Oral 9-cis-Retinoic Acid is active in AIDS related Kaposi's sarcoma: AIDS Associated Malignancy Consortium Study 002

Abstract

51 Background: Topical retinoids are active in cutaneous Kaposi's sarcoma. But for patients with extensive disease, this is an impractical treatment. We sought to improve on the therapeutic range of retinoids with the use of oral 9-cis-retinoic acid (LGD 1057). We determined the safety, tolerance and efficacy of oral LGD1057 tablets in patients with AIDS-Kaposi's sarcoma. Methods: Phase II, open label clinical trial conducted in a multi-center network using a modified Simon two-stage enrollment method. Patients received 60 mg/M2 of LGD1057 each afternoon up to a maximum of 100 mg/M2 as tolerated. Patients were seen biweekly and evaluated at 16 weeks for tumor response using ACTG criteria. Laboratory parameters including CD4 cell counts and HIV RNA, adverse events, and quality of life data were analyzed for safety and tolerance. Results: An interim analysis of 66 patients was completed. Patients who met the study criteria for response, developed toxicity requiring drug discontinuation; or who had received at least 16 weeks of therapy were included. Of the 38 evaluable patients, 79% were white males; median age was 40; and median CD4 count was 229 (range 18-784). The majority (71%) were receiving at least 3 antiretroviral agents at study entry. Most patients (74%) had received prior therapy including 20 patients with local treatment and 16 patients with systemic chemotherapy or immunotherapy. Partial responses were seen in 37% (14), stable disease in 39% (15) and progressive disease in 11% (4) patients. Responses were seen in patients with large tumor burden, low CD4 counts and/or prior treatment with systemic chemotherapy. Eleven (11) patients withdrew for adverse events and 13 had dose reductions or interruptions because of toxicity. Ten patients remained on a dose of 100 mg/M2 for up to 38 weeks. Grade 3 or 4 toxicities included headache (n=8, 21%), elevated triglycerides (n=5, 13%) and skin (alopecia, desquamation, nail changes). Triglyceride (baseline, mean ± s.d., 240 ± 170, week 8, 788 ± 675) and cholesterol levels (baseline, 187 ± 71, week 8, 277 ± 98) rose significantly. Skin toxicity increased over time despite topical vitamin E therapy. Conclusion: Oral LGD1057 is an active agent in AIDS related Kaposi's sarcoma with a response rate of greater than 30% (C.I. 22-55%).