Viral Therapy in Treating Patients With Ovarian Epithelial Cancer, Primary Peritoneal Cancer, or Fallopian Tube Cancer That Did Not Respond to Platinum Chemotherapy

PRIMARY OBJECTIVES:

I. Determine the safety and tolerability of intravenous (IV) and intraperitoneal (IP) administration of wild-type reovirus (REOLYSIN®).

II. Determine the maximum tolerated dose of IP REOLYSIN® when used with a fixed dose of IV REOLYSIN®.

III. Determine the objective response rate (complete response and partial response per Response Evaluation Criteria in Solid Tumors [RECIST] criteria) of treatment with IV and IP REOLYSIN® in patients with recurrent, platinum-refractory ovarian epithelial, peritoneal, or fallopian tube carcinoma. (Phase II) (phase II closed as of 1/7/2011).

SECONDARY OBJECTIVES:

I. To identify viral replication in tumor following IV reovirus. II. To identify anti-reovirus antibodies in patients being treated with IV and IP REOLYSIN® therapy.

III. To identify viral replication in the abdominal washings of patients undergoing IV and IP REOLYSIN® therapy.

IV. To correlate response to therapy with Ras oncogene status. V. To evaluate double-stranded RNA-activated protein kinase activity in tumors. VI. To correlate molecular predictors of response to REOLYSIN® therapy.

OUTLINE: This is a phase I, dose-escalation study of intraperitoneal (IP) wild-type reovirus when administered with fixed dose IV wild-type reovirus.

PHASE I: Patients receive wild-type reovirus IV over 60 minutes on days 1-5 in course 1, followed by insertion of an IP access port. Beginning in course 2, patients receive wild-type reovirus IV over 60 minutes on days 1-5 and wild-type reovirus IP over 10 minutes on days 1 and 2*. Treatment with IV and IP wild-type reovirus repeats every 28 days in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients undergo IP access port insertion before beginning treatment. Patients receive wild-type reovirus IV over 60 minutes on days 1-5 and IP (at the maximum tolerated dose determined in phase I) over 10 minutes on days 1 and 2*. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity (phase II closed as of 1/7/2011). NOTE: *Patients receive IP wild-type reovirus on days 2 and 3 in course 3.

Prior to each IP wild-type reovirus administration, normal saline is administered through the IP catheter and withdrawn for correlative studies in courses 2 and 3 (phase I) or courses 1 and 2 (phase II). Patients also undergo a CT-guided percutaneous tumor biopsy on day 2 of course 3 (phase I or II). Samples are analyzed by immunohistochemistry, RT-PCR, and electron microscopy for the relevant molecular effects of wild-type reovirus on tumor and normal tissue.

After completion of study treatment, patients are followed for up to 12 weeks.

Inclusion criteria

• Histologically confirmed ovarian epithelial, primary peritoneal, or fallopian tube cancer
• Recurrent disease after platinum-based chemotherapy

• Must have experienced disease persistence during primary platinum-based therapy or recurrence within 12 months after completion of platinum-based chemotherapy ("platinum-refractory" or "platinum-resistant" disease)

• A patient receiving a second course of platinum-based chemotherapy for platinum-sensitive disease who then develops persistence or recurrence within 12 months is considered eligible for this trial
• Must have measurable disease by RECIST criteria (phase II) (phase II closed as of 1/7/2011)
• Must have received ≥ 1 prior platinum-based cytotoxic chemotherapy regimen (for primary disease) containing carboplatin, cisplatin, or other organoplatinum compound

• Initial treatment may have included any of the following:

• High-dose therapy
• Consolidation therapy
• Intraperitoneal (IP) therapy
• Extended therapy administered after surgical or nonsurgical assessment
• One additional non-cytotoxic regimen (e.g., monoclonal antibodies, cytokines, or small-molecule inhibitors) for recurrent or persistent disease allowed
• Patients may have received hormonal therapy for management of disease (e.g., SERMs, aromatase inhibitors, progestins, and GnRH agonists)
• No loculated ascites for which IP distribution of virus is not expected to be feasible
• No known brain metastases
• GOG performance status (PS) 0-2 (Karnofsky PS 60-100%)
• Life expectancy > 12 weeks
• Leukocytes ≥ 3,000/mcL
• Absolute neutrophil count ≥ 1,500/mcL
• Hemoglobin ≥ 10 g/dL
• Platelets ≥ 100,000/mcL
• Total bilirubin normal
• AST/ALT ≤ 2.5 times upper limit of normal
• Creatinine normal
• Ejection fraction > 50% by echocardiogram or MUGA
• Cardiac enzymes normal
• Not pregnant or nursing
• Fertile patients must use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for the duration of study participation
• Must be able to avoid direct contact with pregnant or nursing women, infants, or immunocompromised individuals while on study and for ≥ 3 weeks following the last dose of study agent administration
• Cardiac conduction abnormalities (e.g., bundle branch block, heart block) are allowed if their cardiac status has been stable for 6 months before study entry
• At least 4 weeks since most recent cytotoxic chemotherapy (6 weeks for nitrosoureas or mitomycin C)
• Recovered from adverse events due to agents administered more than 4 weeks earlier
• No prior radiotherapy to the abdomen or pelvis
• No other concurrent investigational agents
• No investigational or commercial agents or therapies other than those described below may be administered with the intent to treat the patient's malignancy

Exclusion criteria

• Patients in whom insertion of an IP catheter is not feasible due to surgical contraindications or abdominal and pelvic adhesions
• Known HIV infection or hepatitis B or C
• Clinically significant cardiac disease (New York Heart Association class III or IV cardiac disease) including any of the following:

• Pre-existing arrhythmia
• Uncontrolled angina pectoris
• Myocardial infarction 1 year prior to study entry
• Compromised left ventricular ejection fraction ≥ grade 2 by MUGA or echocardiogram
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements
• Chronic oral steroids at an equivalent dose of prednisone 5 mg daily

• Inhaled steroids allowed
• Patients on immunosuppressive therapy
• Concurrent routine prophylactic use of growth factor (filgrastim [G-CSF] or sargramostim [GM-CSF])