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Am J Hematol. 2016 Jun;91(4):400-5. doi: 10.1002/ajh.24300.

TAK-228 (formerly MLN0128), an investigational oral dual TORC1/2 inhibitor: A phase I dose escalation study in patients with relapsed or refractory multiple myeloma, non-Hodgkin lymphoma, or Waldenström's macroglobulinemia.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
2
John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, New Jersey.
3
Division of Hematology and Oncology, Washington University School of Medicine, St. Louis, Missouri.
4
Sarah Cannon Research Institute, Nashville, Tennessee.
5
Global Biostatistics, Millennium Pharmaceuticals, Inc, Cambridge, Massachusetts, USA, a Wholly Owned Subsidiary of Takeda Pharmaceutical Company Limited.
6
Clinical Pharmacology, Millennium Pharmaceuticals, Inc, Cambridge, Massachusetts, USA, a Wholly Owned Subsidiary of Takeda Pharmaceutical Company Limited.
7
Oncology Clinical Research, Millennium Pharmaceuticals, Inc, Cambridge, Massachusetts, USA, a Wholly Owned Subsidiary of Takeda Pharmaceutical Company Limited.
8
Department of Medicine, University of California San Francisco, San Francisco, California.

Abstract

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.

PMID:
26800393
DOI:
10.1002/ajh.24300
[Indexed for MEDLINE]
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