Pevonedistat and Ruxolitinib in Treating Participants with Myelofibrosis

Inclusion Criteria

• Confirmed diagnosis of primary myelofibrosis or post-polycythemia vera / essential thrombocythemia myelofibrosis classified as high risk, intermediate-2 risk, or intermediate 1 risk by International Prognostic Scoring System (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 complete response (CR) by International Working Group (IWG) criteria
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• 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 (Patients with Gilberts disease must have total bilirubin =< 3 mg/dl for enrollment and pevonedistat treatment)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (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 [e.g., calendar, ovulation, symptothermal, postovulation methods] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception)
• Male patients, even if surgically sterilized (i.e., 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 [e.g., 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 Institutional Review Board (IRB) approved written informed consent document (or that of legally authorized representative, if applicable)

Exclusion Criteria

• History of allogeneic stem cell transplant
• Major surgery within 14 days before the first dose of any study drug or a scheduled surgery during the study period
• Received hydroxyurea therapy within 28 days (4 weeks) before the first dose of any study drug
• Systemic antineoplastic therapy or radiotherapy for other malignant conditions within 14 days before the first dose of any study drug
• Currently receiving any other investigational agents
• Treatment with clinically significant metabolic enzyme inducers within 14 days before the first dose of study drug; clinically significant metabolic enzyme inducers are not permitted during the study
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to pevonedistat, ruxolitinib, or other agents used in the study
• Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of study procedures
• Diagnosis or treated for another malignancy within 2 years before enrollment, or previously diagnosed with another malignancy and have any evidence of residual disease; patients with non-melanoma skin cancer or carcinoma in situ of any time are not excluded if they have undergone resection
• Ongoing or active infection
• Known cardiopulmonary disease defined as: * Unstable angina pectoris * Congestive heart failure (New York Heart Association [NYHA] class III or IV) * Myocardial infarction within 6 months prior to first dose (patients who had ischemic heart disease such as acute coronary syndrome (ACS), myocardial infarction (MI), and/or revascularization more than 6 months prior to enrollment and who are without cardiac symptoms may enroll) * Symptomatic cardiomyopathy * Clinically significant cardiac arrhythmia ** History of polymorphic ventricular fibrillation or Torsade de Pointes ** Permanent atrial fibrillation (a fib), defined as continuous a fib for >= 6 months ** Persistent a fib, defined as sustained a fib lasting > 7 days and/or requiring cardioversion in the 4 weeks before screening ** Grade 3 a fib defined as symptomatic and incompletely controlled medically, or controlled with device (e.g. pacemaker) or ablation ** Patients with Paroxysmal a fib or < grade 3 a fib for a period of at least 6 months are permitted to enroll provided that their rate is controlled on a stable regimen * Implantable cardioverter defibrillator * Moderate to severe aortic and/or mitral stenosis or other valvulopathy (ongoing)
• Clinically significant pulmonary hypertension requiring pharmacologic therapy
• Uncontrolled coagulopathy or bleeding disorder
• Uncontrolled high blood pressure (i.e. systolic blood pressure > 180 mmHg, diastolic blood pressure > 95 mmHg)
• Prolonged rate corrected QT (QTc) interval >= 500 msec, calculated according to institutional guidelines
• Left ventricular ejection fraction (LVEF) < 50% as assessed by echocardiogram or radionuclide angiography
• Known moderate to severe chronic obstructive pulmonary disease, interstitial lung disease, or pulmonary fibrosis
• Known hepatic cirrhosis or severe pre-existing hepatic impairment
• Known central nervous system (CNS) involvement
• Pregnant and/or breastfeeding; women of childbearing potential must have a negative pregnancy test within 14 days of study entry
• Female patients who intend to donate eggs and male patients who intended to donate sperm during the course of this study or for 4 months after receiving the last dose of study treatment
• Female patients who are both lactating and breastfeeding or have positive serum pregnancy test during the screening period or a positive urine pregnancy test on day 1 before first dose of study drug
• Known human immunodeficiency virus (HIV)-positivity
• Chronic, active, or acute viral hepatitis A, B, or C infection, or hepatitis B or C carrier
• Life-threatening illness unrelated to cancer