Originally published as JCO Early Release 10.1200/JCO.2005.11.043 on December 14 2004

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Angiogenesis Inhibitor IM862 Is Ineffective Against AIDS-Kaposi's Sarcoma in a Phase III Trial, but Demonstrates Sustained, Potent Effect of Highly Active Antiretroviral Therapy: From the AIDS Malignancy Consortium and IM862 Study Team

Ariela Noy, David T. Scadden, Jeannette Lee, Bruce J. Dezube, David Aboulafia, Anil Tulpule, Sharon Walmsley, Parkash Gill

From the Memorial Sloan-Kettering Cancer Center, New York, NY; USC Keck School of Medicine, Norris Cancer Institute, Los Angeles, CA; Massachusetts General Hospital, Harvard Medical School; Beth Israel Deaconess Medical Center, Boston, MA; AMC Operations and Statistical Center, University of Birmingham, Birmingham, AL; University of Washington; Virginia Mason Clinic, Seattle, WA; University of Toronto, Toronto Hospital, Toronto, Ontario, Canada

Address reprint requests to Ariela Noy, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021; e-mail: noya{at}mskcc.org.

PURPOSE: IM862 is a synthetic dipeptide (L-glutamine L-tryptophan) with in vitro and in vivo antiangiogenic properties. Phase I/II studies showed minimal toxicity and a response rate of 36% in AIDS-Kaposi's sarcoma. We report a 24-week, randomized, double-blinded, placebo-controlled phase III trial with the phase II dose, 5 mg intranasally every other day.

PATIENTS AND METHODS: Two hundred two HIV-positive patients were enrolled, 104 on IM862 and 98 on placebo.

RESULTS: Baseline characteristics were comparable except current antiretroviral therapy: 88% versus 96% (IM862 v placebo group; P = .042). The median treatment durations were 19.5 versus 24 weeks (IM862 v placebo). No significant difference was detected in response rate (IM862, 23%; 95% CI, 15% to 32% v placebo, 21%; 95% CI, 14% to 31%; P = .46), time to response (8.5 weeks v 14 weeks; P = .024), or duration of response. However, IM862 was associated with both a shorter time to response (8.5 weeks v 14 weeks; P = .024) and shorter median time to progression (16 weeks, 95% CI, 13 to 27 weeks v 35 weeks, 95% CI, 26 to 114 weeks; P = .012).

CONCLUSION: Despite promising phase I and phase II studies, IM862 5 mg every other day was not superior to placebo and may accelerate time to progression. Highly active antiretroviral therapy alone was associated with a substantial rate of sustained tumor response and may have contributed to prior estimates of IM862 response. Therapeutic trials for AIDS-Kaposi's sarcoma must account for ongoing immune reconstitution in the setting of concurrent highly active antiretroviral therapy that may confound estimates of therapeutic activity.

Supported by the Ontario HIV Treatment Network Career Scientist Award (S.W.), grants from the National Cancer Institute (U01CA083118, U01CA070079, U01CA070081, U01CA070068, U01CA070075, U01CA070047, U01CA070054, U01CA070072, U01CA070080, U01CA070081, U01CA083035, U01CA071375, U01CA083038, U01CA070062, U01CA070019), and Cytran, Inc.

Presented in part at the International Conference on Malignancies in AIDS and Other Immune Deficiencies, April 22-24, 2002. Bethesda, MD.

Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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