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.
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
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.
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
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
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
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.