RO4929097 in Treating Patients With Recurrent and/or Metastatic Epithelial Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer

• Overall response rate [ Time Frame: Start of the treatment until disease progression/recurrence ] [ Designated as safety issue: No ]
• Overall survival [ Time Frame: Start of the treatment until death ] [ Designated as safety issue: No ]
• CA-125 response rate [ Time Frame: The time from the date of the first documented CA-125 response to the date of progression ] [ Designated as safety issue: No ]
• Safety [ Time Frame: Start of treatment until end of follow-up ] [ Designated as safety issue: Yes ]

• Overall response rate [ Designated as safety issue: No ]
• Overall survival [ Designated as safety issue: No ]
• CA125 response rate [ Designated as safety issue: No ]
• Safety [ Designated as safety issue: Yes ]

RATIONALE: RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase II trial is studying the side effects and how well RO4929097 works in treating patients with recurrent and/or metastatic epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

OBJECTIVES:

Primary

• To assess the antitumor activity (in terms of progression-free survival rate after 4 courses) of gamma-secretase inhibitor RO4929097 in patients with recurrent and/or metastatic, platinum-resistant epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

Secondary

• To assess the overall response rate and CA-25 response rate in patients treated with this regimen.
• To assess the safety of this regimen in these patients.
• To explore expression of Notch biomarkers in patients treated with this regimen.
• To explore the impact of this regimen on ascitic fluid circulating tumor cells.

OUTLINE: This is a multicenter study.

Patients receive oral gamma-secretase inhibitor RO4929097 once daily on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Blood and tumor tissue samples are collected for correlative studies. Ascitic fluid may also be collected.

After completion of study therapy, patients are followed up every month for at least 1 year.

• Fallopian Tube Cancer
• Ovarian Cancer
• Peritoneal Cavity Cancer

• Drug: gamma-secretase inhibitor RO4929097
  20mg daily, 3 days on / 4days off (3/4 schedule) weekly in a 21-day cycle.
• Other: laboratory biomarker analysis
  Soluble markers of angiogenesis

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed ovarian epithelial carcinoma, fallopian tube carcinoma, or primary peritoneal carcinoma

  • Recurrent or metastatic disease
  • Must have platinum-resistant disease, defined as treatment-free interval < 6 months after completion of platinum-based chemotherapy

• Must meet 1 of the following criteria:

  • Measurable disease defined as ≥ 1 lesion that can be accurately measured in ≥ 1 dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as > 20 mm by conventional techniques or as > 10 mm by spiral CT scan

  • Disease progression defined as CA-125 > 2 times upper limit of normal (ULN)documented on 2 separate determinations (made > 2 weeks apart, with the most recent being completed with the past 7 days) and the following criteria are met:

    • Physical exam is normal
    • Maximum lesion diameter < 20 mm by CT scan with conventional techniques or < 10 mm by spiral CT scan
• No known brain metastases

PATIENT CHARACTERISTICS:

• Life expectancy > 12 weeks
• ECOG performance status (PS) 0-2 (Karnofsky PS 60-100%)
• WBC ≥ 3,000/mm³
• ANC ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 9 g/dL
• Total bilirubin ≤ 2.5 times ULN
• AST and/or ALT ≤ 1.5 times ULN (≤ 5 times ULN for patients with liver metastases)
• Creatinine normal OR creatinine clearance ≥ 60 mL/min
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception ≥ 4 weeks before, during, and for 12 months after completion of study therapy
• Able to swallow tablets

• No serious medical conditions including, but not limited to, any of the following:

  • Myocardial infarction within the past 6 months
  • Symptomatic congestive heart failure
  • Unstable angina pectoris

  • Unstable ventricular arrhythmia

    • Chronic stable atrial fibrillation allowed
  • Uncontrolled hypertension
  • Uncontrolled diabetes mellitus
  • Uncontrolled psychotic disorders
  • Serious infections
  • Active peptic ulcer disease
  • Psychiatric illness/social situations, or any other medical conditions that might be aggravated by treatment or limit compliance with study requirements

• No active second malignancy other than nonmelanoma skin cancers

  • Prior malignancy allowed provided the patient has completed anticancer therapy and is considered to be < 30% of risk of relapse by the treating physician
• Absence of any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to gamma-secretase inhibitor RO4929097 or other agents used in the study
• No malabsorption syndrome, bowel obstruction, or other condition that would interfere with intestinal absorption
• Not serologically positive for hepatitis A, B, or C, or have a history of liver disease, other forms of hepatitis, or cirrhosis
• No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, or hypokalemia despite adequate electrolyte supplementation
• No baseline QTc > 470 msec (female)
• No history of risk factors for QT interval prolongation including, but not limited to, family or personal history of long QT syndrome, recurrent syncope without known etiology, or sudden unexpected death

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Prior radiotherapy allowed provided there is documented progression (either locally or systemically)
• Up to 2 prior lines of chemotherapy for recurrent or metastatic disease allowed
• At least 4 weeks since prior chemotherapy, radiotherapy, or surgery (6 weeks for nitrosoureas or mitomycin C) and recovered to grade ≤ 1 toxicities except peripheral neuropathy and alopecia
• No other concurrent investigational agents
• No concurrent medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®)
• No concurrent medications that are strong inducers, inhibitors, or substrates of CYP3A4
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No need for concurrent medications with known potential to prolong QT interval
• No other concurrent anticancer agents or therapies