Testing the Use of AMG 510 (Sotorasib) and Panitumumab as a Targeted Treatment for KRAS G12C Mutant Solid Tumor Cancers (A ComboMATCH Treatment Trial)

Study Overview
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Brief Summary
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This phase II ComboMATCH treatment trial tests how well AMG 510 (sotorasib) with or without panitumumab in treating patients with KRAS G12C mutant solid tumors that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Sotorasib is in a class of medications called KRAS inhibitors. It works by blocking the action of the abnormal protein that signals cancer cells to multiply. This helps stop or slow the spread of cancer cells. Panitumumab is in a class of medications called monoclonal antibodies. It works by slowing or stopping the growth of cancer cells. Giving combination panitumumab and sotorasib may kill more tumor cells in patients with advanced solid tumors with KRAS G12C mutation.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the efficacy of the combination of AMG 510 (sotorasib) and panitumumab as compared to AMG 510 (sotorasib) alone in patients with advanced/metastatic KRAS G12C mutated solid tumors (except colorectal carcinoma [CRC] and lung non-small cell carcinoma [NSCLC]) as measured by progression free survival (Cohort 1). II. To evaluate the efficacy of the combination of AMG 510 (sotorasib) and panitumumab in patients with advanced/metastatic KRAS G12C mutated solid tumors that have progressed on a prior KRAS G12C inhibitor as measured by response rate (Cohort 2). SECONDARY OBJECTIVES: I. To evaluate the efficacy of the combination of AMG 510 (sotorasib) and panitumumab as compared to AMG 510 alone in patients with advanced/metastatic KRAS G12C mutated solid tumors (except CRC and NSCLC) as measured by response rate, disease control rate, and overall survival (Cohort 1). II, To evaluate the efficacy of the combination of AMG 510 (sotorasib) and panitumumab in patients with advanced/metastatic KRAS G12C mutated solid tumors that have progressed on a prior KRAS G12C inhibitor as measured by disease control rate, progression free survival (PFS), and overall survival (Cohort 2). III. To further evaluate the safety and tolerability of the combination of AMG 510 (sotorasib) and panitumumab. IV. To collect tissue and provide it to the ComboMATCH Registration Protocol to assess concordance between the diagnostic tumor mutation profile generated by the Designated Laboratories, the pre-treatment biopsy mutation profile, and the pre-treatment circulating tumor-derived deoxyribonucleic acid (DNA) (ctDNA) mutation profile from plasma, as described in ComboMATCH Registration Protocol. CORRELATIVE EXPLORATORY OBJECTIVES: I. To investigate the impact of concomitant mutations on the clinical benefit. II. To evaluate if changes in circulating tumor DNA (ctDNA) over time correlate with response to treatment. III. To evaluate the relative mutant allele fraction of KRAS mutation as a predictor of clinical benefit. IV. To evaluate if ERK 1/2 and PI3K pathway activation correlate with response and/or resistance. OUTLINE: Patients are assigned to 1 of 2 cohorts. COHORT I: Patients who have never received a KRAS G12C inhibitor randomized to arms A or B. ARM A: Patients receive sotorasib orally (PO) and panitumumab intravenously (IV) on study. Patients also undergo collection of blood samples and a tumor biopsy before treatment and computed tomography (CT) or magnetic resonance imaging (MRI) at follow up. ARM B: Patients receive sotorasib PO on study. Patients with disease progression may cross-over to cohort II. Patients also undergo collection of blood samples and a tumor biopsy before treatment and CT or MRI at follow up. COHORT II: Patients who have received a KRAS G12C inhibitor assigned to arm C. ARM C: Patients receive combination therapy as in Arm A.

Official Title
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A Randomized Phase II Study of AMG 510 (Sotorasib) With or Without Panitumumab in Advanced Solid Tumors: A ComboMATCH Treatment Trial

Conditions
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Advanced Malignant Solid Neoplasm, Metastatic Malignant Solid Neoplasm

Intervention / Treatment
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* Procedure: Biopsy
* Procedure: Biospecimen Collection
* Procedure: Computed Tomography
* Procedure: Magnetic Resonance Imaging
* Biological: Panitumumab
* Drug: Sotorasib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must have enrolled onto EAY191 and must have been given a treatment assignment to ComboMATCH to EAY191-E5 based on the presence of an actionable mutation as defined in EAY191 Patient must be enrolled on the ComboMATCH Registration Protocol (EAY191) at the time of registration/randomization to the EAY191-E5 study Patient must be >= 18 years of age Patient must have a KRAS G12C alteration as determined by the ComboMATCH screening assessment Patient must have disease that can be safely biopsied and agree to a pre-treatment biopsy or have tissue available from within 12 months prior to EAY191-E5 registration Patient must have histologically confirmed advanced/metastatic solid tumor Patient must have progressed on at least one line of standard of care therapy. NOTE: Patients who have progressed on a prior human epidermal growth factor receptor (EGFR) inhibitor will meet this criterion Patient must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of =< 2 (or Karnofsky Performance Status > 60%) Patient must have at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) Patient must have the ability to retain oral medication and not have any clinically significant gastrointestinal abnormalities that might alter absorption Patient must have completed full treatment cycle prior to EAY191-E5 registration/randomization if they have received prior chemotherapy, biological cancer therapy, radiation therapy or an investigational agent/device. Patients must have recovered to Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or better from any adverse events due to prior cancer therapy (with the exception of alopecia). Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression Human immunodeficiency virus (HIV)-infected patients no effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial Patients with known history or current symptoms of cardiac history, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trail, patients should be class 2B or better Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) Aspartate aminotransferase (AST) (serum (glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase ([SGPT]) < 3 x institutional upper limit of normal Creatinine =< 1.5 x institutional ULN OR creatinine clearance > 50 mL/min/1.73 m^2 for patients with creatinine levels > 1.5 mg/dL COHORT II: Patient must have progressed after treatment at the recommended phase II dose (RP2D) of any KRAS G12C inhibitor Exclusion Criteria: Patient must not have any serious active infection within 4 weeks prior to EAY191-E5 registration/randomization (e.g., requiring hospitalization and/or intravenous [IV] antibiotics) or currently receiving oral or IV antibiotics for the treatment of infection. Patients receiving prophylactic antibiotics are eligible Patient must not have any history of or current evidence of non-infectious interstitial lung disease (ILD)/pneumonitis Patient must not have a history of allergic reactions attributed to either of the study agents or to agents of similar chemical or biologic composition Patient must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study and for at least 6 months after the last dose of protocol treatment. Patients must not breastfeed while receiving protocol treatment and for one week (7 days) after the last dose of AMG 510 (sotorasib) and 2 months after the last dose of panitumumab COHORT I: Patient must not have colorectal cancer or non-small cell lung cancer COHORT I: Patient must not have been previously treated with a KRAS G12C inhibitor COHORT II: Patient must not have been previously treated with a KRAS G12C inhibitor in combination with an EGFR inhibitor

Ages Eligible for Study
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Minimum Age: 18 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: Cohort I Arm A (sotorasib, panitumumab)<br>Patients receive sotorasib PO and panitumumab IV on study. Patients also undergo collection of blood samples and a tumor biopsy before treatment and CT or MRI at follow up. | Procedure: Biopsy<br>* Undergo tumor biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo collection of blood<br>* Other names: Specimen Collection;Procedure: Computed Tomography<br>* Undergo CT scan<br>* Other names: tomography;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Biological: Panitumumab<br>* Given IV<br>* Other names: Vectibix;Drug: Sotorasib<br>* Given PO<br>* Other names: Lumykras;|
| Active Comparator: Cohort I Arm B (sotorasib)<br>Patients receive sotorasib PO on study. Patients with disease progression may cross-over to cohort II. Patients also undergo collection of blood samples and a tumor biopsy before treatment and CT or MRI at follow up. | Procedure: Biopsy<br>* Undergo tumor biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo collection of blood<br>* Other names: Specimen Collection;Procedure: Computed Tomography<br>* Undergo CT scan<br>* Other names: tomography;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Drug: Sotorasib<br>* Given PO<br>* Other names: Lumykras;|
| Experimental: Cohort II (sotorasib, panitumumab)<br>Patients receive combination therapy as in Arm A. | Procedure: Biopsy<br>* Undergo tumor biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo collection of blood<br>* Other names: Specimen Collection;Procedure: Computed Tomography<br>* Undergo CT scan<br>* Other names: tomography;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Biological: Panitumumab<br>* Given IV<br>* Other names: Vectibix;Drug: Sotorasib<br>* Given PO<br>* Other names: Lumykras;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) (Cohort I) | PFS will be compared between the arms using a one-sided log rank test with 10% type I error. Cox's proportional hazards model will be used to estimate the PFS hazard ratio between the treatment arms and a two-sided 80% confidence interval will be reported (to correspond to the one-sided 10% type I error). Confidence intervals on most other quantities will use the two-sided 90% level. | From registration to documented disease progression or death from any cause, assessed up to 3 years | 
| Best objective response (Cohort II) | Will be evaluated using the criteria defined by Response Evaluation Criteria in Solid Tumors (RECIST]) version 1.1 for patients with solid tumors. | From the start of the treatment until disease progression/recurrence, assessed up to 3 years | 
| Overall response rate (ORR) (Cohort II) | The exact 90% confidence interval on the ORR (determined using the method of Atkinson and Brown) will be reported. If the number of analyzable cases is less than 35, a 5% one-sided test will still be used. | From the time measurement criteria are met for complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) (Cohort I) | OS distributions by treatment will be estimated and 90% confidence intervals on estimated rates at 6 and 12 months will be reported. The OS hazard ratio will be estimated using Cox proportional hazards model and a 90% confidence interval reported. | Up to 3 years | 
| ORR (Cohort I) | Will be compared using Fisher's exact test and exact 90% confidence intervals for the rates in each arm will be computed. | Up to 3 years | 
| Disease control rates (Cohort I) | Will be compared using Fisher's exact test and exact 90% confidence intervals for the rates in each arm will be computed. | From the start of the treatment until the criteria for progression are met, assessed up to 3 years | 
| PFS (Cohort II) | Will be estimated and 90% confidence intervals on estimated rates will be reported. | At 6 and 12 months, assessed up to 3 years | 
| OS (Cohort II) | Will be estimated and 90% confidence intervals on estimated rates will be reported. | At 6 and 12 months, assessed up to |