KO-2806 Monotherapy and Combination Therapies in Advanced Solid Tumors

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Solid Tumors With HRAS Alterations, Non Small Cell Lung Cancer (NSCLC), Colorectal Cancer (CRC), Pancreatic Ductal Adenocarcinoma (PDAC), Clear Cell Renal Cell Carcinoma (ccRCC)

Intervention / Treatment
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* Drug: KO-2806
* Drug: Cabozantinib


Participation Criteria
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Eligibility Criteria
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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. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm #1: RAS-altered advanced solid tumors<br>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 | Drug: KO-2806<br>* Oral administration<br>|
| Experimental: Arm #2: Advanced or metastatic ccRCC<br>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 | Drug: KO-2806<br>* Oral administration<br>Drug: Cabozantinib<br>* Oral administration<br>* Other names: Cabometyx;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | NCI-CTCAE v5.0 | First dose of KO-2806 up to and including 28 days after last dose of KO-2806, or if the patient is lost to follow-up, whichever comes first (dose escalation) | 
| Overall Response Rate (ORR) | Assessed per RECIST v1.1 | Up to an estimated period of 24 months (dose expansion) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of dose-limiting toxicities (DLTs) |  | DLTs will be evaluated during the first 28 days of KO-2806 treatment (dose expansion) | 
| Descriptive statistics of adverse events | NCI-CTCAE v5.0 | First dose of KO-2806 up to and including 28 days after last dose of KO-2806, or if the patient is lost to follow-up, whichever comes first (dose expansion) | 
| Objective Response Rate (ORR) | Assessed per RECIST v1.1 | Up to an estimated period of 24 months | 
| Disease control rate (DCR) | Assessed per RECIST v1.1 | Up to an estimated period of 24 months | 
| Duration of response (DoR) | Assessed per RECIST v1.1 | Up to an estimated period of 24 months | 
| Progression-Free Survival (PFS) | Assessed per RECIST v1.1 | Up to an estimated period of 24 months | 
| Overall Survival (OS) | Assessed per RECIST v1.1 | Up to an estimated period of 24 months | 
| AUClast | Area under the curve from time zero to last measurable concentration for KO-2806 (in the absence and presence of food) and combination agent. | Cycle 1. Each cycle is 28 days. (Dose escalation and dose expansion). | 
| AUC0-inf | Area under the curve from time zero to infinity post administration for KO-2806 (in the absence and presence of food) and combination agent | Cycle 1. Each cycle is 28 days. (Dose escalation and dose expansion). | 
| Cmax | Maximum plasma concentration (Cmax) of KO-2806 (in the absence and presence of food) and the combination agent | Cycle 1. Each cycle is 28 days. (Dose escalation and dose expansion). | 
| Tmax | Time to maximal concentration (Tmax) of KO-2806 (in the absence and presence of food) and the combination agent | Cycle 1. Each cycle is 28 days. (Dose escalation and dose expansion). | 
| Estimated terminal elimination rate constant (λz) | Estimated terminal elimination rate constant of KO-2806 and the combination agent | Cycle 1. Each cycle is 28 days. (Dose escalation and dose expansion). | 
| t1/2 | Half-life (t1/2) of KO-2806 (in the absence and presence of food) and the combination agent | Cycle 1. Each cycle is 28 days. (Dose escalation and dose expansion). | 
| CL/F | Oral clearance (CL/F) of KO-2806 and the combination agent | Cycle 1. Each cycle is 28 days. (Dose escalation and dose expansion). | 
| Vd/F | Oral volume of distribution (Vd/F) of KO-2806 and the combination agent | Cycle 1. Each cycle is 28 days. (Dose escalation and dose expansion). | 
| QTcF | QT interval corrected for heart rate (HR) using Fridericia's formula (QTcF) for KO-2806 monotherapy (dose escalation) | Up to day 7 following first dose of KO-2806. Dose escalation. | 
| KO-2806 plasma concentration measurements |  | Up to day 7 following first dose of KO-2806. Dose escalation. | 
| 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 | Renal clearance of KO-2806 excretion in urine | Up to 24 hours following first dose of KO-2806. Dose escalation. | 
| t1/2 of KO-2806 excretion in urine | Half-life of KO-2806 excretion in urine | Up to 24 hours following first dose of KO-2806. Dose escalation. | 
| Relative bioavailability of KO-2806 formulations |  | Up to 24 hours following first dose of KO-2806. Dose expansion. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase 1, Tyrosine Kinase inhibitor (TKI), HRAS, KRAS, NRAS, Farnesyl transferase inhibitor (FTI)