Clinical trial NCT01450319: Cetuximab in Refractory Colorectal Cancer With K-RAS Mutated and Favorable FcγRIIa (CD32) Genotype
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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Colorectal Neoplasms
Keywords: K-RAS
FcγRII/IIIa genotypes
CRC
Colorectal cancer
Lead sponsor: Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
Collaborators: name: Merck, S.L., Spain
First posted: 2011-10-12
Enrollment: 73
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Overall Survival (OS) Time
timeFrame: From the date of informed consent signature until death, assessed up to 3 years
Secondary outcomes:
measure: Percentage of Subjects With Disease Control Rate (DCR)
timeFrame: From the date of informed consent signature until progressive disease, assessed up to 3 years
measure: Progression Free Survival (PFS) Time
timeFrame: From the date of informed consent signature until progressive disease (PD) or death, assessed up to 3 years
measure: Number of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Leading to Discontinuation, AEs Leading to Death
timeFrame: From the date of enrollment up to 30 days after the last dose of study drug administration, assessed up to 3 years
measure: Number of Subjects With Fcγ Receptors (FCγR) IIa/IIIa Polymorphisms
timeFrame: Baseline
measure: Overall Survival (OS) Related to Codon G13D
timeFrame: 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)
measure: Overall Survival (OS) Related to Killer Inhibitory Receptors 2DS4 (KIR2DS4) Functional Receptor (f/d) and Non-functional Receptor (NFR)
timeFrame: 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)
measure: Beta 2-microglobulin
timeFrame: Baseline, Week 8
Other outcomes:
Locations:
city: A Coruña
country: Spain
facility: Research Site
city: Asturias
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Cordoba
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Navarra
country: Spain
facility: Research Site
city: Santiago de Compostela
country: Spain
facility: Research Site
city: Sevilla
country: Spain
facility: Research Site
city: Valencia
country: Spain
facility: Research Site
Study officials:
affiliation: Merck, S.L., Spain
name: Medical Director
role: STUDY_DIRECTOR
References:
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.