KO-2806 Monotherapy and Combination Therapies in Advanced Solid Tumors

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

• Darlifarnib · DRUG

  Oral administration

• Cabozantinib · DRUG

  Oral administration

• Adagrasib · DRUG

  Oral administration

Published eligibility criteria

Verbatim from the registry. Only the site can decide how these apply to a specific patient.

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.

Sites (38)

• Mayo Clinic Comprehensive Cancer Center, Phoenix, Arizona · RECRUITING
• University of Arizona, Tucson, Arizona · RECRUITING
• University of Southern California, Los Angeles, California · RECRUITING
• Cedars-Sinai Medical Center, Los Angeles, California · RECRUITING
• UCLA Department of Medicine, Los Angeles, California · RECRUITING
• Sarah Cannon Research Institute at HealthONE, Denver, Colorado · RECRUITING
• AdventHealth Celebration, Celebration, Florida · RECRUITING
• Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida · RECRUITING
• Florida Cancer Specialists, Sarasota, Florida · RECRUITING
• University of Iowa Hospitals & Clinics, Iowa City, Iowa · RECRUITING
• Dana-Farber Cancer Institute, Boston, Massachusetts · RECRUITING
• Henry Ford Health System, Detroit, Michigan · RECRUITING
• Mayo Clinic Comprehensive Cancer Center, Rochester, Minnesota · RECRUITING
• Washington University School of Medicine, St Louis, Missouri · RECRUITING
• Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey · RECRUITING
• Ohio State University, Columbus, Ohio · RECRUITING
• OU Stephenson Cancer Center, Oklahoma City, Oklahoma · RECRUITING
• UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania · RECRUITING
• SCRI - Oncology Partners, Nashville, Tennessee · RECRUITING
• UT Southwestern Simmons Cancer Center, Dallas, Texas · RECRUITING
• MD Anderson Cancer Center, Houston, Texas · RECRUITING
• University of Wisconsin (Carbone Cancer Center), Madison, Wisconsin · RECRUITING
• Centre Leon Berard, Lyon, France · RECRUITING
• Oncologie médicale - Pitié-Salpêtrière, Paris, France · RECRUITING
• Hopital Européen Georges Pompidou, Paris, France · RECRUITING
• Institut Universitaire du Cancer Toulouse - Oncopole, Toulouse, France · RECRUITING
• Charité - Universitätsmedizin Berlin, Berlin, Germany · RECRUITING
• Universitätsklinikum Ulm, Ulm, Germany · RECRUITING
• Universitätsklinikum Würzburg, Würzburg, Germany · RECRUITING
• Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpighi IRCCS, Bologna, Italy · RECRUITING
• Fondazione Piemonte per l'Oncologia - IRCCs Candiolo, Candiolo, Italy · RECRUITING
• Istituto Nazionale Tumori IRCCS, Naples, Italy · RECRUITING
• Humanitas University, Rozzano, Italy · RECRUITING
• AOU Verona - Centro Ricerche Cliniche di Verona, Verona, Italy · RECRUITING
• Hospital Universitari Vall d'Hebron, Barcelona, Spain · RECRUITING
• Hospital de la Santa Creu i de Sant Pau, Barcelona, Spain · RECRUITING
• Hospital HM Sanchinarro START Madrid-CIOCC, Madrid, Spain · RECRUITING
• Hospital Universitario Virgen del Rocío, Seville, Spain · RECRUITING