Title
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

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

Objective
Primary:
Safety:
-To evaluate the safety and tolerability of KO-2806 when administered as monotherapy and in combination therapy in patients with advanced solid tumors (escalation parts)
-To determine the maximum tolerated dose (MTD)/highest protocol-defined dose (HPDD) and/or the optimal biologically active dose (OBAD) of KO2806 when administered as monotherapy and in combination therapy in patients with advanced solid tumors (escalation parts)
-To define the recommended Phase 2 dose (RP2D) of KO-2806 in combination therapy in patients with advanced solid tumors (expansion part)
Efficacy:
-To evaluate the antitumor activity of KO-2806 when administered in combination therapy in patients with advanced solid tumors (expansion part)

Secondary:
Safety:
-To further evaluate the safety and tolerability of KO-2806 when administered in combination therapy in patients with advanced solid tumors (expansion part)
Efficacy:
-To evaluate the preliminary antitumor activity of KO-2806 when administered as monotherapy or in combination therapy in patients with advanced solid tumors (escalation parts)
-To further evaluate the antitumor activity of KO-2806 when administered in combination therapy in patients with advanced solid tumors (expansion part)
Pharmacokinetics:
-To characterize the PK of KO-2806 when administered as monotherapy and the PK of KO-2806 and the combination agent when administered in combination therapy (escalation and expansion parts)
- Monotherapy only, during the escalation phase:
?To evaluate the effect of food on the PK of KO-2806
? To evaluate the relationship between KO-2806 plasma concentrations and corrected QT (QTc) intervals
? To characterize urine PK
-Combination only, during the expansion phase:
? To evaluate the effect of formulation and mode of administration of KO-2806 on the PK of KO-2806 and the combination agent

Treatment Experimental: Arm #1: RAS-altered advanced solid tumors
Patients with advanced solid tumors and the following:

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 for NSCLC or CRC
KRAS-mutant and/or amplified PDAC

Experimental: Arm #2: Advanced or metastatic ccRCC
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

Key Eligibility Inclusion Criteria:

At least 18 years of age.

Histologically or cytologically confirmed advanced solid tumors



Arm #1 (Monotherapy): 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): Must have received at least 1 prior systemic therapy with IO-based treatment for locally advanced or metastatic RCC with predominantly clear cell subtype



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.

Ongoing treatment with certain anticancer agents.

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 cerebro-vascular 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.

Applicable Disease Sites
Anal; Any Site; Bladder; Brain/Central Nervous System; Breast; Cervix; Colon and Rectum; Endocrine cancers; Esophagus; Gastrointestinal cancers, other; Genitourinary cancers, other; Head and Neck; Ill-Defined Sites; Kidney; Liver; Lung; Melanoma/Skin cancer; Ovary; Pancreas; Prostate; Sarcoma; Stomach; Thyroid; Unknown Sites; Uterus

Participating Institutions
UW Health Eastpark Medical Center; UW Health University Hospital