KEAPSAKE: A Study of Telaglenastat (CB-839) With Standard-of-Care Chemoimmunotherapy in 1L KEAP1/NRF2-Mutated, Nonsquamous NSCLC (KEAPSAKE)
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| ClinicalTrials.gov Identifier: NCT04265534 |
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Recruitment Status :
Recruiting
First Posted : February 11, 2020
Last Update Posted : January 7, 2021
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Sponsor:
Calithera Biosciences, Inc
Information provided by (Responsible Party):
Calithera Biosciences, Inc
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| 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 | Drug: Telaglenastat 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 | Phase 2 |
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 120 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
| Masking Description: | Randomized, placebo controlled |
| Primary Purpose: | Treatment |
| 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) |
| Actual Study Start Date : | July 24, 2020 |
| Estimated Primary Completion Date : | July 2022 |
| Estimated Study Completion Date : | October 2024 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Lung cancer
Drug Information available for:
Pembrolizumab
| Arm | Intervention/treatment |
|---|---|
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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.
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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 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. |
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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.
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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. |
Primary Outcome Measures :
- 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 ]
Secondary Outcome Measures :
- 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 ]
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- Histologically or cytologically documented nonsquamous NSCLC
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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.
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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:
- 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)
- Are at least 7 days post SRS and 4 weeks post-surgical resection of CNS disease, symptomatically stable and off steroids before randomization
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04265534
Contacts
| Contact: Clinical Administrator | 650-870-1000 | clinicaltrials@calithera.com | |
| Contact: Clinical Admin | clinicaltrials@calithera.com |
Locations
Show 69 study locations
Sponsors and Collaborators
Calithera Biosciences, Inc
Investigators
| Study Director: | Emil Kuriakose, MD | Calithera Biosciences, Inc |
| Responsible Party: | Calithera Biosciences, Inc |
| ClinicalTrials.gov Identifier: | NCT04265534 |
| Other Study ID Numbers: |
CX-839-014 |
| First Posted: | February 11, 2020 Key Record Dates |
| Last Update Posted: | January 7, 2021 |
| Last Verified: | January 2021 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Keywords provided by Calithera Biosciences, Inc:
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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 |
Additional relevant MeSH terms:
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Lung Neoplasms Carcinoma, Non-Small-Cell Lung Respiratory Tract Neoplasms Thoracic Neoplasms Neoplasms by Site Neoplasms Lung Diseases Respiratory Tract Diseases Carcinoma, Bronchogenic Bronchial Neoplasms Folic Acid Vitamin B 12 Hydroxocobalamin Dexamethasone Carboplatin |
Pembrolizumab Pemetrexed Vitamins Micronutrients Nutrients Growth Substances Physiological Effects of Drugs Anti-Inflammatory Agents Antiemetics Autonomic Agents Peripheral Nervous System Agents Gastrointestinal Agents Glucocorticoids Hormones Hormones, Hormone Substitutes, and Hormone Antagonists |