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

Study Overview
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Brief Summary
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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).

Official Title
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A Phase 3 Multicenter, Randomized, Open-label, Active-controlled Study of Sotorasib and Panitumumab Versus Investigator's Choice (Trifluridine and Tipiracil, or Regorafenib) for the Treatment of Previously Treated Metastatic Colorectal Cancer Subjects With Kirsten Rat Sarcoma (KRAS) p.G12C Mutation

Conditions
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Colorectal Cancer (CRC)

Intervention / Treatment
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* Drug: Sotorasib
* Drug: Panitumumab
* Drug: Trifluridine and Tipiracil
* Drug: Regorafenib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Sotorasib 960 mg QD + panitumumab<br> | Drug: Sotorasib<br>* Sotorasib will be administered orally<br>* Other names: AMG 510, Lumakras, Lumykras;Drug: Panitumumab<br>* Panitumumab will be administered as intravenous (IV) infusion<br>* Other names: Vectibix;|
| Experimental: Arm B: Sotorasib 240 mg QD + panitumumab<br> | Drug: Sotorasib<br>* Sotorasib will be administered orally<br>* Other names: AMG 510, Lumakras, Lumykras;Drug: Panitumumab<br>* Panitumumab will be administered as intravenous (IV) infusion<br>* Other names: Vectibix;|
| Active Comparator: Arm C : Investigator's choice<br>Participants will be administered trifluridine and tipiracil, or regorafenib | Drug: Trifluridine and Tipiracil<br>* Trifluridine and Tipiracil will be administered orally<br>* Other names: Lonsurf;Drug: Regorafenib<br>* Regorafenib will be administered orally<br>* Other names: Stivarga;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) |  | Approximately 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) |  | Approximately 3 years | 
| Objective Response Rate (ORR) |  | Approximately 3 years | 
| Duration of Response (DOR) |  | Approximately 3 years | 
| Time to Response (TTR) |  | Approximately 3 years | 
| Disease Control Rate (DCR) |  | Approximately 3 years | 
| Investigator Assessed ORR |  | Approximately 3 years | 
| Investigator Assessed PFS |  | Approximately 3 years | 
| Number of Participants with a Treatment-emergent Adverse Event (TEAE) | A TEAE is any untoward medical occurrence in a clinical study participant following first dose of treatment irrespective of a causal relationship with the study treatment. Any clinically significant changes in vital signs and clinical laboratory tests following first dose will be recorded as TEAEs. | Approximately 3 years | 
| Change from Baseline in Fatigue Severity as Measured by Item 3 of the Brief Fatigue Inventory (BFI) | Item 3 of the BFI records a participants' fatigue on a scale from 0 to 10. Higher scores indicate a higher severity of fatigue. An increase in score from baseline indicates a worsening of fatigue. A decrease in score from baseline indicates an improvement in fatigue. | Baseline and Week 8 | 
| Change from Baseline in Pain Severity as Measured by Item 3 of the Brief Pain Inventory (BPI) | Item 3 of the BPI records a participants' pain on a scale from 1 to 10, where pain is 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 indicates a worsening of pain. A decrease in score from baseline indicates a lessening of pain. | 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 Questionnaire (EORTC QLQ-C30) | The physical function domain of the EORTC QLQ-C30 assesses 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 indicates a worsening of physical functioning. A decrease in score from baseline indicates an improvement in physical functioning. | 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 assess 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 indicates an improvement in global health status. A decrease in score from baseline indicates a worsening in global health status. | Baseline and Week 8 | 
| Change from Baseline For All Subscales of the BFI | The BFI is a questionnaire that includes 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 indicate a higher severity of fatigue. An increase in score from baseline indicates a worsening of fatigue. A decrease in score from baseline indicates an improvement in fatigue. | Baseline and Week 8 | 
| Change from Baseline For All Subscales of the BPI | The BPI is a 9-item questionnaire which includes 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 can 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 indicates a worsening of pain. A decrease in score from baseline indicates a lessening of pain. | Baseline and Week 8 | 
| Change from Baseline For All Subscales and Domains of EORTC QLQ-C30 | The EORTC QLQ-C30 is a self-reporting 30-item generic instrument which assesses 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 indicate a worse outcome. An increase in score from baseline indicates a worsening of outcome. A decrease in score from baseline indicates an improvement in outcome. | Baseline and Week 8 | 
| Change from Baseline in Visual Analog Scale (VAS) Scores as Measured by EuroQol-5D level 5 (EQ-5D-5L) | The EQ-5D-5L questionnaire is a 2-page, standardized instrument for use as a measure of health outcome. It is 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 records the participant's self-rated health on a vertical, visual analogue scale where the endpoints are labelled 'Best imaginable health state' and 'Worst imaginable health state'. | 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 is 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. | Approximately 2 years | 
| Average Score of Patient Global Impression of Change (PGIC) | The PGIC scale consists of one item which measures the participants' perception of change in their condition relative to the beginning of the study. Responses are rated on a 7-item response scale ranging from very much improved to very much worse. | Approximately 2 years | 
| Maximum Plasma Concentration (Cmax) of Sotorasib |  | Day 1 to approximately 2 years | 
| Cmax of Panitumumab |  | Day 1 to approximately 2 years | 
| Area Under the Plasma Concentration-time Curve (AUC) of Sotorasib |  | Day 1 to approximately 2 years | 
| AUC of Panitumumab |  | Day 1 to approximately 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sotorasib, AMG 510, Panitumumab, Metastatic colorectal cancer, Kirsten rat sarcoma p.G12C mutation