Clinical trial NCT04956640: Study of LY3537982 in Cancer Patients With a Specific Genetic Mutation (KRAS G12C)
Official title: A Phase 1/2 Study of LY3537982 in Patients With KRAS G12C-Mutant Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Carcinoma, Non-Small-Cell Lung
Colorectal Neoplasms
Endometrial Neoplasms
Ovarian Neoplasms
Pancreatic Neoplasms
Biliary Tract Neoplasms
Keywords: Frontline
1L
First Line
Lead sponsor: Eli Lilly and Company
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2021-07-09
Enrollment: 540
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility 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), (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.

Primary outcomes:
measure: Phase 1a: To determine the recommended phase 2 dose (RP2D) of LY3537982 monotherapy
timeFrame: Cycle 1 (21 Days)
measure: Phase 1b: To assess the safety and tolerability of LY3537982 when administered alone or in combination with other investigational agents
timeFrame: Cycle 1 (21 Days)
measure: Phase 1b: To determine the optimal dose of LY3537982 to be administered to treatment-naïve participants with advanced NSCLC in combination with pembrolizumab
timeFrame: Estimated up to 2 years
measure: 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
timeFrame: Estimated up to 2 years
measure: To assess the antitumor activity of LY3537982 monotherapy in participants with advanced pancreatic cancer with KRAS G12C mutation
timeFrame: Estimated up to 2 years
Secondary outcomes:
measure: To assess preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Objective response rate (ORR)
timeFrame: Estimated up to 2 years
measure: To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Duration of Response (DOR)
timeFrame: Estimated up to 2 years
measure: To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Best Overall Response (BOR)
timeFrame: Estimated up to 2 years
measure: To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Time to response (TTR)
timeFrame: Estimated up to 2 years
measure: To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Disease control rate (DCR)
timeFrame: Estimated up to 2 years
measure: To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Progression-free survival (PFS)
timeFrame: Estimated up to 2 years
measure: To assess the preliminary antitumor activity of LY3537982 when administered alone or in combination with other investigational agents: Overall survival (OS)
timeFrame: Estimated up to 2 years
measure: 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)
timeFrame: Estimated up to 2 years
measure: 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)
timeFrame: Estimated up to 2 years
measure: To characterize the pharmacokinetics (PK) properties of LY3537982: Area under the plasma concentration versus time curve (AUC)
timeFrame: Predose estimated up to 2 years
measure: To characterize the PK properties of LY3537982: Maximum drug concentration (Cmax)
timeFrame: Predose estimated up to 2 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Los Angeles
country: United States
facility: USC Norris Cancer Hospital
state: California
city: Orange
country: United States
facility: Chao Family Comprehensive Cancer Ctr.
state: California
city: New Haven
country: United States
facility: Yale-New Haven Hospital
state: Connecticut
city: Orlando
country: United States
facility: AdventHealth Orlando
state: Florida
city: Sarasota
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Indianapolis
country: United States
facility: Indiana Univ Melvin & Bren Simon Cancer Center
state: Indiana
city: Indianapolis
country: United States
facility: Community Health Network
state: Indiana
city: Baton Rouge
country: United States
facility: Mary Bird Perkins Cancer Center
state: Louisiana
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center
state: New Hampshire
city: Mineola
country: United States
facility: NYU Langone Health- Long Island
state: New York
city: New York
country: United States
facility: NYU Langone
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Chapel Hill
country: United States
facility: The University of North Carolina at Chapel Hill
state: North Carolina
city: Charlotte
country: United States
facility: Novant Health Cancer Institute - Elizabeth
state: North Carolina
city: Winston-Salem
country: United States
facility: Novant Health Cancer Institute - Forsyth
state: North Carolina
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
city: Nashville
country: United States
facility: Sarah Cannon Cancer Center
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt Univeristy School of Medicine
state: Tennessee
city: San Antonio
country: United States
facility: South Texas Accelerated Research Therapeutics (START)
state: Texas
city: West Valley City
country: United States
facility: START Mountain Region
state: Utah
city: Fairfax
country: United States
facility: Inova Health System IRB
state: Virginia
city: Fairfax
country: United States
facility: USO-Virginia Cancer Specialists, PC
state: Virginia
city: Madison
country: United States
facility: University of Wisconsin-Madison Hospital and Health Clinic
state: Wisconsin
city: St Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Sydney
country: Australia
facility: St Vincent's Hospital Sydney
state: New South Wales
city: Adelaide
country: Australia
facility: Cancer Research SA
state: South Australia
city: Frankston
country: Australia
facility: Peninsula and Southeast Oncology
state: Victoria
city: Nedlands
country: Australia
facility: Linear Clinical Research
state: Western Australia
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Toronto
country: Canada
facility: Princess Margaret Hospital (Ontario)
state: Ontario
city: Bordeaux
country: France
facility: Institut Bergonié - Centre Régional de Lutte Contre Le Cancer de Bordeaux et Sud Ouest
state: Aquitaine
city: Lyon
country: France
facility: Centre Leon Berard
state: Rhône-Alpes
city: Montpellier Cedex 5
country: France
facility: Institut du Cancer de Montpellier - Val d'aurelle
city: Toulouse cedex
country: France
facility: Institut Claudius Regaud - IUCT Oncopole
city: Villejuif Cedex
country: France
facility: Gustave Roussy
city: Nagoya
country: Japan
facility: Aichi Cancer Center Hospital
state: Aichi
city: Kashiwa
country: Japan
facility: National Cancer Center Hospital East
state: Chiba
city: Sapporo
country: Japan
facility: Hokkaido University Hospital
state: Hokkaido
city: Kanazawa-shi
country: Japan
facility: Kanazawa University Hospital
state: Ishikawa
city: Chuo-ku
country: Japan
facility: National Cancer Center Hospital
state: Tokyo
city: Wakayama
country: Japan
facility: Wakayama Medical University Hospital
city: Goyang-si
country: Korea, Republic of
facility: National Cancer Center
state: Gyeonggi-do
city: Suwon-si
country: Korea, Republic of
facility: The Catholic University of Korea, St. Vincent's Hospital
state: Gyeonggi-do
city: Hwasun-gun
country: Korea, Republic of
facility: Chonnam National University Hwasun Hospital
state: Jeonranamdo
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
state: Korea
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
state: Korea
Study officials:
affiliation: Eli Lilly and Company
name: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)
role: STUDY_DIRECTOR
References: