Colorectal Neoplasms
Conditions
Keywords
K-RAS, FcγRII/IIIa genotypes, CRC, Colorectal cancer
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.
Interventions
DRUGCetuximab
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.
Sponsors
Merck, S.L., Spain
Merck KGaA, Darmstadt, Germany
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) Time | From the date of informed consent signature until death, assessed up to 3 years | Overall survival was defined as the time from date of informed consent signature until death. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects With Disease Control Rate (DCR) | From the date of informed consent signature until progressive disease, assessed up to 3 years | 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 | From the date of informed consent signature until progressive disease (PD) or death, assessed up to 3 years | 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 | From the date of enrollment up to 30 days after the last dose of study drug administration, assessed up to 3 years | 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 | Baseline | 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 | 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) | 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) | 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) | 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 | Baseline, Week 8 | — |
Countries
Spain
Participant flow
Pre-assignment details
A total of 73 subjects were enrolled in the trial. Out of 73 subjects, 70 subjects received the study drug and start the study and three subjects were excluded from the modified intent-to-treat (MITT) analysis set.
Participants by arm
| Arm | Count |
|---|---|
| Cetuximab Cetuximab was administered intravenously at a dose of 500 milligram per square meter (mg/m\^2) every 2 weeks until disease progression, death, or consent withdrawal. | 70 |
| Total | 70 |
Baseline characteristics
| Characteristic | Cetuximab |
|---|---|
| Age, Continuous | 63.61 Years STANDARD_DEVIATION 10.54 |
| Sex: Female, Male Female | 34 Participants |
| Sex: Female, Male Male | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 69 / 70 |
| serious Total, serious adverse events | 17 / 70 |
Outcome results
Primary
Overall Survival (OS) Time
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
Population: MITT analysis set included all the subjects who received study drug treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cetuximab | Overall Survival (OS) Time | 6.71 Months |
Secondary
Beta 2-microglobulin
Time frame: Baseline, Week 8
Population: MITT analysis set included all the subjects who received study drug treatment. Here n signifies number of evaluable subjects for each category, as specified.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cetuximab | Beta 2-microglobulin | Baseline (n=61) | 2.35 microgram per milliliter (mcg/mL) | Standard Deviation 0.58 |
| Cetuximab | Beta 2-microglobulin | Week 8 (n=29) | 2.37 microgram per milliliter (mcg/mL) | Standard Deviation 1.13 |
Secondary
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.
Time frame: From the date of enrollment up to 30 days after the last dose of study drug administration, assessed up to 3 years
Population: Safety analysis set included all the subjects who received at least one dose of the study drug treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cetuximab | Number of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Leading to Discontinuation, AEs Leading to Death | AEs | 69 Subjects |
| Cetuximab | Number of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Leading to Discontinuation, AEs Leading to Death | SAEs | 17 Subjects |
| Cetuximab | Number of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Leading to Discontinuation, AEs Leading to Death | AEs leading to discontinuation | 2 Subjects |
| Cetuximab | Number of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Leading to Discontinuation, AEs Leading to Death | AEs leading to death | 3 Subjects |
Secondary
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.
Time frame: Baseline
Population: MITT analysis set included all the subjects who received study drug treatment. Subjects may fall into more than one category.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cetuximab | Number of Subjects With Fcγ Receptors (FCγR) IIa/IIIa Polymorphisms | FcγRIIa: H/H | 27 Subjects |
| Cetuximab | Number of Subjects With Fcγ Receptors (FCγR) IIa/IIIa Polymorphisms | FcγRIIa: R/H | 43 Subjects |
| Cetuximab | Number of Subjects With Fcγ Receptors (FCγR) IIa/IIIa Polymorphisms | FcγRIIIa: V/V | 6 Subjects |
| Cetuximab | Number of Subjects With Fcγ Receptors (FCγR) IIa/IIIa Polymorphisms | FcγRIIIa: F/F | 28 Subjects |
| Cetuximab | Number of Subjects With Fcγ Receptors (FCγR) IIa/IIIa Polymorphisms | FcγRIIIa: F/V | 36 Subjects |
Secondary
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).
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)
Population: MITT analysis set included all the subjects who received study drug treatment. Here Number of subjects analyzed signifies total number of evaluable subjects for this outcome measure; n signifies number of evaluable subjects for each category, as specified.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cetuximab | Overall Survival (OS) Related to Codon G13D | G13D (n=14) | 7.2 months |
| Cetuximab | Overall Survival (OS) Related to Codon G13D | No G13D (n=48) | 6.3 months |
Secondary
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).
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)
Population: MITT analysis set included all the subjects who received study drug treatment. Here Number of subjects analyzed signifies number of evaluable subjects for this outcome measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cetuximab | Overall Survival (OS) Related to Killer Inhibitory Receptors 2DS4 (KIR2DS4) Functional Receptor (f/d) and Non-functional Receptor (NFR) | f/d (n=10) | 4.8 months |
| Cetuximab | Overall Survival (OS) Related to Killer Inhibitory Receptors 2DS4 (KIR2DS4) Functional Receptor (f/d) and Non-functional Receptor (NFR) | NFR (n=56) | 7.4 months |
Secondary
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
Time frame: From the date of informed consent signature until progressive disease, assessed up to 3 years
Population: MITT analysis set included all the subjects who received study drug treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cetuximab | Percentage of Subjects With Disease Control Rate (DCR) | 22.86 Percentage of subjects |
Secondary
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.
Time frame: From the date of informed consent signature until progressive disease (PD) or death, assessed up to 3 years
Population: MITT analysis set included all the subjects who received study drug treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cetuximab | Progression Free Survival (PFS) Time | 2.53 Months |