Polycythemia Vera

Randomized, Open Label, Multicenter Phase III Study of Efficacy and Safety in Polycythemia Vera Subjects Who Are Resistant to or Intolerant of Hydroxyurea: JAK Inhibitor INC424 Tablets Versus Best Available Care (The RESPONSE Trial)

 The study is sponsored by Incyte Corporation in collaboration with Novartis Pharmaceuticals.

 NCT01243944

 48 medical centers in North America.

 300 patients.

This phase III, randomized, open label, multi-center trial will compare the JAK inhibitor INC424 to best available care. Eligiblity criteria are as follows: adults with a diagnosis of polycythemia vera for at least 24 weeks who have splenomegaly with leukocytosis and/or thrombocytosis, who are resistant to or intolerant of hydroxyurea, and who have undergone at least two phlebotomies over a 24-week period preceding enrollment. The randomization ratio is 1:1. Best available therapy is selected by the investigator for each subject and may include hydroxyurea (at a tolerated dose), anagrelide, interferon, or an immunomodulatory agent (e.g., lenalidomide or thalidomide). After week 32, subjects are allowed to cross over from best available therapy to INC424.

The trial’s primary outcome measure is the proportion of clinical responses to INC424 by week 32 compared with best available therapy. Clinical response criteria are the absence of phlebotomy, a 35 percent or greater reduction in spleen volume, or both. Secondary objectives include comparison of both the proportion of patients who attain a complete hematologic response by week 32 and the proportion of subjects who obtain a response by week 32 and maintain that response for a total duration of 48 weeks.

 Phlebotomy and low-dose aspirin are accepted as the initial standard of care for patients with low-risk polycythemia vera. However, many patients eventually require treatment with hydroxyurea because of poor tolerance of phlebotomy, progressive splenomegaly, or high risk of thrombotic complications. But treatment with hydroxyurea can result in unacceptable myelosuppression or other intolerable side effects, such as lower extremity ulcers, and the therapeutic index of second-line drugs including anagrelide, interferon, and immunomodulatory agents is suboptimal. Therefore, development of alternative therapeutic agents is warranted. More than 95 percent of polycythemia vera cases are positive for JAK2 activating mutations. The JAK2 inhibitor INC424 has demonstrated clinical response rates of ~45 percent and a favorable toxicity profile in phase II testing in patients with advanced myeloproliferative neoplasms regardless of JAK2 mutational status.

 The RESPONSE trial is a pivotal study as a favorable outcome will expand the therapeutic options for patients with polycythemia vera who are resistant to or intolerant of hydroxyurea. Ongoing studies comparing hydroxyurea to pegylated interferon as initial treatment of patients with high-risk polycythemia vera, however, could influence the sequence in which available therapeutic agents are used. A number of JAK2 inhibitors are in various stages of development, and well-designed clinical trials are required to define optimal use of these agents (including INC424) for the treatment of polycythemia vera and other neoplasms in which aberrant activation of the JAK-STAT pathway underlies disease pathophysiology.