Protocol AMC-087: Phase I Trial of Cabozantinib (XL184) for Advanced Solid Tumors in Persons with HIV Infection
To determine the safety and tolerability of cabozantinib (XL184) as a single agent in solid tumor patients with HIV infection and to determine the maximal tolerated dose (MTD) in this patient population. Secondary Objectives: 1) To investigate possible pharmacokinetic interactions between cabozantinib and antiretroviral therapy in persons with HIV infection. 2) To investigate the effects of therapy on patient immune status and HIV viral load. 3) To preliminarily assess objective response rates associated with treatment for commonly represented tumors.
Patients with known HIV infection and confirmed, advanced solid tumor cancer that is progressing despite standard therapies.
This is a phase I, dose escalation study of cabozantinib (XL184) for advanced solid tumors in persons with HIV infection. Cabozantinib will be administered orally as a once daily dose continuously for 28- day cycles, according to the Protocol Schema. Patients will be stratified into three groups based on which HAART therapy they are receiving. The first group (Stratum A) will be patients on either ritonavir or cobicistat (potent CYP3A4 inhibitor)- containing antiretroviral therapy. Since a potential interaction leading to higher drug levels of cabozantinib in patients on ritonavir or cobicistat is expected, patients will be dose escalated, starting at ~33% of the standard dose (60 mg), using a classic 3 + 3 phase I clinical trial design. Dose increases will be in 20 mg increments to a maximum of 60 mg/day. The second group (Stratum B) will be patients being treated with either efavirenz or etravirine-containing regimens, in whom CYP3A4 induction may lead to lower levels of the study drug. These patients will be treated at the standard dose of cabozantinib, then dose escalated by 20 mg/cohort to a maximum of 100 mg/day in a 3 + 3 design. The third group (Stratum C) will include patients taking antiretrovirals not specified in Stratum A or B, or who are not receiving active antiretroviral therapy. These patients will be treated at the standard dose of 60 mg/day; no dose escalation is planned in this Stratum. In this trial, a dose-limiting toxicity (DLT) will be defined as any cabozantinib-related grade 3 or 4 non-hematologic toxicity during the first cycle of therapy, including grade 3 nausea and/or vomiting and grade 3 diarrhea despite prophylaxis and/or treatment or any of the following grade 4 hematologic toxicities during the first cycle of therapy: thrombocytopenia, neutropenia of more than 5 days duration, and neutropenia of any duration with fever or documented infection; additionally, treatment delay of 14 days or greater during Cycle 1 due to unresolved toxicity or any dose reduction required during Cycle 1 due to a cabozantinib-related adverse event will be considered a DLT. AMC #087 (Version 1.0) 02/25/2013 7 NCI Version Date 02/25/2013 All participating patients will have pharmacokinetic sampling studies. Response evaluation by RECIST 1.1 will be obtained on all patients at baseline and at 8 week intervals. Duration: Treatment may continue indefinitely until one of the following criteria applies: 1) unacceptable toxicity (including DLT in cycle 1); 2) progressive disease; or 3) patient withdrawal or removal.
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