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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04956640
Recruitment Status : Recruiting
First Posted : July 9, 2021
Last Update Posted : May 30, 2023
Sponsor:
Collaborators:
Loxo Oncology, Inc.
Merck Sharp & Dohme LLC
Information provided by (Responsible Party):
Eli Lilly and Company

Study Description
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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.

Condition or disease Intervention/treatment Phase
Carcinoma, Non-Small-Cell Lung Colorectal Neoplams Endometrial Neoplasms Ovarian Neoplasms Pancreatic Neoplasms Drug: LY3537982 Drug: Abemaciclib Drug: Pembrolizumab Drug: LY3295668 Drug: Cetuximab Drug: Pemetrexed Drug: Cisplatin Drug: Carboplatin Phase 1

Detailed Description:

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 400 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1a/1b Study of LY3537982 in Patients With KRAS G12C-Mutant Advanced Solid Tumors
Actual Study Start Date : July 19, 2021
Estimated Primary Completion Date : September 2025
Estimated Study Completion Date : September 2025

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: LY3537982 (Dose Escalation)
LY3537982 administered orally.
 Drug: LY3537982
Oral
Experimental: LY3537982 (Dose Expansion)
LY3537982 administered orally either alone or with another investigational agent.
 Drug: LY3537982
Oral

Drug: Abemaciclib
Oral
Other Names:
  • Verzenio
  • LY2835219

Drug: Pembrolizumab
Intravenous
Other Name: Keytruda

Drug: LY3295668
Oral

Drug: Cetuximab
Intravenous
Other Name: Erbitux

Drug: Pemetrexed
Intravenous
Other Name: LY231514

Drug: Cisplatin
Intravenous

Drug: Carboplatin
Intravenous


Outcome Measures
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Primary Outcome Measures :
  1. 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)

  2. 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)

  3. Phase 1b: To determine the optimal dose of LY3537982 to be administered to treatment-naïve participants with advanced NSCLC in combination with pembrolizumab [ Time Frame: Estimated up to 2 years ]
    Measured by TEAEs


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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) [ Time Frame: Estimated up to 2 years ]
    Intracranial ORR

  9. 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) [ Time Frame: Estimated up to 2 years ]
    Intracranial DOR

  10. 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) [ Time Frame: Estimated up to 2 years ]
    Whole-body ORR

  11. 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

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


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
  • For some parts of the study, 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.
  • For some parts of the study, patients must be PD-L1 positive, (TPS greater than or equal to 1%)

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 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. 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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04956640


Contacts
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Contact: Patient Advocacy 855-569-6305 clinicaltrials@loxooncology.com

Locations
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Sponsors and Collaborators
Eli Lilly and Company
Loxo Oncology, Inc.
Merck Sharp & Dohme LLC
Investigators
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Study Director: Melinda Willard, PhD Loxo Oncology, Inc.
More Information
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Additional Information:

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Responsible Party: Eli Lilly and Company
ClinicalTrials.gov Identifier: NCT04956640    
Other Study ID Numbers: LOXO-RAS-20001
2021-000595-12 ( EudraCT Number )
J3M-OX-JZQA ( Other Identifier: Eli Lilly and Company )
KEYNOTE E27 ( Other Identifier: Merck )
First Posted: July 9, 2021    Key Record Dates
Last Update Posted: May 30, 2023
Last Verified: May 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neoplasms
Carcinoma, Non-Small-Cell Lung
Pancreatic Neoplasms
Ovarian Neoplasms
Endometrial Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Digestive System Neoplasms
Endocrine Gland Neoplasms
 Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Female Urogenital Diseases
Female Urogenital Diseases and Pregnancy Complications
Urogenital Diseases
Genital Neoplasms, Female
Urogenital Neoplasms
Genital Diseases
Gonadal Disorders
Uterine Neoplasms
Uterine Diseases