• Safety and Tolerability of telaglenestat (CB-839) in combination with palbociclib: (CR) 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 from Part 1 patients only within their first 28 day cycle ]
  Incidence and nature of dose-limiting toxicities

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

• Solid Tumors
• NSCLC
• CRC
• KRAS Gene Mutation

• Drug: Telaglenestat (CB-839)
  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.
• Drug: Palbociclib Oral Capsule [Ibrance]
  Palbociclib (Ibrance) is an oral capsule 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.
  Other Name: Ibrance

• Experimental: Cohort 1: Telaglenastat 600 mg and Palbociclib 75 mg
  Interventions:

  • Drug: Telaglenestat (CB-839)
  • Drug: Palbociclib Oral Capsule [Ibrance]
• Experimental: Cohort 2: Telaglenastat 800 mg and Palbociclib 75 mg
  Interventions:

  • Drug: Telaglenestat (CB-839)
  • Drug: Palbociclib Oral Capsule [Ibrance]
• Experimental: Cohort 3: Telaglenastat 800 mg and Palbociclib 100 mg
  Interventions:

  • Drug: Telaglenestat (CB-839)
  • Drug: Palbociclib Oral Capsule [Ibrance]
• Experimental: Cohort 3: Telaglenastat 800 mg and Palbociclib 125 mg
  Interventions:

  • Drug: Telaglenestat (CB-839)
  • Drug: Palbociclib Oral Capsule [Ibrance]
• Experimental: Part 2: Expansion
  The recommended phase 2 dose (RP2D) determined from Part 1 will be the treatment for all cohorts in expansion Part 2.
  Interventions:

  • Drug: Telaglenestat (CB-839)
  • Drug: Palbociclib Oral Capsule [Ibrance]

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)

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:

  1. small molecule TKI therapy (including investigational) within 2 weeks or 5 half-lives prior to expected Cycle 1 Day 1 dose
  2. any type of anti-cancer antibody or cytotoxic chemo within 4 weeks prior to Cycle 1 Day 1 Dose
  3. radiation therapy for bone metastasis within 2 weeks prior or any other external radiation therapy within 4 weeks prior to C1D1
  4. patients with clinically relevant ongoing complications from prior radiation therapy are not eligible