Ipilimumab and Dabrafenib in the 1st Line Tx of Unresectable Stage III/IV Melanoma

Exclusion Criteria

• •Concurrent therapy with any other non-protocol anti-cancer therapy
• •Prior systemic treatments with either ipilimumab or a BRAF inhibitor (such as vemurafenib or dabrafenib).
• •Prior local therapy within 2 weeks (for both phases I and II) or prior systemic therapy within 4 weeks of starting protocol treatment (phase I).
• •For phase II: Any prior systemic therapy for locally advanced or metastatic melanoma. Prior local therapy such as radiation or intratumoral injection is allowed. Previous systemic treatment for any stage III disease that was subsequently rendered NED (no evidence of disease) by surgery is allowed.
• •Brain metastases (except if all known lesions were previously treated with surgery or stereotactic radiosurgery and lesions, if still present, are confirmed stable for greater than or equal to 2 weeks prior to enrollment, and are asymptomatic with no corticosteroid requirements for greater than or equal to weeks prior to randomization, and no enzyme inducing anticonvulsants for greater than or equal to 2 weeks prior to randomization). Brain MRI or CT is required at screening.
• •Anyone with a second malignancy expected to require cytotoxic chemotherapy or immune modulating therapy within 3 months of enrollment
• •Pre-existing autoimmunity: History of inflammatory bowel disease; history of symptomatic autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis \[scleroderma\], systemic lupus erythematosus, autoimmune vasculitis \[e.g., Wegener's Granulomatosis\]); motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre Syndrome). Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
• •No concurrent systemic corticosteroids (or other systemic immunosuppressant's), including oral steroids (i.e. prednisone, dexamethasone), continuous use of topical steroid creams or ointments, or ophthalmologic steroids. If a subject is currently taking corticosteroids, treatment should be discontinued two weeks prior to starting protocol therapy. Occasional use of steroid inhalers is allowed.
• •Any serious or uncontrolled medical disorder or active infection that, in the opinion of the investigator, may increase the risk associated with study participation, study drug administration, or would impair the ability of the subject to receive protocol therapy.
• •Any known positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
• •Herbal remedies (e.g., St. John's wort) within 1 week of enrollment.
• •Drugs that are strong inhibitors or inducers of CYP3A or CYP2C8, p-glycoprotein (Pgp) or Bcrp transporter because they may alter dabrafenib concentrations. The list may be modified based on emerging data; consider therapeutic substitutions for these medications. Patients must be off treatment for at least 1 week prior to enrollment.
• •A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency.
• •The presence of any other medical or psychiatric disorder that, in the opinion of the treating physician, would contraindicate the use of the drugs in this protocol or place the subject at undue risk for treatment complications
• •Pregnancy or breast feeding
• •A history of a severe hypersensitivity reaction to ipilimumab or dabrafenib
• •Any reason why, in the opinion of the investigator, the patient should not participate