Clinical Trials /

Defactinib (VS-6063) Combined With VS-6766 in Patients With Metastatic Uveal Melanoma

NCT04720417

Description:

This is a Phase II study investigating the combination of Defactinib (VS-6063) and VS-6766 in patients with uveal melanoma that has spread (metastasized)to other parts of the body. Aberrant activity within cellular pathways facilitates the uncontrolled cell growth that results in cancers. Defactinib (VS-6063) and VS-6766 are drugs that may inhibit such aberrant activity and thus prevent tumor growth. Giving these two drugs together may be an effective way to treat patients with metastatic uveal melanoma.

Related Conditions:
  • Uveal Melanoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 20P.1113
  • NCT ID: NCT04720417

Conditions

  • Uveal Melanoma

Interventions

DrugSynonymsArms
VS-6063DefactinibTreatment
VS-6766CH5126766Treatment

Purpose

This is a Phase II study investigating the combination of Defactinib (VS-6063) and VS-6766 in patients with uveal melanoma that has spread (metastasized)to other parts of the body. Aberrant activity within cellular pathways facilitates the uncontrolled cell growth that results in cancers. Defactinib (VS-6063) and VS-6766 are drugs that may inhibit such aberrant activity and thus prevent tumor growth. Giving these two drugs together may be an effective way to treat patients with metastatic uveal melanoma.

Detailed Description

      Activating mutations in certain genes of G proteins (GNAQ and GNA11) are found in 80-90% of
      uveal melanoma cases. Mutant GNAQ and GNA11 signal to various cellular pathways, including
      the mitogen activated protein kinase (MAPK) pathway, which is involved in tumor cell growth.
      MEK and RAF are among the protein kinases that make up this pathway. Over activity of this
      pathway is involved in tumor growth. Unfortunately, interventions seeking to inhibit the MAPK
      pathway alone have failed to provide statistically significant clinical benefit in metastatic
      uveal melanoma. FAK is another protein kinase that effects cancer cells and their
      environment. It is associated with drug resistance, as it can be activated in cancer cells
      when it is exposed to other signal inhibitors. Recent research has shown that FAK has the
      potential to help establish an immunosuppressive tumor microenvironment, suggesting FAK may
      have an impact on the facilitation of anti-tumor immunity. Uveal melanoma represents the
      human cancer harboring the highest level of FAK overexpression. The combination of MEK and
      FAK inhibition may synergistically inhibit uveal melanoma growth.
    

Trial Arms

NameTypeDescriptionInterventions
TreatmentExperimentalParticipants will be treated with a combination of Defactinib (VS-6063) plus VS-6766 given on an intermittent schedule. Defactinib (200mg) will be taken orally in repeating 28-day cycles twice a day for 3 weeks followed by 1 week without drug (3 weeks on, 1 week off). VS-6766 (3.2mg) will be taken orally in repeating 28-day cycles twice a week for 3 weeks followed by 1 week without any drug (3 weeks on, 1 week off). Treatment may continue until maximum clinical benefit is obtained, the development of unacceptable side-effects or disease progression is confirmed.
  • VS-6063
  • VS-6766

Eligibility Criteria

        Inclusion Criteria:

          1. Histologically confirmed metastatic uveal melanoma.

          2. Predicted life expectancy of at least 12 weeks.

          3. ECOG performance status of 0 or 1.

          4. Measurable disease according to RECIST 1.1 based on spiral CT or MRI scan, all
             radiology studies must be performed within 28 days prior to registration.

          5. Corrected QT interval (QTc) < 470 ms (as calculated by the Fridericia correction
             formula, averaged over 3 ECGs).

          6. Hematological and biochemical indices within the ranges shown below. These
             measurements must be performed within two weeks (Day -14 to Day 1) before the patient
             goes on the trial. Laboratory Test Value required Hemoglobin (Hb) ≥ 9.0 g/dL Absolute
             neutrophil count (ANC) ≥ 1.5 x 109/L Platelet count ≥ 100 x 109/L Serum bilirubin ≤
             1.5 x upper limit of normal (ULN) Albumin ≥ 3.0 mg/dL Creatine phosphokinase (CPK) ≤
             2.5 x ULN Alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) ≤ 2.5 x ULN
             unless raised due to tumor in which case up to 5 x ULN is permissible Calculated
             creatinine clearance ≥ 45 mL/min by the Cockcroft-Gault formula INR ≤ 1.5 x ULN in
             absence of anticoagulation or therapeutic levels in presence of anticoagulation PTT ≤
             1.5 x ULN in absence of anticoagulation or therapeutic levels in presence of
             anticoagulation

          7. Patients with adequate cardiac function (left ventricular ejection fraction ≥ 50%) by
             echocardiography or MUGA scan.

          8. No active retinopathy/retinal vein occlusion confirmed by full ophthalmological exam.

          9. Adequate recovery from toxicities related to prior treatments to at least Grade 1 by
             CTCAE Version 5.0. Exceptions include alopecia and peripheral neuropathy grade ≤ 2.
             Patients with other toxicities that are stable on supportive therapy may be allowed to
             participate with prior approval by the Sponsor.

         10. Men and women aged 18 years or over.

         11. Females with reproductive potential and their male partners agree to use highly
             effective method of contraceptive (per Clinical Trial Facilitation Group [CFTG]
             recommendations in Appendix C during the trial and for 3 months following the last
             dose of study drug.

         12. Written (signed and dated) informed consent and be capable of cooperating with
             treatment and follow-up.

         13. Absence of any psychological, familial, sociological or geographical condition
             potentially hampering compliance with the study protocol and follow-up schedule.

        Exclusion Criteria:

          1. 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.

          2. 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.

          3. 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.

          4. 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.

          5. 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.

          6. 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.

          7. 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.

          8. Treatment with warfarin. Patients on warfarin for DVT/PE can be converted to
             low-molecular-weight heparin (LMWH).

          9. Acute or chronic pancreatitis.

         10. At high medical risk because of non-malignant systemic disease including active
             uncontrolled infection.

         11. Known to be serologically positive for hepatitis B, hepatitis C or human
             immunodeficiency virus (HIV).

         12. Patients with the inability to swallow oral medications or impaired gastrointestinal
             absorption due to gastrectomy or active inflammatory bowel disease.

         13. History of abdominal fistula, gastro-intestinal perforation, or diverticulitis.

         14. Patients with history of symptomatic cholelithiasis or cholecystitis within six months
             before enrollment.

         15. Concurrent ocular disorders:

               1. Patients with history of retinal vein occlusion (RVO), predisposing factors for
                  RVO, including uncontrolled hypertension, uncontrolled diabetes

               2. 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.

               3. 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.

         16. 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.

         17. 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.

         18. 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Best overall response and disease control rate by response criteria (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1
Time Frame:8 weeks
Safety Issue:
Description:Determination of best overall response (BOR) and disease control rate (DCR; Complete Response [CR] + Partial Response [PR] + Stable Disease [SD]) with corresponding 95% confidence intervals. The method of Simon's Optimal two-stage design will be used. For DCR, the method of Atkinson and Brown will be used to allow for two-stage design.

Secondary Outcome Measures

Measure:Progression-free Survival (PFS)
Time Frame:PFS will be calculated from date of trial entry to time of disease progression or death, whichever comes first.
Safety Issue:
Description:Time until documented disease progression and time until documented death
Measure:Overall Survival (OS)
Time Frame:OS will be calculated from date of trial entry to date of documented death.
Safety Issue:
Description:Time until documented death
Measure:Safety Assessment
Time Frame:Up until 28 days post final administration of study drug
Safety Issue:
Description:Determination of causality of adverse events and grading severity according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Thomas Jefferson University

Last Updated

January 22, 2021