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

Kura Oncology

Status and phase: Enrolling; Phase 1

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

Treatments: Drug: Adagrasib; Drug: Cabozantinib; Drug: Darlifarnib

Study type: Interventional

Funder types: Industry

Identifiers

NCT06026410

KO-2806-001

Details and patient eligibility

About

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.

Enrollment: 300 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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300 participants in 7 patient groups

Arm #1: RAS-altered advanced solid tumors, monotherapy (escalation phase)

Experimental group

Description:

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

Treatment:

Drug: Darlifarnib

Arm #2: Advanced or metastatic RCC, combination therapy (escalation phase)

Experimental group

Description:

Patients who have received at least 1 prior systemic therapy with immuno-oncology (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

Treatment:

Drug: Darlifarnib

Drug: Cabozantinib

Arm #3: Advanced or metastatic NSCLC, CRC, or PDAC, combination therapy (escalation phase)

Experimental group

Description:

Patients with KRAS G12C-mutant locally advanced or metastatic NSCLC, CRC, or PDAC who have received at least 1 prior systemic therapy including available approved standard of care treatments

Treatment:

Drug: Darlifarnib

Drug: Adagrasib

Arm #4: Advanced or metastatic ccRCC, combination therapy (expansion phase)

Experimental group

Description:

Patients must be cabozantinib-naïve and have received at least 1 prior systemic therapy with IO-based treatment for locally advanced or metastatic ccRCC

Treatment:

Drug: Darlifarnib

Drug: Cabozantinib

Arm #5: Advanced or metastatic ccRCC, monotherapy (expansion phase)

Experimental group

Description:

Patients must be cabozantinib-naïve and have received at least 1 prior systemic therapy with IO-based treatment for locally advanced or metastatic ccRCC

Treatment:

Drug: Cabozantinib

Arm #6: Advanced or metastatic ccRCC, cabozantinib rollover to combination therapy (expansion phase)

Experimental group

Description:

Patients must be cabozantinib-naïve and have received at least 1 prior systemic therapy with IO-based treatment for locally advanced or metastatic ccRCC

Treatment:

Drug: Darlifarnib

Drug: Cabozantinib

Arm #7: Advanced or metastatic NSCLC, combination therapy (expansion phase)

Experimental group

Description:

Patients with KRAS G12C-mutant locally advanced or metastatic NSCLC who have received at least 1 prior systemic therapy including available approved standard of care treatments

Treatment:

Drug: Darlifarnib

Drug: Adagrasib