Sotorasib and Panitumumab Versus Investigator's Choice for Participants With Kirsten Rat Sarcoma (KRAS) p.G12C Mutation

Phase 3CompletedNCT05198934

Amgen160 enrolled

Overview

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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

160

Conditions

Colorectal Cancer (CRC)

Interventions

SotorasibDRUG

Sotorasib will be administered orally

PanitumumabDRUG

Panitumumab will be administered as intravenous (IV) infusion

Trifluridine and TipiracilDRUG

Trifluridine and Tipiracil will be administered orally

Eligibility

Sex: ALLMin age: 18 YearsMax age: 100 Years

Medical Language ↔ Plain English

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.

Locations (105)

Outcomes

Primary Outcomes

Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by BICR

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.

Time frame: From randomization until DCO or death; median (min, max) time on trial was 6.23 (0.1, 14.0) months

Secondary Outcomes

Overall Survival (OS)

OS was defined as time from randomization until death from any cause.

Time frame: Approximately 3 years

Objective Response Rate (ORR) Per RECIST Version 1.1 as Assessed by BICR

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.

Time frame: Approximately 3 years

Duration of Response (DOR) Per RECIST Version 1.1 as Assessed by BICR

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.

Data from ClinicalTrials.gov

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Regorafenib will be administered orally

Central Alabama Research

Birmingham, Alabama, United States

City of Hope National Medical Center

Duarte, California, United States

University of California Irvine

Orange, California, United States

Johns Hopkins University School of Medicine

Washington D.C., District of Columbia, United States

Cancer Specialists of North Florida

Jacksonville, Florida, United States

Lakes Research LLC

Miami Lakes, Florida, United States

Northwest Georgia Oncology Centers PC

Marietta, Georgia, United States

University of Michigan

Ann Arbor, Michigan, United States

Revive Research Institute

Farmington Hills, Michigan, United States

Sparrow Clinical Research Institute

Lansing, Michigan, United States

...and 95 more locations

Time frame: Approximately 3 years

Time to Response (TTR) as Assessed by BICR

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.

Time frame: Approximately 3 years

Disease Control Rate (DCR) as Assessed by BICR

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).

Time frame: Approximately 3 years

PFS Per RECIST Version 1.1 as Based on Investigator Assessment

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.

Time frame: Approximately 3 years

ORR Per RECIST Version 1.1 as Based on Investigator Assessment

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.

Time frame: Approximately 3 years

Number of Participants With Treatment-emergent Adverse Events (TEAEs)

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.

Time frame: Approximately 3 years

Change From Baseline in Fatigue Severity as Measured by Item 3 of the Brief Fatigue Inventory - Short Form (BFI-SF)

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.

Time frame: Baseline and Week 8

Change From Baseline in Pain Severity as Measured by Item 3 of the Brief Pain Inventory - Short Form (BPI-SF)

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.

Time frame: Baseline and Week 8

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)

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.

Time frame: Baseline and Week 8

Change From Baseline in Global Health Status as Measured by Questions 29 and 30 of the EORTC QLQ-C30

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.

Time frame: Baseline and Week 8

Change From Baseline for All Subscales of the BFI-SF

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.

Time frame: Baseline and Week 8

Change From Baseline for All Subscales of the BPI-SF

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.

Time frame: Baseline and Week 8

Change From Baseline for All Subscales and Domains of EORTC QLQ-C30

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.

Time frame: Baseline and Week 8

Average Score of VAS Scores as Measured by EQ-5D-5L

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'.

Time frame: Baseline and Week 8

Average Score on Single Question on Symptom Bother GP5 From Functional Assessment of Cancer Therapy - General (FACT-G)

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".

Time frame: Approximately 2 years

Average Score of Patient Global Impression of Change (PGIC)

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.

Time frame: Approximately 2 years

Maximum Plasma Concentration (Cmax) of Sotorasib

Time frame: Approximately 2 years

Cmax of Panitumumab

Time frame: Approximately 2 years

Area Under the Plasma Concentration-time Curve (AUC) of Sotorasib

Time frame: Approximately 2 years

AUC of Panitumumab

Time frame: Approximately 2 years