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

Non-Small Cell Lung Cancer Clinical Trial

— KEAPSAKE  

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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04265534
• Other study ID #: CX-839-014
• Status: Terminated
• Phase: Phase 2
• Start date: July 24, 2020
• Est. completion date: February 9, 2022

Study information

• Verified date: September 2022
• Source: Calithera Biosciences, Inc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 40
• Est. completion date: February 9, 2022
• Est. primary completion date: November 5, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• KEAP1 Gene Mutation
• Lung Neoplasms
• NFE2L2 Gene Mutation
• Non-Small Cell Lung Cancer
• Non-Squamous Non-Small Cell Neoplasm of Lung
• Non-squamous Non-small-cell Lung Cancer
• NRF2 Gene Mutation

Intervention

Drug:
• Telaglenastat
Oral Glutaminase Inhibitor
• Carboplatin Chemotherapy
IV infusion
• Pemetrexed Chemotherapy
IV infusion

Biological:
• Pembrolizumab Immunotherapy
IV infusion

Drug:
• Placebo
Oral placebo

Dietary Supplement:
• Folic acid 400 -1000 µg
Orally, once daily beginning 7 days prior to the first dose of pemetrexed and continue until 21 days after the last dose of pemetrexed.
• Vitamin B12 1000 µg
Vitamin B12 1000 µg Intramuscular injection one week prior to the first dose of pemetrexed and once every 3 cycles (9 weeks) thereafter. Subsequent vitamin B12 injections may be given the same day as pemetrexed administration.

Drug:
• Dexamethasone 4 mg
For prophylaxis, orally twice per day (or equivalent). Taken the day before, day of, and day after pemetrexed administration.

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Calithera Biosciences, Inc

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-Free Survival (PFS), Assessed by Investigator per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1	Duration of investigator-determined PFS per RECIST v1.1 in the intent-to-treat (ITT) population	Up to 24 months
Primary	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
Primary	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	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	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.	Up to 24 months
Secondary	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	DOR is defined as the duration of response for patients achieving a CR or PR	Up to 24 months
Secondary	Overall Survival		Up to 55 months
Secondary	PFS in the Subgroup of Patients with Biochemical Evidence of Activation of the NRF2 Pathway		Up to 24 months
Secondary	ORR in the Subgroup of Patients with Biochemical Evidence of Activation of the NRF2 Pathway		Up to 24 months
Secondary	DOR in the Subgroup of Patients with Biochemical Evidence of Activation of the NRF2 Pathway		Up to 24 months
Secondary	OS in the Subgroup of Patients with Biochemical Evidence of Activation of the NRF2 Pathway		Up to 55 months