Pevonedistat in Combination With Ruxolitinib for Treatment of Patients With Myelofibrosis

• Confirmed diagnosis of primary myelofibrosis or post-polycythemia vera/essential thrombocythemia myelofibrosis classified as high risk, intermediate-2 risk, or intermediate 1 risk by IPSS.

• On treatment with ruxolitinib for at least 3 months and have been on a stable dose for at least 8 weeks and have not achieved a CR by IWG criteria.

• At least 18 years of age.

• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

• Adequate bone marrow and organ function as defined below:

‣ Absolute neutrophil count ≥ 500/mcL, and have not received any growth factor support for at least 4 weeks prior to screening

⁃ Platelets ≥ 50,000/mcL

⁃ Peripheral blood blasts ≤ 10%

⁃ Albumin \> 2.7 g/dL

⁃ Total bilirubin ≤ institutional upper limit of normal (IULN); patients with Gilbert's syndrome may enroll if direct bilirubin ≤ 1.5 x IULN

⁃ ALT and AST ≤ 2.5 x IULN

⁃ Creatinine clearance ≥ 50 mL/min

• Female patients who:

‣ Are postmenopausal for at least 1 year before the screening visit, OR

⁃ Are surgically sterile, OR

⁃ If they are of childbearing potential:

• Agree to practice 1 highly effective method and 1 additional effective (barrier) method of contraception, at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug (female and male condoms should not be used together), OR

∙ Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[eg, calendar, ovulation, symptothermal, postovulation methods\] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)

• Male patients, even if surgically sterilized (ie, status postvasectomy), who:

‣ Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug (female and male condoms should not be used together), OR

⁃ Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[eg, calendar, ovulation, symptothermal, postovulation methods for the female partner\] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)

• Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable)