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

• ClinicalTrials.gov Identifier: NCT04265534
• Recruitment Status: Recruiting
• First Posted: February 11, 2020
• Last Update Posted: January 22, 2021
• Sponsor: Calithera Biosciences, Inc
• Information provided by (Responsible Party): Calithera Biosciences, Inc

Tracking Information

• First Submitted Date: February 7, 2020
• First Posted Date: February 11, 2020
• Last Update Posted Date: January 22, 2021
• Actual Study Start Date: July 24, 2020
• Estimated Primary Completion Date: July 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 10, 2020)

• Progression-Free Survival (PFS), Assessed by Investigator per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Up to 6 months ]

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 10, 2020)

• 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 [ Time Frame: 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.
• 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 [ Time Frame: Up to 24 months ]
  DOR is defined as the duration of response for patients achieving a CR or PR
• Overall Survival [ Time Frame: Up to 55 months ]
• PFS in the Subgroup of Patients with Biochemical Evidence of Activation of the NRF2 Pathway [ Time Frame: Up to 24 months ]
• ORR in the Subgroup of Patients with Biochemical Evidence of Activation of the NRF2 Pathway [ Time Frame: Up to 24 months ]
• DOR in the Subgroup of Patients with Biochemical Evidence of Activation of the NRF2 Pathway [ Time Frame: Up to 24 months ]
• OS in the Subgroup of Patients with Biochemical Evidence of Activation of the NRF2 Pathway [ Time Frame: Up to 55 months ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• 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 Provided
• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

Randomized, placebo controlled

Primary Purpose: Treatment

Condition

• 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

Intervention

• Drug: Telaglenastat
  Oral Glutaminase Inhibitor
  Other Name: CB-839
• Drug: Carboplatin Chemotherapy
  IV infusion
  Other Name: Paraplatin
• Drug: Pemetrexed Chemotherapy
  IV infusion
  Other Name: Alimta
• Biological: Pembrolizumab Immunotherapy
  IV infusion
  Other Name: Keytruda
• Drug: Placebo
  Oral placebo
  Other Name: 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.
• Dietary Supplement: 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.

Study Arms

• Experimental: Telaglenastat with Pembrolizumab and 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.
  Interventions:

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

  • Drug: Carboplatin Chemotherapy
  • 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

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 10, 2020): 120
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: October 2024
• Estimated Primary Completion Date: July 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Histologically or cytologically documented nonsquamous NSCLC

• Stage IV (M1a-c, AJCC 8th Edition) disease not previously treated with systemic therapy for metastatic NSCLC

  a. Patients who received adjuvant or neoadjuvant therapy (with or without immunotherapy) for localized NSCLC are eligible if all adjuvant/neoadjuvant 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.
• Measurable disease per RECIST 1.1.
• Life expectancy of at least 3 months.
• Mutation in KEAP1 or NRF2 documented by NGS from a CAP-accredited and/or CLIA-certified laboratory and STK11/LKB1 mutation status is known for the purpose of stratification.
• Adequate hepatic, renal, cardiac and hematologic function.
• Willingness to use adequate contraception as defined in the study protocol

Exclusion Criteria:

• Squamous cell histology and mixed histology tumors with any small-cell component (other mixed histology and large cell neuroendocrine histology is allowed).
• Known history of malignancy within the past three years except for adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix or other neoplasm that, in the opinion of the principal investigator and with the agreement of the medical monitor, will not interfere with study-specific endpoints.
• Had radiation therapy to the lung > 30 Gy within 6 months prior to randomization.
• Has active autoimmune disease that has required systemic treatment in past 2 years.
• Is currently receiving chronic systemic steroids and/or immunosuppressive drugs.
• Is unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), other than an aspirin dose ≤1.3 g per day, for a 5-day period (8-day period for long-acting agents, such as piroxicam).
• Unable to swallow oral medications.
• Previously had a severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb).
• Known positivity for Hepatitis B or C.
• Is unable or unwilling to take folic acid or vitamin B12 supplementation.
• Interstitial lung disease or a history of pneumonitis that required oral or intravenous glucocorticoid treatment.
• Unable or unwilling to discontinue proton pump inhibitors (PPI) at least 5 days before randomization.
• Major surgery within 3 weeks of randomization.
• Symptomatic ascites or pleural effusion.
• Any condition that may preclude adequate absorption of oral study drug.

• 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. Are at least 7 days post SRS and 4 weeks post-surgical resection of CNS disease, symptomatically stable and off steroids before randomization

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Clinical Administrator; 650-870-1000; clinicaltrials@calithera.com

Contact: Clinical Admin; clinicaltrials@calithera.com

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04265534
• Other Study ID Numbers: CX-839-014
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Calithera Biosciences, Inc
• Study Sponsor: Calithera Biosciences, Inc
• Collaborators: Not Provided

Investigators

• Study Director: Emil Kuriakose, MD; Calithera Biosciences, Inc

• PRS Account: Calithera Biosciences, Inc
• Verification Date: January 2021