Ruxolitinib Phosphate and Panobinostat in Treating Patients with Myelofibrosis

Inclusion Criteria

• Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed
• Intermediate-2 and higher by International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) post polycythemia vera (PV)/essential thrombocythemia (ET) MF and primary myelofibrosis (PMF) patients either in * Chronic phase (MF-chronic phase [CP]) * Accelerated phase (MF-accelerated phase [AP])
• Absolute neutrophil count >= .750 x 10^9/L
• Platelets >= 75 x 10^9/L
• Creatinine =< 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN
• Serum bilirubin =< 1.5 x ULN (unless Gilbert’s syndrome and evidence of hemolysis)
• Serum potassium >= lower limit of normal (LLN)
• Total serum calcium [corrected for serum albumin] or ionized calcium >= LLN
• Serum magnesium >= LLN
• Serum phosphorus >= LLN
• Free thyroxine (T4) within normal limits
• Eastern Cooperative Oncology Group (ECOG) performance status of =< 3
• Any prior therapy with JAK2-tyrosine kinase inhibitor (TKI), hypomethylating agents, histone deacetylase inhibitor (HDACI), mechanistic target of rapamycin inhibitor (mTORi), or immunomodulatory drugs (iMiDs) is allowed as long as it is greater than 3 weeks since last dose of administration and in the case of a JAK2-TKI or HDACI that discontinuation was not due to non-hematologic drug toxicity; an exception to this criteria are patients currently on at least 10mg BID of ruxolitinib for greater than 3 months and who have not shown an optimal response (i.e. without 50% reduction in palpable splenomegaly or 50% reduction in symptom burden); with a reduction of ruxolitinib to 10mg BID these patients may enter onto the study without stopping ruxolitinib

Exclusion Criteria

• Patients who will need valproic acid for any medical condition during the study or within 5 days prior to first PANOBINOSTAT treatment
• Impaired cardiac function or clinically significant cardiac diseases, including any one of the following: * With permanent cardiac pacemaker * Resting bradycardia defined as < 50 beats per minute * Corrected QT using Fridericia's method (QTcF) > 480 msec on screening electrocardiogram (ECG) * Complete left bundle branch block, bifascicular block * Any clinically significant ST segment and/or T-wave abnormalities * Presence of unstable atrial fibrillation (ventricular response rate > 100 beats per minute [bpm]); patients with stable atrial fibrillation can be enrolled provided they do not meet other cardiac exclusion criteria * Symptomatic congestive heart failure (New York Heart Association [NYHA] class III-IV)
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of PANOBINOSTAT or RUXOLITINIB
• Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes or active or uncontrolled infection) including abnormal laboratory values, that could cause unacceptable safety risks or compromise compliance with the protocol
• Patients using medications that have a relative risk of prolonging the QT interval or inducing torsade de pointes if treatment cannot be discontinued or switched to a different medication prior to starting study drug
• Concomitant use of strong CYP3A4 inhibitors
• Patients who have received targeted agents within 2 weeks or within 5 half-lives of the agent and active metabolites (whichever is longer) and who have not recovered from side effects of those therapies
• Chemotherapy within 3 weeks prior to screening are excluded (other than hydroxyurea at stable doses and will be discontinued 24 hours prior to starting study drug)
• Patients with an active bleeding tendency or are receiving any treatment with therapeutic doses of sodium warfarin (Coumadin) or coumadin derivatives; patients will be allowed to enter study on aspirin doses of 81 mg/d
• Patients who have undergone major surgery =< 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy
• Women who are pregnant or breast-feeding or women of childbearing potential (WOCBP) not using an effective method of birth control; WOCBP are defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months); women of childbearing potential must have a negative serum pregnancy test within 24 hrs of receiving the first dose of study medication
• Male patients whose sexual partners are WOCBP not using effective birth control
• Patients with a prior malignancy within the last 5 years (except for basal or squamous cell carcinoma, or in situ cancer of the cervix)
• Disease associated with secondary MF such as metastatic carcinoma, lymphoma, myelodysplasia, hairy cell leukemia, mast cell disease or acute leukemia (including M7 disease or acute panmyelosis with MF)