A Study of APG-1252 in Patients With Myelofibrosis Who Progressed After Initial Therapy

Inclusion Criteria: * Histologically or cytologically confirmed myelofibrosis requiring therapy including: 1. Either primary or post essential thrombocythemia/polycythemia vera 2. Have intermediate-2 or high-risk myelofibrosis by International Prognostic Scoring System (IPSS) scoring system 3. If intermediate-1 myelofibrosis must have palpable splenomegaly ≥ 5 cm below left costal margin 4. Either in chronic (CP) or accelerated phase (AP) 5. Patients can be either JAK2 wild type or JAK2V617F mutated * Patients must be ineligible or unwilling to undergo a stem cell transplantation or receive any other approved standard of care at the time of study entry * Patients have been previously treated with a JAK inhibitor (JAKi) and are intolerant, resistant, refractory or lost response to the JAKi ruxolitinib or fedratinib, or had sub-optimal response to ruxolitinib. Patients in Part 1 will be those ineligible to receive ruxolitinib and other approved standard of care. (Patients will be defined as having received sub-optimal response to ruxolitinib if, they achieved inadequate response to ruxolitinib based therapy after 6 months of treatment, or had been on a stable dose of ruxolitinib based therapy for \< 24 weeks and had shown initial response but in opinion of investigators were unlikely to benefit from continuing dose and schedule of ruxolitinib). * Eastern Cooperative Oncology Group (ECOG) performance score of 0-2 * Adequate bone marrow function: 1. Absolute neutrophil count (ANC) ≥ 0.750 X 10˄9/L 2. Hemoglobin (Hb) ≥ 9.0 g/dL 3. Platelets count ≥ 50 X 10˄9/L (independent of transfusion within14 days of first dose) 4. International normalized ratio (INR), prothrombin time (PT) or activated partial thromboplastin time (aPTT) ≤1.5 X upper limit of normal (ULN) unless the subject is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants * Adequate renal and liver function as indicated by: 1. Direct bilirubin \< 2.0 mg/dL (unless Gilbert's syndrome and evidence of hemolysis) 2. Serum creatinine \< 1.5 mg/dL, if \>1.5 mg/dL, creatinine clearance must be ≥ 50 mL/min 3. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 3 x upper limit of normal (unless considered to be related to myelofibrosis or patient has known history of Gilberts) 4. Alkaline phosphatase \< 2.5 x ULN 5. Albumin ≥ 2.5g/dl * Willingness to use contraception method that is deemed effective by the investigator by female patients of child bearing potential (postmenopausal women amenorrhea for at least 12 months to be considered of non-childbearing potential) and males with partners of child bearing potential, throughout the treatment period and for at least three months following the last dose of study drug * Ability to understand and willingness to sign a written informed consent form * Willingness and ability to comply with study procedures and follow-up examination Exclusion Criteria: * Received standard or experimental therapy within 14 days or 5 half-lives (whichever is greater) before starting study therapy * Previously received other B-cell lymphoma-extra large (Bcl-xL) inhibitors * Receiving concomitant anticancer therapy, except hormonal therapy and patients on ruxolitinib * Disease associated with myelofibrosis such as metastatic carcinoma, lymphoma, myelodysplasia, hairy cell leukemia, mast cell disease or acute leukemia * Radiation within 14 days of study entry, thoracic radiation within 28 days of study entry * Has gastrointestinal conditions that could affect the absorption of oral medication * Has known active central nervous system (CNS) involvements * Lack of toxicity recovery from previous therapy ≤ grade 1 or baseline (except alopecia, hemoglobin, neutropenia and thrombocytopenia) * Use of therapeutic anticoagulants * Failure to recover adequately, as judged by the investigator, from prior surgical procedures. Patients with active wound healing, patients who have had major surgery within 28 days from study entry, and patients who have had minor surgery within 14 days of study entry * Unstable angina, or other significant cardiac condition including: 1. Unstable arrhythmia on treatment including permanent cardiac pacemaker 2. History of symptomatic congestive heart failure (New York Heart Association \[NYHA\] Class III or IV) 3. History of myocardial infarction within 6 months of enrollment 4. Current unstable angina 5. Family history of long QT syndrome or corrected QT interval (QTc) (Fridericia or Bazett) \> 480 msec * Active infection requiring systemic antibiotic/ antifungal medication, known clinically active hepatitis B or C infection, or on antiretroviral therapy for HIV disease * Uncontrolled concurrent illness including, but not limited to: psychiatric illness/social situations that would limit compliance with the study requirements or any other condition or circumstance that would, in the opinion of the investigator, make the patient unsuitable for participation in the study * Women who are pregnant, breast feeding or women of child-bearing potential (WOCBP) not using an effective method of birth control. WOCBP are sexually active mature women who have not undergone a hysterectomy or who have not been achieved post-menopause for at least 12 consecutive months. WOCBP must have a negative serum pregnancy test with 72 hours of receiving the first dose of study medication * Male patients whose sexual partners are WOCBP not using effective birth control