A Phase I-II Preoperative Biomarker Trial of Fenretinide in Ascitic Ovarian Cancer

Abstract

Purpose: To evaluate study feasibility, toxicity, drug concentrations, and activity of escalating doses of the synthetic retinoid fenretinide [N-(4-hydroxyphenyl)retinamide (4-HPR)] in ovarian cancer by measuring serum CA125 and cytomorphometric biomarkers in cancer cells collected from ascitic fluid before and after treatment. Methods: Twenty-two naive patients with ascitic ovarian cancer were treated with escalating doses of 4-HPR at 0, 400, 600, and 800 mg/d for 1 to 4 weeks before surgery. Changes in the proportion of proliferating cells expressed by Ki67 and computer-assisted cytomorphometric variables (nuclear area, DNA index, and chromatin texture) were determined in ascitic cells. Drug levels were measured by high-performance liquid chromatography. Results: Doses up to 800 mg/d were well tolerated, and no adverse reactions occurred. There was no effect of 4-HPR on changes in serum CA125, Ki67 expression, which were assessed in 75% of subjects, and cytomorphometric variables, which were assessed in 80% of subjects. Plasma retinol levels were significantly lower in affected women than healthy donors. 4-HPR plasma concentrations increased slightly with increasing doses and attained a 1.4 Mmol/L concentration with 800 mg/d. Drug levels in malignant ascitic cells and tumor tissue were higher than in plasma but were 50 and 5 times lower, respectively, than in carcinoma cells treated in vitro with 1 Mmol/L 4-HPR. Conclusions: Cell biomarkers can be measured in ascitic cells to assess drug activity. Under our experimental conditions, 4-HPR did not show activity in advanced ovarian cancer cells. However, clinical evidence supports further investigation of fenretinide for ovarian cancer prevention. (Cancer Epidemiol Biomarkers Prev 2006;15(10):1914 -9)

Relationship among pharmacokinetics and pharmacodynamics of fenretinide and plasma retinol reduction in neuroblastoma patients

“…after 200 mg/day [7,8,[12][13] and it was higher (80-90%) after higher doses (900 mg/m 2 bid) [17][18]. Interestingly, in a trial in which the expected effect of 4-HPR on IGF-I was not observed [13], lack of compliance was excluded because retinol concentrations declined to an extent, that was in the same range previously reported with that dose.…”

Analysis of gene expression identifies PLAB as a mediator of the apoptotic activity of fenretinide in human ovarian cancer cells

“…Among the investigated patients, two controls and four treated, PLAB was upmodulated in 2/4 treated patients. The phase I-II trial was run in patients with ascitic ovarian cancer to evaluate toxicity, drug concentrations and markers of activity of escalating doses of 4-HPR (Colombo et al, 2006). 4-HPR doses up to 800 mg/day did not show any noticeable biological activity measured as changes in Ki-67 expression, cytomorphometric parameters and serum CA125.…”

“…Patients with newly diagnosed ascitic ovarian cancer were recruited in a phase I/II study (Colombo et al, 2006). Twentytwo patients were treated with escalating doses of 4-HPR at 0, 400, 600 and 800 mg/day for 1-4 weeks before surgery.…”

Anti-Cancer Activities and Interaction of Imiquimod and Flex-Het, SHetA2, in Melanoma and Ovarian Cancer

“…SHetA2 can be classified as a Retinoid-Related Molecule (RRM), which exert similar biological effects as retinoids, such as inhibition of cell growth and induction of differentiation, but also exert additional effects, such as apoptosis [59]. Retinoids and RRMs have demonstrated some activity in melanoma and ovarian cancer [5,60,61]. The efficacy and lack of toxicity prompted pre-clinical development of SHetA2 in the US National Cancer Institute (NCI) RAID and RAPID programs, which demonstrated lack toxicity of SHetA2 at doses 50 fold above the dose required to reduce xenograft tumor growth [62][63][64][65].…”