RO4929097 in Treating Patients With Recurrent and/or Metastatic Epithelial Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer
Condition: Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer
MeSH terms: Carcinoma; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Fallopian Tube Neoplasms; Recurrence
Intervention: Gamma-Secretase Inhibitor RO4929097; Laboratory Biomarker Analysis
Intervention description: Given PO; Correlative studies
Intervention MeSH terms: 2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide; Gamma Secretase Inhibitors and Modulators
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 45.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No

Summary:

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

Eligibility criteria:

        Inclusion Criteria:

          -  Patients must have histologically or cytologically confirmed ovarian epithelial
             carcinoma, fallopian tube carcinoma, or primary peritoneal carcinoma that is recurrent
             or metastatic; patients must have platinum resistant disease, as defined as treatment
             free interval less than 6 months post completion of platinum-based chemotherapy

          -  Patients must have measurable disease, 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 >= 20 mm with conventional
             techniques or as >= 10 mm with spiral CT scan

               -  OR patients must have evidence of progression based on an elevated CA-125
                  (defined as a value of > 2 x ULN documented on two separate determinations made >
                  2 weeks apart, with the most recent being completed within 7 days prior to start
                  of study treatment) if the physical exam is normal and maximum lesion diameter on
                  the CT scan is < 20 mm with conventional techniques or as < 10 mm with spiral CT
                  scan

          -  Patients must have completed any prior chemotherapy, radiotherapy or surgery >= 4
             weeks (6 weeks for nitrosoureas or mitomycin C) before study entry

               -  Prior radiotherapy is allowed provided that there is documented progression
                  (either locally or systemically)

               -  Patients may have had up to 2 prior lines of chemotherapy for recurrent or
                  metastatic disease

               -  Toxic effects from prior therapy must have resolved to grade 1 or less except for
                  peripheral neuropathy and alopecia

          -  Life expectancy of greater than 12 weeks

          -  ECOG performance status =< 2 (Karnofsky >= 60%)

          -  Patients must have normal organ and marrow function as defined below (within 7 days
             prior to start of study treatment):

          -  Hemoglobin >= 90 g/L

          -  Leukocytes >= 3.0 x 10^9/L

          -  Absolute neutrophil count >= 1.5 x 10^9/L

          -  Platelets >= 100 x 10^9/L

          -  Total bilirubin =< 2.5 ULN (institutional upper limit of normal)

          -  AST (SGOT)/ALT (SGPT) =< 1.5 x institutional upper limit of normal (=< 5 times the ULN
             for patients with liver metastases)

          -  Creatinine within normal institutional limits OR creatinine clearance >= 60
             mL/min/1.73 m^2 for patients with creatinine levels above institutional normal (using
             Cockcroft-Gault Formula)

          -  All radiology studies must be performed =< 4 weeks prior to the start of therapy

          -  No serious medical conditions such as myocardial infarction within 6 months prior to
             entry, congestive heart failure, unstable ventricular arrhythmia, uncontrolled
             hypertension, uncontrolled diabetes mellitus, uncontrolled psychotic disorders,
             serious infections, active peptic ulcer disease, psychiatric illness, or any other
             medical conditions that might be aggravated by treatment or limit compliance

          -  Currently no active, second malignancy other than non-melanoma skin cancers

               -  NOTE: Patients are not considered to have a "current active" malignancy if they
                  have completed anti-cancer therapy and are considered by their physician to be at
                  less than 30% risk of relapse

          -  Absence of any psychological, familial, sociological or geographical condition
             potentially hampering compliance with the study protocol and follow-up schedule; those
             conditions should be discussed with the patient before registration in the trial

          -  The effects of RO4929097on the developing human fetus at the recommended therapeutic
             dose are unknown; for this reason and because Notch signal pathway inhibitors are
             known to cause interruption of the embryonic signaling pathway and may lead to serious
             or life-threatening birth defects, including brain deformities, facial malformation,
             heart problems, or abnormal organs; if women of childbearing potential do not abstain*
             from sexual activity they must use two forms of contraception (i.e., barrier
             contraception and one other method of contraception) at least 4 weeks prior to study
             entry; women of childbearing potential can either be abstinent or use two forms of
             contraception for the duration of study participation and for at least 12 months
             post-treatment; should a woman become pregnant or suspect she is pregnant while she is
             participating in this study and for 12 months after study participation, the patient
             should inform the treating physician immediately

               -  Abstinent from sexual activity at least 4 weeks prior to study entry

               -  Pregnancy Testing: Women of childbearing potential are required to have a
                  negative serum pregnancy test (with a sensitivity of at least 25 mIU/mL) within
                  10-14 days and within 24 hours prior to the first dose of RO4929097 (serum or
                  urine); a pregnancy test (serum or urine) will be administered every 4 weeks if
                  their menstrual cycles are regular or every 2 weeks if their cycles are irregular
                  while on study within the 24-hour period prior to the administration of
                  RO4929097; a positive urine test must be confirmed by a serum pregnancy test;
                  prior to dispensing RO4929097, the investigator or clinical staff must confirm
                  and document the patient's use of two contraceptive methods or abstinence, dates
                  of negative pregnancy test, and confirm the patient's understanding of the
                  potential of RO4929097 to cause serious or life-threatening birth defects

               -  Female patients of childbearing potential are defined as follows:

                    -  Patients with regular menses

                    -  Patients, after menarche with amenorrhea, irregular cycles, or using a
                       contraceptive method that precludes withdrawal bleeding

                    -  Women who have had tubal ligation

               -  Female patients may be considered to NOT be of childbearing potential for the
                  following reasons:

                    -  The patient has undergone total abdominal hysterectomy with bilateral
                       salpingo-oophorectomy or bilateral oophorectomy

                    -  The patient is medically confirmed to be menopausal (no menstrual period)
                       for 24 consecutive months

                    -  Pre-pubertal females; the parent or guardian of young female patients who
                       have not yet started menstruation should verify that menstruation has not
                       begun; if a young female patient reaches menarche during the study, then she
                       is to be considered as a woman of childbearing potential from that time
                       forward

          -  Ability to understand and the willingness to sign a written informed consent document

        Exclusion Criteria:

          -  Patients may not be receiving any other investigational agents

          -  Patients with known brain metastases should be excluded from this clinical trial
             because of their poor prognosis and because they often develop progressive neurologic
             dysfunction that would confound the evaluation of neurologic and other adverse events

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to RO4929097 or other agents used in the study

          -  Patients taking medications with narrow therapeutic indices that are metabolized by
             cytochrome P450 (CYP450), including warfarin sodium (Coumadin ®) are ineligible

          -  Preclinical studies indicate that RO4929097 is a substrate of CYP3A4 and inducer of
             CYP3A4 enzyme activity; caution should be exercised when dosing RO4929097 concurrently
             with CYP3A4 substrates, inducers, and/or inhibitors; patients who are taking
             concurrent medications that are strong inducers, inhibitors or substrates of CYP3A4
             should be switched to alternative medications to minimize any potential risk; if such
             patients cannot be switched to alternative medications, they will be ineligible to
             participate in this study

          -  Patients with malabsorption syndrome, bowel obstruction, or other condition that would
             interfere with intestinal absorption; patients must be able to swallow tablets

          -  Patients who are serologically positive for Hepatitis A, B or C, or have a history of
             liver disease, other forms of hepatitis or cirrhosis are ineligible

          -  Patients with uncontrolled hypocalcemia, hypomagnesemia, hyponatremia,
             hypophosphatemia or hypokalemia defined as less than the lower limit of normal for the
             institution, despite adequate electrolyte supplementation are excluded from this study

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia other than chronic, stable atrial fibrillation, or psychiatric
             illness/social situations that would limit compliance with study requirements

          -  Pregnant women are excluded from this study because RO4929097 is a Notch pathway
             inhibiting agent with the potential for serious or life-threatening birth defects or
             abortifacient effects; because there is an unknown but potential risk for adverse
             events in nursing infants secondary to treatment of the mother with RO4929097,
             breastfeeding should be discontinued if the mother is treated with RO4929097; these
             potential risks may also apply to other agents used in this study

          -  Known HIV-positive patients on combination antiretroviral therapy are ineligible
             because of the potential for pharmacokinetic interactions with RO4929097; in addition,
             these patients are at increased risk of lethal infections when treated with
             marrow-suppressive therapy; appropriate studies will be undertaken in patients
             receiving combination antiretroviral therapy when indicated

          -  Cardiovascular (within 7 days prior to start of study treatment): baseline QTc > 470
             msec (female), QTc > 450 msec (male)

               -  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

               -  History of torsade de pointes or other significant cardiac arrhythmias or the
                  need for concomitant meds with known potential to prolong QT interval or
                  antiarrhythmics