Trial of Fenretinide/LXS Plus Ketoconazole in Recurrent Ovarian Cancer and Primary Peritoneal Carcinoma

Fenretinide (N-(4-hydroxyphenyl)retinamide, 4-HPR), is a cytotoxic retinoid that has
activity against ovarian cancer cell lines invitro in a dose-related manner. A phase II
study of 4-HPR oral capsules in recurrent, platinum-refractory ovarian cancer (NCT00026091)
demonstrated a significantly better overall survival in patients obtaining 4-HPR plasma
levels of > 9 mM, suggesting that obtaining high 4-HPR exposures in all such patients could
yield clinical benefits. Fenretinide has proven clinical tolerability at plasma
concentrations of 1 - 13 mM when given orally using a 100 mg, corn-oil containing capsule
(NCI, IND #40294). However, the 4-HPR oral capsule has low bioavailability, requiring
numerous capsules to be consumed daily, and produces a wide interpatient variability in
steady-state plasma levels obtained.

A novel oral 4-HPR powder formulation (4-HPR/LXS oral powder, ~2.2% by weight 4-HPR) has
been prepared using an organized lipid matrix technology, called Lym-X-Sorb (LXS).
4-HPR/LXS oral powder is suitable for delivery in low milk fat-containing foods and liquids.
A pediatric phase I study in recurrent neuroblastoma (NCT00295919) demonstrated that
4-HPR/LXS oral powder consistently produced higher 4-HPR plasma levels on a mg-per-mg 4-HPR
basis than the corn-oil capsule formulation. Increased 4-HPR exposures were associated with
greater clinical activity, including complete responses (CR), than similar studies conducted
using the fenretinide capsule. A recent adult phase I study of 4-HPR/LXS oral powder
(NCT00589381) also suggested that 4-HPR exposures could be increased above those obtained
using the capsule formulation. Additionally, murine studies have demonstrated that
ketoconazole (at standard human-equivalent doses), acting as an inhibitor of 4-HPR
metabolism, can further increase 4-HPR plasma, tissue and tumor xenograft levels when given
concurrently with 4-HPR/LXS oral powder. Given these data, we hypothesize that concurrently
administering 4-HPR/LXS oral powder + ketoconazole will reliably achieve 4-HPR plasma levels
> 10 mM in recurrent ovarian cancer patients with tolerable systemic toxicity and result in
beneficial anti-tumor activity.

Given the minimal systemic toxicity observed with 4-HPR and the association of improved
survival with higher 4-HPR exposures in the capsule 4-HPR phase II study, we further
hypothesize that 4-HPR/LXS oral powder + ketoconazole: 1) may achieve objective responses
against recurrent ovarian cancer; 2) will improve progression-free and overall survival of
patients by achieving 4-HPR levels > 10 mM in the majority of patients.

This trial is a single arm Phase II study of 4-HPR/LXS oral powder (given TID) +
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 > 10 mM (steady state peak plasma) are
associated with objective tumor responses. (3) Define the EFS, PFS, and/or OS for women
with recurrent ovarian cancer and primary peritoneal carcinoma treated with 4-HPR/LXS oral
powder + ketoconazole given concurrently. SECONDARY STUDY AIMS are: (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.

Inclusion Criteria:

- Patients with histologically confirmed recurrent or metastatic epithelial ovarian
cancer or primary peritoneal carcinoma defined as:

- 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.

- 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.

- 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.

- Unidimensionally measurable disease, as defined in section 10.1.1. Indicator lesions
must not have been irradiated unless they have grown following radiation therapy.

- SWOG Performance Status 0 - 2.

- Patients must have previously received a platinum and paclitaxel containing regimen.

- Patients are allowed to receive ≤ 2 prior chemotherapy regimens for recurrent
disease. Patients who are rechallenged with the same chemotherapy regimen are
considered to have had that regimen only once.

- Projected life expectancy must be at least 3 months.

- Signed informed consent.

- Absolute neutrophil count ≥ 1500/micro liter and platelet count ≥ 100,000 micro
liter.

- Bilirubin ≤ 2 times the institutional limit of normal and ALT or AST ≤3 times the
upper limit of normal.

- Measured or calculated creatinine clearance ≥60 ml/min.

- 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
"normalized" prior to study entry with use of an antilipemic agent (atorvastatin,
fenofibrate)

- 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.

- Patients of childbearing potential must agree to use an approved method of birth
control.

Exclusion Criteria:

- Prior fenretinide is not allowed. Prior 13-cis, 9-cis or all-trans retinoic acid are
allowed.

- Patients with a second malignancy within the last 5 years are not allowed, except for
those with non-melanomatous skin cancer and carcinoma-in-situ of the cervix. All
prior invasive malignancies must be in complete remission.

- The use of concomitant antioxidants, such as vitamin C or E, is not allowed.

- Patients with concurrent medical, psychological or social conditions of such severity
that the investigator deems it unwise to enter the patient on protocol.

- Untreated or symptomatic brain metastases.

- Pregnant or nursing women.