EphB4-HSA Fusion Protein and Cytarabine /or Liposomal Vincristine in Patients With Recurrent or Refractory Acute Leukemia

• Confirmed diagnosis of relapsed or refractory acute leukemia (acute myeloid leukemia, acute lymphoblastic leukemia, blast crisis of chronic myeloid leukemia [CML], secondary AML from prior myelodysplastic syndrome [MDS] / myeloproliferative neoplasm [MPN]); minimum of 5% blasts in the bone marrow or 10% blasts in circulation
• Patients with Philadelphia chromosome (Ph)+ ALL or blast crisis of CML must be refractory (not intolerant) to at least 2 second/third generation ABL kinase inhibitors (TKI)

• For AML: patients must belong to one of the following ?high risk? categories:

  • Primary induction failure (PIF) as defined by failure to achieve at least a 50% reduction in bone marrow blasts after one cycle of high intensity, anthracycline containing induction regimen or failure to achieve complete response (CR)/complete remission with incomplete blood count recovery (CRi) after two cycles of high intensity chemotherapy
  • First early relapse as defined by an initial remission duration of fewer than 6 months
  • Second or subsequent relapse regardless of remission duration, or
  • Relapse after allogeneic or autologous stem cell transplantation (first relapse after stem cell transplant would be eligible, regardless of prior duration of remission)

• Patients with MDS who transform to AML while on hypomethylator agents or patients with AML who progress on hypomethylator agents could be considered for arm A of this trial if

  • They choose not to be treated on or are ineligible for the investigator's competing trial of sEPHB4-HSA + hypomethylator (9L-16-6)
  • They are appropriate for high dose cytarabine treatment

• For ALL: patients must belong to one of the following ?high risk? categories:

  • Primary refractory as defined by failure to achieve CR after induction and at least one salvage therapy
  • Second or subsequent relapse
  • Relapse after allogeneic or autologous stem cell transplantation (requirement for second relapse does not apply post-transplant)
  • All variants of ALL including T-ALL, B / myeloid, lymphoblastic leukemia lymphoma are eligible
• Patients with myeloid diseases (AML, myeloid blast crisis of CML) will be eligible for arm A with cytarabine; patients with lymphoid diseases (ALL, lymphoid blast crisis of CML) will be eligible for arm B with liposomal vincristine; patients with leukemia of ambiguous lineage or bi-phenotypic leukemia (e.g. B/myeloid) may be treated on either arm A or B, at discretion of treating physician
• Performance status Eastern Cooperative Oncology Group (ECOG) 0 to 2
• Life expectancy > 2 months
• Total bilirubin ? 3 X upper limit of normal (ULN), unless attributable to Gilbert syndrome
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) / alanine transaminase [ALT] (serum glutamic pyruvic transaminase [SPGT]) ? 5 X institutional upper limit of normal
• Creatinine: glomerular filtration rate (GFR) > 30 as calculated by modification of diet in renal disease (MDRD) equation
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately

• A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

  • Has not undergone a hysterectomy or bilateral oophorectomy; or
  • Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)
• No major surgery within 4 weeks of first dose of sEPHB4
• Peripheral blood blast count ? 30,000 at time of eligibility assessment (within 7 days of start of therapy); blast counts that increase beyond 30,000 after a patient is deemed eligible will not disqualify the patient
• For subjects with prior allogeneic stem cell transplant, no evidence of active graft-versus host disease (GVHD), and must be ? 2 weeks off immunosuppressive therapy
• Ability to understand and the willingness to sign a written informed consent

Exclusion Criteria:

• Diagnosis of acute promyelocytic leukemia (M3 classification)
• ALL patient refractory to their first induction only or their first relapse, will be excluded; they must be refractory to at least one salvage therapy, or relapse after first salvage, to be eligible
• ALL patients refractory to liposomal vincristine as defined by progression while on therapy or relapse within 3 months of completion of therapy with liposomal vincristine
• Prior malignancy requiring therapy within the last 12 months (excluding non-melanoma skin cancer); hormone therapy for prostate cancer or adjuvant endocrine therapy for breast cancer would not be excluded
• Patient is receiving other investigational agents

• Active central nervous system (CNS) disease

  • Definition: any patient receiving active CNS therapy (defined as more than 1 intrathecal treatment per week or current radiation therapy to brain); if patient has a history of CNS disease: must have cerebrospinal fluid (CSF) sampling within 28 days of enrollment that is negative for leukemia; intrathecal chemotherapy for patients without active CNS disease is allowed (e.g., ongoing primary or secondary prophylaxis for patients who cleared the CSF prior to study enrollment); CSF sample is not required for enrollment for patients with no history of CNS disease

• Chemotherapy within 2 weeks of first dose of sEPHB4-HSA (minimum of 6 weeks for nitrosoureas and 8 weeks for bone marrow transplantation) with the following exceptions:

  • Hydroxyurea allowed prior to, and up to day +5 of cycle 0 of treatment (max 100 mg/kg/day)
  • Corticosteroids allowed until day -3 (max dexamethasone 20mg/day)
  • Maintenance chemotherapy for ALL allowed one week prior to start of treatment (e.g., POMP)
• Grade ? 2 toxicity (other than alopecia) continuing from prior anticancer therapy, including radiation
• Patients with Charcot-Marie-Tooth disease or other demyelinating diseases are excluded from the liposomal vincristine containing arm
• New York Heart Association class 3 or 4 heart failure; myocardial infarction, acute coronary syndrome, diabetes mellitus with ketoacidosis, or chronic obstructive pulmonary disease (COPD) requiring hospitalization in the preceding 6 months; or any other intercurrent medical condition that contraindicates treatment with sEPHB4-HSA or places the patient at undue risk for treatment related complications
• Uncontrolled active systemic infections
• Known history of human immunodeficiency virus (HIV) or active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV); patients with HBV and/or HCV sero-positivity only will be eligible, if nucleic acid amplification testing (NAT) is negative
• Warfarin (any dose) or full-dose anticoagulation with other agents (low molecular weight heparin, antithrombin agents, anti-platelet agents and full dose aspirin) within 7 days prior to first dose of study drug; patients on prophylactic doses of low-molecular weight heparin are allowed