BACKGROUND: The treatment of non-acquired immunodeficiency syndrome-defining cancers may be complicated by drug interactions between highly active antiretroviral therapy (HAART) and chemotherapy. This trial is the first by the AIDS Malignancy Consortium to assess targeted therapies and HAART in human immunodeficiency virus-positive patients (ClinicalTrials.gov identifier: NCT00890747). METHODS: In a modified phase 1 study of sunitinib, patients were stratified into 2 treatment arms based on whether they were receiving therapy with ritonavir, a potent CYP3A4 inhibitor. Patients in treatment arm 1 (non-ritonavir HAART) received standard sunitinib dosing (50 mg/day). Treatment arm 2 (ritonavir-based HAART) used a phase 1, 3 + 3 dose escalation design (from 25 mg/day to 50 mg/day). Cycles were comprised of 4 weeks on treatment followed by a 2-week break (6 weeks total). The pharmacokinetics of sunitinib and its active metabolite (N-desethyl sunitinib) were assessed. RESULTS: Nineteen patients were enrolled and were evaluable. Patients on treatment arm 1 tolerated treatment with no dose-limiting toxicity observed. In treatment arm 2, a dose-limiting toxicity was experienced at a dose of 37.5 mg, and an additional 3 of 5 patients experienced grade 3 neutropenia (toxicity graded as per National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]), an uncommon toxicity of sunitinib. No patient achieved a response, but 10 patients had stable disease, including 8 with prolonged disease stability. Efavirenz, a potent inducer of CYP3A4, resulted in increased exposure of N-desethyl sunitinib, whereas ritonavir caused decreased exposure of the metabolite. Hand-foot syndrome was associated with higher steady-state trough concentrations of sunitinib. CONCLUSIONS: Patients receiving non-ritonavir-based HAART regimens tolerated standard dosing of sunitinib. Patients receiving ritonavir-based therapy who were treated with a dose of 37.5 mg/day experienced higher toxicities. Dose reductions of sunitinib to 37.5 mg may be warranted in patients receiving ritonavir.
BACKGROUND: The treatment of non-acquired immunodeficiency syndrome-defining cancers may be complicated by drug interactions between highly active antiretroviral therapy (HAART) and chemotherapy. This trial is the first by the AIDS Malignancy Consortium to assess targeted therapies and HAART in human immunodeficiency virus-positive patients (ClinicalTrials.gov identifier: NCT00890747). METHODS: In a modified phase 1 study of sunitinib, patients were stratified into 2 treatment arms based on whether they were receiving therapy with ritonavir, a potent CYP3A4 inhibitor. Patients in treatment arm 1 (non-ritonavir HAART) received standard sunitinib dosing (50 mg/day). Treatment arm 2 (ritonavir-based HAART) used a phase 1, 3 + 3 dose escalation design (from 25 mg/day to 50 mg/day). Cycles were comprised of 4 weeks on treatment followed by a 2-week break (6 weeks total). The pharmacokinetics of sunitinib and its active metabolite (N-desethyl sunitinib) were assessed. RESULTS: Nineteen patients were enrolled and were evaluable. Patients on treatment arm 1 tolerated treatment with no dose-limiting toxicity observed. In treatment arm 2, a dose-limiting toxicity was experienced at a dose of 37.5 mg, and an additional 3 of 5 patients experienced grade 3 neutropenia (toxicity graded as per National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]), an uncommon toxicity of sunitinib. No patient achieved a response, but 10 patients had stable disease, including 8 with prolonged disease stability. Efavirenz, a potent inducer of CYP3A4, resulted in increased exposure of N-desethyl sunitinib, whereas ritonavir caused decreased exposure of the metabolite. Hand-foot syndrome was associated with higher steady-state trough concentrations of sunitinib. CONCLUSIONS:Patients receiving non-ritonavir-based HAART regimens tolerated standard dosing of sunitinib. Patients receiving ritonavir-based therapy who were treated with a dose of 37.5 mg/day experienced higher toxicities. Dose reductions of sunitinib to 37.5 mg may be warranted in patients receiving ritonavir.
Authors: Gary M Clifford; Jerry Polesel; Martin Rickenbach; Luigino Dal Maso; Olivia Keiser; Andreas Kofler; Elisabetta Rapiti; Fabio Levi; Gernot Jundt; Thomas Fisch; Andrea Bordoni; Daniel De Weck; Silvia Franceschi Journal: J Natl Cancer Inst Date: 2005-03-16 Impact factor: 13.506
Authors: F J Palella; K M Delaney; A C Moorman; M O Loveless; J Fuhrer; G A Satten; D J Aschman; S D Holmberg Journal: N Engl J Med Date: 1998-03-26 Impact factor: 91.245
Authors: C G Lee; M M Gottesman; C O Cardarelli; M Ramachandra; K T Jeang; S V Ambudkar; I Pastan; S Dey Journal: Biochemistry Date: 1998-03-17 Impact factor: 3.162
Authors: Bruce D Cheson; John M Bennett; Kenneth J Kopecky; Thomas Büchner; Cheryl L Willman; Elihu H Estey; Charles A Schiffer; Hartmut Doehner; Martin S Tallman; T Andrew Lister; Francesco Lo-Coco; Roel Willemze; Andrea Biondi; Wolfgang Hiddemann; Richard A Larson; Bob Löwenberg; Miguel A Sanz; David R Head; Ryuzo Ohno; Clara D Bloomfield; Francesco LoCocco Journal: J Clin Oncol Date: 2003-12-15 Impact factor: 44.544
Authors: Eric A Engels; Malcolm V Brock; Jinbo Chen; Craig M Hooker; Maura Gillison; Richard D Moore Journal: J Clin Oncol Date: 2006-03-20 Impact factor: 44.544
Authors: Rachel A Bender Ignacio; Jeannette Y Lee; Michelle A Rudek; Dirk P Dittmer; Richard F Ambinder; Susan E Krown Journal: J Acquir Immune Defic Syndr Date: 2016-05-01 Impact factor: 3.731
Authors: Thomas S Uldrick; Priscila H Gonçalves; Kathleen M Wyvill; Cody J Peer; Wendy Bernstein; Karen Aleman; Mark N Polizzotto; David Venzon; Seth M Steinberg; Vickie Marshall; Denise Whitby; Richard F Little; John J Wright; Michelle A Rudek; William D Figg; Robert Yarchoan Journal: Oncologist Date: 2017-03-24