Title
A Phase 1/2 Study of LY3537982 in Patients with KRAS G12C-Mutant Advanced Solid Tumors

Description
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. The study will last up to approximately 2 years.
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.

Objective
Primary Outcome Measures:

Phase 1a: To determine the recommended phase 2 dose (RP2D) of LY3537982 monotherapy [ Time Frame: Cycle 1 (21 Days) ] - Measured by the number of patients with dose-limiting toxicities (DLTs)

Phase 1b: To assess the safety and tolerability of LY3537982 when administered alone or in combination with other investigational agents [ Time Frame: Cycle 1 (21 Days) ] - Measured by the number of patients with dose-limiting toxicities (DLTs)

To assess preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Objective response rate (ORR) [ Time Frame: Estimated up to 2 years ] - ORR


To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Duration of Response (DOR) [ Time Frame: Estimated up to 2 years ] - DOR


To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Best Overall Response (BOR) [ Time Frame: Estimated up to 2 years ] - BOR


To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Time to response (TTR) [ Time Frame: Estimated up to 2 years ] - TTR


To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Disease control rate (DCR) [ Time Frame: Estimated up to 2 years ] - DCR


To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Progression-free survival (PFS) [ Time Frame: Estimated up to 2 years ] - PFS


To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Overall survival (OS) [ Time Frame: Estimated up to 2 years ] - OS


To characterize the pharmacokinetics (PK) properties of LY3537982: Area under the plasma concentration versus time curve (AUC) [ Time Frame: Predose estimated up to 2 years ] - PK: AUC of LY3537982


To characterize the PK properties of LY3537982: Maximum drug concentration (Cmax) [ Time Frame: Predose estimated up to 2 years ] - PK: Cmax of LY3537982

Treatment Experimental: LY3537982 (Dose Escalation)
LY3537982 administered orally.

Experimental: LY3537982 (Dose Expansion)
LY3537982 administered orally either alone or with another investigational agent.

Key Eligibility 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).

Must be able to swallow capsule/tablet.

Agree and adhere to contraceptive use, if applicable.

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 they are not currently receiving corticosteroids in excess of 10 milligrams (mg) per day prednisone/prednisolone (or equivalent) and their disease is asymptomatic and radiographically stable for at least 30 days.

Have received prior treatment with any KRAS G12C small molecule inhibitor, except in certain scenarios where such prior therapy is allowed as per protocol.

For Cohorts B2, B3, and B5/C1, patients treated with drugs known to be strong inhibitors or inducers of cytochrome P450 (CYP)3A.

The following patients will be excluded from Cohort B4:


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 undergone prior allogeneic hematopoietic stem cell transplantation within the last 5 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.

Applicable Disease Sites
Anal; Brain/Central Nervous System; Breast; Cervix; Colon and Rectum; Endocrine cancers; Esophagus; Gastrointestinal cancers, other; Genitourinary cancers, other; Head and Neck; Ill-Defined Sites; Kidney; Liver; Lung; Melanoma/Skin cancer; Ovary; Sarcoma; Uterus

Participating Institutions
UW Health Eastpark Medical Center; UW Health University Hospital