NAUTILUS: OKI-179 Plus Binimetinib in Patients with Advanced Solid Tumors in the RAS Pathway (Phase 1b) and NRAS-mutated Melanoma (Phase 2)

NCT05340621 | Completed Phase 1 FDA Drug

• 1 other identifier: OKI-179-230
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 12

Brief Summary

The NAUTILUS study is a Phase 1b/2, multi-center, open-label study in which patients with activating mutations in the RAS pathway (Phase 1b) and patients with NRAS-mutated Melanoma (Phase 2) will be treated with a combination of oral OKI-179 combined with the MEK inhibitor binimetinib.

Conditions

RAS Mutation; NRAS Gene Mutation; Melanoma

Outcome Measures

Primary Outcomes (5)

• Phase 1b: Incidence and severity of dose-limiting toxicities (DLTs)

  Incidence and severity of DLTs will be measured in the DLT-evaluable population during Cycle 1.

  First 28 days of treatment

• Phase 1b: Incidence and severity of adverse events (AEs)

  AEs will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0

  Phase 1b study duration (approximately 1.5 years)

• Phase 1b: Change in clinical laboratory abnormalities

  Changes from baseline through study treatment will be analyzed using NCI CTCAE version 5.0 grade criteria

  Baseline through 30 days after end of study treatment

• Phase 1b: Change in Eastern Cooperative Oncology Group (ECOG) performance status

  Phase 1b study duration (approximately 1.5 years)

• Phase 2: Objective response rate (ORR)

  Objective responses will be determined per RECIST version 1.1 criteria, and the ORR will be defined as the proportion of patients with the best overall confirmed response of complete response (CR) or partial response (PR) in the Efficacy-Evaluable Population

  Phase 2 study duration (approximately 3 years)

Secondary Outcomes (11)

• Phase 1b: Peak plasma concentration (Cmax) of OKI-179 and OKI-006

  First 28 days of treatment

• Phase 1b: Area Under the Plasma Concentration vs. Time Curve (AUC) of OKI-179 and OKI-006

  First 28 days of treatment

• Phase 1b: Objective response rate (ORR)

  Phase 1b study duration (approximately 1.5 years)

• Phase 1b: Clinical Benefit Rate (CBR)

  Phase 1b study duration (approximately 1.5 years)

• Phase 1b: Duration of Response (DOR)

  Phase 1b study duration (approximately 1.5 years)

Study Arms (1)

OKI-179 + binimetinib

EXPERIMENTAL

Drug: OKI-179 + binimetinib

Interventions

OKI-179 + binimetinib DRUG

Phase 1b: With a 3+3 dose escalation design, enrollment in Phase 1b will proceed until the MTD has been defined or the highest dose level has been reached. OKI-179 will be administered on a 4-days-on/3-days-off schedule, while binimetinib will be administered BID continuously. Phase 2: Patients will be treated with the RP2D.

OKI-179 + binimetinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Phase 1b: Solid tumor refractory to standard treatment, for which no standard therapy is available, or if the patient refuses standard therapy
• Phase 1b: Tumor has an activating mutation in the RAS pathway confirmed by any local or central laboratory, including but not limited to RAS, BRAF, NF1, and GNAQ/11
• Phase 1b: Prior MEK inhibitor exposure may be allowed per Sponsor agreement
• Phase 2: Histologically confirmed, metastatic melanoma with a confirmed NRAS mutation determined by a validated NRAS mutation detection kit performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory
• Phase 2: Prior ICI treatment with a programmed cell death 1 (PD-1) or programmed death ligand 1 (PD-L1) checkpoint inhibitor, or ineligible for this type of therapy
• Phase 2: Consent for a tumor biopsy or can provide a recent archival tumor biopsy sample (within 2 years)
• Phase 2: At least 1 measurable lesion based on RECIST version 1.1
• Eastern Cooperative Oncology Group performance status of 0 or 1
• Normal organ and marrow function as defined below:
• Absolute neutrophil count ≥ 1.5 × 109/L
• Platelets ≥ 100,000/μL
• Hemoglobin ≥ 9.0 g/dL (at least 1 week after packed red blood cells, if applicable)
• Total bilirubin within institutional ULN, unless patient has Gilbert's syndrome and has total bilirubin ≤ 2.5 × institutional ULN
• Alanine aminotransferase and aspartate aminotransferase ≤ 2.5 × institutional ULN or \< 5 × institutional ULN in the presence of liver metastasis
• Serum creatinine \< 1.5 × institutional ULN

You may not qualify if:

• Any of the prior treatments, as described below:
• Major surgery within 28 days of C1D1
• Chemotherapy or radiation within 2 weeks of C1D1
• Investigational agents within 4 weeks of C1D1 or \< 5 half-lives, whichever is shorter, or expected toxicity not resolved to CTCAE version 5.0 criteria of Grade ≤ 1, except for alopecia and ICI-related endocrinopathies managed with hormone replacement therapy
• Prior histone deacetylases inhibitors, MEK inhibitors (Phase 2 only), pan-deacetylating agents, or valproic acid for the treatment of cancer
• Untreated or symptomatic brain metastasis. Patients with previously treated brain metastasis who are not on corticosteroids and are clinically stable are eligible for enrollment, as are patients with small (\< 0.5 cm) untreated and asymptomatic brain metastases
• Known hypersensitivity to binimetinib or other MEK inhibitors
• Women who are pregnant or nursing
• Concomitant active malignancies or previous malignancies with \< 2-year disease-free interval at the time of enrollment. Patients with adequately resected basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, stage 1 prostate cancer, or other malignancies deemed to be cured by prior therapy in the judgment of the Investigator may enroll irrespective of the time of diagnosis
• Any severe concurrent medical or psychiatric condition (including active systemic infection requiring intravenous antibiotics, uncontrolled diabetes mellitus, symptomatic congestive heart failure, uncontrolled hypertension, or cardiac arrhythmia) which, in the judgment of the Investigator, would make the patient inappropriate for study participation
• Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following:
• History of acute myocardial infarction, acute coronary syndromes (including unstable angina, coronary artery bypass graft, coronary angioplasty or stenting) \< 6 months prior to start of study treatment
• Symptomatic congestive heart failure (Grade 2 or higher), history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality \< 6 months prior to the start of study treatment, except medically managed atrial fibrillation or paroxysmal supraventricular tachycardia
• Uncontrolled arterial hypertension despite medical management
• History or evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO) or any eye condition that would be considered a risk factor for CSR or RVO, such as uncontrolled glaucoma or ocular hypertension

Sponsors & Collaborators

• OnKure, Inc.: lead

Study Sites (12)

CTCA Phoenix, part of City of Hope

Phoenix, Arizona, 85027, United States

Location

University of California, San Francisco

San Francisco, California, 94143, United States

Location

University of Florida Health Cancer Center

Gainesville, Florida, 32610, United States

Location

Emory University Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

CTCA Atlanta, part of City of Hope

Newnan, Georgia, 30265, United States

Location

CTCA Chicago, part of City of Hope

Zion, Illinois, 60099, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Henry Ford Health System

Detroit, Michigan, 48202, United States

Location

Memorial Sloan-Kettering Cancer Center

New York, New York, 10065, United States

Location

Sarah Cannon Research Institute

Nashville, Tennessee, 37203, United States

Location

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

University of Virginia Health System

Charlottesville, Virginia, 22908, United States

Location

MeSH Terms

Conditions

Melanoma

Interventions

binimetinib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Ryan Sullivan, MD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 22, 2022
• First Posted: April 22, 2022
• Study Start: May 11, 2022
• Primary Completion: January 29, 2025
• Study Completion: January 29, 2025
• Last Updated: March 7, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (12)