Premium
TAK ‐228 (formerly MLN 0128), an investigational oral dual TORC 1/2 inhibitor: A phase I dose escalation study in patients with relapsed or refractory multiple myeloma, non‐Hodgkin lymphoma, or Waldenström's macroglobulinemia
Author(s) -
Ghobrial Irene M.,
Siegel David S.,
Vij Ravi,
Berdeja Jesus G.,
Richardson Paul G.,
Neuwirth Rachel,
Patel Chirag G.,
Zohren Fabian,
Wolf Jeffrey L.
Publication year - 2016
Publication title -
american journal of hematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.456
H-Index - 105
eISSN - 1096-8652
pISSN - 0361-8609
DOI - 10.1002/ajh.24300
Subject(s) - medicine , nausea , gastroenterology , tolerability , neutropenia , macroglobulinemia , rash , waldenstrom macroglobulinemia , mucositis , multiple myeloma , lymphoma , vomiting , phases of clinical research , pharmacokinetics , toxicity , adverse effect
The PI3K/AKT/mTOR signaling pathways are frequently dysregulated in multiple human cancers, including multiple myeloma (MM), non‐Hodgkin lymphoma (NHL), and Waldenström's macroglobulinemia (WM). This was the first clinical study to evaluate the safety, tolerability, maximal‐tolerated dose (MTD), dose‐limiting toxicity (DLT), pharmacokinetics, and preliminary clinical activity of TAK‐228, an oral TORC1/2 inhibitor, in patients with MM, NHL, or WM. Thirty‐nine patients received TAK‐228 once daily (QD) at 2, 4, 6, or 7 mg, or QD for 3 days on and 4 days off each week (QDx3d QW) at 9 or 12 mg, in 28‐day cycles. The overall median age was 61.0 years (range 46–85); 31 patients had MM, four NHL, and four WM. Cycle 1 DLTs occurred in five QD patients (stomatitis, urticaria, blood creatinine elevation, fatigue, and nausea and vomiting) and four QDx3d QW patients (erythematous rash, fatigue, asthenia, mucosal inflammation, and thrombocytopenia). The MTDs were determined to be 4 mg QD and 9 mg QDx3d QW. Thirty‐six patients (92%) reported at least one drug‐related toxicity; the most common grade ≥3 drug‐related toxicities were thrombocytopenia (15%), fatigue (10%), and neutropenia (5%). TAK‐228 exhibited a dose‐dependent increase in plasma exposure and no appreciable accumulation with repeat dosing; mean plasma elimination half‐life was 6–8 hr. Of the 33 response‐evaluable patients, one MM patient had a minimal response, one WM patient achieved partial response, one WM patient had a minor response, and 18 patients (14 MM, two NHL, and two WM) had stable disease. These findings encourage further studies including combination strategies. Am. J. Hematol. 91:400–405, 2016. © 2016 Wiley Periodicals, Inc.