A Phase II Study of BVD-523 in Metastatic Uveal Melanoma

This research study is a Phase II clinical trial. Phase II clinical trials test the safety
and effectiveness of an investigational drug to learn whether the drug works in treating a
specific disease. "Investigational" means that the drug is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved BVD-523 as a treatment for
any disease.

BVD-523 has been tested in patients with solid tumors to determine the highest dose of
BVD-523 that can be safely given to patients.

In this research study, the investigators are evaluating the role of BVD-523 in the treatment
of patients with uveal melanoma. Genetic changes within metastatic uveal melanoma activate
proteins in the MAPK protein signaling pathway which leads to tumor growth. In the laboratory
BVD-523 works against one of these proteins called ERK to decrease tumor growth. In this
study, the investigators are testing BVD-523 to see if it works to treat metastatic uveal
melanoma.

Inclusion Criteria:

- Participants must have histologically or cytologically confirmed stage IV uveal
melanoma

- Participants must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
non-nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional
techniques or as ≥10 mm with spiral CT scan, MRI, or calipers by clinical exam. See
Section 11 for the evaluation of measurable disease.

- Patients can have received any number of prior therapies for treatment of their uveal
melanoma excluding prior treatment with an ERK inhibitor. Patients who have received
prior MEK inhibition or other MAPK targeted agents will be allowed on study.

- Age ≥ 18 years of age.

- ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)

- Life expectancy of greater than 6 months

- Participants must have normal organ and marrow function as defined below:

- leukocytes ≥3,000/mcL

- hemoglobin ≥9.0 g/dL

- absolute neutrophil count ≥1,500/mcL

- platelets ≥100,000/mcL

- total bilirubin ≤1.5 × institutional upper limit of normal AST(SGOT)/ALT(SGPT)
≤2.5 × institutional upper limit of normal, unless there is known liver
involvement in which case ≤5.0 × institutional upper limit of normal

- creatinine within normal institutional limits OR

- creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels
above institutional normal.

- Participants must have adequate cardiac function, e.g. left ventricular ejection
fraction (LVEF) of >50% as assessed by multi-gated acquisition (MUGA) or
ultrasound/echocardiography (ECHO); corrected QT interval (QTc) <470ms.

- Presence of metastatic disease that would be amenable to the required biopsies.
Ideally pre and post biopsies should be from the same lesion and otherwise from
lesions in the same organ. If not possible, then biopsy of the lesions in different
organs will be permitted.

- The effects of BVD-523 on the developing human fetus are unknown. For this reason and
because ERK inhibitors could potentially be teratogenic, women of child-bearing
potential and men must agree to use adequate contraception (hormonal or barrier method
of birth control; abstinence) prior to study entry, for the duration of study
participation, and 4 months after completion of BVD-523 administration. Should a woman
become pregnant or suspect she is pregnant while she or her partner is participating
in this study, she should inform her treating physician immediately. Men treated or
enrolled on this protocol must also agree to use adequate contraception prior to the
study, for the duration of study participation, and 4 months after completion of
BVD-523 administration.

- Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

- Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C), small molecule targeted therapy (i.e. - kinase
inhibitors) within 3 weeks or the last dose of antibody therapy within 4 weeks prior
to entering the study or those who have not recovered from adverse events due to
agents administered more than 4 weeks earlier.

- Participants who are receiving any other investigational agents.

- Major surgery within 4 weeks of the first dose of BVD-523. Tumor embolization
procedure or ablation procedure within 2 weeks of first dose of BVD-523.

- Participants with known brain metastases or evidence of leptomeningeal involvement are
eligible only if these lesions are treated and both clinically and radiographically
stable for at least four weeks. Patients are eligible if they are being treated with a
stable dosage of steroids/anticonvulsants, requiring no dose increase for 4 weeks.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to BVD-523.

- Participants receiving any medications or substances that are known to be strong
inhibitors of CYP1A2, CYP2D6, and CYP3A4 or strong inducers of CYP3A4 are ineligible.
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. As part of the
enrollment/informed consent procedures, the patient will be counseled on the risk of
interactions with other agents, and what to do if new medications need to be
prescribed or if the patient is considering a new over-the-counter medicine or herbal
product.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Pregnant women are excluded from this study because BVD-523 is an ERK with the
potential for teratogenic or abortifacient effects. Because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with BVD-523 breastfeeding should be discontinued if the mother is treated with
BVD-523.

- Gastrointestinal (GI) condition which could impair absorption of study medication or
inability to ingest study medication.

- A history of current evidence/risk of retinal vein occlusion (RVO) or central serous
retinopathy (CSR)

- Concomitant malignancies or previous malignancies with less than 2 years of
disease-free interval at the time of enrollment (except non-melanoma skin cancer,
cervical cancer in situ, prostate cancer with undetectable PSA). Other concurrent
malignancies must be discussed with the medical monitor prior to enrollment.

- Patients with melanoma of cutaneous, mucosal or acral-lentiginous origin or of unknown
primary.