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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03875313
Recruitment Status : Terminated (Slow Enrollment)
First Posted : March 14, 2019
Results First Posted : February 17, 2022
Last Update Posted : February 17, 2022
Sponsor:
Information provided by (Responsible Party):
Calithera Biosciences, Inc

Tracking Information
First Submitted Date  ICMJE March 5, 2019
First Posted Date  ICMJE March 14, 2019
Results First Submitted Date  ICMJE January 24, 2022
Results First Posted Date  ICMJE February 17, 2022
Last Update Posted Date February 17, 2022
Actual Study Start Date  ICMJE May 20, 2019
Actual Primary Completion Date July 29, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 24, 2022)
  • Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Excluding Deaths Due to Disease Progression [ Time Frame: Start of treatment to 28 days post treatment; mean overall duration of talazoparib exposure was 88.7 days. ]
    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 [ 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. ]
    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) [ Time Frame: During Cycle 1 on Days 1 through 28, inclusive ]
    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) [ Time Frame: Maximum duration of follow-up for ORR was 12.9 months. ]
    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) [ Time Frame: Maximum duration of follow-up for cORR was 12.9 months. ]
    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) [ Time Frame: Maximum duration of follow-up for CBR was 12.9 months. ]
    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) [ Time Frame: Maximum duration of follow-up for PFS was 12.9 months. ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: March 13, 2019)
  • Safety and tolerability of CB-839 in combination with talazoparib: Number of participants with treatment related adverse events [ Time Frame: Start of treatment to 28 days post treatment ]
    Number of participants with treatment related adverse events as assessed by CTCAE v5.0
  • Maximum tolerated dose and/ or Recommended Phase 2 Dose [ Time Frame: Measured for Part 1 patients within the first 28 day cycle ]
    Incidence and nature of dose-limiting toxicities
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: March 13, 2019)
  • Maximum plasma concentration of CB-839 and talazoparib [ Time Frame: At the beginning of cycle 2 (each cycle is 28 days) ]
    Non-compartmental method of analysis will be used to analyze the plasma concentrations
  • Anti-tumor activity of CB-839 in combination with talazoparib [ Time Frame: Approximately every 8 weeks until disease progression, approximately 18 months ]
    Change in tumor size from baseline
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of CB-839 (Telaglenastat) in Combination With Talazoparib in Patients With Solid Tumors
Official Title  ICMJE 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
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Solid Tumor
  • Clear Cell Renal Cell Carcinoma
  • TNBC - Triple-Negative Breast Cancer
  • Colorectal Cancer
  • CRC
  • RCC
  • ccRCC
Intervention  ICMJE
  • Drug: CB-839
    CB-839 oral tablets administered twice daily with food at the assigned dose level on 28 day cycles with talazoparib.
    Other Name: telaglenastat
  • Drug: Talazoparib
    Talazoparib oral tablets administered at the standard dose once daily with or without food on 28 day cycles with CB-839.
    Other Name: Talzenna
Study Arms  ICMJE
  • Experimental: 600 mg CB-839 + 1 mg Talazoparib
    600 mg CB-839 taken twice daily and 1 mg talazoparib taken once daily in participants with advanced or metastatic solid tumors.
    Interventions:
    • Drug: CB-839
    • Drug: Talazoparib
  • Experimental: 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 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.
    Interventions:
    • Drug: CB-839
    • Drug: Talazoparib
  • Experimental: 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 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.
    Interventions:
    • Drug: CB-839
    • Drug: Talazoparib
  • Experimental: 800 mg CB-839 + 1 mg Talazoparib: CRC
    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.
    Interventions:
    • Drug: CB-839
    • Drug: Talazoparib
  • Experimental: 800 mg CB-839 + 1 mg Talazoparib: Other Histology
    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).
    Interventions:
    • Drug: CB-839
    • Drug: Talazoparib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: November 23, 2020)
33
Original Estimated Enrollment  ICMJE
 (submitted: March 13, 2019)
92
Actual Study Completion Date  ICMJE July 29, 2020
Actual Primary Completion Date July 29, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03875313
Other Study ID Numbers  ICMJE CX-839-011
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Calithera Biosciences, Inc
Study Sponsor  ICMJE Calithera Biosciences, Inc
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Sam Whiting, MD, PhD Calithera Biosciences, Inc
PRS Account Calithera Biosciences, Inc
Verification Date February 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP