Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Uterine Cervical Neoplasms

Carcinoma

Uterine Neoplasms

Genital Neoplasms, Female

Urogenital Neoplasms

Uterine Cervical Diseases

Uterine Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Antineoplastic Agents

All Drugs and Chemicals

Cisplatin

-Participants will receive 7 weeks of standard of care chemoradiation.

-Participants will receive 2 weeks of telaglenastat and 7 weeks of standard of care chemoradiation plus telaglenastat.

Telaglenastat

* Standard of care
* External beam radiation therapy delivered daily 4 days a week and 1 day per week of brachytherapy.

Radiation treatment

* Standard of care
* Weekly administration of cisplain

Julie K Schwarz, M.D., Ph.D.

Stephanie Markovina, M.D., Ph.D.

Andrea Hagemann, M.D., MSCI

Dineo Khabele, M.D.

Lindsay Kuroki, M.D.

L. Stewart Massad, M.D.

Carolyn McCourt, M.D.

Maggie Mullen, M.S.

David Mutch, M.D.

Matthew Powell, M.D.

Premal Thaker, M.D.

David DeNardo, Ph.D.

Gary Patti, Ph.D.

Li Ding, Ph.D.

Esther Lu, Ph.D.

Advanced cervical cancer patients treated with standard of care (SOC) chemoradiation plus glutaminase inhibition with telaglenastat (CB-839) will have increased progression-free survival (PFS) compared to historical rates for patients receiving SOC chemoradiation alone.

Randomization will occur on a 5:1 basis to experimental arm and control arm. The first 5 participants randomized to the experimental arm will be considered the safety lead-in.

Glutaminase Inhibition and Chemoradiation in Advanced Cervical Cancer

Phase II Study of Glutaminase Inhibition and Chemoradiation in Advanced Cervical Cancer

* PFS is defined as the duration of time from start of telaglenastat to time of progression or death, whichever occurs first.
* Progressive disease: New foci of abnormal FDG uptake not present on the pretreatment FDG-PET study

* Toxicity evaluation will report events according to Common Terminology Criteria for Adverse Events v5.0 (CTCAE)
* Acute toxicity is defined as any toxicity occurring within 90 days from first receiving study radiotherapy or death, whatever event is observed first.

* Toxicity evaluation will report events according to Common Terminology Criteria for Adverse Events v5.0 (CTCAE)
* Late toxicities include any toxicity that is determined possibly, probably, or definitely related to treatment, within 24 months after completion of treatment.

-OS is defined as the days from the start of Telaglenastat treatment to the date of death, censored at the last follow-up otherwise.

National Cancer Institute (NCI)

Calithera Biosciences, Inc

Washington University School of Medicine

Respiratory Tract (Lung and Bronchial) Diseases

Skin and Connective Tissue Diseases

Rare Diseases

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Melanoma

Carcinoma, Renal Cell

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Adenocarcinoma

Kidney Neoplasms

Urologic Neoplasms

Kidney Diseases

Urologic Diseases

Male Urogenital Diseases

Renal Cell Carcinoma

Clear Cell Renal Cell Carcinoma

Neuroendocrine Tumor

Neuroepithelioma

Amino Acids

Nivolumab

Mitogens

Tyrosine Kinase Inhibitors

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Tyrosine

Telaglenastat 600 mg in combination with standard dose nivolumab in participants with advanced/metastatic clear cell renal cell carcinoma (ccRCC), melanoma, and non-small cell lung cancer (NSCLC).

Telaglenastat 800 mg/standard dose nivolumab combination in participants with advanced/metastatic ccRCC who have previously received at least one tyrosine kinase inhibitor (TKI) but are treatment naïve to checkpoint modulators programmed death-1/programmed death ligand-1 (PD-1/PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), or any other agent that specifically targets a T-cell checkpoint or co-stimulation pathway.

Telaglenastat 800 mg/standard dose nivolumab combination in participants with advanced/metastatic ccRCC who received nivolumab in most recent treatment line that had documented radiological disease progression OR are currently receiving nivolumab with stable disease for at least 24 weeks.

Telaglenastat 800 mg/standard dose nivolumab combination in participants with advanced/metastatic ccRCC that had documented radiological disease progression while receiving an anti-PD-1/PD-L1 therapy in any prior line of therapy.

Telaglenastat 800 mg/standard dose nivolumab combination in participants with unresectable or metastatic melanoma that had documented radiological disease progression while receiving an anti-PD-1 therapy in their most recent line of therapy.

Telaglenastat 800 mg/standard dose nivolumab combination in participants with NSCLC that does not harbor an activating mutation in the epidermal growth factor receptor (EGFR) oncogene and who received nivolumab in most recent treatment line and had documented radiological disease progression OR are currently receiving nivolumab with Stable Disease for at least 24 weeks.

CB-839

Sam Whiting, MD, PhD

This study is an open-label Phase 1/2 evaluation of CB-839 in combination with nivolumab in participants with clear cell renal cell carcinoma, melanoma, and non-small cell lung cancer.

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

A Phase 1/2 Study of the Safety, Pharmacokinetics, and Pharmacodynamics of the Glutaminase Inhibitor CB-839 in Combination With Nivolumab in Patients With Advanced/Metastatic Melanoma, Renal Cell Carcinoma and Non-Small Cell Lung Cancer

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.

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.

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.

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.

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 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.

Per protocol, serious adverse events exclude those of Grade 5 disease progression.

Telaglenastat 600 mg in combination with standard dose nivolumab in participants with advanced/metastatic ccRCC, melanoma, and NSCLC.

Telaglenastat 600 mg + Standard Dose Nivolumab

Telaglenastat 800 mg/standard dose nivolumab combination in participants with advanced/metastatic ccRCC who have previously received at least one TKI but are treatment naïve to checkpoint modulators PD-1/PD-L1, CTLA-4, or any other agent that specifically targets a T-cell checkpoint or co-stimulation pathway.

Telaglenastat 800 mg + Standard Dose Nivolumab: ccRCC Naïve to Checkpoint Inhibitors

Telaglenastat 800 mg + Standard Dose Nivolumab: ccRCC Recently Treated With Nivolumab

Telaglenastat 800 mg + Standard Dose Nivolumab: ccRCC With Prior PD-1 Therapy

Telaglenastat 800 mg + Standard Dose Nivolumab: Melanoma With Prior PD-1 Therapy

Telaglenastat 800 mg/standard dose nivolumab combination in participants with NSCLC that does not harbor an activating mutation in the EGFR oncogene and who received nivolumab in most recent treatment line and had documented radiological disease progression OR are currently receiving nivolumab with Stable Disease for at least 24 weeks.

Telaglenastat 800 mg + Standard Dose Nivolumab: NSCLC With Prior PD-1 Therapy

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Study Director

≥ 1 TEAE

≥ 1 TEAE ≥ grade 3

≥ 1 TEAE related to nivolumab

≥ 1 TEAE related to telaglenastat

≥ 1 TEAE ≥ grade 3 related to nivolumab

≥ 1 TEAE ≥ grade 3 related to telaglenastat

≥ 1 grade 5 TEAE related to nivolumab

≥ 1 grade 5 TEAE related to telaglenastat

≥ 1 TEAE leading to discontinuation (DC) of nivolumab

≥ 1 TEAE leading to DC of telaglenastat

≥ 1 TEAE leading to DC of nivolumab and telaglenastat

≥ 1 TEAE leading to DC of nivolumab or telaglenastat

≥ 1 TEAE requiring nivolumab dose interruption or reduction

≥ 1 TEAE requiring telaglenastat dose interruption or reduction

≥ 1 TEAE requiring nivolumab and telaglenastat dose interruption or reduction

≥ 1 TEAE requiring nivolumab or telaglenastat dose interruption or reduction

≥ 1 grade 5 TEAE

≥ 1 serious TEAE

≥ 1 serious TEAE ≥ grade 3

≥ 1 serious TEAE related to nivolumab

≥ 1 serious TEAE related to telaglenastat

≥ 1 serious TEAE ≥ grade 3 related to nivolumab

≥ 1 serious TEAE ≥ grade 3 related to telaglenastat

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)

Hematology Values

Clinical Laboratory Values

Vital Sign Values

Weight

Number of Participants With Clinically Significant Treatment-Emergent Values in Hematology, Serum Chemistry Panel, Vital Signs or Weight

Overall Response Rate (ORR) Per Investigator Assessed Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

Duration of Response (DOR) Per Investigator Assessed RECIST v1.1

Participants with an event (PD per RECIST v1.1 or death from any cause).

Progression-Free Survival (PFS) Per RECIST v1.1

Overall Survival

Overall Study

Breast Neoplasms

Triple Negative Breast Neoplasms

Breast Diseases

Gastrointestinal Agents

Anti-Arrhythmia Agents

Vasodilator Agents

Analgesics

Irinotecan

Bevacizumab

Fluorouracil

Estrogens

Oxaliplatin

Endothelial Growth Factors

Pancrelipase

Progesterone

Adenosine

Talazoparib

Poly(ADP-ribose) Polymerase Inhibitors

Pancreatin

Enzyme Inhibitors

600 mg CB-839 taken twice daily and 1 mg talazoparib taken once daily in participants with advanced or metastatic solid tumors.

800 mg CB-839 taken twice daily and 1 mg talazoparib taken once daily in participants with incurable/locally advanced or metastatic clear cell renal cell carcinoma (ccRCC) who received ≥ 2 prior systemic regimens including ≥ 1 vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR TKI) therapy.

800 mg CB-839 taken twice daily and 1 mg talazoparib taken once daily in participants with incurable/locally advanced or metastatic triple-negative breast cancer (TNBC) estrogen receptor (ER)-, progesterone receptor (PR)-, and human epidermal growth factor receptor 2 (HER2)-negative who received ≥ 1 prior line of cytotoxic chemotherapy with no prior poly adenosine diphosphate ribose polymerase (PARP) inhibitor therapy for TNBC or platinum-based chemotherapy for metastatic TNBC.

800 mg CB-839 taken twice daily and 1 mg talazoparib taken once daily in participants with with incurable/locally advanced or metastatic colorectal cancer (CRC) who received appropriate oxaliplatin or irinotecan- and fluorouracil (5-FU)-based chemotherapy with or without bevacizumab.

800 mg CB-839 taken twice daily and 1 mg talazoparib taken once daily in participants with other tumor types (prostate, urinary bladder, pancreas, and stomach).

CB-839 oral tablets administered twice daily with food at the assigned dose level on 28 day cycles with talazoparib.

Talazoparib oral tablets administered at the standard dose once daily with or without food on 28 day cycles with CB-839.

This is a Phase 1b/2 study to determine the recommended phase 2 dose (RP2D), safety and tolerability, pharmacokinetics (PK) and clinical activity of the glutaminase inhibitor CB-839 with the poly adenosine diphosphate ribose polymerase (PARP) inhibitor talazoparib in participants with advanced/metastatic solid tumors.

Study of CB-839 (Telaglenastat) in Combination With Talazoparib in Patients With Solid Tumors

A Phase 1b/2 Open Label, Dose Escalation and Expansion Study of the Glutaminase Inhibitor CB-839 in Combination With the PARP Inhibitor Talazoparib in Patients With Advanced or Metastatic Solid Tumors

AEs were grades as assessed by CTCAE v 5.0. A TEAE is defined as any AE occurring on or after the first dose of study drug, or existing events that worsened after the first dose during the study, up to 28 days after the last dose.

An AE is considered "related" if the investigator assessed the relationship as "possibly related" or "probably related." Disease progression includes events in the preferred terms of disease progression and malignant neoplasm progression. Grade 5 disease progression events are excluded from this table.

Hematology parameters conducted included red blood cell (RBC) count, hematocrit, hemoglobin, mean corpuscular volume (MCV), platelet count, white blood cell (WBC) count, neutrophils, lymphocytes, monocytes, eosinophils, and basophils, performed at the discretion of the investigator. Clinical chemistry parameters included aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin, direct bilirubin, albumin, total protein, blood urea nitrogen (BUN), creatinine, sodium, potassium, chloride, calcium, carbon dioxide, glucose, and lactate dehydrogenase (LDH), performed at the discretion of the investigator.

A DLT was defined as an AE determined by the investigator to be possibly or probably related to study drug that also was:

* Any ≥ Grade (Gr) 4 non-hematological toxicity
* Gr 3 non-hematologic toxicity, except: fatigue; nausea/vomiting that responds within 24 hours after initiating maximal supportive care; rash or itching that resolves to ≤ Gr 1 within 2 weeks.
* Any clinically meaningful Gr 3 non-hematologic laboratory value if medical intervention is required OR the abnormality leads to hospitalization, OR the abnormality persists for \> 1 week (except Gr 3/4 elevation in serum amylase and/or lipase not associated with clinical or radiological evidence of pancreatitis).
* Gr ≥ 3 febrile neutropenia
* Gr ≥ 4 anemia; neutropenia lasting \> 7 days; thrombocytopenia
* Gr 3 thrombocytopenia associated with: a bleeding event that requires a platelet transfusion OR a life-threatening bleeding event occurring due to low platelet count which results in urgent intervention.

ORR was defined by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 as the percentage of participants with documented complete response (CR) or partial response (PR) since the date of treatment initiation. 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. Stable disease must have been a minimum of 51 days from date of treatment initiation. Exact binomial confidence intervals (Clopper Pearson).

Overall Response Rate is defined by RECIST v1.1 as the percentage of participants with documented confirmed CR or confirmed PR since the date of treatment initiation. 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. CR or PR must have been sustained a minimum of 28 days when confirmation was reported. Stable disease must have been a minimum of 51 days from date of treatment initiation. Exact binomial confidence intervals (Clopper Pearson).

Clinical Benefit Rate is defined by RECIST v1.1 as the percentage of participants with documented CR, PR, or stable disease (SD) since the date of treatment initiation. 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. CR or PR must have been sustained a minimum of 28 days when confirmation was reported. SD=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study. SD must have been a minimum of 102 days from date of treatment initiation and documented on at least 2 consecutive post-baseline scans. Exact binomial confidence intervals (Clopper Pearson).

PFS was defined as the time from treatment initiation to the date of documented disease progression (PD) within 2 consecutive scheduled radiographic disease assessments or death for any cause, whichever occurs first. PD: ≥ 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition, the sum must also demonstrate an absolute increase of ≥ 5 mm. (The appearance of one or more new lesions is also considered progression). Participants with no documentation of PD or death on-study, PD or death occurs after missing 2 consecutive scheduled radiographic disease assessments, or new anti-cancer therapy were censored at the date of last available tumor assessment. Participants missing baseline disease assessments were censored at the date of first dose. Kaplan-Meier product-limit estimates. Brookmeyer-Crowley methodology for a non-parametric 95% CI was used.

Per protocol, the serious and nonserious adverse event tables exclude grade 5 disease progression events.

600 mg CB-839 + 1 mg Talazoparib

800 mg CB-839 taken twice daily and 1 mg talazoparib taken once daily in participants with incurable/locally advanced or metastatic ccRCC who received ≥ 2 prior systemic regimens including ≥ 1 VEGFR TKI therapy.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Glutaminase Inhibition and Chemoradiation in Advanced Cervical Cancer	NCT05521997	Advanced Cervic... Cervical Cancer Cervix Cancer Cancer of the C...	Telaglenastat Radiation treat... Cisplatin	18 Years -	Washington University School of Medicine
Study CB-839 in Combination With Nivolumab in Patients With Melanoma, Clear Cell Renal Cell Carcinoma (ccRCC) and Non-Small Cell Lung Cancer (NSCLC)	NCT02771626	Clear Cell Rena... Melanoma Non-small Cell ...	CB-839 Nivolumab	18 Years -	Calithera Biosciences, Inc
Study of CB-839 (Telaglenastat) in Combination With Talazoparib in Patients With Solid Tumors	NCT03875313	Solid Tumor Clear Cell Rena... TNBC - Triple-N... Colorectal Canc... CRC RCC ccRCC	CB-839 Talazoparib	18 Years -	Calithera Biosciences, Inc
Study CB-839 in Combination With Nivolumab in Patients With Melanoma, Clear Cell Renal Cell Carcinoma (ccRCC) and Non-Small Cell Lung Cancer (NSCLC)	NCT02771626	Clear Cell Rena... Melanoma Non-small Cell ...	CB-839 Nivolumab	18 Years -	Calithera Biosciences, Inc
Study of CB-839 in Combination w/ Paclitaxel in Participants of African Ancestry and Non-African Ancestry With Advanced Triple Negative Breast Cancer (TNBC)	NCT03057600	Triple Negative... TNBC - Triple-N...	Paclitaxel CB-839	18 Years -	Calithera Biosciences, Inc
Study of CB-839 (Telaglenastat) in Combination With Talazoparib in Patients With Solid Tumors	NCT03875313	Solid Tumor Clear Cell Rena... TNBC - Triple-N... Colorectal Canc... CRC RCC ccRCC	CB-839 Talazoparib	18 Years -	Calithera Biosciences, Inc
CB-839 With Everolimus vs. Placebo With Everolimus in Participants With Renal Cell Carcinoma (RCC)	NCT03163667	Clear Cell Rena...	Placebo CB-839 everolimus	18 Years -	Calithera Biosciences, Inc
CB-839 With Everolimus vs. Placebo With Everolimus in Participants With Renal Cell Carcinoma (RCC)	NCT03163667	Clear Cell Rena...	Placebo CB-839 everolimus	18 Years -	Calithera Biosciences, Inc

Spots Global Cancer Trial Database for glutaminase inhibitor