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

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.

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