatment, except for previously cured basal cell carcinoma of skin or carcinoma in situ of the cervix or urinary bladder treated more than 2 years before recruitment
  • Participation in another treatment study with an investigational drug within the last 30 days
  • Pregnancy or lactation
  • Any medical, psychological, psychiatric or social uncontrolled problem which may interfere in the participation of the subject in the study or in the evaluation of the study results
  • Psychological, familiar or geographic conditions not allowing the adequate follow-up and adherence to the study protocol
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01450319

Locations
Spain
Research Site
A Coruña, Spain
Research Site
Asturias, Spain
Research Site
Barcelona, Spain
Research Site
Cordoba, Spain
Research Site
Madrid, Spain
Research Site
Navarra, Spain
Research Site
Santiago de Compostela, Spain
Research Site
Sevilla, Spain
Research Site
Valencia, Spain
Sponsors and Collaborators
Merck KGaA
Merck, S.L., Spain
Investigators
Study Director: Medical Director Merck, S.L., Spain
  More Information

Responsible Party: Merck KGaA
ClinicalTrials.gov Identifier: NCT01450319     History of Changes
Other Study ID Numbers: EMR 062202-529  2010-023580-18 
Study First Received: October 7, 2011
Results First Received: May 10, 2016
Last Updated: May 10, 2016
Health Authority: Spain: Spanish Agency of Medicines
Spain: Agencia Española de Medicamentos y Productos Sanitarios

Keywords provided by Merck KGaA:
K-RAS
FcγRII/IIIa genotypes
CRC
Colorectal cancer

Additional relevant MeSH terms:
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
Antineoplastic Agents

ClinicalTrials.gov processed this record on July 28, 2016