EGEN-001 and Pegylated Liposomal Doxorubicin Hydrochloride in Treating Patients With Recurrent or Persistent Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer

PRIMARY OBJECTIVES:

I. To determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of
EGEN-001 when administered in combination with pegylated liposomal doxorubicin hydrochloride
(PLD; Doxil; Lipodox) every 28 days and the associated DLTs based on adverse events that
occur in cycle 1 for this combination in women with recurrent or persistent epithelial
ovarian, fallopian tube, or primary peritoneal cancer.

II. To examine the tolerability of the combination at the MTD of EGEN-001 assessed in
combination with PLD.

III. To determine recommended phase II dose (RP2D) of EGEN-001 in combination with PLD.

SECONDARY OBJECTIVES:

I. To estimate the objective response rate (complete and partial) in patients with measurable
disease.

TERTIARY OBJECTIVES:

I. Determine the levels and time course of interleukin-12 (IL-12), interferon-gamma
(IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) and vascular endothelial growth factor
(VEGF) following EGEN-001 treatment.

II. Assess the effect of EGEN-001 treatment on the nature of the cellular immune responses by
measuring cell-specific ribonucleic acid (RNA) transcripts.

OUTLINE: This is a dose-escalation study of EGEN-001.

Patients receive pegylated liposomal doxorubicin hydrochloride intravenously (IV) over 60
minutes on day 1 and EGEN-001 intraperitoneally (IP) over 30-60 minutes on days 1, 8, 15, and
22. Courses repeat every 28 days in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up quarterly for up to 1 year.

Inclusion Criteria:

- Patients must have histologic diagnosis of epithelial ovarian, fallopian tube, or
primary peritoneal carcinoma which is now persistent or recurrent; histologic
documentation of the original primary tumor is required via the pathology report

- Patients with the following histologic epithelial cell types are eligible: high-grade
serous adenocarcinoma, endometrioid adenocarcinoma, undifferentiated carcinoma, clear
cell adenocarcinoma, mixed epithelial carcinoma, or adenocarcinoma not otherwise
specified (N.O.S.)

- Patients must have recurrence documented by elevated CA-125 (biochemical recurrence)
or clinically evident measurable or non-measurable recurrent disease as defined below:

- Biochemical recurrence is defined as a CA-125 greater than or equal to two times
the upper normal limit; patients whose CA-125 is less than 100 U/mL must undergo
a second confirmatory value within a period of not more than 4 weeks; patients
with a level greater than or equal to 100 U/mL may be entered without
confirmatory measurement; the CA-125 assessment for eligibility must be done at
least 4 weeks after paracentesis or other surgical procedures

- Detectable (non-measurable) disease is defined as symptomatic ascites or pleural
effusions, solid and/or cystic abnormalities on radiographic imaging that do not
meet RECIST 1.1 definitions for target lesions and/or biopsy-proven recurrence

- Measurable disease will be defined by RECIST 1.1; measurable disease is defined
as at least one lesion that can be accurately measured in at least one dimension
(longest diameter to be recorded); each lesion must be ? 10 mm when measured by
computed tomography (CT), magnetic resonance imaging (MRI), or caliper
measurement by clinical exam; or ? 20 mm when measured by chest x-ray; lymph
nodes must be ? 15 mm in short axis when measured by CT or MRI

- Patients with measurable disease must have had at least one ?target lesion?
to be used to assess response on this protocol as defined by RECIST 1.1;
tumors within a previously irradiated field will be designated as
?non-target? lesions unless progression is documented or a biopsy is
obtained to confirm persistence at least 90 days following completion of
radiation therapy

- Absolute neutrophil count (ANC) >= 1,500/mcl; this ANC cannot have been induced or
supported by granulocyte colony-stimulating factors

- Platelets >= 100,000/mcl

- Creatinine =< 1.5 times institutional upper limit of normal (ULN)

- Bilirubin =< 1.5 times ULN

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x ULN

- Alkaline phosphatase =< 2.5 x ULN

- Left ventricular ejection fraction (LVEF) greater than or equal to institutional lower
limit of normal (LLN) as determined by gated cardiac radionucleotide scan (multi-gated
acquisition scan [MUGA]) or echocardiogram

- Neuropathy (sensory and motor) less than or equal to grade 1

- Patients must have recovered from effects of recent surgery, radiotherapy, or
chemotherapy

- Patients should be free of active infection requiring parenteral antibiotics

- Any hormonal therapy directed at the malignant tumor must be discontinued at least one
week prior to registration; continuation of hormone-replacement therapy is permitted

- Any other prior therapy directed at the malignant tumor, including biological and
immunologic agents, must be discontinued at least three weeks prior to registration

- Patients must have had one prior platinum-based chemotherapeutic regimen for
management of primary disease containing carboplatin, cisplatin, or another
organoplatinum compound; this initial treatment may have included intraperitoneal
therapy, consolidation, non-cytotoxic agents, or extended therapy administered after
surgical or non-surgical assessment

- Patients are allowed to receive, but are not required to receive, two additional
cytotoxic regimens for management of recurrent or persistent disease, with no more
than 1 non-platinum, non-taxane regimen

- Prior treatment with pegylated liposomal doxorubicin hydrochloride [Doxil] or other
anthracyclines is NOT allowed

- Patients are allowed to receive, but are not required to receive, non-cytotoxic
therapy (such as bevacizumab) as part of their primary treatment regimen

- Patients who have received only one prior cytotoxic regimen (platinum-based regimen
for management of primary disease), must have a platinum-free interval of less than 12
months, have progressed during platinum-based therapy, or have persistent disease
after a platinum-based therapy

- Gynecology Oncology Group (GOG) performance status of 0 or 1

- Patients of childbearing potential must have a negative pregnancy test prior to the
study entry and be practicing an effective form of contraception; if applicable,
patients must discontinue breastfeeding prior to study entry

- Patients who have met the pre-entry requirements

- Patients must have signed an Institutional Review Board (IRB)-approved informed
consent and authorization permitting release of personal health information

Exclusion Criteria:

- Patients who have received prior treatment with EGEN-001

- Patients who have received prior PLD, doxorubicin, or other anthracyclines

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to EGEN-001 or other agents used in this study

- Patients who have received oral or parenteral corticosteroids within 2 weeks of study
entry or who have a clinical requirement for ongoing systemic immunosuppressive
therapy

- Patients receiving treatment for active autoimmune disease; ?active? refers to any
condition currently requiring therapy; examples of autoimmune disease include systemic
lupus erythematosus, multiple sclerosis, inflammatory bowel disease and rheumatoid
arthritis

- Patients with other invasive malignancies, with the exception of non-melanoma skin
cancer and other specific malignancies as noted below are excluded if there is any
evidence of other malignancy being present within the last three years; patients are
also excluded if their previous cancer treatment contraindicates this protocol therapy

- Patients who have received prior radiotherapy to any portion of the abdominal cavity
or pelvis are excluded; prior radiation for localized cancer of the breast, head and
neck, or skin is permitted, provided that it was completed more than three years prior
to registration, and the patient remains free of recurrent or metastatic disease

- Patients who have received prior chemotherapy for any abdominal or pelvic tumor (other
than ovarian, fallopian tube and primary peritoneal) are excluded; patients may have
received prior adjuvant chemotherapy for localized breast cancer, provided that it was
completed more than three years prior to registration, and that the patient remains
free of recurrent or metastatic disease

- Patients with known active hepatitis

- Patients with concurrent severe medical problems unrelated to the malignancy that
would significantly limit full compliance with the study or expose the patient to
extreme risk or decreased life expectancy

- Patients of childbearing potential, not practicing adequate contraception, patients
who are pregnant, or patients who are breastfeeding are not eligible for this trial

- Patients with history or evidence upon physical examination of central nervous system
(CNS) disease, including primary brain tumor, seizures not controlled with standard
medical therapy, any brain metastases, or history of cerebrovascular accident (CVA,
stroke), transient ischemic attack (TIA) or subarachnoid hemorrhage within six months
of the first date of treatment on this study

- Uncontrolled hypertension, defined as systolic > 140 mm Hg or diastolic > 90 mm Hg

- Myocardial infarction or unstable angina within 6 months prior to registration

- History of serious ventricular arrhythmia (i.e., ventricular tachycardia or
ventricular fibrillation) or cardiac arrhythmias requiring anti-arrhythmic medications
(except for atrial fibrillation that is well controlled with anti-arrhythmic
medication)

- Corrected QT (QTc) interval >= 450 ms on baseline EKG (electrocardiogram)

- Baseline ejection fraction =< 50% as assessed by echocardiogram or multi gated
acquisition scan (MUGA)

- New York Heart Association (NYHA) class II or higher congestive heart failure

- Grade 2 or higher peripheral ischemia (brief [< 24 hrs] episode of ischemia managed
non-surgically and without permanent deficit)

- Patients with any condition/anomaly that would interfere with the appropriate
placement of the IP catheter for study drug administration including: abdominal
surgery within 4 weeks of study entry (for reasons other than IP port placement),
intestinal dysfunction, or suspected extensive adhesions from prior history or finding
at laparoscopy