Recombinant EphB4-HSA Fusion Protein With Standard Chemotherapy Regimens in Treating Patients With Advanced or Metastatic Solid Tumors

PRIMARY OBJECTIVES:

I. To document the safety and tolerability of sEphB4-HSA (recombinant ephB4-HSA fusion
protein) intravenously (IV) weekly when administered in combination with: arm A) gemcitabine
(gemcitabine hydrochloride) and nab-paclitaxel (paclitaxel albumin-stabilized nanoparticle
formulation), arm B) docetaxel, arm C) gemcitabine and cisplatin.

SECONDARY OBJECTIVES:

I. To describe the adverse event profile of sEphB4-HSA IV weekly when administered in
combination with: arm A) gemcitabine and nab-paclitaxel, arm B) docetaxel, arm C) gemcitabine
and cisplatin.

II. To characterize the pharmacokinetics of sEphB4-HSA when combined with: arm A) gemcitabine
and nab-paclitaxel, arm B) docetaxel, arm C) gemcitabine and cisplatin.

III. To assess, in a preliminary fashion, the anti-tumor efficacy of sEphB4-HSA in
combination with the various chemotherapy regimens in each of the 4 cohorts separately: Arm A
cohort 1-patients with advanced pancreatic cancer; Arm B cohort 2-patients with head and neck
cancer; Arm B cohort 3-patients with non-small cell lung cancer; Arm C cohort 3: patients
with cholangiocarcinoma.

TERTIARY OBJECTIVES:

I. To evaluate the expression of EPH receptor B4 (EphB4) and ephrinB2 in the archival tumor
samples and explore potential associations with outcome.

II. To bank specimens for future correlative biomarkers studies based on the results of
ongoing biomarkers analyses in the phase I of sEphB4-HSA as a single agent.

OUTLINE: This is a dose de-escalation study of recombinant EphB4-HSA fusion protein. Patients
are assigned to 1 of 3 treatment arms.

ARM A: Patients receive recombinant EphB4-HSA fusion protein IV over 1 hour on days 1, 8, 15,
and 22 (beginning course 2), paclitaxel albumin-stabilized nanoparticle formulation IV over
30 minutes and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Courses
repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive recombinant EphB4-HSA fusion protein IV over 1 hour on days 1, 8, and
15 (beginning course 2) and docetaxel IV over 1 hour on day 1. Courses repeat every 21 days
in the absence of disease progression or unacceptable toxicity.

ARM C: Patients receive recombinant EphB4-HSA fusion protein IV over 1 hour on days 1, 8, and
15 (beginning course 2), cisplatin IV over 120 minutes and gemcitabine hydrochloride IV over
30 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease
progression or unacceptable toxicity.

In all arms, patients with chemotherapy related toxicity may continue treatment with
recombinant EphB4-HSA fusion protein alone. Patients with toxicity related to recombinant
EphB4-HSA fusion protein may continue treatment with chemotherapy at the discretion of the
investigator.

After completion of study treatment, patients are followed up periodically.

Inclusion Criteria:

- Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of
0 or 1

- Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors
(RECIST) version (v)1.1

- Patients must have a life expectancy of at least 12 weeks

- Patients must be able to comprehend and provide written informed consent

- Women of childbearing potential (WOCBP) and male patients with WOCBP partner must be
using an adequate method of contraception to avoid pregnancy throughout the study and
for up to 12 weeks after the last dose of investigational product in such a manner
that the risk of pregnancy is minimized; WOCBP include any female who has experienced
menarche and who has not undergone successful surgical sterilization (hysterectomy,
bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal; post
menopause is defined as:

- Amenorrhea >= 12 consecutive months without another cause or

- For women with irregular menstrual periods and on hormone replacement therapy
(HRT), a documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL

- Women who are using oral contraceptives, other hormonal contraceptives (vagina
products, skin patches, or implanted or injectable products), or mechanical
products such as an intrauterine device or barrier methods (diaphragm, condoms,
spermicides) to prevent pregnancy, or are practicing abstinence or where their
partner is sterile (e.g., vasectomy) should be considered to be of childbearing
potential

- WOCBP must have a negative serum test (minimum sensitivity 25 IU/L or equivalent units
of human chorionic gonadotropin [HCG]) within 72 hours prior to the start of
investigational product

- Patients with hepatitis B infection must be on appropriate antiviral therapy

- ARM A COHORT 1: Patients must have advanced pancreatic adenocarcinoma (unresectable or
metastatic)

- ARM A COHORT 1: Patients must not have received prior therapy for metastatic or
advanced disease; adjuvant therapy that is gemcitabine based is allowed as long as the
adjuvant treatment was completed >= 6 months before the diagnosis of recurrent disease

- ARM A COHORT 1: Absolute neutrophil count >= 1,500/ul

- ARM A COHORT 1: Platelet count >= 100,000/ul

- ARM A COHORT 1: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =<
2 x upper limit of normal (ULN); if liver metastases are present then must be < 5 X
the ULN

- ARM A COHORT 1: Total bilirubin =< 1.5 x ULN

- ARM A COHORT 1: Creatinine =< 1.5 x institutional ULN, or creatinine clearance >= 50
mL/min (calculated with the Cockcroft-Gault formula)

- ARM A COHORT 1: Serum albumin >= 2.5 g/dL

- ARM B COHORT 2: Patients must have a histologically confirmed diagnosis of head and
neck (squamous cell) carcinoma

- ARM B COHORT 2: Patients must have failed treatment with platinum based therapy with
or without cetuximab; previous therapy with a platinum concurrent with radiation
followed by progression of disease within 6 months will count as failure of one prior
line of cisplatin based therapy

- ARM B COHORT 2: Absolute neutrophil count >= 1,500/ul

- ARM B COHORT 2: Platelet count >= 100,000/ul

- ARM B COHORT 2: AST and ALT =< 2 X ULN; if liver metastases are present then must be <
5 X the ULN

- ARM B COHORT 2: Total bilirubin =< 1.5 x institutional upper limit of normal (IULN)

- ARM B COHORT 2: Serum albumin >= 2.5 g/dL

- ARM B COHORT 2: Creatinine =< 1.5 x institutional ULN, or creatinine clearance >= 50
mL/min (calculated with the Cockcroft-Gault formula)

- ARM B COHORT 3: Patients must have a histologically confirmed diagnosis of non-small
cell lung cancer

- ARM B COHORT 3: Patients must have failed one prior line of systemic therapy for the
treatment of advanced non-small cell lung cancer; prior adjuvant therapy with
subsequent recurrence within 6 months of completion of therapy will count as one prior
line of systemic therapy and such patients will be eligible

- ARM B COHORT 3: Absolute neutrophil count >= 1,500/ul

- ARM B COHORT 3: Platelet count >= 100,000/ul

- ARM B COHORT 3: AST and ALT =< 2 X ULN; if liver metastases are present then must be <
5 X the ULN

- ARM B COHORT 3: Total bilirubin =< 1.5 x IULN

- ARM B COHORT 3: Serum albumin >= 2.5 g/dL

- ARM B COHORT 3: Creatinine =< 1.5 x institutional ULN, or creatinine clearance >= 50
mL/min (calculated with the Cockcroft-Gault formula)

- ARM C COHORT 4: Patients must have a histologically or cytologically proven diagnosis
of advanced (unresectable or metastatic) gallbladder cancer or cholangiocarcinoma and
be candidates for first line therapy with gemcitabine and cisplatin

- ARM C COHORT 4: Patients must not have received prior systemic chemotherapy for
advanced or metastatic disease; prior adjuvant chemotherapy or concurrent chemotherapy
and radiation are allowed if they were completed >= 6 months prior to the diagnosis of
recurrent disease

- ARM C COHORT 4: Absolute neutrophil count >= 1,500/ul

- ARM C COHORT 4: Platelet count >= 100,000/ul

- ARM C COHORT 4: AST and ALT =< 5 x ULN

- ARM C COHORT 4: Total bilirubin =< 2 X IULN

- ARM C COHORT 4: Serum albumin >= 2.5 g/dL

- ARM C COHORT 4: Creatinine =< 1.5 x institutional ULN, or creatinine clearance >= 50
mL/min (calculated with the Cockcroft-Gault formula)

- ARM C COHORT 4: Patients who have had decompression of the biliary tree within the
last 14 days, must have a stable bilirubin level as confirmed by two measurements that
are within 5 to 7 days of each other; (the second measurement must be obtained within
7 days prior to registration); both the first and second measurement must be =< 2 X
IULN; stability is defined as the second measurement being no more than one point
higher than the first

Exclusion Criteria:

- Patients must not have received any anti-cancer therapy (cytotoxic chemotherapy,
targeted therapy or radiation) within the past 28 days prior to initiation of study
therapy

- Patients must not have an active major systemic infection requiring systemic
antibiotics 72 hours or less prior to the first dose of study drug

- Patients must not have untreated central nervous system (CNS) metastases; patients
whose CNS metastases have been treated by surgery or radiotherapy, who are no longer
on corticosteroids, and who are neurologically stable may be enrolled

- Patients must not have any of the following: New York Heart Association (NYHA) class 3
or 4 congestive heart failure; myocardial infarction within the past 12 months, 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 contra-indicates treatment with sEphB4HSA or
places the patient at undue risk for treatment related complications

- Patients must not have any other condition, including mental illness or substance
abuse, deemed by the Investigator to be likely to interfere with a patient's ability
to sign informed consent, cooperate and participate in the study, or interferes with
the interpretation of the results

- Patients must not be pregnant of lactating

- Patients must not be on any dose of warfarin or are on full dose anticoagulation with
other agents, including 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

- Patients must not have had any active bleeding in the last =< 4 weeks or have an
otherwise known bleeding diathesis

- Patients must not have corrected QT (QTc)F (Fridericia Correction Formula) > 480 on 2
out of 3 electrocardiograms (EKG's) (if first EKG is =< 480, no need to repeat, if
first EKG is > 480 repeat twice for a total of 3 EKG's)

- Patients must not have uncontrolled hypertension as defined by systolic blood pressure
(SBP) >= 160 mmHg or diastolic blood pressure (DBP) >= 90 mmHg; patients whose blood
pressure can be controlled medically are allowed to be rescreened once blood pressure
(BP) is under control

- Patients must not have > grade sensory neuropathy

- Patients must not have known human immunodeficiency virus (HIV) infection

- ARM A COHORT 1: Patients must not have prior nab-paclitaxel exposure

- ARM A COHORT 1: Patients must not have a history of slowly progressive dyspnea and
unproductive cough, or of conditions such as sarcoidosis, silicosis, idiopathic
pulmonary fibrosis, pulmonary hypersensitivity pneumonitis, or multiple allergies

- ARM B COHORT 2: Patients must not have prior exposure to docetaxel

- ARM B COHORT 2: Patients with head and neck cancer must not have radiologic evidence
of major arterial involvement

- ARM B COHORT 3: Patients must not have prior exposure to docetaxel

- ARM B COHORT 3: Patients must not have had more than one prior line of systemic
therapy for advanced non-small cell lung cancer (including treatment with a targeted
agent); prior adjuvant therapy completed more than 6 months prior to disease
recurrence will not count as a prior line of systemic therapy for advanced disease

- ARM B COHORT 3: Patients must not have active clinically significant hemoptysis

- ARM B COHORT 3: Patients must not have a central lesion with radiologic evidence of
arterial involvement

- ARM C COHORT 4: Patients must not have prior cisplatin exposure