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

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Brief Title

Defactinib and VS-6766 for the Treatment of 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

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.
    

Detailed Description

      PRIMARY OBJECTIVE:

      I. 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:

      I. 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:

      I. 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.

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

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Best overall response

Secondary Outcome

 Progression-free Survival (PFS)

Condition

Metastatic Uveal Melanoma

Intervention

Defactinib Hydrochloride

Study Arms / Comparison Groups

 Treatment (defactinib, VS-6766)
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

18

Start Date

January 26, 2021

Completion Date

July 2024

Primary Completion Date

October 2023

Eligibility Criteria

        Inclusion Criteria:

          1. Histologically confirmed metastatic uveal melanoma.

          2. Predicted life expectancy of at least 12 weeks.

          3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

          4. 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])

          5. Hemoglobin (Hb) >= 9.0 g/dL (performed within two weeks [day -14 to day 1] before the
             patient goes on the trial)

          6. 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)

          7. Platelet count >= 100 x 10^9/L (performed within two weeks [day -14 to day 1] before
             the patient goes on the trial)

          8. 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)

          9. Albumin >= 3.0 mg/dL (performed within two weeks [day -14 to day 1] before the patient
             goes on the trial)

         10. Creatine phosphokinase (CPK) =< 2.5 x ULN (performed within two weeks [day -14 to day
             1] before the patient goes on the trial)

         11. 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)

         12. 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)

         13. 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)

         14. 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)

         15. Patients with adequate cardiac function (left ventricular ejection fraction >= 50%) by
             echocardiography or multigated acquisition scan (MUGA) scan

         16. No active retinopathy or retinal vein occlusion confirmed by full ophthalmological
             exam

         17. 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

         18. Aged 18 years or over

         19. 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)

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

         21. 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.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Takami Sato, 215-955-8874, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT04720417

Organization ID

20P.1113


Responsible Party

Sponsor

Study Sponsor

Thomas Jefferson University

Collaborators

 Verastem, Inc.

Study Sponsor

Takami Sato, Principal Investigator, Thomas Jefferson University


Verification Date

February 2021