title: 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.
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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Irene M
authors.initials: IM
authors.lastname: Ghobrial
authors.affiliation: John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, New Jersey.
authors.forename: David S
authors.initials: DS
authors.lastname: Siegel
authors.affiliation: Division of Hematology and Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Ravi
authors.initials: R
authors.lastname: Vij
authors.affiliation: Sarah Cannon Research Institute, Nashville, Tennessee.
authors.forename: Jesus G
authors.initials: JG
authors.lastname: Berdeja
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.affiliation: Global Biostatistics, Millennium Pharmaceuticals, Inc, Cambridge, Massachusetts, USA, a Wholly Owned Subsidiary of Takeda Pharmaceutical Company Limited.
authors.forename: Rachel
authors.initials: R
authors.lastname: Neuwirth
authors.affiliation: Clinical Pharmacology, Millennium Pharmaceuticals, Inc, Cambridge, Massachusetts, USA, a Wholly Owned Subsidiary of Takeda Pharmaceutical Company Limited.
authors.forename: Chirag G
authors.initials: CG
authors.lastname: Patel
authors.affiliation: Oncology Clinical Research, Millennium Pharmaceuticals, Inc, Cambridge, Massachusetts, USA, a Wholly Owned Subsidiary of Takeda Pharmaceutical Company Limited.
authors.forename: Fabian
authors.initials: F
authors.lastname: Zohren
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Wolf
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001583:Benzoxazoles / Q000494:pharmacology / Q000627:therapeutic use*; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000175:diagnosis / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D008875:Middle Aged; D009101:Multiple Myeloma / Q000175:diagnosis / Q000188:drug therapy*; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D012008:Recurrence; D019233:Retreatment; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016896:Treatment Outcome; D008258:Waldenstrom Macroglobulinemia / Q000175:diagnosis / Q000188:drug therapy*; D000225:Adenine / Q000031:analogs & derivatives
chemical_list: D000970:Antineoplastic Agents; D001583:Benzoxazoles; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases; C572449:sapanisertib; D000225:Adenine