Supplementary Methods and Figure Supplemental Figure 1. Images demonstrating improvement in KS lesions in two patients obtaining partial response to bortezomib despite receiving treatment in the lowest 2 dose cohorts. Both patients met criteria for partial response after 2 cycles of bortezomib. A. Images for "Patient 2" (dose level 1) demonstrate fading of lesion pigmentation after cycle 2 and further fading after cycle 8; less well-appreciable from photographs is the observed flattening of initially raised lesions. B. After only 2 cycles of bortezomib, "Patient 5" (dose level 2) experienced resolution of several lesions and fading of others.
ARTICLE ABSTRACT
AIDS-related Kaposi sarcoma is often incompletely controlled, requiring serial therapies. Kaposi sarcoma herpesvirus (KSHV) induces transformation of endothelial cells, where it resides in a predominately latent state. We hypothesized proteasome inhibition would have direct antitumor activity, induce lytic activation of KSHV, and inhibit HIV infectivity, improving control of both Kaposi sarcoma and HIV. The primary objective was determining the MTD of bortezomib in AIDS-Kaposi sarcoma. Secondary objectives included estimating the impact of bortezomib on Kaposi sarcoma response, KSHV plasma DNA copy number (PDCN), and HIV viral loads (VL).
A 3+3 dose escalation design was employed evaluating four dose levels of bortezomib (0.75, 1, 1.2, or 1.6 mg/m2) administered intravenously on days 1, 8, and 15 of 28-day cycles in patients with relapsed/refractory (r/r) AIDS-Kaposi sarcoma taking antiretroviral therapy.
Seventeen patients enrolled. No dose-limiting toxicities occurred and the MTD was not reached. The most common adverse events included diarrhea, fatigue and nausea. Among 15 evaluable patients, partial response (PR) occurred in nine (60%), with a PR rate of 83% in the 1.6 mg/m2 cohort; the remainder had stable disease (SD). Median time to response was 2.1 months. Median change in KSHV PDCN was significantly different between those with PR versus SD. During cycle 1, seven of 11 evaluable patients had decreases in HIV VL.
Bortezomib is well-tolerated and active in AIDS-Kaposi sarcoma. The 60% PR rate is notable given the dose-finding nature of the study in a r/r population. Changes in KSHV PDCN and HIV VL trended as hypothesized.
