Back to resultsStudy of CB-839 (Telaglenastat) in Combination With Talazoparib in Patients With Solid Tumors
Primary Purpose
Solid Tumor, Clear Cell Renal Cell Carcinoma, TNBC - Triple-Negative Breast Cancer
Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
CB-839
Talazoparib
Sponsored by
About this trial
This is an interventional treatment trial for Solid Tumor focused on measuring Tumor Metabolism, Glutaminase Inhibitor, CB-839, telaglenastat, talazoparib, PARP Inhibitor, DNA Damage, DNA Repair, Homologous recombination deficiency, HRD, BRCA 1, BRCA 2
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.
Sites / Locations
- University of Alabama
- Winship Cancer Institute of Emory University
- University of Iowa
- Massachusetts General Hospital
- Columbia University
- MD Anderson
- South Texas Accelerated Research Therapeutics, LLC
- Huntsman Cancer Institute
- University of Wisconsin
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm Type
Experimental
Experimental
Experimental
Experimental
Experimental
Arm Label
600 mg CB-839 + 1 mg Talazoparib
800 mg CB-839 + 1 mg Talazoparib: ccRCC
800 mg CB-839 + 1 mg Talazoparib: TNBC
800 mg CB-839 + 1 mg Talazoparib: CRC
800 mg CB-839 + 1 mg Talazoparib: Other Histology
Arm Description
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).
Outcomes
Primary Outcome Measures
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.
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.
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.
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).
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).
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).
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.
Secondary Outcome Measures
Full Information
NCT ID
NCT03875313
First Posted
March 5, 2019
Last Updated
February 16, 2022
Sponsor
Calithera Biosciences, Inc
1. Study Identification
Unique Protocol Identification Number
NCT03875313
Brief Title
Study of CB-839 (Telaglenastat) in Combination With Talazoparib in Patients With 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
Study Type
Interventional
2. Study Status
Record Verification Date
February 2022
Overall Recruitment Status
Terminated
Why Stopped
Slow Enrollment
Study Start Date
May 20, 2019 (Actual)
Primary Completion Date
July 29, 2020 (Actual)
Study Completion Date
July 29, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Calithera Biosciences, Inc
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Solid Tumor, Clear Cell Renal Cell Carcinoma, TNBC - Triple-Negative Breast Cancer, Colorectal Cancer, CRC, RCC, ccRCC
Keywords
Tumor Metabolism, Glutaminase Inhibitor, CB-839, telaglenastat, talazoparib, PARP Inhibitor, DNA Damage, DNA Repair, Homologous recombination deficiency, HRD, BRCA 1, BRCA 2
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
33 (Actual)
8. Arms, Groups, and Interventions
Arm Title
600 mg CB-839 + 1 mg Talazoparib
Arm Type
Experimental
Arm Description
600 mg CB-839 taken twice daily and 1 mg talazoparib taken once daily in participants with advanced or metastatic solid tumors.
Arm Title
800 mg CB-839 + 1 mg Talazoparib: ccRCC
Arm Type
Experimental
Arm Description
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.
Arm Title
800 mg CB-839 + 1 mg Talazoparib: TNBC
Arm Type
Experimental
Arm Description
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.
Arm Title
800 mg CB-839 + 1 mg Talazoparib: CRC
Arm Type
Experimental
Arm Description
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.
Arm Title
800 mg CB-839 + 1 mg Talazoparib: Other Histology
Arm Type
Experimental
Arm Description
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).
Intervention Type
Drug
Intervention Name(s)
CB-839
Other Intervention Name(s)
telaglenastat
Intervention Description
CB-839 oral tablets administered twice daily with food at the assigned dose level on 28 day cycles with talazoparib.
Intervention Type
Drug
Intervention Name(s)
Talazoparib
Other Intervention Name(s)
Talzenna
Intervention Description
Talazoparib oral tablets administered at the standard dose once daily with or without food on 28 day cycles with CB-839.
Primary Outcome Measure Information:
Title
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Excluding Deaths Due to Disease Progression
Description
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.
Time Frame
Start of treatment to 28 days post treatment; mean overall duration of talazoparib exposure was 88.7 days.
Title
Number of Participants With Laboratory Abnormalities (Hematology, Clinical Chemistry) at More Than 1 Clinic Visit
Description
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.
Time Frame
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.
Title
Number of Participants With Dose-Limiting Toxicities (DLTs)
Description
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.
Time Frame
During Cycle 1 on Days 1 through 28, inclusive
Title
Overall Response Rate (ORR)
Description
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).
Time Frame
Maximum duration of follow-up for ORR was 12.9 months.
Title
Confirmed ORR (cORR)
Description
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).
Time Frame
Maximum duration of follow-up for cORR was 12.9 months.
Title
Clinical Benefit Rate (CBR)
Description
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).
Time Frame
Maximum duration of follow-up for CBR was 12.9 months.
Title
Progression-Free Survival (PFS)
Description
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.
Time Frame
Maximum duration of follow-up for PFS was 12.9 months.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sam Whiting, MD, PhD
Organizational Affiliation
Calithera Biosciences, Inc
Official's Role
Study Director
Facility Information:
Facility Name
University of Alabama
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294
Country
United States
Facility Name
Winship Cancer Institute of Emory University
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
University of Iowa
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Columbia University
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
MD Anderson
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
South Texas Accelerated Research Therapeutics, LLC
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States
Facility Name
Huntsman Cancer Institute
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
20000
Country
United States
Facility Name
University of Wisconsin
City
Madison
State/Province
Wisconsin
ZIP/Postal Code
53792
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
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Study of CB-839 (Telaglenastat) in Combination With Talazoparib in Patients With Solid Tumors
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