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)

The Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPNs) are a group of hematopoietic stem cell malignancies that include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). PV and ET can evolve into myelofibrosis, termed post PV/ET MF. ET, PV and PMF have variable tendencies to transform to blast phase disease with a dismal prognosis. JAK2V617F is a point activating mutation resulting in the constitutive activity of the JAK-STAT pathway within hematopoietic cells in approximately 96%, 50%, and 50% of patients with PV, ET, and MF, respectively.

Polycythemia Vera is characterized by an absolute increase in red cell mass. Patients with PV have a median survival if untreated of approximately 18 months from the time of diagnosis and treated of approximately 18 years. PV-related symptoms include headache, weakness, dizziness, epigastric distress, and pruritus. PV-related signs include hypertension, gout, left upper abdominal quadrant pain, high hematocrit, leukocytosis, and thrombocytosis. Major causes of reduced survival include thrombosis (29%), bleeding (7%), evolution to myelofibrosis (3%), transformation to acute leukemia (23%), and solid tumors (16%). PV patients are stratified for risk of thrombosis by age >60 and history of prior thrombotic events. Therapy for low risk PV includes low dose aspirin and therapeutic phlebotomy to maintain a hematocrit <45% in a man and 42% in a woman. Cardiovascular risk factor modification such as weight loss, control of hypertension and hypercholesterolemia, and smoking cessation are also important adjunctive approaches to all patients with PV. High risk patients are also treated with cytoreductive therapy in the form of hydroxyurea to further reduce the risk of thrombotic complications.

Essential Thrombocythemia is characterized by persistent isolated thrombocytosis and tendency for arterial and venous thrombosis. A similar pattern of symptoms as noted above with PV are also seen in patients with ET. The median survival of patients with ET is similar to that of age and sex matched cohort and in some patients is limited by thrombotic complications (22%), evolution to MF (10%), and acute leukemia (2%) (Barbui. J Clin Oncol. 2011; 29(23):3179). Risk stratification for occurrence of thrombosis is based on age >60 years and/or history of thrombosis. Additionally, cardiovascular risk factors and persistent thrombocytosis >1.5 x 109/L are believed to influence thrombotic risk and leukemic transformation has been shown to be associated with anemia, older age, and leukocytosis. JAK2V617F is present in approximately 50% of cases and helps establish a diagnosis of a clonal thrombocytosis, and has been shown in some studies to predict for a higher risk of thrombosis and potential for transformation to PV. Management is aimed at reducing thrombotic risk with the use of low dose aspirin in low risk patients (no risk factors) and cytoreductive therapy in high risk patients (at least one risk factor). Hydroxyurea, anagrelide, and interferon (IFN) have all been used to maintain a platelet count below 400 x 109/L in patients with a history of thrombosis (secondary prophylaxis). Currently, hydroxyurea is considered standard of care for high risk ET patients based on the results of the PT-1 study which demonstrated superiority of hydroxyurea over anagrelide in arterial thrombosis risk reduction and worsening marrow reticulin fibrosis in patients receiving anagrelide (Harrison N Engl J Med. 2005;353(1):33). Hydroxyurea is associated with a risk of oral and skin ulcers, rash, and unacceptable myelosuppression that can sometimes limit use in patients with ET/PV. Additionally, some patients are unable to achieve adequate control of blood counts at doses below 2000 mg/daily and this has been termed "resistance". Importantly, although a theoretical concern of leukemogenic potential of hydroxyurea exists, based on the mechanism of action of this chemotherapeutic agent, there are no definitive prospective studies clearly documenting an increased risk of leukemic transformation.

More recently, a renewed interest in interferon-α for the treatment of PV as an alternative therapeutic approach has led to the evaluation of pegylated interferon-α 2a (Pegasys, Roche) in several phase II studies. Pegasys has an improved toxicity profile over intron-a and can be self-administered by the patient on a weekly basis. Currently, Pegasys is being evaluated in two large international trials within the myeloproliferative disorder research consortium (MPD-RC). The MPD-RC 111 study is a phase II study intended to evaluate the response by European LeukemiaNet (ELN) criteria in patients with high risk ET/PV who are intolerant or resistant to hydroxyurea therapy treated with Pegasys. In addition, patients with documented JAK2V617F and splanchnic vein thrombosis are also eligible for this clinical trial. MPD-RC 112 is a phase III study for newly diagnosed high risk PV/ET patients in which patients are randomized to either Pegasys or hydroxyurea with a primary endpoint of response rate comparison between the two treatment arms.

The use of intron-a (rIFN-α) and Pegasys has been extensively studied in patients with PV and reported rates of discontinuation in the first year of therapy range from 14-40%. Objective hematologic responses are seen in approximately 80% of treated patients and achievement in complete phlebotomy free state in 60% of PV patients. Trials of Pegasys in the treatment of PV have further demonstrated major molecular responses of 19% and complete eradication of JAK2V617F in 14-24% of patients. Although hematologic remission can often be achieved within months of starting rIFN-α treatment, molecular responses require longer term administration and are rarely seen before completion of 12 months of therapy. Additionally, sustained molecular remissions have been documented in patients that have discontinued therapy for up to 30 months of follow up. In a retrospective review of 118 MPN patients receiving Pegasys throughout multiple MPN centers included 55 PV patients with an ORR of 87% (54% CR, 33% PR) by ELN criteria [21]. In this review, the most common non-hematologic toxicities were Grade 1-3 fatigue in 24 patients (20%), Grade 1 liver function test (LFT) elevation in 7 (6%), and Grade 1-2 skin/allergic reaction in 6 (5%). Adverse effects leading to discontinuation were primarily non-hematologic, although one patient (<1%) discontinued Pegasys therapy due to Grade 2 anemia.