Defactinib and VS-6766 for the Treatment of Patients With Metastatic Uveal Melanoma

NCT04720417 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: 20P.1113JT 16166
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

Brief Summary

This phase II trial studies the effect of combining defactinib and VS-6766 in treating patients with uveal melanoma that has spread to other places in the body (metastatic). The way cells communicate with one another (different cell signaling pathways) are overactive in uveal melanoma tumor cells. Giving defactinib together with VS-6766 may block pathways that are important for the growth of uveal melanoma cells, and may result in shrinkage or stabilization of the cancer and prolonged time to disease progression and survival.

Conditions

Metastatic Uveal Melanoma

Outcome Measures

Primary Outcomes (2)

• Best Overall Response

  Defined as complete response (CR) + partial response (PR) + stable disease (SD) and determined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

  From baseline through last follow-up visit (up to 24 months per participant)

• Disease Control Rate

  Defined as CR+PR+SD and determined by RECIST criteria version 1.1. All estimates of rates will be presented with corresponding 95% exact confidence intervals. For disease control rates, the method of Atkinson and Brown will be used to allow for the two-stage design.

  From baseline through last follow-up visit (up to 24 months per participant)

Secondary Outcomes (3)

• Progression-free Survival (PFS)

  From first dose of study drug until disease progression or death (whichever occurs first). Up to 24 months per participant.

• Overall Survival (OS)

  From first dose of study drug until disease progression or death (whichever occurs first). Up to 14 months.

• Incidence of Adverse Events

  From baseline through last follow-up visit (up to 14 months)

Other Outcomes (10)

• Changes in Tumor Metabolic Activity

  Baseline up to 28 days after the last dose of treatment

• Changes in Signaling to the ERK Pathways

  Baseline up to 28 days after the last dose of treatment

• Changes in Cell Proliferation (Ki67)

  Baseline up to 2 years after the last patient is enrolled

Study Arms (1)

Treatment (defactinib, VS-6766)

EXPERIMENTAL

Patients receive defactinib PO BID and VS-6766 PO BIW (Monday and Thursday or Tuesday and Friday) for 3 weeks in every cycle. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

Drug: Defactinib Hydrochloride; Drug: Raf/MEK Inhibitor VS-6766; Procedure: Biopsy

Interventions

Defactinib Hydrochloride DRUG

Given PO

Also known as: 1073160-26-5, Benzamide, N-methyl-4-((4-(((3-(methyl(methylsulfonyl)amino)-2-pyrazinyl)methyl)amino)-5-(trifluoromethyl)-2-pyrimidinyl)amino)-Hydrochloride (1:1), PF-04554878, VS-6063

Treatment (defactinib, VS-6766)

Raf/MEK Inhibitor VS-6766 DRUG

Given PO

Also known as: CH5126766, 946128-88-7, CH-5126766, CKI-27, R-7304, RG 7304, RG-7304, RO-5126766 FREE BASE, RO5126766, VS 6766, VS-6766, AVUTOMETINIB

Treatment (defactinib, VS-6766)

Biopsy PROCEDURE

Undergo tumor biopsy

Also known as: BIOPSY_TYPE, Bx

Treatment (defactinib, VS-6766)

Eligibility Criteria

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

You may qualify if:

• Histologically confirmed metastatic uveal melanoma
• Predicted life expectancy of at least 12 weeks
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 based on spiral computed tomography (CT) or magnetic resonance imaging (MRI) scan, all radiology studies must be performed within 28 days prior to registration. Corrected QT interval (QTc) \< 470 ms (as calculated by the Fridericia correction formula, averaged over 3 electrocardiograms \[ECGs\])
• Hemoglobin (Hb) \>= 9.0 g/dL (performed within two weeks \[day -14 to day 1\] before the patient goes on the trial)
• Absolute neutrophil count (ANC) \>= 1.5 x 10\^9/L (performed within two weeks \[day -14 to day 1\] before the patient goes on the trial)
• Platelet count \>= 100 x 10\^9/L (performed within two weeks \[day -14 to day 1\] before the patient goes on the trial)
• Serum bilirubin =\< 1.5 x upper limit of normal (ULN) (performed within two weeks \[day -14 to day 1\] before the patient goes on the trial)
• Albumin \>= 3.0 mg/dL (performed within two weeks \[day -14 to day 1\] before the patient goes on the trial)
• Creatine phosphokinase (CPK) =\< 2.5 x ULN (performed within two weeks \[day -14 to day 1\] before the patient goes on the trial)
• Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) =\< 2.5 x ULN unless raised due to tumor in which case up to 5 x ULN is permissible (performed within two weeks \[day -14 to day 1\] before the patient goes on the trial)
• Calculated creatinine clearance \>= 45 mL/min by the Cockcroft-Gault formula (performed within two weeks \[day -14 to day 1\] before the patient goes on the trial)
• International normalized ratio (INR) =\< 1.5 in absence of anticoagulation or therapeutic levels in presence of anticoagulation (performed within two weeks \[day -14 to day 1\] before the patient goes on the trial)
• Partial thromboplastin time (PTT) =\< 1.5 x ULN in absence of anticoagulation or therapeutic levels in presence of anticoagulation (performed within two weeks \[day -14 to day 1\] before the patient goes on the trial)
• Patients with adequate cardiac function (left ventricular ejection fraction \>= 50%) by echocardiography or multigated acquisition scan (MUGA) scan

You may not qualify if:

• Radiotherapy (except for palliative reasons), endocrine therapy, biological therapy, immunotherapy or chemotherapy during the previous four weeks (six weeks for nitrosoureas, Mitomycin-C) before treatment.
• Ongoing toxic manifestations of previous treatments. Exceptions to this are alopecia or certain Grade 1 toxicities, which in the opinion of the Investigator and the DDU should not exclude the patient.
• Known untreated or active central nervous system (CNS) metastases (progressing or requiring corticosteroids for symptomatic control). Patients with a history of treated CNS metastases are eligible, provided they meet all of the following criteria:
• Evaluable or measurable disease outside the CNS is present.
• Radiographic demonstration of improvement upon the completion of CNS- directed therapy and no evidence of interim progression between the completion of CNS- directed therapy and the baseline disease assessment for at least 28 days.
• Gilbert syndrome diagnosed with elevated indirect (unconjugated) bilirubin ( \>1.2 mg/dl) at least two occasions with normal direct bilirubin in the absence of hemolysis or structural liver damage.
• Ability to become pregnant (or already pregnant or lactating). However, those female patients who have a negative serum or urine pregnancy test before enrollment and agree to use two medically approved forms of contraception (oral, injected or implanted hormonal contraception and condom, have an intra-uterine device and condom, diaphragm with spermicidal gel and condom) from time of consent, during the trial and for six months afterwards are considered eligible.
• Male patients with partners of child-bearing potential (unless they agree to take measures not to father children by using one form of medically approved contraception \[condom plus spermicide\] during the trial and for six months afterwards). Men with pregnant or lactating partners should be advised to use barrier method contraception (for example, condom plus spermicidal gel) to prevent exposure to the fetus or neonate.
• Major surgery within 4 weeks prior to entry to the study (excluding placement of vascular access), or minor surgery within 2 weeks of entry into the study and from which the patient has not yet recovered.
• Treatment with warfarin. Patients on warfarin for DVT/PE can be converted to low-molecular-weight heparin (LMWH).
• Acute or chronic pancreatitis.
• At high medical risk because of non-malignant systemic disease including active uncontrolled infection.
• Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV).
• Patients with the inability to swallow oral medications or impaired gastrointestinal absorption due to gastrectomy or active inflammatory bowel disease.
• History of abdominal fistula, gastro-intestinal perforation, or diverticulitis.

Sponsors & Collaborators

• Thomas Jefferson University: lead
• Verastem, Inc.: collaborator

Study Sites (1)

Sidney Kimmel Cancer Center at Thomas Jefferson University

Philadelphia, Pennsylvania, 19107, United States

Location

Related Publications (1)

• Ramms DJ, Raimondi F, Arang N, Herberg FW, Taylor SS, Gutkind JS. Galphas-Protein Kinase A (PKA) Pathway Signalopathies: The Emerging Genetic Landscape and Therapeutic Potential of Human Diseases Driven by Aberrant Galphas-PKA Signaling. Pharmacol Rev. 2021 Oct;73(4):155-197. doi: 10.1124/pharmrev.120.000269.

  PMID: 34663687 DERIVED

MeSH Terms

Conditions

Uveal Melanoma

Interventions

benzamide; defactinib; RO5126766; Biopsy

Condition Hierarchy (Ancestors)

Melanoma; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Uveal Neoplasms; Eye Neoplasms; Neoplasms by Site; Eye Diseases; Uveal Diseases

Intervention Hierarchy (Ancestors)

Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Specimen Handling; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Investigative Techniques

Results Point of Contact

• Title: Rino Seedor, MD
• Organization: Thomas Jefferson University

Rino.Seedor@Jefferson.edu

215-955-8874

Study Officials

• Rino Seedor, MD

  Thomas Jefferson University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

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

Study Record Dates

• First Submitted: December 7, 2020
• First Posted: January 22, 2021
• Study Start: January 26, 2021
• Primary Completion: April 30, 2024
• Study Completion: April 30, 2024
• Last Updated: July 15, 2025
• Results First Posted: July 15, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)