FIT-001: KO-2806 Monotherapy and Combination Therapies in Advanced Solid Tumors

Sponsor

Kura Oncology, Inc. (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT06026410

Collaborator

(none)

270

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Solid Tumors With HRAS Alterations Non Small Cell Lung Cancer (NSCLC) Colorectal Cancer (CRC) Pancreatic Ductal Adenocarcinoma (PDAC) Clear Cell Renal Cell Carcinoma (ccRCC)	Drug: KO-2806 Drug: Cabozantinib	Phase 1

Study Design

Study Type:

Interventional

Anticipated Enrollment :

270 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official 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

Anticipated Study Start Date :

Sep 1, 2023

Anticipated Primary Completion Date :

Jan 1, 2027

Anticipated Study Completion Date :

Apr 1, 2027

Arms and Interventions

Arm	Intervention/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	Drug: KO-2806 Oral administration
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	Drug: KO-2806 Oral administration Drug: Cabozantinib Oral administration Other Names: Cabometyx

Arm

Intervention/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

Drug: KO-2806

Oral administration

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

Drug: KO-2806

Oral administration

Drug: Cabozantinib

Oral administration

Other Names:

Cabometyx

Outcome Measures

Primary Outcome Measures

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 [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)]
NCI-CTCAE v5.0
Overall Response Rate (ORR) [Up to an estimated period of 24 months (dose expansion)]
Assessed per RECIST v1.1

Secondary Outcome Measures

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 [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)]
NCI-CTCAE v5.0
Objective Response Rate (ORR) [Up to an estimated period of 24 months]
Assessed per RECIST v1.1
Disease control rate (DCR) [Up to an estimated period of 24 months]
Assessed per RECIST v1.1
Duration of response (DoR) [Up to an estimated period of 24 months]
Assessed per RECIST v1.1
Progression-Free Survival (PFS) [Up to an estimated period of 24 months]
Assessed per RECIST v1.1
Overall Survival (OS) [Up to an estimated period of 24 months]
Assessed per RECIST v1.1
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
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).]
Oral clearance (CL/F) of KO-2806 and the combination agent
Vd/F [Cycle 1. Each cycle is 28 days. (Dose escalation and dose expansion).]
Oral volume of distribution (Vd/F) of KO-2806 and the combination agent
QTcF [Up to day 7 following first dose of KO-2806. Dose escalation.]
QT interval corrected for heart rate (HR) using Fridericia's formula (QTcF) for KO-2806 monotherapy (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 [Up to 24 hours following first dose of KO-2806. Dose escalation.]
Renal clearance of KO-2806 excretion in urine
t1/2 of KO-2806 excretion in urine [Up to 24 hours following first dose of KO-2806. Dose escalation.]
Half-life of KO-2806 excretion in urine
Relative bioavailability of KO-2806 formulations [Up to 24 hours following first dose of KO-2806. Dose expansion.]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.