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A Phase 1/2 Study of LY3537982 in Patients with KRAS G12C-Mutant Advanced Solid Tumors (LOXO-RAS-20001)

Study of LY3537982 in Cancer Patients with a Specific Genetic Mutation (KRAS G12C) (LOXO-RAS-20001)

Masaki Takeshi

Eli Lilly Japan K.K.

5-1-28, Isogamidori, Chuo-ku, Kobe, Hyogo

LTG_CallCenter@lists.lilly.com

Clinical Development Operations

Eli Lilly Japan

5-1-28, Isogamidori, Chuo-ku, Kobe, Hyogo

+81-120-023-812

LTG_CallCenter@lists.lilly.com

Not Recruiting

Sept. 16, 2021

Interventional

non-randomized controlled trial

open(masking not used)

uncontrolled control

single assignment

treatment purpose

1. Patients have measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).
2. Patients must have disease with evidence of KRAS G12C mutation in tumor tissue or circulating tumor deoxyribonucleic acid (DNA).
3. Participants must have a histological or a cytologically proven diagnosis of locally advanced, unresectable, and/or metastatic cancer and meet cohort-specific criteria.
4. Have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
5. Have adequate organ function.
6. Have discontinued all previous treatments for cancer with resolution of any significant ongoing adverse events (AEs), (except in certain scenarios).
7. Must be able to swallow capsule/tablet.
8. Agree and adhere to contraceptive use, if applicable.
9. 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.
10. For one part of the study, participants must have received at least one prior oxaliplatin- or irinotecan-containing regimen for advanced or metastatic CRC.

1. Disease suitable for local therapy administered with curative intent.
2. Have an active, ongoing, or untreated infection.
3. Have a serious pre-existing medical condition(s) that, in the judgment of the investigator, would preclude participation in this study.
4. Have a serious cardiac condition.
5. Have a second active primary malignancy or have been diagnosed and/or treated for an additional malignancy within 3 years prior to enrollment.
6. 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.
7. Have received prior treatment with any KRAS G12C small molecule inhibitor, except in certain scenarios where such prior therapy is allowed as per protocol.
8. 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.
9. 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.
10. Known allergic reaction against any of the components of the study treatments.

Both

NSCLC; CRC; Endometrial Neoplasms; Ovarian Neoplasms; Pancreatic Neoplasms; Biliary Tract Neoplasms

Drug: LY3537982
Oral
Other Name: Olomorasib
Drug: Pembrolizumab
Intravenous
Other Name: Keytruda
Drug: Cetuximab
Intravenous
Other Name: Erbitux
Drug: Pemetrexed
Intravenous
Other Name: LY231514, Alimta
Drug: Cisplatin
Intravenous
Drug: Carboplatin
Intravenous
Experimental: LY3537982 (Dose Escalation)
LY3537982 administered orally.
Intervention: Drug: LY3537982
Experimental: LY3537982 (Dose Expansion)
LY3537982 administered orally either alone or with another investigational agent.
Interventions:
Drug: LY3537982
Drug: Pembrolizumab
Drug: Cetuximab
Drug: Pemetrexed
Drug: Cisplatin
Drug: Carboplatin
Experimental: LY3537982 (Dose Optimization)
LY3537982 administered orally either alone or with another investigational agent
Drug: LY3537982
Drug: Pembrolizumab
Drug: Cetuximab

Frontline, 1L, First Line

Phase 1a: To determine the recommended phase 2 dose (RP2D) of LY3537982 monotherapy. 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. 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-naive participants with advanced NSCLC in combination with pembrolizumab. 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

To assess the antitumor activity of LY3537982 monotherapy in participants with advanced pancreatic cancer with KRAS G12C mutation

To assess preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Objective response rate (ORR)
To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Duration of Response (DOR)
To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with
other investigational agents: Best Overall Response (BOR)
To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Time to response (TTR)
To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Disease control rate (DCR)
To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Progression-free survival (PFS)
To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Overall survival (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)
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)
To characterize the pharmacokinetics (PK) properties of LY3537982: Area under the plasma concentration versus time curve (AUC)
To characterize the PK properties of LY3537982: Maximum drug concentration (Cmax)

+81-3-3542-2511

Aug. 25, 2021

No

United States/Sounth Korea/France/Canada/Australia