Clinical Trials /

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

NCT04265534

Description:

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.

Related Conditions:
  • Non-Squamous Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • 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)

Clinical Trial IDs

  • ORG STUDY ID: CX-839-014
  • NCT ID: NCT04265534

Conditions

  • 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

Interventions

DrugSynonymsArms
TelaglenastatCB-839Telaglenastat with Pembrolizumab and Chemotherapy
Carboplatin ChemotherapyParaplatinPlacebo with Pembrolizumab and Chemotherapy
Pemetrexed ChemotherapyAlimtaPlacebo with Pembrolizumab and Chemotherapy
Pembrolizumab ImmunotherapyKeytrudaPlacebo with Pembrolizumab and Chemotherapy
PlaceboOral placeboPlacebo with Pembrolizumab and Chemotherapy
Dexamethasone 4 mgPlacebo with Pembrolizumab and Chemotherapy

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Telaglenastat with Pembrolizumab and ChemotherapyExperimentalThe 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.
  • Telaglenastat
  • Carboplatin Chemotherapy
  • Pemetrexed Chemotherapy
  • Pembrolizumab Immunotherapy
  • Dexamethasone 4 mg
Placebo with Pembrolizumab and ChemotherapyPlacebo ComparatorPlacebo 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.
  • Carboplatin Chemotherapy
  • Pemetrexed Chemotherapy
  • Pembrolizumab Immunotherapy
  • Placebo
  • Dexamethasone 4 mg

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-Free Survival (PFS), Assessed by Investigator per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
Time Frame:Up to 24 months
Safety Issue:
Description:Duration of investigator-determined PFS per RECIST v1.1 in the intent-to-treat (ITT) population

Secondary Outcome Measures

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

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Calithera Biosciences, Inc

Trial Keywords

  • 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

Last Updated

August 9, 2021