Phase 1, First-in-Human, Multicenter, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Antitumor Activity of KO-2806 When Administered as Monotherapy and in Combination Therapy in Adult Patients with Advanced Solid Tumors

This first-in-human (FIH) dose-escalation and dose-validation/expansion study will assess
KO-2806, a farnesyltransferase inhibitor (FTI), as a monotherapy and in combination, in
adult patients with advanced solid tumors.

Inclusion Criteria:

- At least 18 years of age.

- Histologically or cytologically confirmed advanced solid tumors

- Arm #1 (KO-2806 monotherapy): Patients who have progressed on, or are
refractory to, standard of care (SOC) treatments with advanced solid tumors,
specifically: HRAS-mutant and/or amplified tumors (any solid tumor type); HRAS
overexpression (only for HNSCC tumors); KRAS and/or NRAS, and/or HRAS-mutant
and/or amplified NSCLC or CRC; KRAS-mutant and/or amplified PDAC

- Arm #2 (Combination): Patients who have received at least 1 prior systemic
therapy with IO-based treatment for locally advanced or metastatic RCC with
predominantly clear cell subtype; non-clear cell RCC patients who are either
treatment-naïve or have received any prior systemic treatment for locally
advanced and metastatic RCC.

- Arm #3 (Combination): Patients who have received at least 1 prior systemic
therapy including available approved SOC treatments for KRAS G12C-mutant
locally advanced or metastatic NSCLC, CRC, or PDAC.

- Arm #4 (Combination): Patients must be cabozantinib-naïve and have received at
least 1 prior systemic therapy with IO-based treatment for locally advanced or
metastatic ccRCC, but no more than 3 prior systemic anticancer therapies.

- Arm #5 (Cabozantinib monotherapy): Patients must be cabozantinib-naïve and have
received at least 1 prior systemic therapy with IO-based treatment for locally
advanced or metastatic ccRCC, but no more than 3 prior systemic anticancer
therapies.

- Arm #6 (Cabozantinib rollover to combination): Patients must be
cabozantinib-naïve and have received at least 1 prior systemic therapy with
IO-based treatment for locally advanced or metastatic ccRCC, but no more than 3
prior systemic anticancer therapies.

- Arm #7 (Combination): Patients who have received at least 1 prior systemic
therapy including available approved SOC treatments for KRAS G12C-mutant
locally advanced or metastatic NSCLC

- Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

- Karnofsky Performance Status of 70 or higher with no clinically significant
deterioration over the previous 2 weeks.

- Acceptable liver, renal, endocrine, and hematologic function.

- Other protocol-defined inclusion criteria may apply.

Exclusion Criteria:

- Any use of anticancer therapy within 14 days or 5 half-lives (whichever is shorter)
of Cycle 1 Day 1.

- Prior treatment with an FTI or HRAS inhibitor.

- Major surgery, other than local procedures, within 28 days prior to Cycle 1 Day 1,
without complete recovery.

- Spinal cord compression, leptomeningeal disease, or clinically active CNS
metastases.

- Toxicity (excluding alopecia) from prior therapy that has not been completely
resolved to baseline at the time of consent.

- Active or prior documented autoimmune or inflammatory disorders within the past 5
years prior to Cycle 1 Day 1 (with exceptions).

- Active, uncontrolled bacterial, viral, or fungal infections requiring systemic
therapy.

- Inability to swallow, impairment of gastrointestinal (GI) function or GI disease
that may significantly alter the absorption of the trial drugs.

- Inadequate cardiac and/or vascular function, including receipt of treatment for
unstable angina, myocardial infarction, and/or cerebrovascular attack within the
prior 6 months, mean QTcF ≥470 ms, or Class II or greater congestive heart failure.

- Other invasive malignancy within 2 years.

- Other protocol-defined exclusion criteria may apply.