Clinical Trials /

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

NCT03519984

Description:

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.

Related Conditions:
  • Acute Leukemia
  • Chronic Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: EphB4-HSA Fusion Protein and Cytarabine /or Liposomal Vincristine in Patients With Recurrent or Refractory Acute Leukemia
  • Official Title: A Phase I Dose Escalation Study With Expansion to Evaluate the Safety of SEPHB4-HSA in Combination With Cytarabine or Liposomal Vincristine in Patients With Relapsed or Refractory Acute Leukemia

Clinical Trial IDs

  • ORG STUDY ID: 9L-17-15
  • SECONDARY ID: NCI-2018-00680
  • SECONDARY ID: 9L-17-15
  • SECONDARY ID: P30CA014089
  • NCT ID: NCT03519984

Conditions

  • Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
  • Blasts 5 Percent or More of Bone Marrow Nucleated Cells
  • Myelodysplastic/Myeloproliferative Neoplasm
  • Philadelphia Chromosome Positive
  • Recurrent Acute Lymphoblastic Leukemia
  • Recurrent Adult Acute Myeloid Leukemia
  • Refractory Acute Lymphoblastic Leukemia
  • Refractory Acute Myeloid Leukemia
  • Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • Secondary Acute Myeloid Leukemia
  • T Acute Lymphoblastic Leukemia

Interventions

DrugSynonymsArms
Cytarabine.beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-Beta-D-arabinofuranosylcytosine, 1.beta.-D-Arabinofuranosylcytosine, 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-, 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-, Alexan, Ara-C, ARA-cell, Arabine, Arabinofuranosylcytosine, Arabinosylcytosine, Aracytidine, Aracytin, Aracytine, Beta-cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453Arm A (sEPHB4-HSA, cytarabine)
Recombinant EphB4-HSA Fusion ProteinsEphB4-HSAArm A (sEPHB4-HSA, cytarabine)
Vincristine LiposomalLipid-Encapsulated Vincristine, Liposomal Vincristine, Onco TCS, Vincacine, VincaXome, Vincristine Liposome, Vincristine, LiposomalArm B (sEPHB4-HSA, vincristine liposomal)

Purpose

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.

Detailed 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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (sEPHB4-HSA, cytarabine)ExperimentalParticipants receive recombinant EphB4-HSA fusion protein 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.
  • Cytarabine
  • Recombinant EphB4-HSA Fusion Protein
Arm B (sEPHB4-HSA, vincristine liposomal)ExperimentalParticipants 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.
  • Recombinant EphB4-HSA Fusion Protein
  • Vincristine Liposomal

Eligibility Criteria

        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:

               -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 24 months
Safety Issue:
Description:Will be assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.03 and summarized for each course separately.

Secondary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:Up to 24 months
Safety Issue:
Description:Will be calculated for all patients who achieve a CR or CRi from first documentation ofCR or CRi to recurrence or death.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Southern California

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