TY - JOUR
T1 - Pilot trial AMC-063
T2 - Safety and Efficacy of Bortezomib in AIDS-associated Kaposi Sarcoma
AU - on behalf of the AIDS Malignancy Consortium (AMC)
AU - Reid, Erin G.
AU - Suazo, Adrienne
AU - Lensing, Shelly Y.
AU - Dittmer, Dirk P.
AU - Ambinder, Richard F.
AU - Maldarelli, Frank
AU - Gorelick, Robert J.
AU - Aboulafia, David
AU - Mitsuyasu, Ronald
AU - Dickson, Mark A.
AU - Wachsman, William
N1 - Funding Information:
Bench to Bedside Award (3U01CA121947-03S2; to E.G. Reid and F. Maldarelli), NIH Cancer Center Support Grant (NCI CCC 5P50 CA23100-25): UCSD Cancer Clinical Investigator Team Leadership Award (to E.G. Reid), UCLA Center for AIDS Research (P30 AI028697; to R. Mitsuyasu), UCLA Clinical Translational Sciences Institute (UL1 TR0001881; R. Mitsuyasu), NIDCR RO1 DE018304 (to D.P. Dittmer), and PHS grant CA019014 (to D.P. Dittmer). This work was also supported in part with federal funds from the NCI, NIH, under contract No. HHSN261200800001E.
Funding Information:
We gratefully acknowledge the participating patients and their caregivers, as well as all AMC subinvestigators and research staff contributing to the conduct of this protocol. This study was supported by NCI U01 AMC grant (UM1CA121947), NIH
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/2/1
Y1 - 2020/2/1
N2 - Purpose: 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). Patients and Methods: A 3þ3 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. Results: 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. Conclusions: 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.
AB - Purpose: 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). Patients and Methods: A 3þ3 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. Results: 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. Conclusions: 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.
UR - http://www.scopus.com/inward/record.url?scp=85079018105&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85079018105&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-19-1044
DO - 10.1158/1078-0432.CCR-19-1044
M3 - Article
C2 - 31624104
AN - SCOPUS:85079018105
SN - 1078-0432
VL - 26
SP - 558
EP - 565
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 3
ER -