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.
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 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 31, 2023
Eligibility 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.
Gender
All
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Rino Seedor, MD, 215-955-4687, [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
Rino Seedor, MD, Principal Investigator, Thomas Jefferson University
Verification Date
January 2023