Data from Weekly <i>nab</i>-Rapamycin in Patients with Advanced Nonhematologic Malignancies: Final Results of a Phase I Trial

• DOI: 10.1158/1078-0432.c.6520649
• Publication Date: 2023-04-01T07:52:54Z
• Authors: Ana M. Gonzalez-A...; Funda Meric-Bernstam; Sant Chawla; Gerald Falchook; David Hong; Argun Akcakanat; Huiqin Chen; Aung Naing; Siqing Fu; Jennifer Wheler; Stacy Moulder; Thorunn Helgason; Shaoyi Li; Ileana Elias; Neil Desai; Razelle Kurzrock

&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Purpose:&lt;/b&gt; This dose-finding phase I study investigated the maximum-tolerated dose (MTD) and safety of weekly nanoparticle albumin-bound rapamycin (&lt;i&gt;nab&lt;/i&gt;-rapamycin) in patients with untreatable advanced nonhematologic malignancies.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Experimental Design:&lt;/b&gt;&lt;i&gt;nab&lt;/i&gt;-Rapamycin was administered for 3 weeks followed by 1 week rest, a starting 45 mg/m&lt;sup&gt;2&lt;/sup&gt;. Additional doses were 56.25, 100, 150, 125 mg/m&lt;sup&gt;2&lt;/sup&gt;.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; Of 27 enrolled patients, 26 treated. Two dose-limiting toxicities (DLT) occurred at 150 mg/m&lt;sup&gt;2&lt;/sup&gt; [grade aspartate aminotransferase (AST) elevation grade 4 thrombocytopenia], two DLTs (grade suicidal ideation hypophosphatemia). Thus, MTD declared 100 Most treatment-related adverse events (TRAE) 1/2, including thrombocytopenia (58%), hypokalemia (23%), mucositis (38%), fatigue (27%), rash diarrhea nausea (19%), anemia hypophosphatemia neutropenia (15%), hypertriglyceridemia (15%). Only one TRAE (dyspnea) hematologic event (anemia) MTD. One patient kidney cancer had partial response 2 remained on 365 days (patient mesothelioma) 238 neuroendocrine tumor). The peak concentration (&lt;i&gt;C&lt;/i&gt;&lt;sub&gt;max&lt;/sub&gt;) area under concentration–time curve (AUC) increased between mg/m&lt;sup&gt;2&lt;/sup&gt;, except relatively low AUC &lt;i&gt;nab&lt;/i&gt;-Rapamycin significantly inhibited mTOR targets S6K 4EBP1.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; clinical single-agent &lt;i&gt;nab&lt;/i&gt;-rapamycin established (3 weeks) given intravenously, which well tolerated preliminary evidence stable disease, produced fairly dose-proportional pharmacokinetic profile unresectable malignancies. &lt;i&gt;Clin Cancer Res; 19(19); 5474–84. ©2013 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;