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About
This phase I trial studies the side effects and best dose of recombinant EphB4-HSA fusion protein when given together with cytarabine or vincristine liposomal in treating participants with acute leukemia that has come back or has not responded to treatment. Drugs used in chemotherapy, such as recombinant ephb4-HSA fusion protein, cytarabine, and vincristine liposomal, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving the drugs in different combinations may kill more cancer cells.
Full description
PRIMARY OBJECTIVES:
I. Characterize the DLTs (dose limiting toxicities) and overall toxicity profile of recombinant EphB4-HSA fusion protein (sEPHB4-HSA) as a single agent and in combination with cytarabine or liposomal vincristine in patients with acute leukemia.
SECONDARY OBJECTIVES:
I. Estimate the clinical response (including minimal residual disease [MRD]) in blood and bone marrow of sEPHB4-HSA in combination with cytarabine in patients with relapsed/refractory acute myeloid leukemia.
II. Estimate the clinical response (including MRD) in blood and bone marrow of sEPHB4-HSA in combination with liposomal vincristine in patients with relapsed/refractory acute lymphoid leukemia.
III. Estimate the single agent clinical response of sEPHB4-HSA in blood and bone marrow of patients with relapsed/refractory acute myeloid leukemia (AML) or acute lymphoid leukemia (ALL).
IV. Assess pharmacokinetics of sEPHB4-HSA as a single agent and in combination with cytarabine or liposomal vincristine in patients with leukemia.
EXPLORATORY OBJECTIVES:
I. Estimate progression-free survival and overall survival in patients treated with sEPHB4-HSA in combination with cytarabine or liposomal vincristine.
II. Estimate percentage of patients proceeding to allogeneic stem cell transplantation.
III. Correlate expression of EPHB4 leukemic blasts and ephrinB2 in bone marrow microenvironment with response to sEPHB4-HSA.
IV. Evaluate the effect of sEPHB4-HSA on downstream protein mediators of the EPHB4 pathway (phosphorylated [p]AKT, pS6) on leukemic blasts and determine if these can be used as biomarkers of response to treatment.
V. Profile the immuno-modulatory effects of sEPHB4-HSA on peripheral blood leukocytes and in the tumor microenvironment.
OUTLINE: This is a dose-escalation study of recombinant EphB4-HSA fusion protein. Participants are randomized to 1 of 2 arms.
ARM A: Participants receive recombinant EphB4-HSA fusion protein intravenously (IV) over 60 minutes on days 1, 8, 15, and 22 and cytarabine IV over 4 hours on days 1-5. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.
ARM B: Participants receive recombinant EphB4-HSA fusion protein IV over 60 minutes on days 1, 8, 15, and 22 and vincristine liposomal IV over 60 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, participants are followed up at 3 months.
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Inclusion criteria
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:
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
For ALL: patients must belong to one of the following ?high risk? categories:
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:
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
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:
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
Primary purpose
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3 participants in 2 patient groups
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Data sourced from clinicaltrials.gov
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