Clinical trial NCT04265534: KEAPSAKE: A Study of Telaglenastat (CB-839) With Standard-of-Care Chemoimmunotherapy in 1L KEAP1/NRF2-Mutated, Nonsquamous NSCLC
Official title: A Phase 2 Randomized, Multicenter, Double-Blind Study of the Glutaminase Inhibitor Telaglenastat With Pembrolizumab and Chemotherapy Versus Placebo With Pembrolizumab and Chemotherapy in First-Line, Metastatic KEAP1/NRF2-Mutated, Nonsquamous, Non-Small Cell Lung Cancer (NSCLC)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Non-Small Cell Lung Cancer
Non-squamous Non-small-cell Lung Cancer
Non-Squamous Non-Small Cell Neoplasm of Lung
KEAP1 Gene Mutation
NRF2 Gene Mutation
NFE2L2 Gene Mutation
Keywords: NSCLC
KEAP1
NRF2
NFE2l2
LKB1
STK11
Next Generation Sequencing
NGS
Mutation
Pembrolizumab
Pemetrexed
Carboplatin
Randomized
Placebo
Chemotherapy
Targeted Therapy
Telaglenastat
Glutamine
Glutaminase
Glutathione
Immunotherapy
Front-line
First-line
Non-squamous
Keytruda
Alimta
Guardant360
Lead sponsor: Calithera Biosciences, Inc
Sponsor class: INDUSTRY
First posted: 2020-02-11
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

1. Histologically or cytologically documented non-squamous NSCLC
2. 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.
3. 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
4. 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
5. Age ≥ 18 years on the day of signing informed consent
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
7. Estimated life expectancy of at least 3 months
8. 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
9. 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.
10. Adequate organ function laboratory findings (defined per protocol)
11. 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:

1. 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)
2. 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
3. Radiation therapy to the lung \> 30 Gy within 6 months prior to randomization
4. Clinically active diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, abdominal carcinomatosis
5. 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.
6. Treatment with chronic systemic steroids greater than 10 mg equivalent of prednisone per day
7. 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)
8. Unable to swallow oral medications
9. Known sensitivity to any component of the study treatment (pembrolizumab, carboplatin, pemetrexed, and/or telaglenastat) or previous severe hypersensitivity to another monoclonal antibody (mAb)
10. Unable or unwilling to take folic acid or vitamin B12 supplementation (per pemetrexed label)
11. Unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) as specified in pemetrexed label
12. Interstitial lung disease or a history of pneumonitis that required oral or intravenous glucocorticoid treatment
13. Unable or unwilling to discontinue proton pump inhibitor (PPI) use ≥ 5 days prior to randomization
14. Patient known to be positive for Human Immunodeficiency Virus (HIV)
15. 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
16. 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
17. Regular use of illicit drugs or history (within past year) of substance abuse (including alcohol)
18. Patients who are pregnant or lactating
19. 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
20. 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.
21. Symptomatic ascites or pleural effusion. Patients who are clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) are eligible
22. 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
23. 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
24. 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
25. 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
26. Has had an allogeneic tissue/solid organ transplant

Primary outcomes:
measure: Progression-Free Survival (PFS), Assessed by Investigator per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
timeFrame: Up to 24 months
measure: 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
timeFrame: Up to 55 months
measure: 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
timeFrame: Up to 6 months
Secondary outcomes:
measure: 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
timeFrame: Up to 24 months
measure: 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
timeFrame: Up to 24 months
measure: Overall Survival
timeFrame: Up to 55 months
measure: PFS in the Subgroup of Patients with Biochemical Evidence of Activation of the NRF2 Pathway
timeFrame: Up to 24 months
measure: ORR in the Subgroup of Patients with Biochemical Evidence of Activation of the NRF2 Pathway
timeFrame: Up to 24 months
measure: DOR in the Subgroup of Patients with Biochemical Evidence of Activation of the NRF2 Pathway
timeFrame: Up to 24 months
measure: OS in the Subgroup of Patients with Biochemical Evidence of Activation of the NRF2 Pathway
timeFrame: Up to 55 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Mobile
country: United States
facility: University of South Alabama - Mitchell Cancer Center
state: Alabama
city: Yuma
country: United States
facility: Yuma Regional Medical Center
state: Arizona
city: Fountain Valley
country: United States
facility: Compassionate Cancer Care
state: California
city: Fullerton
country: United States
facility: St. Joseph Heritage Healthcare
state: California
city: Loma Linda
country: United States
facility: Loma Linda University Medical Center
state: California
city: Los Angeles
country: United States
facility: University of Southern California (USC)
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Los Angeles
country: United States
facility: UCLA
state: California
city: Orange
country: United States
facility: University of California Irvine, Chao Family Comprehensive Cancer Center
state: California
city: Santa Rosa
country: United States
facility: St. Joseph Heritage Healthcare - Santa Rosa
state: California
city: Washington
country: United States
facility: Johns Hopkins Sibley Memorial Hospital
state: District of Columbia
city: Washington
country: United States
facility: Sibley Memorial Hospital
state: District of Columbia
city: Boca Raton
country: United States
facility: Boca Raton Regional Hospital Lynn Cancer Institute
state: Florida
city: Fort Lauderdale
country: United States
facility: Holy Cross Hospital - Bines Cancer Center
state: Florida
city: Fort Myers
country: United States
facility: Florida Cancer Specialist - South (SCRI)
state: Florida
city: Hollywood
country: United States
facility: Memorial Cancer Institute at Memorial Hospital West
state: Florida
city: Miami
country: United States
facility: University of Miami Sylvester Comprehensive Cancer Center
state: Florida
city: Ocala
country: United States
facility: Ocala Oncology Center
state: Florida
city: Saint Petersburg
country: United States
facility: Florida Cancer Specialist - North (SCRI)
state: Florida
city: Tallahassee
country: United States
facility: Florida Cancer Specialist - Panhandle (SCRI)
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: West Palm Beach
country: United States
facility: Florida Cancer Specialist - East (SCRI)
state: Florida
city: Athens
country: United States
facility: University Cancer and Blood Center
state: Georgia
city: Atlanta
country: United States
facility: Piedmont Cancer Institute
state: Georgia
city: Atlanta
country: United States
facility: Emory University Hospital
state: Georgia
city: Marietta
country: United States
facility: Northwest Georgia Oncology
state: Georgia
city: Honolulu
country: United States
facility: Hawaii Cancer Care
state: Hawaii
city: Rolling Meadows
country: United States
facility: Oncology of Northshore
state: Illinois
city: Skokie
country: United States
facility: Orchard Healthcare Research Inc.
state: Illinois
city: Fort Wayne
country: United States
facility: Fort Wayne Medical Oncology and Hematology
state: Indiana
city: South Bend
country: United States
facility: Beacon Health
state: Indiana
city: Westwood
country: United States
facility: University of Kansas Medical Center (KUMC)
state: Kansas
city: Covington
country: United States
facility: Pontchartrain Cancer Center
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins Bayview Memorial Hospital
state: Maryland
city: Bethesda
country: United States
facility: Center for Cancer and Blood Disorders
state: Maryland
city: Columbia
country: United States
facility: Maryland Oncology Hematology - USOR
state: Maryland
city: Frederick
country: United States
facility: Frederick Health - James M. Stockman Cancer Institute
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Cancer Institute
state: Michigan
city: Kalamazoo
country: United States
facility: Bronson Methodist Hospital (West Michigan Cancer Center)
state: Michigan
city: Ypsilanti
country: United States
facility: St. Joseph Mercy Hospital Cancer Care Center
state: Michigan
city: Coon Rapids
country: United States
facility: Minnesota Oncology Hematology, P.A.
state: Minnesota
city: Edina
country: United States
facility: Minnesota Oncology Hematology, P.A.
state: Minnesota
city: Maplewood
country: United States
facility: Minnesota Oncology Hematology, P.A.
state: Minnesota
city: Minneapolis
country: United States
facility: Minnesota Oncology Hematology, P.A.
state: Minnesota
city: Saint Paul
country: United States
facility: Minnesota Oncology Hematology, P.A.
state: Minnesota
city: Woodbury
country: United States
facility: Minnesota Oncology Hematology, P.A.
state: Minnesota
city: Bolivar
country: United States
facility: Central Care Cancer Center
state: Missouri
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Omaha
country: United States
facility: Nebraska Methodist Hospital
state: Nebraska
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center
state: New Hampshire
city: Belleville
country: United States
facility: New Jersey Cancer Care and Blood Disorders (NJCCBD)
state: New Jersey
city: Berkeley Heights
country: United States
facility: Summit Medical Group
state: New Jersey
city: Paramus
country: United States
facility: The Valley Hospital - Luckow Pavilion
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico Comprehensive Cancer Center
state: New Mexico
city: Albany
country: United States
facility: New York Oncology Hematology, P.C. (400 Patoon Creek Blvd.)
state: New York
city: Albany
country: United States
facility: New York Oncology Hematology, P.C. (43 New Scotland Ave.)
state: New York
city: Buffalo
country: United States
facility: Roswell Park Comprehensive Cancer Center
state: New York
city: Clifton Park
country: United States
facility: New York Oncology Hematology, P.C.
state: New York
city: Mineola
country: United States
facility: Pelmutter Cancer Center at Winthrop
state: New York
city: New York
country: United States
facility: New York University Langone (NYU)
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College - New York Presbyterian Hospital
state: New York
city: Burlington
country: United States
facility: Cone Health at Alamance Regional
state: North Carolina
city: Greensboro
country: United States
facility: Cone Health Cancer Center
state: North Carolina
city: Canton
country: United States
facility: Aultman Hospital
state: Ohio
city: Cincinnati
country: United States
facility: TriHealth Cancer Institute
state: Ohio
city: Columbus
country: United States
facility: Ohio State University, James Cancer Hospital and Solove Research Institute
state: Ohio
city: Columbus
country: United States
facility: Ohio Health
state: Ohio
city: Toledo
country: United States
facility: Toledo Clinic Cancer Center
state: Ohio
city: Tulsa
country: United States
facility: Oklahoma Cancer Specialists and Research Institute (OCSRI)
state: Oklahoma
city: Portland
country: United States
facility: Providence Portland Medical Center
state: Oregon
city: Portland
country: United States
facility: Oregon Health & Science University (OHSU) Knight Cancer Institute
state: Oregon
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
city: State College
country: United States
facility: Pennsylvania State University Milton S. Hershey Medical Center
state: Pennsylvania
city: Sioux Falls
country: United States
facility: Sanford Health
state: South Dakota
city: Chattanooga
country: United States
facility: Tennessee Oncology - Chattanooga (SCRI)
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology - Nashville (SCRI)
state: Tennessee
city: Austin
country: United States
facility: Texas Oncology - Austin Midtown
state: Texas
city: Austin
country: United States
facility: Texas Oncology - Austin Central
state: Texas
city: Austin
country: United States
facility: Texas Oncology - South Austin
state: Texas
city: Beaumont
country: United States
facility: Texas Oncology Beaumont - USOR
state: Texas
city: Denison
country: United States
facility: Texas Oncology - Denison
state: Texas
city: Fort Worth
country: United States
facility: Texas Oncology - Fort Worth Cancer Center
state: Texas
city: Houston
country: United States
facility: Oncology Consultants
state: Texas
city: Laredo
country: United States
facility: Oncology and Hematology of South Texas
state: Texas
city: Salt Lake City
country: United States
facility: Utah Cancer Specialist
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah - Huntsman Cancer Institute
state: Utah
city: Blacksburg
country: United States
facility: Oncology and Hematology Associates of Southwest Virginia
state: Virginia
city: Fairfax
country: United States
facility: Virginia Cancer Specialists
state: Virginia
city: Low Moor
country: United States
facility: Oncology and Hematology Associates of Southwest Virginia
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University (VCU) Massey Cancer Center
state: Virginia
city: Roanoke
country: United States
facility: Oncology and Hematology Associates of Southwest Virginia
state: Virginia
city: Salem
country: United States
facility: Oncology and Hematology Associates of Southwest Virginia
state: Virginia
city: Wytheville
country: United States
facility: Oncology and Hematology Associates of Southwest Virginia
state: Virginia
city: Seattle
country: United States
facility: University of Washington Seattle Cancer Care Alliance (SCCA)
state: Washington
city: Tacoma
country: United States
facility: Northwest Medical Specialities
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Carbone Cancer Center
state: Wisconsin
city: Milwaukee
country: United States
facility: Froedtert Hospital and the Medical College of Wisconsin (MCW)
state: Wisconsin
Study officials:
affiliation: Calithera Biosciences, Inc
name: Emil Kuriakose, MD
role: STUDY_DIRECTOR
References: