Clear Cell Renal Cell Carcinoma (ccRCC), Colorectal Cancer (CRC), Non Clear Cell Renal Cell Carcinoma (nccRCC), Non Small Cell Lung Cancer (NSCLC), Pancreatic Ductal Adenocarcinoma (PDAC), Renal Cell Carcinoma (Kidney Cancer), Solid Tumors With HRAS Alterations
Conditions
Keywords
HRAS, KRAS, NRAS, Farnesyltransferase inhibitor (FTI), Tyrosine Kinase inhibitor (TKI), Phase 1, KRAS G12C inhibitor, NSCLC, ccRCC, RCC, PDAC, CRC
Brief summary
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.
Interventions
DRUGDarlifarnib
Oral administration
DRUGCabozantinib
Oral administration
DRUGAdagrasib
Oral administration
Sponsors
Kura Oncology, Inc.
Mirati Therapeutics Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
France, Germany, Italy, Spain, United States
Contacts
CONTACTKura Medical Information
Outcome results
None listed