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Metastatic Uveal MelanomaPhase 2NCT04720417

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

A Phase 2 study testing Defactinib Hydrochloride, Raf/MEK Inhibitor VS-6766 and Biopsy in people with Metastatic Uveal Melanoma, run by Thomas Jefferson University at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Metastatic Uveal Melanoma
What is being tested?
Defactinib Hydrochloride, Raf/MEK Inhibitor VS-6766 and Biopsy
Type of treatment
Surgery or procedure
Could I receive a placebo?
No, everyone receives an active treatment
How many people
13 participants
Where
1 siteUnited States
Study dates
26 Jan 2021to 30 Apr 2024
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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)
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  • 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
  • No active retinopathy or retinal vein occlusion confirmed by full ophthalmological exam in the eye unaffected by uveal melanoma
  • Adequate recovery from toxicities related to prior treatments to at least grade 1 by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Exceptions include alopecia and peripheral neuropathy grade =< 2. Subjects with other toxicities that are stable on supportive therapy may be allowed to participate with prior approval by the sponsor
  • Men and women aged 18 years or over
  • Females with reproductive potential and their male partners agree to use highly effective method of contraceptive (per Clinical Trial Facilitation Group [CFTG] recommendations during the trial and for 3 months following the last dose of study drug)
  • Written (signed and dated) informed consent and be capable of cooperating with treatment and follow-up
  • Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule

Who cannot join

  • 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.
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  • 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.
  • Patients with history of symptomatic cholelithiasis or cholecystitis within six months before enrollment.
  • Concurrent ocular disorders in the eye unaffected by uveal melanoma:
  • Patients with history of retinal vein occlusion (RVO), predisposing factors for RVO, including uncontrolled hypertension, uncontrolled diabetes
  • Patients with history of retinal pathology or evidence of visible retinal pathology that is considered a risk factor for RVO, intraocular pressure > 21 mm Hg as measured by tonometry, or other significant ocular pathology, such as anatomical abnormalities that increase the risk for RVO.
  • Patients with a history of corneal erosion (instability of corneal epithelium), corneal degeneration, active or recurrent keratitis, and other forms of serious ocular surface inflammatory conditions.
  • Concurrent congestive heart failure, prior history of class III/ IV cardiac disease (New York Heart Association [NYHA]), myocardial infarction within the last 6 months, unstable arrhythmias, unstable angina or severe obstructive pulmonary disease.
  • Patients exposed to strong CYP3A4 and strong CYP2C9 inhibitors within 7 days prior to the first dose. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the Physicians' Desk Reference may also provide this information.
  • Is a participant or plans to participate in another interventional clinical trial, whilst taking part in this Phase II study of VS-6766 in combination with VS-
  • 6063. Participation in an observational trial would be acceptable. 19. Patients with a history of hypersensitivity to any of the inactive ingredients (hydroxypropylmethylcellulose, mannitol, magnesium stearate) of the investigational product. 20. Prior corticosteroids as anti-cancer therapy within a minimum of 14 days of first receipt of study drugs. 21. Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Sidney Kimmel Cancer Center at Thomas Jefferson University

    Philadelphia, Pennsylvania, 19107

Other trials in United States

About this study

Official title: A Phase II Trial of Defactinib (VS-6063) Combined With VS-6766 (CH5126766) in Patients With Metastatic Uveal Melanoma

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.

Read the detailed description

PRIMARY OBJECTIVE:

  1. To investigate the potential efficacy of the combination of defactinib hydrochloride (defactinib [VS-6063]) and Raf/MEK serine/threonine kinase inhibitor RO5126766 (VS-6766) in patients with metastatic uveal melanoma.

SECONDARY OBJECTIVES:

  1. To assess the effectiveness of defactinib in combination with VS-6766 in patients with metastatic uveal melanoma (MUM).

II. To assess the safety and toxicity profile of the combination of defactinib and VS6766.

EXPLORATORY OBJECTIVES:

  1. To study the pharmacodynamic profile of defactinib in combination with VS-6766 in pre-treatment, on-treatment, and post-treatment tumor biopsies.

II. To investigate mechanisms of resistance to the combination of defactinib and VS-6766.

III. To investigate the potential efficacy of circulating cell free deoxyribonucleic acid (DNA) for prediction/monitoring.

OUTLINE:

Patients receive defactinib orally (PO) twice daily (BID) and VS-6766 PO twice a week (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. Patients undergo tumor biopsy at baseline, after cycle 1 or 2, and post-treatment.

After completion of study treatment, patients are followed every 3 months until death or up to 2 years after the last patient is enrolled.

Being tested
Defactinib Hydrochloride, Raf/MEK Inhibitor VS-6766, Biopsy
Medical subject headings
Uveal Melanoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Defactinib HydrochlorideDrug

    Also called 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

    Given PO

  • Raf/MEK Inhibitor VS-6766Drug

    Also called CH5126766, 946128-88-7, CH-5126766, CKI-27

    Given PO

  • BiopsyProcedure or surgery

    Also called BIOPSY_TYPE, Bx

    Undergo tumor biopsy

Study groups in NCT04720417
Study groupRoleWhat they receive
Treatment (defactinib, VS-6766)ExperimentalPatients 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.
Receives: Drug: Defactinib Hydrochloride; Drug: Raf/MEK Inhibitor VS-6766; Procedure: Biopsy

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

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

  2. 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.

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

Secondary outcomes (3)

  1. Progression-free Survival (PFS)

    A Kaplan Meier graph and median PFS will be presented overall and by cohort.

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

  2. Overall Survival (OS)

    A Kaplan Meier graph will be presented overall and by cohort.

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

  3. Incidence of Adverse Events

    Will determine causality of each adverse event to defactinib and VS-6766 and grading severity according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Estimates of toxicity rates will be presented with corresponding 95% exact confidence intervals. Safety variables will be summarized by descriptive statistics. Laboratory variables will be described using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Adverse events (AEs) will be reported for each dose level and presented as tables of frequency of AEs by body system and by worse severity grade observed.

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted22 Jan 2021
  2. Study start26 Jan 2021
  3. Primary completion30 Apr 2024
  4. Study completion30 Apr 2024

Why it stopped: Trial enrollment was stopped early by study sponsors (before the anticipated accrual of 18 patients) due to no patients having significant reduction in disease.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
13 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04720417
Sponsor's protocol ID
20P.1113
Other IDs
JT 16166
Status last verified
Jul 2025
First submitted
7 Dec 2020
Last updated
15 Jul 2025
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 34663687

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Defactinib Hydrochloride, Raf/MEK Inhibitor VS-6766 and Biopsy in people with Metastatic Uveal Melanoma, run by Thomas Jefferson University at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 21 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 15 Jul 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 15 Jul 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Best Overall Response (time frame: From baseline through last follow-up visit (up to 24 months per participant)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04720417, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Jul 2025.

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