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

Primary Purpose

Colorectal Neoplasms

Status
Completed
Phase
Phase 2
Locations
Spain
Study Type
Interventional
Intervention
Cetuximab
Sponsored by
Merck KGaA, Darmstadt, Germany
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Colorectal Neoplasms focused on measuring K-RAS, FcγRII/IIIa genotypes, CRC, Colorectal cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Research Site
  • Research Site
  • Research Site
  • Research Site
  • Research Site
  • Research Site
  • Research Site
  • Research Site
  • Research Site

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Cetuximab

Arm Description

Outcomes

Primary Outcome Measures

Overall Survival (OS) Time
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)
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
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
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
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
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)
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

Full Information

First Posted
October 7, 2011
Last Updated
October 7, 2016
Sponsor
Merck KGaA, Darmstadt, Germany
Collaborators
Merck, S.L., Spain
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1. Study Identification

Unique Protocol Identification Number
NCT01450319
Brief Title
Cetuximab in Refractory Colorectal Cancer With K-RAS Mutated and Favorable FcγRIIa (CD32) Genotype
Acronym
MUTEX
Official Title
Phase II Clinical Study of Cetuximab in Refractory Colorectal Cancer With K-RAS Mutated and Favourable FcγR IIa (CD32) Genotype
Study Type
Interventional

2. Study Status

Record Verification Date
October 2016
Overall Recruitment Status
Completed
Study Start Date
December 2011 (undefined)
Primary Completion Date
December 2014 (Actual)
Study Completion Date
December 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Merck KGaA, Darmstadt, Germany
Collaborators
Merck, S.L., Spain

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Colorectal Neoplasms
Keywords
K-RAS, FcγRII/IIIa genotypes, CRC, Colorectal cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
73 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cetuximab
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Cetuximab
Other Intervention Name(s)
Erbitux
Intervention Description
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.
Primary Outcome Measure Information:
Title
Overall Survival (OS) Time
Description
Overall survival was defined as the time from date of informed consent signature until death.
Time Frame
From the date of informed consent signature until death, assessed up to 3 years
Secondary Outcome Measure Information:
Title
Percentage of Subjects With Disease Control Rate (DCR)
Description
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
Time Frame
From the date of informed consent signature until progressive disease, assessed up to 3 years
Title
Progression Free Survival (PFS) Time
Description
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.
Time Frame
From the date of informed consent signature until progressive disease (PD) or death, assessed up to 3 years
Title
Number of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Leading to Discontinuation, AEs Leading to Death
Description
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.
Time Frame
From the date of enrollment up to 30 days after the last dose of study drug administration, assessed up to 3 years
Title
Number of Subjects With Fcγ Receptors (FCγR) IIa/IIIa Polymorphisms
Description
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.
Time Frame
Baseline
Title
Overall Survival (OS) Related to Codon G13D
Description
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).
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)
Title
Overall Survival (OS) Related to Killer Inhibitory Receptors 2DS4 (KIR2DS4) Functional Receptor (f/d) and Non-functional Receptor (NFR)
Description
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).
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)
Title
Beta 2-microglobulin
Time Frame
Baseline, Week 8

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Director
Organizational Affiliation
Merck, S.L., Spain
Official's Role
Study Director
Facility Information:
Facility Name
Research Site
City
A Coruña
Country
Spain
Facility Name
Research Site
City
Asturias
Country
Spain
Facility Name
Research Site
City
Barcelona
Country
Spain
Facility Name
Research Site
City
Cordoba
Country
Spain
Facility Name
Research Site
City
Madrid
Country
Spain
Facility Name
Research Site
City
Navarra
Country
Spain
Facility Name
Research Site
City
Santiago de Compostela
Country
Spain
Facility Name
Research Site
City
Sevilla
Country
Spain
Facility Name
Research Site
City
Valencia
Country
Spain

12. IPD Sharing Statement

Citations:
PubMed Identifier
33833048
Citation
Manzanares-Martin B, Cebrian Aranda A, Del Puerto-Nevado L, Gonzalez R, Solanes S, Gomez-Espana MA, Garcia-Foncillas J, Aranda E. Improving selection of patients with metastatic colorectal cancer to benefit from cetuximab based on KIR genotypes. J Immunother Cancer. 2021 Apr;9(4):e001705. doi: 10.1136/jitc-2020-001705.
Results Reference
derived

Learn more about this trial

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

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