Open Label Phase I Study of Single Agent Oral RG7388 in Patients With Polycythemia Vera and Essential Thrombocythemia (With Pilot Feasibility Study in Combination With Pegylated Interferon Alfa 2a for Patients Who do Not Respond to the Single Agent at Each Dose Level)
This research looks at two conditions, Essential Thrombocythemia (ET) and Polycythemia Vera (PV). ET causes people to produce too many blood cells called platelets and PV causes too many platelets and red blood cells to be made. Platelets are particles which circulate in the blood stream and normally prevent bleeding and bruising. Having too many platelets in the blood increases the risk of developing blood clots, which can result in life threatening events like heart attacks and strokes. When the number of red blood cells is increased in PV this will slow the speed of blood flow in the body and increase the risk of developing blood clots. The purpose of Part A of this study is to test the safety and tolerability of drug RG7388 patients and identify the recommended phase II dose in a single agent dose escalation study. The investigators want to find out what effects, good and/or bad it has on the disease. The purpose of Part B of this study is to test the safety and tolerability of the combination of RG7388 and Pegylated Interferon Alfa-2a or Pegasys in PV/ET patients from Part A who did not achieve at least a partial response by the end of three cycles of single agent RG7388. Essential Thrombocythemia (ET) and Polycythemia Vera (PV) have been difficult diseases to treat. RG7388 is a selective inhibitor of the p53-MDM2 binding that frees p53 from negative control and activates the p53 pathway in cancer cells, leading to cell cycle arrest and apoptosis in vitro and in vivo. It has been used to treat solid tumors and Acute Myelogenous Leukemia (AML) in clinical trials. Pegasys is a drug that is the standard of care for patients who have Chronic Hepatitis B (CHB). RG7388 is a drug that is not yet approved by the Federal Drug Administration (FDA) for the treatment of patients with essential thrombocythemia or polycythemia vera. Pegasys is a drug that is approved by the FDA for the treatment of CHB. The use of RG7388 alone and in combination with Pegasys is experimental.
⁃ (Patient should meet all the criteria)
⁃ JAK2V617F-positive PV or JAK2V617F-positive ET (confirmed by WHO diagnostic criteria)
⁃ High risk ET/PV [age >60; history of thrombosis] or low risk disease with symptoms [recurrent headaches, paresthesias, pruritus]
⁃ Previously treated with at least one other agent [hydroxyurea, interferon, anagrelide] and determined to be either intolerant/resistant
• ≥18 years of age
⁃ Eastern Cooperative Oncology Group (ECOG) Performance status 0-2
⁃ Acceptable pre-study organ function during screening as defined as: Total bilirubin ≤ 1.5 times the upper limit of normal (ULN) unless due to Gilbert's disease or hemolysis, Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times ULN, Serum creatinine ≤ 1.5 x ULN
⁃ Women of childbearing potential and males must agree to use adequate contraception (i.e., hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a female subject become pregnant or suspect she is pregnant while participating in this study, she should inform the treating physician immediately
⁃ Ability to understand and willingness to sign a written informed consent document.