Colorectal Neoplasms
Conditions
Keywords
Colorectal cancer, RAS wild-type, Tepotinib, Cetuximab, Erbitux, Epidermal growth factor receptor resistance, Hepatocyte growth factor, Panitumumab, Mesenchymal epithelial transition
Brief summary
The purpose of this study was to assess the preliminary antitumor activity, safety and tolerability of tepotinib in combination with cetuximab in participants with RAS/BRAF wild-type left-sided Metastatic Colorectal Cancer (mCRC) having acquired resistance to anti-epidermal growth factor receptor (EGFR) antibody targeted therapy due to mesenchymal epithelial transition (MET) amplification.
Interventions
DRUGTepotinib
Participants received Tepotinib film-coated tablets at a dose of 500 milligrams (mg) orally, once daily (QD) until disease progression (according to Response Evaluation Criteria in Solid Tumors Version 1.1 \[RECIST v1.1\]), death, Adverse event (AE) leading to discontinuation, study withdrawal, or withdrawal of consent, whichever occurs first.
BIOLOGICALCetuximab
Participants received weekly intravenous infusions of Cetuximab at a dose of 250 milligrams per square meter (mg/m\^2) until disease progression (according to Response Evaluation Criteria in Solid Tumors Version 1.1 \[RECIST v1.1\]), death, Adverse event (AE) leading to discontinuation, study withdrawal, or withdrawal of consent, whichever occurs first.
Sponsors
Merck KGaA, Darmstadt, Germany
EMD Serono Research & Development Institute, Inc.
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
* Advanced (locally advanced or metastatic) left sided (from splenic flexure to rectum - National Comprehensive Cancer Network \[NCCN\] version 4.2020) colorectal cancer (CRC) with RAS/BRAF wild-type at study entry confirmed prior to enrollment, with previous anti-epidermal growth factor receptor (anti-EGFR) therapy and acquired resistance on the most recent anti-EGFR monoclonal antibody therapy (panitumumab or cetuximab) by radiological documentation of disease progression according to RECIST Version 1.1 * Mesenchymal epithelial transition (MET) amplification detected by a positive liquid biopsy and/or tissue with appropriate regulatory status (collected after disease progression of the previous anti-EGFR therapy) * Measurable disease by Investigator in accordance with RECIST Version 1.1 * Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 * Life expectancy greater than 3 months * Participants having at least one systemic treatment for mCRC including 1 anti-EGFR monoclonal antibody therapy as the most recent line of therapy for mCRC before study treatment and must have shown a radiologically confirmed by RECIST Version 1.1 complete response (CR) or partial response (PR), both for at least 4 months or stable disease (SD) for at least 6 months to that therapy prior to disease progression * Less than 2 months between the last administration of the most recent EGFR containing regimen and first dosing in this study * Adequate hematological function, hepatic and renal functions as defined in the protocol * Signed and dated informed consent indicating that the participants had been informed of all the pertinent aspects of the trial prior to enrollment * Contraceptive use by males or females will be consistent with local regulations on contraception methods for those participating in clinical studies * Other protocol defined inclusion criteria could apply
Exclusion criteria
* Participants with symptomatic central nervous system (CNS) metastases who are neurologically unstable or have required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS metastases. Also excluded are participants with carcinomatous meningitis * Participants who have brain metastasis as the only measurable lesion * Prior chemotherapy, biological therapy, radiation therapy, hormonal therapy for anti-cancer purposes, targeted therapy, or other investigational anticancer therapy (not including palliative radiotherapy at focal sites) within 21 days prior to the first dose of study intervention, except for the anti-EGFR containing regimen including associated chemotherapy if applicable, which may be continued until enrollment of the participant in the study * Any unresolved toxicity Grade 2 or more according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0, from previous anticancer therapy excluding neuropathy, alopecia and rash * Severe hypersensitivity reactions to monoclonal antibodies (Grade greater than or equal to \[\>=\] 3 NCI-CTCAE v 5.0), any history of anaphylaxis, or uncontrolled asthma (i.e., 3 or more occurrences of partially controlled asthma) * Discontinuation of the most recent cetuximab or panitumumab containing therapy due to an adverse event * Prior treatment with other agents targeting the hepatocyte growth factor (HGF)/Mesenchymal epithelial transition (MET) pathway * Impaired cardiac function: Left ventricular ejection fraction less than \[\<\] 45 percent \[%\] defined by echocardiography (a screening assessment not required for participants without a history of congestive heart failure unless clinically indicated); Serious arrhythmia; Unstable angina pectoris; New York Heart Association heart failure Class III and IV; Myocardial infarction within the last 12 months prior to study entry and Symptomatic pericardial effusion; Corrected QT interval by Fridericia (QTcF) greater than (\>) 480 milliseconds (ms) * Hypertension uncontrolled by standard therapies (not stabilized to less than \[\< \]150/90 millimeter of mercury \[mmHg\]) * History of neoplasm other than mCRC * History of difficulty swallowing, malabsorption, or other chronic gastrointestinal disease, or conditions that may hamper compliance and/or absorption of the test products * Known infection with human immunodeficiency virus, or an active infection with hepatitis B or hepatitis C virus * Major surgery within 28 days prior to Day 1 of study intervention * History of Interstitial lung disease (ILD) or interstitial pneumonitis including radiation pneumonitis that required steroid treatment * Other protocol defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) According to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Day 1 to Day 21 of Cycle 1 (each cycle is of 21 days) | DLTs are defined as any of the following toxicities and judged by Investigator and/ Sponsor to be not attributable to the disease/disease-related processes under investigation: Grade 4 neutropenia for more than 7 days; Grade greater than or equal to \[\>=\] 3 febrile neutropenia with absolute neutrophil count \< 1000 per cube millimeter (per mm\^3) and a single temperature of \> 38.3 degree Celsius/a sustained temperature of \>= 38 degree Celsius for more than 1 hour; Grade 4/Grade 3 thrombocytopenia with non-traumatic bleeding; Grade 3 uncontrolled nausea/vomiting and/diarrhea that has not improved within 72 hours despite adequate and optimal treatment; Grade 4 vomiting and/diarrhea; Grade \>= 3 skin toxicity that has not resolved to Grade 2 after 14 days of adequate treatment; Any other Grade \>= 3 non-hematological AE will be defined as DLT. Exceptions are alopecia/an isolated lipase and/amylase elevation of Grade \>= 3 without clinical/radiological evidence of pancreatitis. |
| Number of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Assessed by Investigators | Time from first study treatment assessed up to 218 days | OR is defined as a best overall response (BOR) of complete response (CR) or partial response (PR). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) Assessed by Investigators | Time from first study treatment until death, assessed up to 218 days | OS is defined as the time (in months) from first administration of study intervention to the date of death. OS was to be estimated using Kaplan-Meier (KM) plots. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs | Time from first study treatment up to 30 days after the last dose, assessed up to 226 days | An adverse event (AE) is defined as any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether considered related to the study intervention or not. A serious AE 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 or was otherwise considered medically important. TEAEs were defined as events that started or worsened after first dose of study intervention until 30 days after last dose. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs is defined as reasonably related to the study intervention. |
| Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | Time from first study treatment up to 30 days after the last dose, assessed up to 226 days | Vital sign assessment included assessments of height, weight, temperature, pulse rate, respiratory rate, and blood pressure. Clinical significance was determined by the investigator. Number of participants who had any clinically significant changes from baseline in vital signs were reported. |
| Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Assessed by Investigator | Time from the first dose of study drug until occurrence of PD, death due to any cause or last tumor assessment (assessed up to 218 days) | For participants with objective response, DoR is the time from when the complete response (CR) or partial response (PR) (whichever is first) criteria are first met until progression disease (PD) or death due to any cause within the period of 2 scheduled tumor assessments (84 or 168 days) after the last tumor assessment, whichever occurs first. PD is defined as at least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. |
| Number of Participants With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings | Time from first study treatment up to 30 days after the last dose, assessed up to 226 days | 12-lead ECG recordings included heart rate and measures PR, QRS, QT and QTcF intervals. 12-lead ECG recordings were obtained after the participants have rested for at least 5 minutes in semi-supine or supine position. Clinical significance was determined by the investigator. The number of participants with clinically significant changes from baseline in 12-lead ECG findings were reported. |
| Number of Participants With At Least 1 Postive Anti-Drug Antibodies (ADAs) for Cetuximab | At Day 1 of cycle 1 (each cycle is of 21 days) and at End of Treatment (14 days after last dose, assessed up to 210 days) | Serum samples were analyzed by a validated electrochemiluminescence immunoassay method to detect the presence of antidrug antibodies (ADA). Number of participants with positive ADA were reported. |
| Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | Time from first study treatment up to 30 days after the last dose, assessed up to 226 days | Laboratory investigation included hematology, biochemistry, coagulation, routine urinalysis and other screening tests (Follicle-stimulating hormone (FSH) and estradiol, Serum or highly sensitive urine human chorionic gonadotropin (hCG) pregnancy test, Serology (HIV antibody, hepatitis B surface antigen \[HBsAg\], and hepatitis C virus antibody) and all of the safety labs were performed locally. Clinical significance was determined by the investigator. The number of participants with clinically significant changes from baseline in laboratory parameters were reported. |
| Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Assessed by Investigators | Time from the first dose of study drug until occurrence of PD, death due to any cause or last tumor assessment (assessed up to 218 days) | PFS is defined as the time (in months) from first administration of study intervention to the date of the first documentation of progression disease (PD) or death due to any cause within the period of 2 scheduled tumor assessments (84 or 168 days) after the last tumor assessment, whichever occurs first. PD is defined as at least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was to be estimated using Kaplan-Meier (KM) plots. |
Countries
Belgium, Czechia, France, Italy, Russia, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
A total of 57 participants were screened. Out of which, 3 participants were enrolled and 2 participants received treatment in this study.
Participants by arm
| Arm | Count |
|---|---|
| Tepotinib + Cetuximab Participants received Tepotinib film-coated tablets at a dose of 500 milligrams (mg) orally, once daily (QD) in combination with weekly intravenous infusions of Cetuximab at a dose of 250 milligrams per square meter (mg/m\^2) until disease progression (according to Response Evaluation Criteria in Solid Tumors Version 1.1 \[RECIST v1.1\]), death, Adverse event (AE) leading to discontinuation, study withdrawal, or withdrawal of consent, whichever occurs first. | 3 |
| Total | 3 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Participant did not receive treatment | 1 |
Baseline characteristics
| Characteristic | Tepotinib + Cetuximab |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 2 |
| other Total, other adverse events | 2 / 2 |
| serious Total, serious adverse events | 0 / 2 |
Outcome results
Primary
Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) According to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Version 5.0
DLTs are defined as any of the following toxicities and judged by Investigator and/ Sponsor to be not attributable to the disease/disease-related processes under investigation: Grade 4 neutropenia for more than 7 days; Grade greater than or equal to \[\>=\] 3 febrile neutropenia with absolute neutrophil count \< 1000 per cube millimeter (per mm\^3) and a single temperature of \> 38.3 degree Celsius/a sustained temperature of \>= 38 degree Celsius for more than 1 hour; Grade 4/Grade 3 thrombocytopenia with non-traumatic bleeding; Grade 3 uncontrolled nausea/vomiting and/diarrhea that has not improved within 72 hours despite adequate and optimal treatment; Grade 4 vomiting and/diarrhea; Grade \>= 3 skin toxicity that has not resolved to Grade 2 after 14 days of adequate treatment; Any other Grade \>= 3 non-hematological AE will be defined as DLT. Exceptions are alopecia/an isolated lipase and/amylase elevation of Grade \>= 3 without clinical/radiological evidence of pancreatitis.
Time frame: Day 1 to Day 21 of Cycle 1 (each cycle is of 21 days)
Population: DLT analysis set: all participants treated in the safety run-in period who received at least 75% of the tepotinib and cetuximab planned dose and completed the DLT period (3 weeks after start of treatment with study intervention), or who experienced a DLT during the DLT period regardless of the received amount of each study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tepotinib + Cetuximab | Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) According to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | 0 Participants |
Primary
Number of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Assessed by Investigators
OR is defined as a best overall response (BOR) of complete response (CR) or partial response (PR). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all target lesions.
Time frame: Time from first study treatment assessed up to 218 days
Population: Full analysis set (FAS) included all participants who were administered at least one dose of any study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tepotinib + Cetuximab | Number of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Assessed by Investigators | 0 Participants |
Secondary
Duration of Response (DoR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Assessed by Investigator
For participants with objective response, DoR is the time from when the complete response (CR) or partial response (PR) (whichever is first) criteria are first met until progression disease (PD) or death due to any cause within the period of 2 scheduled tumor assessments (84 or 168 days) after the last tumor assessment, whichever occurs first. PD is defined as at least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
Time frame: Time from the first dose of study drug until occurrence of PD, death due to any cause or last tumor assessment (assessed up to 218 days)
Population: None of the participants showed objective response.
Secondary
Number of Participants With At Least 1 Postive Anti-Drug Antibodies (ADAs) for Cetuximab
Serum samples were analyzed by a validated electrochemiluminescence immunoassay method to detect the presence of antidrug antibodies (ADA). Number of participants with positive ADA were reported.
Time frame: At Day 1 of cycle 1 (each cycle is of 21 days) and at End of Treatment (14 days after last dose, assessed up to 210 days)
Population: Immunogenicity analysis set included all participants who received at least one dose of study intervention and had at least one valid antidrug antibody (ADA) result.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tepotinib + Cetuximab | Number of Participants With At Least 1 Postive Anti-Drug Antibodies (ADAs) for Cetuximab | 0 Participants |
Secondary
Number of Participants With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings
12-lead ECG recordings included heart rate and measures PR, QRS, QT and QTcF intervals. 12-lead ECG recordings were obtained after the participants have rested for at least 5 minutes in semi-supine or supine position. Clinical significance was determined by the investigator. The number of participants with clinically significant changes from baseline in 12-lead ECG findings were reported.
Time frame: Time from first study treatment up to 30 days after the last dose, assessed up to 226 days
Population: SAF included all participants who were administered at least one dose of any study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tepotinib + Cetuximab | Number of Participants With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings | 0 Participants |
Secondary
Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters
Laboratory investigation included hematology, biochemistry, coagulation, routine urinalysis and other screening tests (Follicle-stimulating hormone (FSH) and estradiol, Serum or highly sensitive urine human chorionic gonadotropin (hCG) pregnancy test, Serology (HIV antibody, hepatitis B surface antigen \[HBsAg\], and hepatitis C virus antibody) and all of the safety labs were performed locally. Clinical significance was determined by the investigator. The number of participants with clinically significant changes from baseline in laboratory parameters were reported.
Time frame: Time from first study treatment up to 30 days after the last dose, assessed up to 226 days
Population: SAF included all participants who were administered at least one dose of any study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tepotinib + Cetuximab | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters | 0 Participants |
Secondary
Number of Participants With Clinically Significant Changes From Baseline in Vital Signs
Vital sign assessment included assessments of height, weight, temperature, pulse rate, respiratory rate, and blood pressure. Clinical significance was determined by the investigator. Number of participants who had any clinically significant changes from baseline in vital signs were reported.
Time frame: Time from first study treatment up to 30 days after the last dose, assessed up to 226 days
Population: SAF included all participants who were administered at least one dose of any study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tepotinib + Cetuximab | Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | 0 Participants |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs
An adverse event (AE) is defined as any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether considered related to the study intervention or not. A serious AE 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 or was otherwise considered medically important. TEAEs were defined as events that started or worsened after first dose of study intervention until 30 days after last dose. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs is defined as reasonably related to the study intervention.
Time frame: Time from first study treatment up to 30 days after the last dose, assessed up to 226 days
Population: Safety analysis set (SAF) included all participants who were administered at least one dose of any study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tepotinib + Cetuximab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs | TEAEs | 2 Participants |
| Tepotinib + Cetuximab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs | Treatment-related TEAEs | 2 Participants |
Secondary
Overall Survival (OS) Assessed by Investigators
OS is defined as the time (in months) from first administration of study intervention to the date of death. OS was to be estimated using Kaplan-Meier (KM) plots.
Time frame: Time from first study treatment until death, assessed up to 218 days
Population: FAS included all participants who were administered at least one dose of any study intervention.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tepotinib + Cetuximab | Overall Survival (OS) Assessed by Investigators | NA months |
Secondary
Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Assessed by Investigators
PFS is defined as the time (in months) from first administration of study intervention to the date of the first documentation of progression disease (PD) or death due to any cause within the period of 2 scheduled tumor assessments (84 or 168 days) after the last tumor assessment, whichever occurs first. PD is defined as at least a 20 percent (%) increase in the sum of the longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was to be estimated using Kaplan-Meier (KM) plots.
Time frame: Time from the first dose of study drug until occurrence of PD, death due to any cause or last tumor assessment (assessed up to 218 days)
Population: FAS included all participants who were administered at least one dose of any study intervention.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tepotinib + Cetuximab | Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Assessed by Investigators | NA months |