PD 0360324 and Cyclophosphamide in Treating Patients With Recurrent High-Grade Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

PRIMARY OBJECTIVES:

I. To establish the safety of anti-CSF1 monoclonal antibody PD-0360324 (PD 0360324) followed
by cyclophosphamide in patients with epithelial ovarian, fallopian tube, and primary
peritoneal cancers.

II. To examine the density of CD8+ T cells in tumor biopsies before and after PD 0360324.

SECONDARY OBJECTIVES:

I. To evaluate response rate and progression free survival associated with low dose oral
cyclophosphamide after PD 0360324 treatment.

II. To evaluate M-CSF concentrations before and after treatment with PD 0360324 and during
cyclophosphamide therapy.

TERTIARY OBJECTIVES:

I. To evaluate the immunologic effects of PD 0360324 on peripheral blood and ovarian cancer
tissue.

II. To explore the relationships between drug concentration and immunologic biomarkers and
response.

OUTLINE:

Patients receive anti-CSF1 monoclonal antibody PD 0360324 intravenously (IV) over 30 minutes
on days 1, 8, 15, and 22. Starting on day 43, patients receive cyclophosphamide orally (PO)
once daily (QD). Courses with cyclophosphamide repeat every 28 days in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 and 90 days.

Inclusion Criteria:

- Written informed consent

- Histology showing recurrent high grade epithelial ovarian, peritoneal, or fallopian
tube cancer

- Platinum resistant or refractory disease as defined by progression of disease on a
platinum-containing regimen or recurrence of disease within 180 days of previous
platinum treatment

- Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST)
1.1; measurable disease is defined at least two lesions that can be accurately
measured in at least one dimension (longest dimension to be recorded); each "target"
lesion must be > 20 mm when measured by palpitation or >10 mm when measured by spiral
computed tomography (CT), plain x-ray, magnetic resonance imaging (MRI), or positron
emission tomography (PET)/CT; PET/CT will be acceptable at baseline if PET/CT was
previously performed and available; imaging must be performed within -28 to -7 days of
starting therapy; the target lesion must be distinct from other tumor areas selected
for pre-treatment biopsies

- Subject must be willing to undergo protocol directed biopsies and blood draw for
immune profiling

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

- Life expectancy of >= 4 months in the attending physician's estimation

- Estimated creatinine clearance > 40 mL/min by the Cockcroft-Gault formula

- White blood cell (WBC) >= 3.0 x 10^3/ul

- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (> 1500 per mm^3)

- Platelet count >= 100 x 10^9/L (> 100,000 per mm^3)

- Hemoglobin >= 9.0 g/dL

- Female subjects must either be of non-reproductive potential (i.e., post-menopausal by
history: >=60 years old and no menses for > 1 year without an alternative medical
cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history
of bilateral oophorectomy) or must have a negative serum pregnancy test upon study
entry

- Subject must be willing and able to comply with the protocol for the duration of the
study including undergoing treatment and scheduled visits and examinations including
follow up

- Signed informed consent for protocol PA13-0291

Exclusion Criteria:

- Absence of a biopsiable lesion as determined by radiologist

- Chemotherapy, hormonal, or biologic treatment for ovarian, fallopian tube, or primary
peritoneal cancer in the last 21 days

- History of another primary malignancy except for:

- Malignancy treated with curative intent and with no known active disease >=5
years before the first dose of study drug and of low potential risk for
recurrence;

- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease; or

- Adequately treated carcinoma in situ without evidence of disease, e.g. cervical
cancer in situ

- Current or prior use of immunosuppressive medication within 21 days before the first
dose of PD 0360324, with the exceptions of intranasal and inhaled corticosteroids and
systemic corticosteroids at physiological doses (defined as not exceeding 10 mg/day of
prednisone, or an equivalent dose of over corticosteroid)

- Prior immunotherapy with immune checkpoint inhibitors

- Any unresolved toxicity (> Common Terminology Criteria for Adverse Events [CTCAE]
grade 1) from previous anti-cancer therapy with the exception of alopecia; subjects
with irreversible toxicity that is not reasonably expected to be exacerbated by the
investigational product may be included (e.g., hearing loss, peripheral neuropathy)

- Subjects with an active infection requiring antibiotics or at an increased risk of
latent infection that may affect safe study participation

- Subjects with existing periorbital edema

- Subjects with aspartate aminotransferase (AST) or alanine transaminase (ALT) >= 2 x
upper limit of normal (ULN)

- Subjects with creatine kinase > ULN

- Subjects with clinically significant active ischemic heart disease, cardiac muscle
disease (including cardiomyopathy or congestive heart failure) or myodegenerative
disorders that may affect safe study participation

- Receipt of live attenuated vaccination within 30 days prior to study entry or within
30 days prior to study entry

- History of allergic or anaphylactic reaction to any therapeutic or diagnostic
monoclonal antibody (IgG protein) or molecules made of components of monoclonal
antibodies (e.g., Enbrel which is the Fc portion of an antibody or Lucentis which is a
Fab)

- Pregnant or breastfeeding women or women of child-bearing potential who are not
willing to use two highly effective methods of contraception (i.e., a hormonal
contraceptive, intrauterine device, diaphragm with spermicide, condom with spermicide,
or abstinence)

- Uncontrolled intercurrent illness including, but not limited to, bowel obstruction,
uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic
ulcer disease or gastritis, active bleeding diatheses including any subject known to
have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency
virus (HIV), tuberculosis, or psychiatric illness/social situations that would limit
compliance with study requirements or compromise the ability of the subject to give
written informed consent, or undergo study procedures

- History of leptomeningeal carcinomatosis or brain metastasis