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

Study Overview
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Brief Summary
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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 telaglenestat (CB-839) with the CDK4/6 Inhibitor, palbociclib in participants with advanced/metastatic solid tumors.

Official Title
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A Phase 1b/2, Open Label, Dose Escalation and Expansion Study of the Glutaminase Inhibitor Telaglenastat (CB-839) in Combination With CDK4/6 Inhibitor Palbociclib in Patients With Advanced or Metastatic Solid Tumors

Conditions
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NSCLC, Solid Tumors, CRC, KRAS Gene Mutation

Intervention / Treatment
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* Drug: Telaglenestat (CB-839)
* Drug: Palbociclib Oral Capsule or Tablet [Ibrance]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part 1: Have documented incurable/locally advanced or metastatic solid tumors that have either relapsed or are refractory or intolerant to the standard therapies of proven clinical benefit. Part 2: Availability of archival tumor tissue block or slides (Fresh tumor biopsy will be required if archival tissue is not available) Part 2, Cohort 1: Incurable/locally advanced or metastatic KRAS-mutant CRC previously treated with systemic therapy (examples include: oxaliplatin-, irinotecan-and 5 FU-based chemotherapy (unless contraindicated) with or without bevacizumab) Part 2, Cohort 2: Incurable/locally advanced or metastatic KRAS-mutant NSCLC previously treated with systemic chemotherapy including platinum-based and anti-PD-1/PDL-1 therapy (unless contraindicated) Part 2, Cohort 3: Advance KRAS-mutant Pancreatic Ductal Adenocarcinoma (PDAC) harboring a mutation or loss in CDKN2A (PDAC) and received treatment with one or more lines of systemic chemotherapy with FOLFIRINOX and/or gemcitabine/abraxane in the neoadjuvant, adjuvant, or metastatic disease setting or unable to receive standard of care chemotherapy Cohort 4 may be opened only if Cohort 3 achieves predefined criteria for efficacy -Part 2 Cohort 4: Advanced KRAS-mutant Pancreatic Ductal Adenocarcinoma (PDAC). · Histological or cytological diagnosis of advanced or metastatic KRAS-mutant with CDKN2A wild type (PDAC) and received treatment with one or more lines of systemic chemotherapy with FOLFIRINOX and/or gemcitabine/abraxane in the neoadjuvant, adjuvant, or metastatic disease setting or unable to receive standard of care chemotherapy. For both Part 1 and 2: Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 Ability to provide written consent in accordance with federal, local and institutional guidelines PER RECIST v1.1 evaluable disease (for part 1) or measurable disease (for Part 2) Recovery to baseline or to Grade 1 CTCAE v5.0 of toxicities that were related to prior therapies Exclusion Criteria: Prior treatment with CB-839 or palbociclib Unable to receive oral medication Infection requiring more than 5 days of parenteral antibiotics, antivirals, or antifungals within two weeks prior to C1D1 Unable to discontinue proton pump inhibitor use before study treatment Refractory nausea and vomiting, uncontrolled diarrhea, malabsorption, significant small bowel resection or gastric bypass surgery, use of feeding tubes or other situation that may preclude adequate absorption Active and/or untreated central nervous system metastasis. Patients with treated brain metastasis must have (1) documented radiographic stability of at least 4 weeks in duration demonstrating on baseline central nervous system 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 TKI therapy (including investigational) within 2 weeks or 5 half-lives prior to expected Cycle 1 Day 1 dose any type of anti-cancer antibody or cytotoxic chemo within 4 weeks prior to Cycle 1 Day 1 Dose 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
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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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: Cohort 1: Telaglenastat 600 mg and Palbociclib 75 mg<br> | Drug: Telaglenestat (CB-839)<br>* Teleglenastat is an oral tablet administered twice daily with food at the assigned dose level. Dose is taken with palbociclib each day in 28-day cycles.<br>Drug: Palbociclib Oral Capsule or Tablet [Ibrance]<br>* Palbociclib (Ibrance) is an oral capsule or tablet administered once daily with food on Days 1-21 of every 28-day cycle in combination with telaglenestat. Days 22-28 of every cycle, palbociclib is not taken.<br>* Other names: Ibrance;|
| Experimental: Cohort 2: Telaglenastat 800 mg and Palbociclib 75 mg<br> | Drug: Telaglenestat (CB-839)<br>* Teleglenastat is an oral tablet administered twice daily with food at the assigned dose level. Dose is taken with palbociclib each day in 28-day cycles.<br>Drug: Palbociclib Oral Capsule or Tablet [Ibrance]<br>* Palbociclib (Ibrance) is an oral capsule or tablet administered once daily with food on Days 1-21 of every 28-day cycle in combination with telaglenestat. Days 22-28 of every cycle, palbociclib is not taken.<br>* Other names: Ibrance;|
| Experimental: Cohort 3: Telaglenastat 800 mg and Palbociclib 100 mg<br> | Drug: Telaglenestat (CB-839)<br>* Teleglenastat is an oral tablet administered twice daily with food at the assigned dose level. Dose is taken with palbociclib each day in 28-day cycles.<br>Drug: Palbociclib Oral Capsule or Tablet [Ibrance]<br>* Palbociclib (Ibrance) is an oral capsule or tablet administered once daily with food on Days 1-21 of every 28-day cycle in combination with telaglenestat. Days 22-28 of every cycle, palbociclib is not taken.<br>* Other names: Ibrance;|
| Experimental: Cohort 3: Telaglenastat 800 mg and Palbociclib 125 mg<br> | Drug: Telaglenestat (CB-839)<br>* Teleglenastat is an oral tablet administered twice daily with food at the assigned dose level. Dose is taken with palbociclib each day in 28-day cycles.<br>Drug: Palbociclib Oral Capsule or Tablet [Ibrance]<br>* Palbociclib (Ibrance) is an oral capsule or tablet administered once daily with food on Days 1-21 of every 28-day cycle in combination with telaglenestat. Days 22-28 of every cycle, palbociclib is not taken.<br>* Other names: Ibrance;|
| Experimental: Part 2: Expansion<br>The recommended phase 2 dose (RP2D) determined from Part 1 will be the treatment for all cohorts in expansion Part 2. | Drug: Telaglenestat (CB-839)<br>* Teleglenastat is an oral tablet administered twice daily with food at the assigned dose level. Dose is taken with palbociclib each day in 28-day cycles.<br>Drug: Palbociclib Oral Capsule or Tablet [Ibrance]<br>* Palbociclib (Ibrance) is an oral capsule or tablet administered once daily with food on Days 1-21 of every 28-day cycle in combination with telaglenestat. Days 22-28 of every cycle, palbociclib is not taken.<br>* Other names: Ibrance;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of telaglenestat (CB-839) in combination with palbociclib: (CR) number of participants with treatment related adverse events | Number of participants with treatment related adverse events as assessed by CTCAE v5.0 | Start of treatment to 28 days post treatment | 
| Maximum tolerated dose and/or Recommended Phase 2 Dose: | Incidence and nature of dose-limiting toxicities | Measured from Part 1 patients only within their first 28 day cycle | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum plasma concentration of telaglenastat and palbociclib: | Non-compartmental method of analysis will be used to analyze the plasma concentrations | PKs are drawn on two different days (Day 8 and Day 15) during Cycle 1 | 
| Anti-tumor activity of telaglenestat and palbociclib: | Change in tumor size from baseline | Approximately every 8 weeks until disease progression, for approximately 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tumor Metabolism, Glutaminase Inhibitor, CB-839, Palbociclib, PALBO, Telaglenestat, CDK4/6, CDK4, CDK6