KO-2806 Monotherapy and Combination Therapies in Advanced Solid Tumors

• Darlifarnib (Drug), also known as KO-2806: Oral administration
• Cabozantinib (Drug), also known as Cabometyx: Oral administration
• Adagrasib (Drug), also known as Krazati: Oral administration

Primary outcomes

• Rate of dose-limiting toxicities (DLTs) [DLTs will be evaluated during the first 28 days of KO-2806 treatment (dose escalation)]
• Descriptive statistics of adverse events (AEs) [First dose of KO-2806 up to and including 28 days after last dose of KO-2806 (dose escalation)]: NCI-CTCAE v5.0
• Incidence of dose interruptions, reductions, and discontinuations due to AE [First dose of KO-2806 up to last dose of KO-2806 or up to 24 months of treatment (dose escalation)]
• Objective Response Rate (ORR) [Up to an estimated period of 24 months (dose expansion)]: Assessed per RECIST v1.1

Secondary outcomes

• Incidence of dose interruptions, reductions, and discontinuations due to AE [First dose of KO-2806 up to last dose of KO-2806 or up to 24 months of treatment (dose expansion)]
• Descriptive statistics of AEs [First dose of KO-2806 up to and including 28 days after last dose of KO-2806 (dose expansion)]: NCI-CTCAE v5.0
• Objective Response Rate (ORR) [Up to an estimated period of 24 months (dose escalation)]: Assessed per RECIST v1.1
• Disease control rate (DCR) [Up to an estimated period of 24 months (dose escalation and expansion)]: Assessed per RECIST v1.1
• Duration of response (DoR) [Up to an estimated period of 24 months (dose escalation and expansion)]: Assessed per RECIST v1.1
• Time to response (TTR) [Up to an estimated period of 24 months (dose escalation and expansion)]: Assessed per RECIST v1.1
• Progression-Free Survival (PFS) [Up to an estimated period of 24 months (dose escalation and expansion)]: Assessed per RECIST v1.1
• Overall Survival (OS) [First dose of KO-2806 until death, or up to an estimated period of 37 months (dose escalation and expansion)]: For patients with no events, OS will be censored at the last known to be alive date
• AUClast [Cycle 1. Each cycle is 28 days. (Dose escalation and dose expansion)]: Area under the curve from time zero to last measurable concentration for KO-2806 (in the absence and presence of food) and combination agent.
• AUC0-inf [Cycle 1. Each cycle is 28 days. (Dose escalation and dose expansion)]: Area under the curve from time zero to infinity post administration for KO-2806 (in the absence and presence of food) and combination agent
• Cmax [Cycle 1. Each cycle is 28 days. (Dose escalation and dose expansion)]: Maximum plasma concentration (Cmax) of KO-2806 (in the absence and presence of food) and the combination agent
• Cmin [Cycle 1. Each cycle is 28 days. (Dose escalation and dose expansion)]: Minimum plasma concentration (Cmin) of KO-2806 (in the absence and presence of food) and the combination agent
• Tmax [Cycle 1. Each cycle is 28 days. (Dose escalation and dose expansion)]: Time to maximal concentration (Tmax) of KO-2806 (in the absence and presence of food) and the combination agent
• Estimated terminal elimination rate constant (λz) [Cycle 1. Each cycle is 28 days. (Dose escalation and dose expansion)]: Estimated terminal elimination rate constant of KO-2806 and the combination agent
• t1/2 [Cycle 1. Each cycle is 28 days. (Dose escalation and dose expansion)]: Half-life (t1/2) of KO-2806 (in the absence and presence of food) and the combination agent
• CL/F [Cycle 1. Each cycle is 28 days. (Dose escalation and dose expansion)]: Total apparent clearance (CL/F) of KO-2806 and the combination agent
• Vd/F [Cycle 1. Each cycle is 28 days. (Dose escalation and dose expansion)]: Total apparent volume of distribution (Vd/F) of KO-2806 and the combination agent
• QTcF [Up to 28 days following last dose of KO-2806, cabozantinib, or adagrasib. (Dose escalation and dose expansion)]: QT interval corrected for heart rate (HR) using Fridericia's formula (QTcF) for KO-2806 monotherapy and in combination
• KO-2806 plasma concentration measurements [Up to day 28 following first dose of KO-2806 and adagrasib. (Dose escalation and dose expansion)]
• Amount of KO-2806 excretion in urine [Up to 24 hours following first dose of KO-2806. (Dose escalation)]
• CLr of KO-2806 excretion in urine [Up to 24 hours following first dose of KO-2806. (Dose escalation)]: Renal clearance of KO-2806 excretion in urine

Sex: All, ages: 18 Years to any

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.