Trial Information

Phase I/II Trial of Fenretinide/LXS Oral Powder (NSC 374551) 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.