Colorectal Cancer (CRC)
Conditions
Keywords
Sotorasib, AMG 510, Panitumumab, Metastatic colorectal cancer, Kirsten rat sarcoma p.G12C mutation
Brief summary
The aim of the study is to compare progression-free survival (PFS) in previously treated participants with Kirsten rat sarcoma (KRAS) p.G12C mutated colorectal cancer (CRC) receiving sotorasib 240 mg once daily (QD) and panitumumab vs investigator's choice (trifluridine and tipiracil, or regorafenib), and sotorasib 960 mg QD and panitumumab vs investigator's choice (trifluridine and tipiracil, or regorafenib).
Interventions
DRUGSotorasib
Sotorasib will be administered orally
DRUGPanitumumab
Panitumumab will be administered as intravenous (IV) infusion
Trifluridine and Tipiracil will be administered orally
DRUGRegorafenib
Regorafenib will be administered orally
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Participant has provided informed consent/assent prior to initiation of any study specific activities/procedures. * Age ≥18 years. * Pathologically documented metastatic colorectal adenocarcinoma with Kirsten rat sarcoma (KRAS) p.G12C mutation as determined by prospective central testing, using the analytically validated Qiagen Therascreen KRAS RGQ polymerase chain reaction Kit in CRC as an investigational device demonstrating a KRAS p.G12C mutation is present. Local testing and documentation of KRAS p.G12C mutation should have been previously performed as part of standard of care. * Participants will have received at least 1 prior line of therapy for metastatic disease. Participants must have received and progressed or experienced disease recurrence on or after fluoropyrimidine, irinotecan, and oxaliplatin given for metastatic disease unless the participant, in the opinion of the investigator, is not a candidate for fluoropyrimidine, irinotecan, or oxaliplatin, in which case, the participant may be eligible after investigator discussion with Amgen medical monitor provided participant has received at least one prior line of therapy for metastatic disease and provided trifluridine and tipiracil or regorafenib is deemed the appropriate next line of therapy for the participant. * Measurable disease per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria. Lesions previously radiated are not considered measurable unless they have progressed after radiation. * Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤2. * Life expectancy of \>3 months, in the opinion of the investigator. * Adequate hematologic and end-organ function, defined as the following within 2 weeks prior to cycle 1 day 1: * Absolute neutrophil count (ANC) ≥1.5 x 10\^9/L (without granulocyte colony stimulating factor support within 2 weeks of laboratory test used to determine eligibility). * Hemoglobin ≥9.0 g/dL (without transfusion within 2 weeks of laboratory test used to determine eligibility). * Platelet count ≥100 x 10\^9/L (without transfusion within 2 weeks of laboratory test used to determine eligibility). * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 times the upper limit of normal (ULN). * Serum bilirubin ≤1.0 x ULN. For participants with Gilbert's disease, total bilirubin or direct bilirubin needs to be ≤1.0 x ULN. * International normalized ratio (INR) and activated partial thromboplastin time (or partial thromboplastin time) ≤1.5 x ULN. Prothrombin time (PT) ≤1.5 x ULN may be used instead of INR for sites whose labs do not report INR. * Estimated glomerular filtration rate based on Modification of Diet in Renal Disease (MDRD) calculation ≥30 mL/min/1.73 m\^2. * Fridericia's Correction Formula (QTcF) ≤470 msec.
Exclusion criteria
* Active brain metastases. Participants who have had brain metastases resected or have received radiation therapy ending at least 4 weeks prior to study day 1 are eligible if they meet all of the following criteria: a) residual neurological symptoms grade ≤2; b) on stable doses of dexamethasone or equivalent for at least 2 weeks, if applicable; and c) follow-up magnetic resonance imaging (MRI) performed within 28 days of day 1 shows no progression or new lesions appearing. * History or presence of hematological malignancies unless curatively treated with no evidence of disease ≥2 years. * History of other malignancy within the past 3 years, with the following exceptions: * Malignancy treated with curative intent and with no known active disease present for ≥3 years before enrollment and felt to be at low risk for recurrence by the treating physician. * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. * Adequately treated cervical carcinoma in situ without evidence of disease. * Adequately treated breast ductal carcinoma in situ without evidence of disease. * Prostatic intraepithelial neoplasia without evidence of prostate cancer. * Adequately treated urothelial papillary non-invasive carcinoma or carcinoma in situ. * Leptomeningeal disease. * Significant gastrointestinal (GI) disorder that results in significant malabsorption, requirement for intravenous (IV) alimentation, or inability to take oral medication. * History of interstitial pneumonitis or pulmonary fibrosis or evidence of interstitial pneumonitis or pulmonary fibrosis. * Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within 6 months prior to randomization, unstable arrhythmias or unstable angina. * Previous treatment with a KRAS G12C inhibitor.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by BICR | From randomization until DCO or death; median (min, max) time on trial was 6.23 (0.1, 14.0) months | PFS was defined as time from randomization until disease progression or death from any cause, whichever occurred first, for all participants. Progression was assessed using RECIST v1.1 per BICR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Approximately 3 years | OS was defined as time from randomization until death from any cause. |
| Objective Response Rate (ORR) Per RECIST Version 1.1 as Assessed by BICR | Approximately 3 years | Objective response was defined as best overall response (BOR) of complete response (CR) or partial response (PR), as defined by RECIST version 1.1. CR was defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis \<10 mm. PR was defined as at least a 30% decrease in the sum of diameter (SOD) of target lesions, taking as reference the baseline sum diameters. Responses were assessed based on BICR. |
| Duration of Response (DOR) Per RECIST Version 1.1 as Assessed by BICR | Approximately 3 years | DOR was defined as time from first evidence of PR or CR until progressive disease (PD) or death due to any cause, whichever occurs first. CR was defined as disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (target or non-target) must have a reduction in their short axis \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. PD was defined as at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. |
| Time to Response (TTR) as Assessed by BICR | Approximately 3 years | TTR was defined as time from randomization to the first evidence of PR or CR based on BICR. CR was defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. |
| Disease Control Rate (DCR) as Assessed by BICR | Approximately 3 years | DCR was defined as the percentage of participants with the BOR of CR, PR or stable disease (SD) of at least 7 weeks based on BICR. CR was defined as disappearance of all target lesions. All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD was defined as at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on trial (this includes baseline sum if that is the smallest on trial). |
| PFS Per RECIST Version 1.1 as Based on Investigator Assessment | Approximately 3 years | PFS by investigator assessment was defined as the time from randomization until PD or death due to any cause, whichever occurs first. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the baseline SOD of target lesions. |
| ORR Per RECIST Version 1.1 as Based on Investigator Assessment | Approximately 3 years | ORR was defined as BOR of CR or PR, as defined by RECIST version 1.1. CR was defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters. Responses were assessed based on investigator assessment. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Approximately 3 years | TEAEs were events with onset after the administration of the first dose of any trial treatment up to EOT or 30 days of the last dose of any trial treatment, or prior to first dose of crossed over treatment, whichever occurred earlier. Clinically significant changes in vital signs, and clinical laboratory tests were included as TEAEs. |
| Change From Baseline in Fatigue Severity as Measured by Item 3 of the Brief Fatigue Inventory - Short Form (BFI-SF) | Baseline and Week 8 | Item 3 of the BFI-SF recorded a participants' fatigue on a scale from 0 to 10. Higher scores indicated a higher severity of fatigue. An increase in score from baseline indicated a worsening of fatigue. A decrease in score from baseline indicated an improvement in fatigue. |
| Change From Baseline in Pain Severity as Measured by Item 3 of the Brief Pain Inventory - Short Form (BPI-SF) | Baseline and Week 8 | Item 3 of the BPI-SF recorded a participants' pain on a scale from 1 to 10, where pain was mild (score of 1 to 4), moderate (score of 5 to 6), or severe (score of 7 to 10). An increase in score from baseline indicated a worsening of pain. A decrease in score from baseline indicates a lessening of pain. |
| Change From Baseline in Physical Functioning as Measured by the Physical Function Domain of the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire - Core 30 Item (EORTC QLQ-C30) | Baseline and Week 8 | The physical function domain of the EORTC QLQ-C30 assessed a participants' quality of life regarding their physical function on a scale from 1 to 4, with higher scores indicating a worse outcome. An increase in score from baseline indicated a worsening of physical functioning. A decrease in score from baseline indicated an improvement in physical functioning. |
| Change From Baseline in Global Health Status as Measured by Questions 29 and 30 of the EORTC QLQ-C30 | Baseline and Week 8 | Questions 29 and 30 of the EORTC QLQ-C30 assessed a participants' global health status on a scale from 1 to 7, with higher scores indicating a better outcome. An increase in score from baseline indicated an improvement in global health status. A decrease in score from baseline indicated a worsening in global health status. |
| Change From Baseline for All Subscales of the BFI-SF | Baseline and Week 8 | The BFI-SF was a questionnaire that included 3 items to assess fatigue severity and 5 items to assess interference due to fatigue, with each item reported on a numeric rating scale from 0 to 10. Higher scores indicated a higher severity of fatigue. An increase in score from baseline indicated a worsening of fatigue. A decrease in score from baseline indicated an improvement in fatigue. |
| Change From Baseline for All Subscales of the BPI-SF | Baseline and Week 8 | The BPI-SF was a 9-item questionnaire which included 2 body diagrams, four items to assess pain severity, four items to assess pain interference and one question about percentage of pain relief by analgesics. The level of pain and pain interference assessed could be divided into categories based on score of mild (1 to 4), moderate (5 to 6), and severe (7 to 10). An increase in score from baseline indicated a worsening of pain. A decrease in score from baseline indicated a lessening of pain. |
| Change From Baseline for All Subscales and Domains of EORTC QLQ-C30 | Baseline and Week 8 | The EORTC QLQ-C30 was a self-reporting 30-item generic instrument which assessed 5 functional domains (physical, role, emotional, cognitive, social), 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, financial difficulties), and a global health status/quality of life (QOL) scale. Higher scores indicated a worse outcome. An increase in score from baseline indicated a worsening of outcome. A decrease in score from baseline indicated an improvement in outcome. |
| Average Score of VAS Scores as Measured by EQ-5D-5L | Baseline and Week 8 | The EQ-5D-5L questionnaire was a 2-page, standardized instrument for use as a measure of health outcome. It was comprised of a 5-dimension health status measure and a visual analogue scale. The 5-dimension health status measure evaluates: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression based on a 5-level scale: no problems, slight problems, moderate problems, severe problems, and extreme problems. The visual analogue scale recorded the participant's self-rated health on a vertical, visual analogue scale where the endpoints were labelled 'Best imaginable health state' and 'Worst imaginable health state'. |
| Average Score on Single Question on Symptom Bother GP5 From Functional Assessment of Cancer Therapy - General (FACT-G) | Approximately 2 years | The GP5 from the FACT-G was a single item included in the Physical Well-Being subscale of the FACT-G. Responses to the item: "I am bothered by side effects of treatment" are rated on a 5-point Likert scale from "not at all" to "very much". |
| Average Score of Patient Global Impression of Change (PGIC) | Approximately 2 years | The PGIC scale consisted of one item which measures the participants' perception of change in their condition relative to the beginning of the trial. Responses are rated on a 7-item response scale ranging from very much improved to very much worse. |
| Maximum Plasma Concentration (Cmax) of Sotorasib | Approximately 2 years | — |
| Cmax of Panitumumab | Approximately 2 years | — |
| Area Under the Plasma Concentration-time Curve (AUC) of Sotorasib | Approximately 2 years | — |
| AUC of Panitumumab | Approximately 2 years | — |
Countries
Australia, France, Germany, Greece, Italy, Japan, Mexico, South Korea, Spain, Taiwan, United Kingdom, United States
Contacts
STUDY_DIRECTORMD
Amgen
Participant flow
Recruitment details
Participants were enrolled at 67 trial centers across Asia, Europe, North America, and Australia starting on 19 April 2022. The primary analysis results presented here, for primary analysis presented here are based on data cut-off (DCO) 19 June 2023. The trial is still ongoing.
Pre-assignment details
Participants with previously treated metastatic colorectal cancer (CRC) with the kirsten rat sarcoma (KRAS) p.G12C mutation were enrolled and randomized 1:1:1 to receive either sotorasib 240 mg daily (QD) and panitumumab, sotorasib 960 mg QD and panitumumab, or investigator's choice (trifluridine and tipiracil, or regorafenib). Investigator's choice was declared prior to randomization.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 60.2 years STANDARD_DEVIATION 11.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 53 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race/Ethnicity, Customized Asian | 40 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants |
| Race/Ethnicity, Customized Other/Unknown | 10 Participants |
| Race/Ethnicity, Customized White | 42 Participants |
| Sex: Female, Male Female | 81 Participants |
| Sex: Female, Male Male | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 20 / 54 | 18 / 53 | 18 / 53 |
| other Total, other adverse events | 48 / 51 | 52 / 53 | 52 / 53 |
| serious Total, serious adverse events | 15 / 51 | 17 / 53 | 14 / 53 |
Outcome results
None listed