Biliary Tract Neoplasms, Carcinoma, Non-Small-Cell Lung, Colorectal Neoplasms, Endometrial Neoplasms, Ovarian Neoplasms, Pancreatic Neoplasms
Conditions
Keywords
Frontline, 1L, First Line
Brief summary
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
This is an open-label, multicenter Phase 1/2 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 4 parts: Phase 1a dose escalation, Phase 1b dose expansion, Phase 1b dose optimization, and Phase 2. KRAS G12C mutations will be identified through standard of care testing.
Interventions
DRUGLY3537982
Oral
DRUGPembrolizumab
Intravenous
DRUGCetuximab
Intravenous
DRUGPemetrexed
Intravenous
DRUGCisplatin
Intravenous
DRUGCarboplatin
Intravenous
Sponsors
Eli Lilly and Company
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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. * For one part of the study, participants must have received at least one prior oxaliplatin- or irinotecan-containing regimen for advanced or metastatic CRC.
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. * For some parts of the study only: have untreated active central nervous system (CNS) metastases and/or leptomeningeal disease. 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. Patients with active CNS metastases are eligible for one part 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. * 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 35 days after the last dose of study medication. * Known allergic reaction against any of the components of the study treatments.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1a: To determine the recommended phase 2 dose (RP2D) of LY3537982 monotherapy | 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 | Cycle 1 (21 Days) | Measured by the number of patients with dose-limiting toxicities (DLTs) |
| Phase 1b: To determine the optimal dose of LY3537982 to be administered to treatment-naïve participants with advanced NSCLC in combination with pembrolizumab | Estimated up to 2 years | Measured by TEAEs |
| To determine the optimal dose of LY3537982 to be administered to participants who have received at least one prior oxaliplatin- or irinotecan-containing regimen for advanced or metastatic CRC in combination with cetuximab | Estimated up to 2 years | — |
| To assess the antitumor activity of LY3537982 monotherapy in participants with advanced pancreatic cancer with KRAS G12C mutation | Estimated up to 2 years | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To assess preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Objective response rate (ORR) | 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) | 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) | 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) | 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) | 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) | 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) | Estimated up to 2 years | OS |
| 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) | Estimated up to 2 years | Intracranial DOR |
| 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) | Estimated up to 2 years | Whole-body ORR |
| To characterize the pharmacokinetics (PK) properties of LY3537982: Area under the plasma concentration versus time curve (AUC) | Predose estimated up to 2 years | PK: AUC of LY3537982 |
| To characterize the PK properties of LY3537982: Maximum drug concentration (Cmax) | Predose estimated up to 2 years | PK: Cmax of LY3537982 |
Countries
Australia, Canada, France, Japan, South Korea, United States
Contacts
STUDY_DIRECTORCall 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 8 AM - 8 PM Eastern time (UTC/GMT - 5 hours, EST)
Eli Lilly and Company
Outcome results
None listed