Study of LY3537982 in Cancer Patients With a Specific Genetic Mutation (KRAS G12C)

Study Overview
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Brief Summary
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The purpose of this study is to find out whether the study drug, LY3537982, is safe and effective in cancer patients who have a specific genetic mutation (KRAS G12C). Patients must have already received or were not able to tolerate the standard of care, except for specific groups who have not had cancer treatment. The study will last up to approximately 4 years.

Detailed Description
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This is an open-label, multicenter Phase 1 study to evaluate safety, tolerability, and preliminary efficacy of oral LY3537982 in patients with KRAS G12C-mutant solid tumors. This study will be conducted in 2 parts, Part 1a is a dose escalation and Part 1b is a dose expansion. Part 1a will establish a recommended Phase 2 dose. Part 1b will have multiple arms of either monotherapy or in combination with other drugs. KRAS G12C mutations will be identified through standard of care testing.

Official Title
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A Phase 1a/1b Study of LY3537982 in Patients With KRAS G12C-Mutant Advanced Solid Tumors

Conditions
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Carcinoma, Non-Small-Cell Lung, Colorectal Neoplams, Endometrial Neoplasms, Ovarian Neoplasms, Pancreatic Neoplasms, Biliary Tract Neoplasms

Intervention / Treatment
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* Drug: LY3537982
* Drug: Abemaciclib
* Drug: Pembrolizumab
* Drug: LY3295668
* Drug: Cetuximab
* Drug: Pemetrexed
* Drug: Cisplatin
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients have measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Patients must have disease with evidence of KRAS G12C mutation in tumor tissue or circulating tumor deoxyribonucleic acid (DNA). Participants must have a histological or a cytologically proven diagnosis of locally advanced, unresectable, and/or metastatic cancer and meet cohort-specific criteria. Have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. Have adequate organ function. Have discontinued all previous treatments for cancer with resolution of any significant ongoing adverse events (AEs), (except in certain scenarios). Must be able to swallow capsule/tablet. Agree and adhere to contraceptive use, if applicable. For some parts of the study, (i.e., one of the two arms with LY3537982 in combination with pembrolizumab and the arm of LY3537982 in combination with pembrolizumab, pemetrexed, and platinum therapy) histologically or cytologically confirmed Stage IIIB-IIIC or Stage IV NSCLC that is previously untreated in the advanced/metastatic setting and not suitable for curative intent radical surgery or radiation therapy. Previously untreated patients who received adjuvant and neoadjuvant therapy are eligible if the last dose of the systemic treatment was completed at least 6 months prior to enrollment. For untreated patients in the arm with LY3537982 in combination with pembrolizumab noted above, a single cycle of pembrolizumab may be initiated within 21 days prior to enrollment. For untreated patients in the arm of LY3537982 in combination with pembrolizumab, pemetrexed, and platinum therapy, a single cycle of any or all of the drugs other than LY3537982 may be initiated within 21 days prior to enrollment. Start of study treatment may be delayed to allow sufficient time for recovery from treatment-related toxicity. Exclusion Criteria: Disease suitable for local therapy administered with curative intent. Have an active, ongoing, or untreated infection. Have a serious pre-existing medical condition(s) that, in the judgment of the investigator, would preclude participation in this study. Have a serious cardiac condition. Have a second active primary malignancy or have been diagnosed and/or treated for an additional malignancy within 3 years prior to enrollment. Have symptomatic central nervous system (CNS) malignancy or metastasis and/or carcinomatous meningitis. Patients with treated CNS metastases are eligible for this study if their disease is asymptomatic, radiographically stable for at least 30 days, and they do not require treatment with steroids in the two-week period prior to study treatment. This only applies to some parts of the study. Have received prior treatment with any KRAS G12C small molecule inhibitor, except in certain scenarios where such prior therapy is allowed as per protocol. Patients treated with drugs known to be strong inhibitors or inducers of cytochrome P450 (CYP)3A may be excluded. The following patients will be excluded from some parts of the study: Experienced certain serious side effects with prior immunotherapy. Have an active autoimmune disease that has required systemic anti-autoimmune treatment in the past 2 years. Have received a live vaccine within 30 days prior to the first dose of study drug. Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the trial through 180 days after the last dose of study medication. Known allergic reaction against any of the components of the study treatments.

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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY3537982 (Dose Escalation)<br>LY3537982 administered orally. | Drug: LY3537982<br>* Oral<br>|
| Experimental: LY3537982 (Dose Expansion)<br>LY3537982 administered orally either alone or with another investigational agent. | Drug: LY3537982<br>* Oral<br>Drug: Abemaciclib<br>* Oral<br>* Other names: LY2835219;Drug: Pembrolizumab<br>* Intravenous<br>* Other names: Keytruda;Drug: LY3295668<br>* Oral<br>Drug: Cetuximab<br>* Intravenous<br>* Other names: Erbitux;Drug: Pemetrexed<br>* Intravenous<br>* Other names: Alimta;Drug: Cisplatin<br>* Intravenous<br>Drug: Carboplatin<br>* Intravenous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1a: To determine the recommended phase 2 dose (RP2D) of LY3537982 monotherapy | Measured by the number of patients with dose-limiting toxicities (DLTs) | Cycle 1 (21 Days) | 
| Phase 1b: To assess the safety and tolerability of LY3537982 when administered alone or in combination with other investigational agents | Measured by the number of patients with dose-limiting toxicities (DLTs) | Cycle 1 (21 Days) | 
| Phase 1b: To determine the optimal dose of LY3537982 to be administered to treatment-naïve participants with advanced NSCLC in combination with pembrolizumab | Measured by TEAEs | Estimated up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Objective response rate (ORR) | ORR | Estimated up to 2 years | 
| To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Duration of Response (DOR) | DOR | Estimated up to 2 years | 
| To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Best Overall Response (BOR) | BOR | Estimated up to 2 years | 
| To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Time to response (TTR) | TTR | Estimated up to 2 years | 
| To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Disease control rate (DCR) | DCR | Estimated up to 2 years | 
| To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Progression-free survival (PFS) | PFS | Estimated up to 2 years | 
| To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Overall survival (OS) | OS | Estimated up to 2 years | 
| To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Intracranial ORR based on modified RECIST v1.1 (Certain arms of the study only) | Intracranial ORR | Estimated up to 2 years | 
| To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Intracranial DOR based on modified RECIST v1.1 (Certain arms of the study only) | Intracranial DOR | Estimated up to 2 years | 
| To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Whole-body ORR based on RECIST v1.1 and modified RECIST v1.1 (Certain arms of the study only) | Whole-body ORR | Estimated up to 2 years | 
| To characterize the pharmacokinetics (PK) properties of LY3537982: Area under the plasma concentration versus time curve (AUC) | PK: AUC of LY3537982 | Predose estimated up to 2 years | 
| To characterize the PK properties of LY3537982: Maximum drug concentration (Cmax) | PK: Cmax of LY3537982 | Predose estimated up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Frontline, 1L, First Line