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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
Recruitment Status : Recruiting
First Posted : February 11, 2020
Last Update Posted : September 2, 2021
Sponsor:
Information provided by (Responsible Party):
Calithera Biosciences, Inc

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

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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


Arm Intervention/treatment
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.
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.

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.
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 :
  1. 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

  2. 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 ]
  3. 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 :
  1. 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.

  2. 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

  3. Overall Survival [ Time Frame: Up to 55 months ]
  4. PFS in the Subgroup of Patients with Biochemical Evidence of Activation of the NRF2 Pathway [ Time Frame: Up to 24 months ]
  5. ORR in the Subgroup of Patients with Biochemical Evidence of Activation of the NRF2 Pathway [ Time Frame: Up to 24 months ]
  6. DOR in the Subgroup of Patients with Biochemical Evidence of Activation of the NRF2 Pathway [ Time Frame: Up to 24 months ]
  7. OS in the Subgroup of Patients with Biochemical Evidence of Activation of the NRF2 Pathway [ Time Frame: Up to 55 months ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:

  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

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
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Contact: Clinical Administrator 650-870-1000 info@keapsakeclinicaltrial.com
Contact: Clinical Admin info@keapsakeclinicaltrial.com

Locations
Show Show 105 study locations
Sponsors and Collaborators
Calithera Biosciences, Inc
Investigators
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Study Director: Emil Kuriakose, MD Calithera Biosciences, Inc
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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: September 2, 2021
Last Verified: July 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Calithera Biosciences, Inc:
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
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents