Study CB-839 in Combination With Nivolumab in Patients With Melanoma, Clear Cell Renal Cell Carcinoma (ccRCC) and Non-Small Cell Lung Cancer (NSCLC)

• CB-839 (Drug), also known as telaglenastat: Glutaminase inhibitor
• Nivolumab (Drug), also known as Opdivo, BMS-936558: PD-1 inhibitor

Primary outcomes

• Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Dose Interruption, Reduction, or Study Drug Discontinuation (Excluding Grade 5 Disease Progression) [From the first dose of study drug up to 28 days post last dose. Median duration of telaglenastat treatment was 92 days and that for nivolumab treatment was 84 days.]: An adverse event (AE) is any untoward, undesired, or unplanned event that does not need to be causally related to treatment. A serious adverse event (SAE) is an AE that: results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in a persistent or significant disability or incapacity, results in a congenital anomaly or birth defect, or important medical events that may not result in death, be life-threatening, or require hospitalization may be considered SAEs when, based on appropriate medical judgment, they may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Relatedness to study medication was graded as either, probably, possibly, unlikely, or unrelated. Events were categorized according to the Common Toxicity Criteria for Adverse Events (CTCAE) Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life-threatening, Grade 5=death.
• Number of Participants With Clinically Significant Treatment-Emergent Values in Hematology, Serum Chemistry Panel, Vital Signs or Weight [From the first dose of study drug up to 28 days post last dose. Median duration of telaglenastat treatment was 92 days and that for nivolumab treatment was 84 days.]: Hematology assessments included: hemoglobin; hematocrit, red blood cell count, white blood cell count with differential, and platelet count. Serum chemistry panel included: sodium, potassium, chloride, carbon dioxide, calcium, glucose, blood urea nitrogen, total protein, albumin, total bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, creatinine, thyroid stimulating hormone. Vital sign assessments included systolic and diastolic blood pressures, pulse (heart) rate, respiratory rate, temperature, and body weight.
• Overall Response Rate (ORR) Per Investigator Assessed Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 [up to a maximum of 2.8 years]: ORR is defined as the percentage of participants with complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR or PR was required to be sustained for 4 weeks when confirmation was reported. * CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. * PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
• Duration of Response (DOR) Per Investigator Assessed RECIST v1.1 [up to a maximum of 2.8 years]: DOR is defined as the time between the first documentation of a PR or a CR to the first documentation of progressive disease (PD) or death, whichever occurred first. DOR was censored at the date of last radiographic disease if the patient was alive and progression free at the time of database lock, PD, or death occurred after missing data for 2 consecutive radiographic disease assessments, or patient received non-protocol treatment prior to documentation of disease progression. * CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. * PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. * PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Secondary outcomes

• Progression-Free Survival (PFS) Per RECIST v1.1 [up to a maximum of 2.8 years]: PFS was defined as time from the first dose date to the earlier of either PD per RECIST v1.1 or death from any cause. The duration of PFS was censored at the date of last radiographic disease if the patient was alive and progression-free at the time of analysis data cutoff, disease progression, or death occurred after missing data for 2 consecutive radiographic disease assessments, or patient received non-protocol treatment prior to documentation of disease progression. \- PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
• Overall Survival [up to a maximum of 2.8 years]: Overall survival was defined as the time from the first dose date to death due to any cause. For participants alive at time of analysis, overall survival was censored at the time when the participant was last known to be alive.

Sex: All, ages: 18 Years to any

Addition eligibility criteria based on tumor type apply

Inclusion Criteria:

* Ability to provide written informed consent in accordance with federal, local, and institutional guidelines
* Histological or cytological diagnosis of metastatic cancer or locally advanced cancer that is not amenable to local therapy
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1
* Life Expectancy of at least 3 months
* Adequate hepatic, renal, cardiac, and hematologic function
* Measurable disease by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 criteria
* Resolution of treatment-related toxicities except alopecia

Exclusion Criteria:

* Unable to receive oral medications
* Unable to receive oral or intravenous (IV) hydration
* Intolerance to prior anti-PD-1/PD-L1 therapy
* Prior severe hypersensitivity reaction to another monoclonal antibody (mAb)
* Any other current or previous malignancy within 3 years except protocol allowed malignancies
* Chemotherapy, TKI therapy, radiation therapy or hormonal therapy within 2 weeks
* Immunotherapy or biological therapy, or investigational agent within 3 weeks (Note: Some cohort exceptions allow anti-PD-1 therapy)
* Active known or suspected exclusionary autoimmune disease
* Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other systemic immunosuppressive medications within 2 weeks
* History of known risks factors for bowel perforation
* Symptomatic ascites or pleural effusion
* Major surgery within 28 days before Cycle 1 Day 1
* Active infection requiring parenteral antibiotics, antivirals, or antifungals within 2 weeks prior to first dose of study drug
* Patients who have human immunodeficiency virus (HIV), Hepatitis B or C
* Conditions that could interfere with treatment or protocol-related procedures
* Active and/or untreated central nervous system (CNS) disease or non-stable brain metastases

Participant flow

Outcome results

• Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Dose Interruption, Reduction, or Study Drug Discontinuation (Excluding Grade 5 Disease Progression) (Primary), Count of participants, Participants: Telaglenastat 600 mg + Standard Dose Nivolumab 8; Telaglenastat 800 mg + Standard Dose Nivolumab: ccRCC Naïve to Checkpoint Inhibitors 26; Telaglenastat 800 mg + Standard Dose Nivolumab: ccRCC Recently Treated With Nivolumab 17; Telaglenastat 800 mg + Standard Dose Nivolumab: ccRCC With Prior PD-1 Therapy 9; Telaglenastat 800 mg + Standard Dose Nivolumab: Melanoma With Prior PD-1 Therapy 36; Telaglenastat 800 mg + Standard Dose Nivolumab: NSCLC With Prior PD-1 Therapy 21
• Number of Participants With Clinically Significant Treatment-Emergent Values in Hematology, Serum Chemistry Panel, Vital Signs or Weight (Primary), Count of participants, Participants: Telaglenastat 600 mg + Standard Dose Nivolumab 0; Telaglenastat 800 mg + Standard Dose Nivolumab: ccRCC Naïve to Checkpoint Inhibitors 3; Telaglenastat 800 mg + Standard Dose Nivolumab: ccRCC Recently Treated With Nivolumab 1; Telaglenastat 800 mg + Standard Dose Nivolumab: ccRCC With Prior PD-1 Therapy 0; Telaglenastat 800 mg + Standard Dose Nivolumab: Melanoma With Prior PD-1 Therapy 1; Telaglenastat 800 mg + Standard Dose Nivolumab: NSCLC With Prior PD-1 Therapy 1
• Overall Response Rate (ORR) Per Investigator Assessed Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (Primary), Number, percentage of participants: Telaglenastat 600 mg + Standard Dose Nivolumab 0 (0.0 to 36.9); Telaglenastat 800 mg + Standard Dose Nivolumab: ccRCC Naïve to Checkpoint Inhibitors 24.0 (9.4 to 45.1); Telaglenastat 800 mg + Standard Dose Nivolumab: ccRCC Recently Treated With Nivolumab 5.9 (0.1 to 28.7); Telaglenastat 800 mg + Standard Dose Nivolumab: ccRCC With Prior PD-1 Therapy 0 (0 to 33.6); Telaglenastat 800 mg + Standard Dose Nivolumab: Melanoma With Prior PD-1 Therapy 5.4 (0.7 to 18.2); Telaglenastat 800 mg + Standard Dose Nivolumab: NSCLC With Prior PD-1 Therapy 0.0 (0.0 to 17.6)
• Duration of Response (DOR) Per Investigator Assessed RECIST v1.1 (Primary), Median, months: Telaglenastat 600 mg + Standard Dose Nivolumab ; Telaglenastat 800 mg + Standard Dose Nivolumab: ccRCC Naïve to Checkpoint Inhibitors 13.01 (11.01 to NA); Telaglenastat 800 mg + Standard Dose Nivolumab: ccRCC Recently Treated With Nivolumab 3.71 (NA to NA); Telaglenastat 800 mg + Standard Dose Nivolumab: ccRCC With Prior PD-1 Therapy ; Telaglenastat 800 mg + Standard Dose Nivolumab: Melanoma With Prior PD-1 Therapy 9.59 (4.53 to 14.65); Telaglenastat 800 mg + Standard Dose Nivolumab: NSCLC With Prior PD-1 Therapy
• Progression-Free Survival (PFS) Per RECIST v1.1 (Secondary), Median, months: Telaglenastat 600 mg + Standard Dose Nivolumab 3.42 (1.74 to 9.33); Telaglenastat 800 mg + Standard Dose Nivolumab: ccRCC Naïve to Checkpoint Inhibitors 3.72 (1.84 to 12.85); Telaglenastat 800 mg + Standard Dose Nivolumab: ccRCC Recently Treated With Nivolumab 3.71 (1.87 to 5.52); Telaglenastat 800 mg + Standard Dose Nivolumab: ccRCC With Prior PD-1 Therapy 1.87 (1.81 to 5.52); Telaglenastat 800 mg + Standard Dose Nivolumab: Melanoma With Prior PD-1 Therapy 2.07 (1.87 to 3.75); Telaglenastat 800 mg + Standard Dose Nivolumab: NSCLC With Prior PD-1 Therapy 2.20 (1.74 to 5.59)
• Overall Survival (Secondary), Median, months: Telaglenastat 600 mg + Standard Dose Nivolumab NA (8.25 to NA); Telaglenastat 800 mg + Standard Dose Nivolumab: ccRCC Naïve to Checkpoint Inhibitors 24.54 (16.30 to NA); Telaglenastat 800 mg + Standard Dose Nivolumab: ccRCC Recently Treated With Nivolumab 22.57 (14.62 to NA); Telaglenastat 800 mg + Standard Dose Nivolumab: ccRCC With Prior PD-1 Therapy NA (26.25 to NA); Telaglenastat 800 mg + Standard Dose Nivolumab: Melanoma With Prior PD-1 Therapy 10.91 (8.87 to 18.14); Telaglenastat 800 mg + Standard Dose Nivolumab: NSCLC With Prior PD-1 Therapy 8.61 (4.11 to 19.71)

Adverse events

Time frame: All Cause Mortality: up to a maximum of 2.8 years. Adverse Events: from the first dose of study drug up to 28 days post last dose. Median duration of telaglenastat treatment was 92 days and that for nivolumab treatment was 84 days.

Serious adverse events by term

Other adverse events by term

• Results publication: Aden D, Sureka N, Zaheer S, Chaurasia JK, Zaheer S. Metabolic Reprogramming in Cancer: Implications for Immunosuppressive Microenvironment. Immunology. 2025 Jan;174(1):30-72. doi: 10.1111/imm.13871. Epub 2024 Oct 27. PMID 39462179

• Study Protocol (PDF, 2017-11-14)
• Statistical Analysis Plan (PDF, 2020-07-08)

• Sam Whiting, MD, PhD, Study director, Calithera Biosciences, Inc