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

Study Overview
=================
Brief Summary
-----------------
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.

Official Title
-----------------
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

Conditions
-----------------
CRC, Solid Tumor, Clear Cell Renal Cell Carcinoma, TNBC - Triple-Negative Breast Cancer, Colorectal Cancer, RCC, ccRCC

Intervention / Treatment
-----------------
* Drug: CB-839
* Drug: Talazoparib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: (Part 1) -Documented incurable/locally advanced or metastatic solid tumors that have either relapsed or are refractory or intolerant to standard therapies of proven clinical benefit. (Part 2) Meets 1 of the 3 defined cohorts: Cohort 1: Documented incurable/locally advanced or metastatic ccRCC Cohort 2: Documented incurable/locally advanced or metastatic defined as ER, PR negative (<1%) and HER2 negative (immunohistochemistry 0 to 1+ or fluorescence in situ hybridization [FISH] negative) Cohort 3: incurable/locally advanced or metastatic CRC For both Parts 1 & 2: Recovery to baseline or ≤ Grade 1 Common Terminology Criteria for Adverse Events (CTCAE) v.5.0 from toxicities related to the prior therapy Adequate renal, hepatic, and hematological function Per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 evaluable disease (Part 1) or measurable disease (Part 2) Ability to provide written consent in accordance with federal, local and institutional guidelines Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 Exclusion Criteria for both Parts 1 & 2: Prior treatment with CB-839 or a PARP inhibitor Unable to received oral medications Active and/or untreated central nervous system metastasis. Patients with treated brain metastases must have (1) documented radiographic stability of at least 4 weeks duration demonstrated on baseline central nervous system (CNS) imaging prior to study treatment and (2) be symptomatically stable and off steroids for at least 2 weeks before administration of any study treatment. Major surgery within 28 days prior to first dose of study drug Receipt of any anticancer therapy within the following windows: small molecule tyrosine kinase inhibitor therapy (including investigational) within the prior 2 weeks or 5 half-lives prior to C1D1, whichever is longer; any type of anti-cancer antibody or cytotoxic chemotherapy within 4 weeks prior to C1D1; radiation therapy for bone metastasis within 2 weeks prior or any other external radiation therapy within 4 weeks prior to C1D1; patients with clinically relevant ongoing complications from prior radiation therapy are not eligible.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 600 mg CB-839 + 1 mg Talazoparib<br>600 mg CB-839 taken twice daily and 1 mg talazoparib taken once daily in participants with advanced or metastatic solid tumors. | Drug: CB-839<br>* CB-839 oral tablets administered twice daily with food at the assigned dose level on 28 day cycles with talazoparib.<br>* Other names: telaglenastat;Drug: Talazoparib<br>* Talazoparib oral tablets administered at the standard dose once daily with or without food on 28 day cycles with CB-839.<br>* Other names: Talzenna;|
| Experimental: 800 mg CB-839 + 1 mg Talazoparib: ccRCC<br>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. | Drug: CB-839<br>* CB-839 oral tablets administered twice daily with food at the assigned dose level on 28 day cycles with talazoparib.<br>* Other names: telaglenastat;Drug: Talazoparib<br>* Talazoparib oral tablets administered at the standard dose once daily with or without food on 28 day cycles with CB-839.<br>* Other names: Talzenna;|
| Experimental: 800 mg CB-839 + 1 mg Talazoparib: TNBC<br>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. | Drug: CB-839<br>* CB-839 oral tablets administered twice daily with food at the assigned dose level on 28 day cycles with talazoparib.<br>* Other names: telaglenastat;Drug: Talazoparib<br>* Talazoparib oral tablets administered at the standard dose once daily with or without food on 28 day cycles with CB-839.<br>* Other names: Talzenna;|
| Experimental: 800 mg CB-839 + 1 mg Talazoparib: CRC<br>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. | Drug: CB-839<br>* CB-839 oral tablets administered twice daily with food at the assigned dose level on 28 day cycles with talazoparib.<br>* Other names: telaglenastat;Drug: Talazoparib<br>* Talazoparib oral tablets administered at the standard dose once daily with or without food on 28 day cycles with CB-839.<br>* Other names: Talzenna;|
| Experimental: 800 mg CB-839 + 1 mg Talazoparib: Other Histology<br>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). | Drug: CB-839<br>* CB-839 oral tablets administered twice daily with food at the assigned dose level on 28 day cycles with talazoparib.<br>* Other names: telaglenastat;Drug: Talazoparib<br>* Talazoparib oral tablets administered at the standard dose once daily with or without food on 28 day cycles with CB-839.<br>* Other names: Talzenna;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Excluding Deaths Due to Disease Progression | 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. | Start of treatment to 28 days post treatment; mean overall duration of talazoparib exposure was 88.7 days. | 
| Number of Participants With Laboratory Abnormalities (Hematology, Clinical Chemistry) at More Than 1 Clinic Visit | 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. | Hematology: screening, cycle 1 day 1, cycle 1 day 15, cycle 2 day 1, end of treatment (EOT). Clinical chemistry parameters: screening, cycle 1 day 1, cycle 1 day 8, cycle 1 day 15, cycle 1 day 22, cycle 2 day 1, cycle 2 day 15, EOT. | 
| Number of Participants With Dose-Limiting Toxicities (DLTs) | 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. | During Cycle 1 on Days 1 through 28, inclusive | 
| Overall Response Rate (ORR) | 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). | Maximum duration of follow-up for ORR was 12.9 months. | 
| Confirmed ORR (cORR) | 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). | Maximum duration of follow-up for cORR was 12.9 months. | 
| Clinical Benefit Rate (CBR) | 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). | Maximum duration of follow-up for CBR was 12.9 months. | 
| Progression-Free Survival (PFS) | 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. | Maximum duration of follow-up for PFS was 12.9 months. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Tumor Metabolism, Glutaminase Inhibitor, CB-839, telaglenastat, talazoparib, PARP Inhibitor, DNA Damage, DNA Repair, Homologous recombination deficiency, HRD, BRCA 1, BRCA 2