This trial is a single arm Phase i/ii study of 4-HPR/LXS oral powder (given BiD) + ketoconazole given daily, concurrently, x 7 days, every three weeks, to women with recurrent ovarian cancer.
PRiMaRY STuDY aiMS are:
(1) To define the systemic toxicity profile of 4-HPR/LXS oral powder + ketoconazole given concurrently for 6 months or until disease progression;
(2) Determine if 4-HPR exposures [Greater Than] 10 uM (steady state peak plasma) are associated with objective tumor responses.
(3) Define the eFS, PFS, and/or oS for women with recurrent ovarian cancer, fallopian tube cancers and primary peritoneal carcinoma treated with 4-HPR/LXS oral powder + ketoconazole given concurrently.
SeConDaRY STuDY aiM:
(1) To determine the pharmacokinetics of 4-HPR in women when given as 4-HPR/LXS oral powder + ketoconazole over a 6 month period or until disease progression. For the latter, levels of 4-HPR, and its metabolites, will be determined in plasma and peripheral blood mononuclear cells (PBMC) six hours after the aM dose of 4-HPR/LXS oral powder on Day 6 of the First, Third, and Sixth Courses of therapy. The study calls for 40 post-progression patients (~20/year) with primary analysis planned at two years after initiating the study.
1 Patients with recurrent epithelial ovarian cancer, fallopian tubes or primary peritoneal carcinoma defined as:
2. Biochemical recurrence: defined as a CA-125 greater than or equal to two times the upper normal limit. Patients whose CA125 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.
3. Measurable disease (RECIST): defined as at least one lesion that can be accurately measured in at least one dimension (longest dimension to be recorded). Each lesion must be more than or equal to 20 mm when measured by conventional techniques, MRI or CT, or more than or equal to 10 mm when measured by spiral CT.
4. Non-measurable disease: includes patients with symptomatic ascites or pleural effusions, lesions that do not meet RECIST criteria as defined in (2) or biopsy proven recurrence. Patients with clinically evident nonmeasurable disease must have either an elevated CA125 as defined in (1) or histological confirmation of recurrence.
5.Unidimensionally measurable disease, as defined in section 10.1.1. Indicator lesions must not have been irradiated unless they have grown following radiation therapy.
5. SWOG Performance Status 0 - 2.
6. Patients must have previously received a platinum and paclitaxel containing regimen.
Eligible patients will be divided into two cohorts:
7. Patients are allowed to receive <= 3 prior chemotherapy regimens for recurrent disease. Patients who are rechallenged with the same chemotherapy regimen are considered to have had that regimen only once.
8. Heavily pretreated patients with recurrent ovarian cancer not eligible for any higher priority studies.
9. Projected life expectancy must be at least 3 months.
10. Signed informed consent.
11. Absolute neutrophil count >= 1500/[MICRO-SYMBOL]l and platelet count >= 100,000 [MICRO-SYMBOL]l.
12. Bilirubin <= 1.5 times the institutional upper limit of normal and ALT or AST <=3 times the upper limit of normal. Coagulation function tests not suggestive of severe liver dysfunction. Baseline hepatitis tiers without evidence of active hepatitis
13. Measured or calculated creatinine clearance >=40 ml/min.
14. Fasting triglycerides <= 5x time the upper limit of normal. Patients above this level may be eligible with permission of the Study Chair. Triglycerides may be
* prior to study entry with use of an antilipemic agent (atrovastatin, fenofibrate)
15. Patients must have recovered from acute toxicities from surgery, radiation or chemotherapy. At least 3 weeks will have elapsed since any prior therapy directed at the malignant tumor.
16. Patients of childbearing potential must agree to use an approved method of birth control.
17. Patient may have either platinum sensitive or platinum resistant recurrent ovarian cancer
18. Patients must have received at least one prior salvage regimen for recurrent ovarian cancer
19. Cardiac function: Baseline QTc interval <= 450 msecs.