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Pembrolizumab

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Dexamethasone acetate

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Hydroxocobalamin

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Glutamine

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 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

Carboplatin Chemotherapy

Pemetrexed Chemotherapy

Pembrolizumab Immunotherapy

Placebo

Orally, once daily beginning 7 days prior to the first dose of pemetrexed and continue until 21 days after the last dose of pemetrexed.

Folic acid 400 -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.

Vitamin B12 1000 μg

For prophylaxis, orally twice per day (or equivalent). Taken the day before, day of, and day after pemetrexed administration.

Dexamethasone 4 mg

Emil Kuriakose, MD

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.

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

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)

Duration of investigator-determined PFS per RECIST v1.1 in the intent-to-treat (ITT) population

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.

DOR is defined as the duration of response for patients achieving a CR or PR

Calithera Biosciences, Inc

sapanisertib

Bradley J Sumrow, MD

This is a multicenter, randomized, open-label Phase 2 study of sapanisertib in biomarker-defined populations of sqNSCLC. Patients with NFE2L2 (the name for gene encoding the protein called NRF2)-mutated or wild-type sqNSCLC should have disease that has progressed on or after at least two prior systemic therapies for metastatic disease including platinum-doublet chemotherapy and a programmed cell death 1 ligand 1 (PD-L1) inhibitor. The study will evaluate sapanisertib monotherapy in patients with relapsed/refractory sqNSCLC as two separate groups: Group A: NFE2L2-mutated sqNSCLC and Group B: NFE2L2-WT sqNSCLC.

NFE2L2 mutation status for all patients will be identified using local or central next generation sequencing (NGS) testing on archival or fresh tissue or circulating tumor deoxyribonucleic acid (ctDNA), the results of which must be reviewed and approved by the Sponsor prior to enrollment. Each group will be randomized 1:1 to one of two doses/schedules of sapanisertib. Approximately 30 NFE2L2-mutant and 20 NFE2L2-wild type patients will be enrolled. Patients will be treated with sapanisertib until disease progression per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), unacceptable toxicity, withdrawal of consent, or death.

2 dosing schedules: 3 mg once per day (3 mg total) OR 2 mg twice per day (4 mg total)

Group A: 30 participants randomized 1:1 to one of two dosing schedules

Group B: approximately 20 participants randomized 1:1 to one of two dosing schedules

A Study of Sapanisertib in Relapsed/Refractory NFE2L2-Mutated and Wild-Type Squamous Non-Small Cell Lung Cancer

A Randomized, Open-Label Phase 2 Study of the TORC 1/2 Inhibitor Sapanisertib in Relapsed/Refractory NFE2L2 (NRF2)-Mutated and Wild-Type (WT) Squamous Non-Small Cell Lung Cancer (sqNSCLC)

We do not plan to share the individual participant data with other researchers

ORR is defined as the percentage of participants with complete response (CR) or partial response (PR) according to the RECIST v1.1 criteria as assessed by the investigator.

An adverse event (AE) is any untoward, undesired, or unplanned medical occurrence in a patient administered a medicinal product whether or not considered drug related. A serious adverse event (SAE) is an AE that occurs after receiving study treatment (or after signing informed consent and before receiving study treatment if due to a protocol-mandated procedure) that either results in death, is life-threatening, requires inpatient hospitalization, results in persistent or significant disability, results in congenital anomaly or birth defect, or otherwise meets criteria as an important medical event.

DOR will be calculated as the time between the first documentation of partial response (PR) or a complete response (CR) to the first documentation of progressive disease or death, whichever occurs first.

PFS is defined as the time from randomization to the first occurrence of disease progression as determined by the investigator using RECIST v1.1 or death from any cause, whichever occurs first.

OS is defined as the time from randomization to death due to any cause.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
KEAPSAKE: A Study of Telaglenastat (CB-839) With Standard-of-Care Chemoimmunotherapy in 1L KEAP1/NRF2-Mutated, Nonsquamous NSCLC	NCT04265534	Non-Small Cell ... Non-squamous No... Non-Squamous No... KEAP1 Gene Muta... NRF2 Gene Mutat... NFE2L2 Gene Mut...	Telaglenastat Carboplatin Che... Pemetrexed Chem... Pembrolizumab I... Placebo Folic acid 400 ... Vitamin B12 100... Dexamethasone 4...	18 Years -	Calithera Biosciences, Inc
KEAPSAKE: A Study of Telaglenastat (CB-839) With Standard-of-Care Chemoimmunotherapy in 1L KEAP1/NRF2-Mutated, Nonsquamous NSCLC	NCT04265534	Non-Small Cell ... Non-squamous No... Non-Squamous No... KEAP1 Gene Muta... NRF2 Gene Mutat... NFE2L2 Gene Mut...	Telaglenastat Carboplatin Che... Pemetrexed Chem... Pembrolizumab I... Placebo Folic acid 400 ... Vitamin B12 100... Dexamethasone 4...	18 Years -	Calithera Biosciences, Inc
A Study of Sapanisertib in Relapsed/Refractory NFE2L2-Mutated and Wild-Type Squamous Non-Small Cell Lung Cancer	NCT05275673	Non-Small Cell ... Squamous Non-sm... Squamous Non-Sm... NFE2L2 Gene Mut...	sapanisertib	18 Years -	Calithera Biosciences, Inc

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