Treating HIV+ patients for non-AIDS-defining cancers (NADCs) in the era of targeted chemotherapy: An AIDS malignancy consortium study of sunitinib in patients on ART.

Abstract

TPS161 Background: The cumulative NADC incidence is approaching that of AIDS-defining cancers in HIV-infected persons in populations where effective antiretroviral therapy (ART) is commonly used. Marked increases in risk are seen in certain cancers, including lung, liver, head and neck, anogenital, and Hodgkin's lymphoma. Treatment of NADCs may be complicated by drug-drug interactions between ART and chemotherapy, including ART-mediated induction or inhibition of metabolizing enzymes, especially of the CYP450 family. To study these interactions, with the goal of formulating treatment recommendations on the use of targeted anticancer agents to treat NADCs in HIV+ patients, the AIDS Malignancy Consortium has launched the first clinical study to address this emerging epidemic. Sunitinib is a multi-targeted TKI of PDGFR, VEGFR1/3, KIT, FLT3, SCF, and RET. It is a prodrug which is metabolized into the active metabolite SU012662 by CYP3A4, which is then further inactivated by CYP3A4. Methods: The primary objectives of AMC 061 is to determine the safety and to investigate the effect of ART on the PK of sunitinib in HIV+ cancer patients. Secondary objectives include investigating: the efficacy of using sunitinib to treat NADCs; the effects of sunitinib on ART pharmacokinetics, CD4 count, and HIV viral load; and pharmacogenetic correlations. Subjects are stratified into three groups based on their ART therapy: (1) non- nucleoside reverse transcriptase inhibitor (NNRTI)-based therapy, (2) non-ritonavir protease inhibitor (PI)-based therapy, and (3) ritonavir PI-based therapy. A phase I dose escalation design is used to determine the MTD of sunitinib (25, 37.5, or 50 mg daily) in each group, with both inter- and intra-patient dose escalation allowed. Between 21 and 42 patients will be enrolled. Intensive PK and PD monitoring is performed throughout Cycle 1. The trial was initiated in late 2009, and is open at AMC sites and those of the NCI Organ Dysfunction Working Group. As of 1/2010, three patients have been enrolled. Treatment has been well tolerated and no DLTs have been experienced. Updated information on the safety and initial PK analyses will be presented. No significant financial relationships to disclose.