Pilot trial of the safety, tolerability, and retinoid levels of N-(4-hydroxyphenyl) retinamide in combination with tamoxifen in patients at high riskfor developing invasive breast cancer

Purpose: N-(4-hydroxyphenyl) retinamide([4-HPR], Fenretinide; R.W. Johnson Pharmaceutical Research Institute, Springhouse, PA) and tamoxifen (TAM) hav e synergistic antitumor and chemopreventive activity against mammary cancer in preclinical studies. We performed a pilot study of this combination in women at high risk for developing breast cancer. Patients and Methods: Thirty-two women were treated with four cycles of 4-H PR, 200 mg orally (PO) for 25 days of each 28-day cycle, and TAM, 20 mg PO once daily for 23 months beginning after 1 month of 4-HPR alone. Tolerabili ty, dark adaptometry, tissue biopsies, and retinoid plasma concentrations ( Cp) were evaluated. Results: Symptomatic reversible nyctalopia developed in two patients (6%) o n 4-HPR, but 16 (73%) of 22 patients had reversible changes in dark adaptat ion, which correlated with relative decrease in Cp retinol (P less than or equal to .01), Four patients stopped treatment for side effects, and 84% of patients had hot flashes. Other commonly reported (grade less than or equa l to 2) reversible toxicities included skin and ocular dryness, fatigue, an d mood changes. Serum high-density lipoprotein increased and cholesterol de creased from baseline to month 4. Baseline mean +/- SD Cp retinol was 708 /- 280 ng/mL. Mean +/- SD Cp of 4-HPR, N-(4-methoxyphenyl) retinamide (4-MP R), and retinol after 1 month of 4-HPR were 0.34 +/- 0.21 mu mol/L, 0.28 +/ - 0.21 mu mol/L, and 282 +/- 127 ng/mL, respectively. Mean retinoid Cps did not change after 3 months of Q-HPR + TAM. Conclusions: TAM administration did not affect Cp 4-HPR or 4-MPR. Reversibl e nyctalopia correlated with relative decrease in Cp retinol but was not sy mptomatic for most patients. TAM + 4-HPR has acceptable tolerability for th is high-risk cohort. (C) 2000 by American Society of Clinical Oncology.