A Phase 2 Study of Avutometinib (VS-6766) Plus Defactinib

NCT05512208 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: OU-SCC-DURAFAK
• Study Type: interventional
• Target: 55
• Locations: 1 country
• Sites: 4

Brief Summary

The purpose of this research is to test the effectiveness and safety of the study drugs (VS-6766 and defactinib), and see what effects (good and bad) these drugs have on the patients with endometrioid cancer, mucinous ovarian cancer, high-grade serous ovarian cancer, or solid gynecological cancer.

Conditions

Endometrioid Cancer; Mucinous Ovarian Cancer; High Grade Serous Ovarian Cancer; Cervical Cancer; Solid Tumor

Keywords

Avutometinib; defactinib; VS-6766

Outcome Measures

Primary Outcomes (1)

• Proportion of Patients with objective response rate

  To evaluate the efficacy of Avutometinib (VS-6766) + defactinib in endometrioid, MOC, HGSOC and solid gynecological cancer patients with RAS/BRAF/NF1 mutations on confirmed overall response rate (ORR; partial response \[PR\] + complete response \[CR\] defined according to RECIST 1.1) as assessed by the investigator.

  2 years

Secondary Outcomes (5)

• Incidence of Adverse Events

  2 years

• Duration of Response

  2 years

• Progression Free Survival

  2 years

• Disease Control Rate

  2 years

• Overall Survival

  2 years

Study Arms (1)

Avutometinib (VS-6766) + Defactinib

EXPERIMENTAL

Avutometinib (VS-6766): will be administered at 3.2 mg orally twice a week Defactinib: will be administered at 200 mg orally twice a day (BID).

Drug: Avutometinib (VS-6766) + defactinib

Interventions

Avutometinib (VS-6766) + defactinib DRUG

Avutometinib (VS-6766): will be administered at 3.2 mg orally twice a week Defactinib: will be administered at 200 mg orally twice a day (BID). Treatment will be for 3 weeks, followed by a 1-week rest period, in each 4-week (28 day) cycle.

Avutometinib (VS-6766) + Defactinib

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Female subjects ≥ 18 years of age.
• Histologically proven gynecological cancers (endometrioid, MOC, HGSOC and solid gynecological cancers) with mutated RAS, BRAF (type I, II, and/or III), NF-1 loss of function, and/or RAS activation.
• Mutational status will be taken from the previous next-gen sequencing (NGS) or molecular testing results and reviewed by the Principal Investigator prior to the start of treatment.
• Adequate pathology material (as defined in the lab manual) must be available prior to treatment assignment to be used for confirmation.
• Tumor with known RAS mutation, BRAF (type I, II, and/or III) mutation, NF-1 and/or RAS activation status determined from previous NGS or molecular testing. Adequate archival tumor tissue less than 5 years old or fresh biopsy tissue samples (as defined in the lab manual) must be available.
• Progression (radiographic or clinical) or recurrence of gynecological cancer after at least one prior systemic therapy for metastatic disease. Below are additional prior treatments that are allowed once the requirement of prior platinum therapy is satisfied.
• a. Prior systemic therapy for metastatic disease (FIGO stage II-IV) may consist of chemotherapy administered as single agent or a platinum or another chemotherapy doublet with or without bevacizumab, with or without maintenance therapy or radiation therapy; and/or hormonal therapy.
• Measurable disease according to RECIST 1.1.
• An Eastern Cooperative Group (ECOG) performance status ≤ 2.
• Must have adequate organ function defined by the following laboratory parameters:
• Adequate hematologic function including: hemoglobin \[Hb\] ≥9.0 g/dL; platelets ≥100,000/mm3; and absolute neutrophil count \[ANC\] ≥1500/mm3). If a red blood cell transfusion has been administered the Hb must remain stable and ≥9 g/dL for at least 1 week prior to first dose of study therapy.
• Adequate hepatic function: (i) total bilirubin ≤1.5 × upper limit of normal \[ULN\] for the institution; subjects with Gilbert syndrome may enroll if total bilirubin is \<3.0 mg/dL (51 μmole/L) upon discussion with the Principal Investigator (PI). (ii) alanine aminotransferase (ALT) and alanine aminotransferase (AST) ≤2.5 × ULN (or \<5x ULN in subjects with liver metastases).
• Adequate renal function with creatinine clearance rate of ≥50 mL/min as calculated by the Cockcroft-Gault formula or serum creatinine of ≤ 1.5 x ULN.
• International normalized ratio (INR) ≤ 1.5 and partial thromboplastin time (PTT) ≤ 1.5 x ULN in the absence of anticoagulation or therapeutic levels in the presence of anticoagulation.
• Albumin ≥3.0 g/dL (451 μmole/L).

You may not qualify if:

• Systemic anti-cancer therapy within 4 weeks of the first dose of study therapy.
• Prior MEKi or RAFi exposure.
• Low grade serous ovarian cancer (LGSOC).
• History of prior malignancy with recurrence \<3 years from the time of enrollment. Subjects with basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, and in situ cervical cancer that has undergone potentially curative therapy with no evidence of disease recurrence for ≥1 year since completion of the appropriate therapy may be included. Subjects with other malignancies associated with very low risk of metastasis or death may be included upon discussion with the PI.
• Subjects who are deemed in the opinion of their treating physician to be appropriate candidates for a debulking surgery. These subjects should preferentially receive surgery prior to consideration of trial therapy.
• Major surgery within 4 weeks (excluding placement of vascular access), minor surgery within 2 weeks, or palliative radiotherapy within 1 week (7 days) of the first dose of study therapy.
• Treatment with warfarin. Subjects on warfarin for DVT/PE can be converted to low-molecular weight heparin (LMWH) or direct oral anticoagulants (DOACs).
• Exposure to strong CYP2C9 and CYP3A4 inhibitors or inducers within 14 days prior to the first dose and during the course of therapy. See Table 14 and Table 15 for representative lists of CYP inhibitors and inducers. For additional guidance, see https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-druginteractions-table-substrates-inhibitors-and-inducers.
• Exposure to P-glycoprotein (P-gp) inhibitors or inducers within 14 days prior to the first dose and during the course of the study. See Table 16 for a representative list of P-gp inhibitors and inducers.
• Symptomatic brain metastases requiring steroids or other interventions. These metastases may manifest as altered mental status, persistent headaches, persistent nausea, focal weakness or numbness, and seizures. Subjects with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study entry, have discontinued corticosteroid treatment for these metastases for at least 2 weeks prior to first dose of study therapy, and are neurologically stable, with no evidence of interim progression. Subjects with new asymptomatic CNS metastases detected during the screening period must receive radiation therapy and/or surgery for CNS metastases. Following treatment, these subjects may then be eligible if all other criteria are met.
• Known SARS-Cov2 infection (clinical symptoms) ≤28 days prior to first dose of study therapy.
• Known hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection that is active and/or requires therapy.
• Active skin disorder that has required systemic therapy within the past year.
• History of rhabdomyolysis.
• Concurrent ocular disorders:

Sponsors & Collaborators

• University of Oklahoma: lead
• Verastem, Inc.: collaborator

Study Sites (4)

AdventHealth

Orlando, Florida, 32804, United States

RECRUITING

Louisiana State University Medical Center New Orleans

New Orleans, Louisiana, 70112, United States

RECRUITING

University of New Mexico Comprehensive Cancer Center

Albuquerque, New Mexico, 87131, United States

RECRUITING

Stephenson Cancer Center

Oklahoma City, Oklahoma, 73117, United States

RECRUITING

MeSH Terms

Conditions

Uterine Cervical Neoplasms

Interventions

defactinib

Condition Hierarchy (Ancestors)

Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Uterine Cervical Diseases; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases

Study Officials

• Christina Washington, MD

  OU Health Stephenson Cancer Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

SCC IIT Office

CONTACT

4052718777; SCC-IIT-Office@ouhsc.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: A single-stage exploratory, Phase 2, multicenter, parallel cohort, open label study designed to evaluate efficacy and safety of VS-6766 + defactinib.

Study Record Dates

• First Submitted: August 9, 2022
• First Posted: August 23, 2022
• Study Start: February 6, 2023
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2029
• Last Updated: October 22, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (4)