ENTRATA: CB-839 With Everolimus vs. Placebo With Everolimus in Patients With RCC

A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study Comparing CB-839 in Combination
with Everolimus (CBE) vs. Placebo with Everolimus (PboE) in Patients with Advanced or
Metastatic Renal Cell Carcinoma (RCC)

Inclusion Criteria:

- Karnofsky Performance Score (KPS) ≥ 70%

- Estimated Life Expectancy of at least 3 mo

- Documented histological or cytological diagnosis of renal cell carcinoma with a
clear-cell component.

- Measurable Disease per RECIST 1.1 as determined by the Investigator

- Must have received at least two prior lines of systemic therapy, including at least
one VEGFR-targeting TKI (e.g., sunitinib, sorafenib, pazopanib, cabozantinib)

a) Radiographic progression of mRCC must have occurred (per investigator assessment)
on or after the most recent systemic therapy and within 6 mo prior to C1D1.

- Prior treatment with other anti-cancer therapies including cytokines, monoclonal
antibodies, immunotherapies, and cytotoxic chemotherapy is allowed

Exclusion Criteria:

- Prior treatment with mTOR inhibitors (everolimus or temsirolimus) or CB-839

- Receipt of any anticancer therapy within the following windows before randomization:

- TKI therapy within 2 weeks or 5 half-lives, whichever is longer

- Any type of anti-cancer antibody within 4 weeks

- Cytotoxic chemotherapy within 4 weeks

- Investigational therapy within 4 weeks or 5 half-lives, whichever is longer

- Radiation therapy for bone metastasis within 2 weeks, any other external
radiation therapy within 4 weeks before randomization. Patients with clinically
relevant ongoing complications from prior radiation therapy are not eligible.

- Unable to receive medications PO or any condition that may prevent adequate absorption
of oral study medication

- Major surgery within 28 days prior to randomization

- Patients with active and/or untreated central nervous system (CNS) cancer are not
eligible. Patients with treated brain metastasis must have 1) documented radiographic
stability of at least 4 weeks duration demonstrated on baseline contrast-enhanced CNS
imaging (eg contrast-enhanced MRI of the brain) prior to randomization and 2) must be
symptomatically stable and off steroids for at least 2 weeks before randomization.

- Requirement for continued proton pump inhibitor after randomization

- Chronic treatment with corticosteroids or other immunosuppressive agents except (i)
inhaled or topical steroids or replacement dose corticosteroids equivalent to ≤ 10 mg
prednisone and (ii) patients receiving physiological doses of hydrocortisone for
adrenal insufficiency