Preliminary results of a phase II study of oral thalidomide in patients with AIDS-related Kaposl's sarcoma (KS)

Abstract

18 Background: Thalidomide is an oral drug that has been shown by D'Amato, Folkman et al. to inhibit angiogenesis in a rabbit cornea assay (PNAS 91:4082, 1994). Because KS tumors are highly vascular, we hypothesized that thalidomide may have activity in this disease. Methods. Oral thalidomide was administered for up to fifty-two weeks in an ongoing phase II dose titration trial. Entry requirements included a history of cutaneous KS progressive over the two months prior to enrollment. Dosing started at 200 mg/day with escalation every two weeks as tolerated to a maximum of 1000 mg/day. A minor modification of the AIDS Clinical Trails Group KS criteria was utilized to assess responses. Results: Thirteen patients (pls.) have accrued to date. Median (range) age was 39 (31-49) years; entry median (range) CD4 count was 255 (14-646) cells/mm3. As assessed using the TIS staging (JCO 7:1201, 1989) strategy for KS, 8 were poor risk, and 5 were good risk. Three pts. had toxicity requiring treatment termination: one pt. had a grade 3 rash with fever that recurred with drug rechallenge; one developed myositis; and one developed depression. Two of these 3 pts. were not evaluable for response. Of 11 evaluable pts., 4 (3 of the 4 poor risk by TIS criteria), have attained a partial response (PR) (response rate 36%; 95% CI: 7.6% - 64.4%). Two of these responded while on stable combination nucleoside anti-HIV therapy; one was on a stable 3-drug anti-HIV regimen, and one patient was started on triple antiretroviral therapy after beginning thalidomide but prior to attaining PR. Two of the pts, who responded had received prior systemic cytotoxic chemotherapy. The responses were first observed at weeks four (3/11) and eight (1/11) at daily doses of 300 mg, 400mg (2 pts.), and 800 mg. Two pts. with partial responses (PR) still have not progressed at 42 and 22 weeks, while two pts. achieving a PR progressed after 16 and 49 weeks. Two pts. progressed without achieving a PR after 16 and 24 weeks, while 5 pts. have had stable disease to date. Of those, one pt. has had no evidence of progression for 52 weeks, and 4 have stable disease on-study at 24, 14 and 4 (2 pts.) weeks. Three pts. had grade 3 neutropenia on study. Five pts. had sedation which resolved with dose reduction. Inducible protein-10, TNF-α, and interleukin-6 were measured but overall no clear trends were observed. Conclusion: Thalidomide is well tolerated in AIDS KS at doses of up to 1000 mg/day. This drug appears to be active in KS and in some cases to induce durable responses. This trial is ongoing, and further study will help define the potential role of thalidomide in the therapy of KS.