KEAPSAKE: A Study of Telaglenastat (CB-839) With Standard-of-Care Chemoimmunotherapy in 1L KEAP1/NRF2-Mutated, Nonsquamous NSCLC

Phase 2

Terminated

Conditions: Non-Small Cell Lung Cancer
KEAP1 Gene Mutation
NRF2 Gene Mutation
Non-squamous Non-small-cell Lung Cancer
Non-Squamous Non-Small Cell Neoplasm of Lung
NFE2L2 Gene Mutation

Interventions: Drug: Carboplatin Chemotherapy
Drug: Telaglenastat
Drug: Pemetrexed Chemotherapy
Biological: Pembrolizumab Immunotherapy
Drug: Placebo
Dietary Supplement: Folic acid 400 -1000 μg
Dietary Supplement: Vitamin B12 1000 μg
Drug: Dexamethasone 4 mg

Registration Number: NCT04265534

Lead Sponsor: Calithera Biosciences, Inc

Brief Summary: This is a Phase 2, randomized, multicenter, double-blind study of the glutaminase inhibitor telaglenastat with standard-of-care pembrolizumab and chemotherapy versus placebo with standard-of-care pembrolizumab and chemotherapy for first line treatment of metastatic disease in patients with KEAP1/NRF2-mutated, stage IV, nonsquamous, non-small cell lung cancer (NSCLC). The study primary endpoints are PFS per RECIST v. 1.1 and safety. KEAP1/NRF2 mutation status (for eligibility) and STK11/LKB1 status (for stratification) will be determined by next generation sequencing. A commercial liquid biopsy (circulating tumor DNA) NGS test will be provided to study participants free of charge.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 40

Inclusion Criteria

Histologically or cytologically documented non-squamous NSCLC
Stage IV (M1a-c, AJCC 8th Edition, Amin 2017) disease not previously treated with systemic therapy for metastatic NSCLC

a. Patients who received adjuvant or neo-adjuvant therapy (with or without immunotherapy) for localized NSCLC are eligible if all adjuvant/neo-adjuvant therapy (including immunotherapy) was completed at least 6 months prior to the development of metastatic disease.
No known actionable mutation in EGFR, ALK, ROS1, BRAF, NTRK or other known actionable mutation for which there is approved therapy in the first-line lung cancer setting
Must have at least one radiographically measurable lesion per RECIST v1.1 defined as a lesion that is ≥ 10 mm in longest diameter or lymph node that is ≥ 15 mm in short axis imaged by computed tomography (CT) scan or magnetic resonance imaging (MRI)

a. Target lesions situated in a previously irradiated area may be considered measurable if progression has been demonstrated subsequent to radiation therapy
Age ≥ 18 years on the day of signing informed consent
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Estimated life expectancy of at least 3 months
Recovery to baseline or ≤ grade 1 National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 from toxicities related to the prior treatment, unless after discussion with the medical monitor, the AE(s) are deemed clinically non-significant and/or stable on supportive therapy
Has sponsor-approved eligible mutation in KEAP1 or NRF2 documented by NGS from a CAP-accredited and/or CLIA-certified laboratory (study-provided NGS or other NGS) and STK11 mutation status is known for the purpose of stratification.
Adequate organ function laboratory findings (defined per protocol)
Reproductive status:

a. A female patient of childbearing potential must: i. Have a negative serum pregnancy test within 7 days prior to randomization ii. Agree to use methods of contraception outlined in Section 8.1.2 during the study through 120 days following the last dose of telaglenastat or pembrolizumab, or through 180 days following the last dose of chemotherapeutic drugs iii. Postmenopausal females (no menses for > 1 year without an alternate medical cause) and surgically sterilized females are exempt from these requirements b. Male patients who are sexually active with heterosexual partners of childbearing potential must agree to contraceptive requirements outlined in Section 8.1.2 and refrain from donating sperm during the study through 120 days following the last dose of telaglenastat or pembrolizumab, or through 180 days following the last dose of chemotherapeutic drugs

Exclusion Criteria

Squamous cell histology and mixed histology tumors with any small-cell/neuroendocrine component (other mixed histology should be reviewed with the medical monitor for eligibility)
Any other concurrent malignancy requiring local or systemic therapy. Patients with other previously treated malignancy(ies) are allowed if the specific neoplasm, in the opinion of the principal investigator and with the agreement of the medical monitor, is not expected to interfere with study-specific endpoints
Radiation therapy to the lung > 30 Gy within 6 months prior to randomization
Clinically active diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, abdominal carcinomatosis
Active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs)

a. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
Treatment with chronic systemic steroids greater than 10 mg equivalent of prednisone per day
Unstable/inadequate cardiac function, defined as the following:
1. Myocardial infarction or symptomatic ischemia within 6 months prior to randomization
2. Uncontrolled or clinically significant conduction abnormalities (e.g., patients with ventricular tachycardia on anti-arrhythmics are excluded; patients with 1st degree atrioventricular [AV] block or asymptomatic left anterior fascicular block [LAFB]/right bundle branch block [RBBB] are eligible)
3. Congestive heart failure (New York Heart Association class III to IV)
Unable to swallow oral medications
Known sensitivity to any component of the study treatment (pembrolizumab, carboplatin, pemetrexed, and/or telaglenastat) or previous severe hypersensitivity to another monoclonal antibody (mAb)
Unable or unwilling to take folic acid or vitamin B12 supplementation (per pemetrexed label)
Unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) as specified in pemetrexed label
Interstitial lung disease or a history of pneumonitis that required oral or intravenous glucocorticoid treatment
Unable or unwilling to discontinue proton pump inhibitor (PPI) use ≥ 5 days prior to randomization
Patient known to be positive for Human Immunodeficiency Virus (HIV)
Known active Hepatitis B or C. Active Hepatitis B is defined as a known positive HBsAg result. Active Hepatitis C is defined by a known positive Hepatitis C antibody result and known quantitative Hepatitis C virus RNA results greater than the lower limits of detection of the assay. Patients receiving antiviral therapy for Hepatitis B or C also are not eligible
Any condition including social, psychiatric or medical (including uncontrolled significant concurrent illness) that in the opinion of the Investigator could interfere with treatment or protocol-related procedures
Regular use of illicit drugs or history (within past year) of substance abuse (including alcohol)
Patients who are pregnant or lactating
Major surgery < 3 weeks prior to randomization. In addition, patients with ongoing clinically relevant complications from prior surgery are not eligible and they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment
Any radiation therapy within 2 weeks prior to randomization (with exception of SRS for brain metastases). In addition, patients with ongoing clinically relevant complications from prior radiation therapy, patients requiring corticosteroids to treat radiation toxicity and patients who developed radiation pneumonitis are not eligible.
Symptomatic ascites or pleural effusion. Patients who are clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) are eligible
Refractory nausea and vomiting, uncontrolled diarrhea, malabsorption, significant small bowel resection or gastric bypass surgery, use of feeding tubes or other situation that may preclude adequate absorption or oral study drug
Infection requiring more than 5 days of parenteral antibiotics, antivirals, or antifungals within two weeks prior to randomization. Anti-infective therapy must be completed at least 7 days before randomization
Patients with active and/or untreated central nervous system metastasis including carcinomatous meningitis (leptomeningeal disease) are not eligible. Patients with previously treated brain metastases are eligible if they meet the following criteria:
1. Received definitive treatment with stereotactic radiosurgery (SRS) or surgery to all known central nervous system (CNS) lesions (whole brain radiotherapy is not an eligible modality)
2. Be at least 4 weeks post-surgical resection of CNS disease, symptomatically stable and off steroids before randomization
Any live-virus vaccination within 28 days prior to randomization. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist ®) are live attenuated vaccines and are not allowed
Has had an allogeneic tissue/solid organ transplant

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Telaglenastat with Pembrolizumab and Chemotherapy	Dexamethasone 4 mg	The glutaminase inhibitor telaglenastat will be administered orally, twice daily with food, every day in combination with standard-of-care pembrolizumab plus chemotherapy by intravenous (IV) infusion every 3 weeks.
Telaglenastat with Pembrolizumab and Chemotherapy	Folic acid 400 -1000 μg	The glutaminase inhibitor telaglenastat will be administered orally, twice daily with food, every day in combination with standard-of-care pembrolizumab plus chemotherapy by intravenous (IV) infusion every 3 weeks.
Telaglenastat with Pembrolizumab and Chemotherapy	Vitamin B12 1000 μg	The glutaminase inhibitor telaglenastat will be administered orally, twice daily with food, every day in combination with standard-of-care pembrolizumab plus chemotherapy by intravenous (IV) infusion every 3 weeks.
Placebo with Pembrolizumab and Chemotherapy	Carboplatin Chemotherapy	Placebo will be administered orally twice daily with food every day in combination with standard-of-care pembrolizumab plus chemotherapy by IV infusion every 3 weeks.
Placebo with Pembrolizumab and Chemotherapy	Pemetrexed Chemotherapy	Placebo will be administered orally twice daily with food every day in combination with standard-of-care pembrolizumab plus chemotherapy by IV infusion every 3 weeks.
Telaglenastat with Pembrolizumab and Chemotherapy	Carboplatin Chemotherapy	The glutaminase inhibitor telaglenastat will be administered orally, twice daily with food, every day in combination with standard-of-care pembrolizumab plus chemotherapy by intravenous (IV) infusion every 3 weeks.
Telaglenastat with Pembrolizumab and Chemotherapy	Pemetrexed Chemotherapy	The glutaminase inhibitor telaglenastat will be administered orally, twice daily with food, every day in combination with standard-of-care pembrolizumab plus chemotherapy by intravenous (IV) infusion every 3 weeks.
Telaglenastat with Pembrolizumab and Chemotherapy	Pembrolizumab Immunotherapy	The glutaminase inhibitor telaglenastat will be administered orally, twice daily with food, every day in combination with standard-of-care pembrolizumab plus chemotherapy by intravenous (IV) infusion every 3 weeks.
Placebo with Pembrolizumab and Chemotherapy	Pembrolizumab Immunotherapy	Placebo will be administered orally twice daily with food every day in combination with standard-of-care pembrolizumab plus chemotherapy by IV infusion every 3 weeks.
Placebo with Pembrolizumab and Chemotherapy	Placebo	Placebo will be administered orally twice daily with food every day in combination with standard-of-care pembrolizumab plus chemotherapy by IV infusion every 3 weeks.
Placebo with Pembrolizumab and Chemotherapy	Folic acid 400 -1000 μg	Placebo will be administered orally twice daily with food every day in combination with standard-of-care pembrolizumab plus chemotherapy by IV infusion every 3 weeks.
Placebo with Pembrolizumab and Chemotherapy	Vitamin B12 1000 μg	Placebo will be administered orally twice daily with food every day in combination with standard-of-care pembrolizumab plus chemotherapy by IV infusion every 3 weeks.
Placebo with Pembrolizumab and Chemotherapy	Dexamethasone 4 mg	Placebo will be administered orally twice daily with food every day in combination with standard-of-care pembrolizumab plus chemotherapy by IV infusion every 3 weeks.
Telaglenastat with Pembrolizumab and Chemotherapy	Telaglenastat	The glutaminase inhibitor telaglenastat will be administered orally, twice daily with food, every day in combination with standard-of-care pembrolizumab plus chemotherapy by intravenous (IV) infusion every 3 weeks.

Primary Outcome Measures

Name	Time	Method
Progression-Free Survival (PFS), Assessed by Investigator per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1	Up to 24 months	Duration of investigator-determined PFS per RECIST v1.1 in the intent-to-treat (ITT) population
Safety and Tolerability of Telaglenastat Plus Standard-of-Care Pembrolizumab and Chemotherapy Assessed by Type, Incidence, Severity, Seriousness, and Study Drug Relatedness of Adverse Events per CTCAE v5.0	Up to 55 months
Recommended Phase 2 Dose of Telaglenastat in Combination with Standard-of-Care Pembrolizumab and Chemotherapy Assessed by Incidence and Nature of Protocol Defined Dose-Limiting Toxicities (DLTs) During the Safety Run-in Period	Up to 6 months

Secondary Outcome Measures

Name	Time	Method
Overall Survival	Up to 55 months
Duration of Response (DOR) for Patients Treated with Telaglenastat plus Standard-of-Care Pembrolizumab and Chemotherapy versus Placebo plus Standard-of-Care Pembrolizumab and Chemotherapy	Up to 24 months	DOR is defined as the duration of response for patients achieving a CR or PR
PFS in the Subgroup of Patients with Biochemical Evidence of Activation of the NRF2 Pathway	Up to 24 months
ORR in the Subgroup of Patients with Biochemical Evidence of Activation of the NRF2 Pathway	Up to 24 months
DOR in the Subgroup of Patients with Biochemical Evidence of Activation of the NRF2 Pathway	Up to 24 months
Objective Response Rate (ORR) for Patients Treated with Telaglenastat plus Standard-of-Care Pembrolizumab and Chemotherapy versus Placebo plus Standard-of-Care Pembrolizumab and Chemotherapy	Up to 24 months	ORR is defined as the percentage of patients with complete response (CR) or partial response (PR) according to the RECIST v1.1 criteria as assessed by the investigator.
OS in the Subgroup of Patients with Biochemical Evidence of Activation of the NRF2 Pathway	Up to 55 months

Trial Locations

Locations (93): Florida Cancer Specialist - Panhandle (SCRI)
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Tallahassee, Florida, United States
University of Southern California (USC)
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Los Angeles, California, United States
St. Joseph Heritage Healthcare
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Fullerton, California, United States
Compassionate Cancer Care
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Fountain Valley, California, United States
Yuma Regional Medical Center
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Yuma, Arizona, United States
Sibley Memorial Hospital
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Washington, District of Columbia, United States
Loma Linda University Medical Center
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Loma Linda, California, United States
University of South Alabama - Mitchell Cancer Center
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Mobile, Alabama, United States
UPMC Hillman Cancer Center
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Pittsburgh, Pennsylvania, United States
Oncology Consultants
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Houston, Texas, United States
TriHealth Cancer Institute
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Cincinnati, Ohio, United States
Comprehensive Cancer Centers of Nevada
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Las Vegas, Nevada, United States
Tennessee Oncology - Nashville (SCRI)
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Nashville, Tennessee, United States
Utah Cancer Specialist
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Salt Lake City, Utah, United States
Henry Ford Cancer Institute
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Detroit, Michigan, United States
University of Alabama at Birmingham
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Birmingham, Alabama, United States
Providence Portland Medical Center
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Portland, Oregon, United States
Oregon Health & Science University (OHSU) Knight Cancer Institute
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Portland, Oregon, United States
Nebraska Methodist Hospital
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Omaha, Nebraska, United States
Froedtert Hospital and the Medical College of Wisconsin (MCW)
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Milwaukee, Wisconsin, United States
Cone Health at Alamance Regional
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Burlington, North Carolina, United States
Moffitt Cancer Center
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Tampa, Florida, United States
Center for Cancer and Blood Disorders
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Bethesda, Maryland, United States
University of California Irvine, Chao Family Comprehensive Cancer Center
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Orange, California, United States
Boca Raton Regional Hospital Lynn Cancer Institute
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Boca Raton, Florida, United States
St. Joseph Heritage Healthcare - Santa Rosa
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Santa Rosa, California, United States
Holy Cross Hospital - Bines Cancer Center
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Fort Lauderdale, Florida, United States
Johns Hopkins Sibley Memorial Hospital
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Washington, District of Columbia, United States
Ocala Oncology Center
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Ocala, Florida, United States
University of Miami Sylvester Comprehensive Cancer Center
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Miami, Florida, United States
Florida Cancer Specialist - North (SCRI)
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Saint Petersburg, Florida, United States
Florida Cancer Specialist - South (SCRI)
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Fort Myers, Florida, United States
Florida Cancer Specialist - East (SCRI)
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West Palm Beach, Florida, United States
University Cancer and Blood Center
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Athens, Georgia, United States
Northwest Georgia Oncology
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Marietta, Georgia, United States
Piedmont Cancer Institute
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Atlanta, Georgia, United States
Orchard Healthcare Research Inc.
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Skokie, Illinois, United States
University of Kansas Medical Center (KUMC)
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Westwood, Kansas, United States
Johns Hopkins Bayview Memorial Hospital
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Baltimore, Maryland, United States
Pontchartrain Cancer Center
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Covington, Louisiana, United States
Beacon Health
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South Bend, Indiana, United States
Maryland Oncology Hematology - USOR
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Columbia, Maryland, United States
Frederick Health - James M. Stockman Cancer Institute
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Frederick, Maryland, United States
Massachusetts General Hospital
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Boston, Massachusetts, United States
Bronson Methodist Hospital (West Michigan Cancer Center)
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Kalamazoo, Michigan, United States
Minnesota Oncology Hematology, P.A.
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Woodbury, Minnesota, United States
Washington University
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Saint Louis, Missouri, United States
Central Care Cancer Center
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Bolivar, Missouri, United States
New Jersey Cancer Care and Blood Disorders (NJCCBD)
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Belleville, New Jersey, United States
Summit Medical Group
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Berkeley Heights, New Jersey, United States
The Valley Hospital - Luckow Pavilion
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Paramus, New Jersey, United States
University of New Mexico Comprehensive Cancer Center
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Albuquerque, New Mexico, United States
New York Oncology Hematology, P.C.
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Clifton Park, New York, United States
Pelmutter Cancer Center at Winthrop
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Mineola, New York, United States
Columbia University Medical Center
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New York, New York, United States
New York University Langone (NYU)
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New York, New York, United States
Memorial Sloan Kettering Cancer Center
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New York, New York, United States
Weill Cornell Medical College - New York Presbyterian Hospital
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New York, New York, United States
Aultman Hospital
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Canton, Ohio, United States
Toledo Clinic Cancer Center
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Toledo, Ohio, United States
Cone Health Cancer Center
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Greensboro, North Carolina, United States
Ohio Health
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Columbus, Ohio, United States
Ohio State University, James Cancer Hospital and Solove Research Institute
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Columbus, Ohio, United States
Oklahoma Cancer Specialists and Research Institute (OCSRI)
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Tulsa, Oklahoma, United States
Pennsylvania State University Milton S. Hershey Medical Center
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State College, Pennsylvania, United States
Tennessee Oncology - Chattanooga (SCRI)
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Chattanooga, Tennessee, United States
Texas Oncology - Denison
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Denison, Texas, United States
Texas Oncology - Austin Midtown
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Austin, Texas, United States
Texas Oncology Beaumont - USOR
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Beaumont, Texas, United States
Texas Oncology - Fort Worth Cancer Center
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Fort Worth, Texas, United States
Oncology and Hematology of South Texas
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Laredo, Texas, United States
Virginia Cancer Specialists
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Fairfax, Virginia, United States
Northwest Medical Specialities
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Tacoma, Washington, United States
University of Washington Seattle Cancer Care Alliance (SCCA)
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Seattle, Washington, United States
University of Wisconsin Carbone Cancer Center
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Madison, Wisconsin, United States
UCLA
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Los Angeles, California, United States
Cedars-Sinai Medical Center
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Los Angeles, California, United States
Sanford Health
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Sioux Falls, South Dakota, United States
St. Joseph Mercy Hospital Cancer Care Center
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Ypsilanti, Michigan, United States
Memorial Cancer Institute at Memorial Hospital West
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Hollywood, Florida, United States
University of Utah - Huntsman Cancer Institute
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Salt Lake City, Utah, United States
Oncology of Northshore
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Rolling Meadows, Illinois, United States
Fort Wayne Medical Oncology and Hematology
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Fort Wayne, Indiana, United States
Dartmouth-Hitchcock Medical Center
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Lebanon, New Hampshire, United States
New York Oncology Hematology, P.C. (400 Patoon Creek Blvd.)
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Albany, New York, United States
New York Oncology Hematology, P.C. (43 New Scotland Ave.)
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Albany, New York, United States
Roswell Park Comprehensive Cancer Center
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Buffalo, New York, United States
Oncology and Hematology Associates of Southwest Virginia
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Wytheville, Virginia, United States
Emory University Hospital
🇺🇸
Atlanta, Georgia, United States
Texas Oncology - South Austin
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Austin, Texas, United States
Texas Oncology - Austin Central
🇺🇸
Austin, Texas, United States
Hawaii Cancer Care
🇺🇸
Honolulu, Hawaii, United States
Virginia Commonwealth University (VCU) Massey Cancer Center
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Richmond, Virginia, United States