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

• ClinicalTrials.gov Identifier: NCT04720417
• Recruitment Status: Recruiting
• First Posted: January 22, 2021
• Last Update Posted: January 26, 2023
• Sponsor: Thomas Jefferson University
• Collaborator: Verastem, Inc.
• Information provided by (Responsible Party): Thomas Jefferson University

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Metastatic Uveal Melanoma	Drug: Defactinib Hydrochloride; Drug: Raf/MEK Inhibitor VS-6766; Procedure: Biopsy	Phase 2

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. 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 18 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Defactinib (VS-6063) Combined With VS-6766 (CH5126766) in Patients With Metastatic Uveal Melanoma
• Actual Study Start Date: January 26, 2021
• Estimated Primary Completion Date: October 31, 2023
• Estimated Study Completion Date: July 2024

Arms and Interventions

Arm

Intervention/treatment

Experimental: Treatment (defactinib, VS-6766); 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; Given PO; Other Names: 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; Drug: Raf/MEK Inhibitor VS-6766; Given PO; Other Names: CH5126766; 946128-88-7; CH-5126766; CKI-27; R-7304; RG 7304; RG-7304; RO-5126766 FREE BASE; RO5126766; VS 6766; VS-6766; AVUTOMETINIB; Procedure: Biopsy; Undergo tumor biopsy; Other Names: BIOPSY_TYPE; Bx

Outcome Measures

Primary Outcome Measures :

1. Best overall response [ Time Frame: Up to 2 years after the last patient is enrolled ]
   Defined as complete response (CR) + partial response (PR) + stable disease (SD) and determined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
2. Disease control rate [ Time Frame: Up to 2 years after the last patient is enrolled ]
   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.

Secondary Outcome Measures :

1. Progression-free Survival (PFS) [ Time Frame: From trial entry until the time of documented disease progression or death (whichever occurs first), assessed up to 2 years after the last patient is enrolled ]
   A Kaplan Meier graph and median PFS will be presented overall and by cohort.
2. Overall Survival (OS) [ Time Frame: From trial entry until the time of documented death, assessed up to 2 years after the last patient is enrolled ]
   A Kaplan Meier graph will be presented overall and by cohort.
3. Incidence of adverse events [ Time Frame: Up to 2 years after the last patient is enrolled ]
   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.

Other Outcome Measures:

1. Changes in tumor metabolic activity [ Time Frame: Baseline up to 28 days after the last dose of treatment ]
   Tumor samples will be analyzed
2. Changes in signaling to the ERK, YAP, FAK, and PI3K TOR pathways [ Time Frame: Baseline up to 28 days after the last dose of treatment ]
   Tumor samples will be analyzed.
3. Changes in cell proliferation (Ki67) [ Time Frame: Baseline up to 2 years after the last patient is enrolled ]
   Tumor samples will be analyzed.
4. Changes in apoptosis induction (caspase activation) [ Time Frame: Baseline up to 28 days after the last dose of treatment ]
   Tumor samples will be analyzed.
5. Changes in tumor microenvironment [ Time Frame: Baseline up to 28 days after the last dose of treatment ]
   Tumor samples will be analyzed.
6. Detection of biomarkers of resistance [ Time Frame: Up to 28 days after the last dose of treatment ]
   Tumor samples will be analyzed. The specific type and number of biomarkers from the tumor samples will be decided during the course of the study and documented in the study records.
7. Circulating free deoxyribonucleic acid (DNA) [ Time Frame: Up to 28 days after the last dose of treatment ]
   Will correlate circulating free DNA with cancer remission and predicting cancer relapse.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• 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
• 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

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 in the eye unaffected by uveal melanoma:

    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.

Contacts and Locations

Contacts

Contact: Rino Seedor, MD; 215-955-4687; rino.seedor@jefferson.edu

Locations

United States, Pennsylvania

Sidney Kimmel Cancer Center at Thomas Jefferson University; Recruiting

Philadelphia, Pennsylvania, United States, 19107

Contact: Rino Seedor, MD 215-955-4687 rino.seedor@jefferson.edu

Principal Investigator: Rino Seedor, MD

Sponsors and Collaborators

Thomas Jefferson University

Verastem, Inc.

Investigators

• Principal Investigator: Rino Seedor, MD; Thomas Jefferson University

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Thomas Jefferson University
• ClinicalTrials.gov Identifier: NCT04720417
• Other Study ID Numbers: 20P.1113
• First Posted: January 22, 2021
• Last Update Posted: January 26, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

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