Intraperitoneal Infusion of Autologous Monocytes With Sylatron (Peginterferon Alfa-2b) and Actimmune (Interferon Gamma-1b) in Women With Recurrent or Refractory Ovarian Cancer, Fallopian Tube Cancer or Primary Peritoneal Cancer

Background:

- Monocytes can differentiate into classic M1 macrophages inhibiting tumor proliferation
and promoting natural killer (NK) cell differentiation.

- Human alpha interferons (interferon alfa, IFN-alpha), interferon gamma (IFN-gamma) and
monocytes have strong anti-neoplastic response in vitro and in vivo

- IFN-alpha and IFN-gamma have been shown in early phase clinical trials to be safely
administered intraperitoneally.

- Intraperitoneal monocytes alone or activated with IFN-gamma are safe and feasible as
demonstrated in phase I clinical studies.

- We have shown that the combination of human monocytes, IFN-alpha2a and IFN-gamma1b, or
pegylated IFN-alpha, act synergistically against tumor cells in vitro and in mouse
models.

Objectives:

-To identify a maximum tolerated dose of intraperitoneal autologous monocytes and Sylatron(R)
(Peginterferon alfa-2b) and Actimmune(R) (Interferon gamma-1b).

Eligibility:

- Advanced metastatic or unresectable epithelial ovarian cancer, primary peritoneal cancer
or fallopian tube cancer that is relapsed and resistant or refractory to prior
platinum-based standard care systemic regimen.

- Patients must be off prior chemotherapy, radiation therapy, hormonal therapy or
biological therapy for at least 4 weeks.

- ECOG performance status 0-1 and adequate organ and marrow function.

Design:

- This is an open label single arm phase I trial to determine the maximum tolerated dose
of intraperitoneal monocytes and Sylatron(R) (Peginterferon alfa-2b) and Actimmune(R)
(Interferon gamma-1b).

- Autologous monocytes obtained through apheresis will be mixed with Sylatron(R)
(Peginterferon alfa-2b) and Actimmune(R) (Interferon gamma-1b) in a 3 + 3 dose
escalation and administered intraperitoneally once every 28 days. A new product will be
manufactured for each treatment cycle.

- Once the maximum tolerated dose is obtained, an expansion cohort will be enrolled to
better quantify response rate and time to disease progression.

- Research samples including peripheral blood and ascites will be obtained prior to the
initiation of study therapy andprior to the start of each cycle. Tissue biopsies will be
obtained in the dose expansion phase to characterize the immune infiltration.

- Patients will be evaluated every 2 cycles for response using RECIST v1.1 and every cycle
for safety using CTCAE v4.0.

- INCLUSION CRITERIA:

- Patients must have histologically or cytologically confirmed advanced metastatic or
unresectable epithelial ovarian cancer, primary peritoneal cancer or fallopian tube
cancer that is relapsed and resistant (recurred less than 6 months after chemotherapy)
or refractory (progressed on chemotherapy) to prior platinum- and taxane-based
standard care systemic regimen. Or patients who are eligible for aditional platinum
therapy. Histopathologic diagnosis must be confirmed in the Laboratory of Pathology
(LP), NCI.

- Patients must have measurable or evaluable disease. Measurable disease is defined as
at least one lesion that can be accurately measured in at least one dimension (longest
diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as
greater than or equal to 20 mm with conventional techniques or as greater than or
equal to 10 mm with spiral CT scan.

- Patients must be at least 4 weeks from previous therapy (chemotherapy, hormonal
therapy, and radiation therapy, immunotherapy and monoclonal antibodies, alternative
therapy or investigational therapeutic agents). There is no limitation on the amount
of prior therapies allowed. Patients with ovarian cancer 4 weeks from previous therapy
have been found to have normal monocyte function (unpublished).

- Patients who have had cranial radiation therapy need to have completed it greater than
or equal to 8 weeks prior to enrollment.

- Patients are permitted to receive investigational imaging agents while on study.

- Patients who have had major surgery must be fully recovered and require a recovery
period of greater than or equal to 4 weeks prior to enrolling on study.

- Age greater than or equal to 18 years. Because no dosing or adverse event data are
currently available on the use of intraperitoneal monocytes, IFN-alpha 2 or IFN-gamma
in patients <18 years of age, children are excluded from this study, but will be
eligible for future pediatric trials.

- ECOG performance status less than or equal to 1 (Karnofsky greater than or equal to
70%).

- Adequate renal function, defined as serum creatinine less than or equal to 1.5 X upper
limit of normal(ULN), or measured creatinine clearance greater than or equal to 60
mL/min/1.73m^2.

- Adequate hepatic function, defined as AST and ALT levels less than or equal to 3 X ULN
and total bilirubin < 1.5 X ULN, unless known diagnosis of Gilbert s syndrome, where
bilirubin less than or equal to 5 mg/dl will be permitted. Gilbert s syndrome will be
defined as elevated unconjugated bilirubin, with conjugated (direct) bilirubin within
the normal range and less than 20% of the total. Total bilirubin will be permitted up
to 5 mg/dl, if patients have historical readings consistent with the definition of
Gilbert s syndrome prior to entering study.

- Adequate bone marrow function, defined as absolute neutrophil (ANC) greater than or
equal to 1,500/mm^3 (greater than or equal to 1.5 X106/L), platelet count greater than
or equal to 75,000/mm3 (greater than or equal to 75 X10^6/L), and hemoglobin greater
than or equal to 10 g/dL (transfusion to obtain hemoglobin greater than or equal to 10
g/dL within 24 hours prior to dosing is allowed).

- The effects of intraperitoneal monocytes, IFN-alpha 2, and IFN-gamma on the developing
human fetus are unknown. For this reason and because interferons based on animal data
may cause fetal harm, women of child-bearing potential (excludes women with recurrent
ovarian cancer) and men must agree to use adequate contraception (hormonal or barrier
method of birth control; abstinence) prior to study entry and for the duration of
study participation. Should a woman become pregnant or suspect she is pregnant while
she is participating in this study, she should inform her treating physician
immediately.

- Ability of subject to understand and the willingness to sign a written informed
consent document.

EXCLUSION CRITERIA:

- Patients who are receiving any other investigational agents (with exception of imaging
agents as indicated above in the inclusion criteria).

- Patients cannot have previously been treated with interferons (e.g., for chronic
active hepatitis).

- Lack of recovery of prior adverse events to Grade less than or equal to 1 severity
(National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]
v 4.03) (except alopecia) due to therapy administered prior to the initiation of study
drug dosing. Stable persistent grade 2 peripheral neuropathy may be allowed as
determined on a case-bycase basis at the discretion of the Investigator as interferon
has not been shown to cause or exacerbate peripheral neuropathy.

- Patients with active infection will not be eligible, but may become eligible once
infection has resolved and at least 7 days have elapsed after antibiotics use was
completed.

- Concomitant chronic (daily or almost daily for greater than or equal to 1 month prior)
use of steroids or non-steroidal anti-steroidal anti-inflammatory drugs NSAIDS.

- Patients with a recent history (within last 5 years) of autoimmune disease or
inflammatory diseases will be excluded, because interferons may worsen these
conditions. Exceptions will be allowed for vitiligo and hypothyroidism that has been
stable on thyroid replacement medications for >6 weeks.

- Impaired cardiac function or clinically significant cardiac disease including the
following:

- New York Heart Association class III or IV congestive heart failure

- Myocardial infarction within the last 12 months

- Subjects known to have impaired LVEF according to institutional standards

- History of allergic reactions attributed to compounds of chemical or biologic
composition similar to interferons or other agents used in the study.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations within the last 12 months that
would limit compliance with study requirements. Patients with history of
neuropsychiatric disorders or Major Depressive Disorder (DSM 5 definition:
http://dsm.psychiatryonline.org/doi/full/10.1176/appi.books.9780890425596.dsm04)
requiring medical treatment will not be eligible to enroll, based on the black box
warning (SYLATRON (peginterferon alfa-2b) for injection, for subcutaneous use. Merck
Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ).
Exception to this is if patients experienced transient post-partum depression that
resolved and patient has been off treatment for >10 years. Patients who are taking
oral anti-depressants for normal sadness, bereavement, or grief will not be excluded.

- Pregnant women are excluded from this study because interferons based on animal data
may cause fetal harm. Because there is an unknown but potential risk for adverse
events in nursing infants secondary to treatment of the mother with interferons,
breastfeeding should be discontinued if the mother is treated with intraperitoneal
interferons. These potential risks may also apply to other agents used in this study.

- Patients on combination antiretroviral therapy for the treatment of HIV are ineligible
because of the potential for pharmacokinetic interactions with interferons alfa and
gamma.

- Patients receiving any medications or substances that are potent inhibitors or
inducers of CYP1A2 or CYP2D6 are ineligible.