Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Antineoplastic Agents

All Drugs and Chemicals

Talazoparib

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

During 28 day study cycles, participants will receive:

* Telaglenastat 2x daily at a predetermined dose
* Talazoparib 1x daily at a predetermined dose

If a beneficial response is seen with the Arm 1 Telaglenastat + Talazoparib combination, participants will receive telaglenastat alone 2x daily at a predetermined dose with the addition of talazoparib at 1x daily at a predetermined dose if the disease gets worse.

Telaglenastat

Richard J Lee, MD, PhD

The purpose of this research is to test the effectiveness of an experimental drug combination for people with metastatic castration-resistant prostate cancer (mCRPC).

The names of the study drugs involved in this study are:

* Telaglenastat (CB-839)
* Talazoparib

This research study is a Phase II clinical trial, researching the effectiveness of the combination of telaglenastat and talazoparib in participants with metastatic castration-resistant prostate cancer (mCRPC).

The U.S. Food and Drug Administration (FDA) has not approved telaglenastat or the combination of telaglenastat and talazoparib as a treatment for any disease.

The FDA has not approved talazoparib for metastatic castration-resistant prostate cancer (mCRPC) but it has been approved for other uses.

Telaglenastat is a drug designed to stop cancer growth by blocking glutaminase activity. Glutaminase is an enzyme in the body that is overproduced by some cancers and can fuel cancer growth. Telaglenastat can lower or block glutaminase and may slow the growth or spread of some cancers.

Talazoparib is a drug that interferes with the repair activity of proteins called poly adenosine diphosphate ribose polymerases (PARP), which are found in normal and cancer cells and are involved in the repair of DNA - the genetic material found in every cell. This interference may lead to increased amounts of DNA defects and cancer cell death which may help to slow the growth of cancer cells.

The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits.

There are different points in this study in which participation will start. The first group of participants will receive the combination of telaglenastat and talazoparib for the entirety of the study. If telaglenastat plus talazoparib is beneficial to the first group this will lead to the enrollment of the next group, since telaglenastat as a single drug has not been evaluated in prostate cancer. The next group will receive telaglenastat alone with the addition of talazoparib if the disease gets worse.

It is expected that about 30 people will take part in this research study.

Telaglenastat + Talazoparib In Prostate Cancer

A Phase II Study of the Glutaminase Inhibitor Telaglenastat (CB-839) in Combination With the PARP Inhibitor Talazoparib in Participants With Metastatic Castration-Resistant Prostate Cancer

The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: \[contact information for Sponsor Investigator or designee\]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.

The number and proportion of adverse events, graded as defined by CTCAE version 5.0 will be tabulated by type and grade. This analysis will be performed overall and separately for Cohort 1 and 2. Within a given patient, a given adverse event will be counted only once at the highest grade.

Calithera Biosciences, Inc

Pfizer

Prostate Cancer Foundation

Massachusetts General Hospital

Principal Investigator

Uterine Cervical Neoplasms

Carcinoma

Uterine Neoplasms

Genital Neoplasms, Female

Uterine Cervical Diseases

Uterine Diseases

Genital Diseases, Female

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

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.

* 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)

Washington University School of Medicine

Respiratory Tract (Lung and Bronchial) Diseases

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Micronutrients

Anti-Inflammatory Agents

Antiemetics

Gastrointestinal Agents

Hematinics

Vitamins

Amino Acids

Pembrolizumab

Carboplatin

Dexamethasone

Pemetrexed

Immunomodulating Agents

Dexamethasone acetate

Folic Acid

Vitamin B Complex

Vitamin B 12

Hydroxocobalamin

Trace Elements

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Folic Acid Antagonists

Folinic Acid

Methylcobalamin

Folate

Vitamin B9

Vitamin B12

Cobalamin

Cyanocobalamin

Glutamine

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.

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.

Carboplatin Chemotherapy

Pemetrexed Chemotherapy

Pembrolizumab Immunotherapy

Placebo

Orally, once daily beginning 7 days prior to the first dose of pemetrexed and continue until 21 days after the last dose of pemetrexed.

Folic acid 400 -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.

Vitamin B12 1000 μg

For prophylaxis, orally twice per day (or equivalent). Taken the day before, day of, and day after pemetrexed administration.

Dexamethasone 4 mg

Emil Kuriakose, MD

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.

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

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)

Duration of investigator-determined PFS per RECIST v1.1 in the intent-to-treat (ITT) population

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.

DOR is defined as the duration of response for patients achieving a CR or PR

Skin and Connective Tissue Diseases

Rare Diseases

Breast Neoplasms

Triple Negative Breast Neoplasms

Carcinoma, Renal Cell

Adenocarcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Kidney Neoplasms

Urologic Neoplasms

Kidney Diseases

Urologic Diseases

Breast Diseases

Skin Diseases

Renal Cell Carcinoma

Clear Cell Renal Cell Carcinoma

Anti-Arrhythmia Agents

Vasodilator Agents

Analgesics

Irinotecan

Bevacizumab

Fluorouracil

Estrogens

Oxaliplatin

Endothelial Growth Factors

Mitogens

Tyrosine Kinase Inhibitors

Pancrelipase

Progesterone

Adenosine

Pancreatin

Tyrosine

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.

CB-839

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

Sam Whiting, MD, PhD

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.

800 mg CB-839 + 1 mg Talazoparib: ccRCC

800 mg CB-839 taken twice daily and 1 mg talazoparib taken once daily in participants with incurable/locally advanced or metastatic TNBC ER-, PR-, and HER2-negative who received ≥ 1 prior line of cytotoxic chemotherapy with no prior PARP inhibitor therapy for TNBC or platinum-based chemotherapy for metastatic TNBC.

800 mg CB-839 + 1 mg Talazoparib: TNBC

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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Telaglenastat + Talazoparib In Prostate Cancer	NCT04824937	Prostate Cancer...	Telaglenastat Talazoparib	18 Years -	Massachusetts General Hospital
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
KEAPSAKE: A Study of Telaglenastat (CB-839) With Standard-of-Care Chemoimmunotherapy in 1L KEAP1/NRF2-Mutated, Nonsquamous NSCLC	NCT04265534	Non-Small Cell ... Non-squamous No... Non-Squamous No... KEAP1 Gene Muta... NRF2 Gene Mutat... NFE2L2 Gene Mut...	Telaglenastat Carboplatin Che... Pemetrexed Chem... Pembrolizumab I... Placebo Folic acid 400 ... Vitamin B12 100... Dexamethasone 4...	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
KEAPSAKE: A Study of Telaglenastat (CB-839) With Standard-of-Care Chemoimmunotherapy in 1L KEAP1/NRF2-Mutated, Nonsquamous NSCLC	NCT04265534	Non-Small Cell ... Non-squamous No... Non-Squamous No... KEAP1 Gene Muta... NRF2 Gene Mutat... NFE2L2 Gene Mut...	Telaglenastat Carboplatin Che... Pemetrexed Chem... Pembrolizumab I... Placebo Folic acid 400 ... Vitamin B12 100... Dexamethasone 4...	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

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