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 Waldenstr€ om'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,

Silencing c-Myc translation as a therapeutic strategy through targeting PI3Kδ and CK1ε in hematological malignancies

“…The dual mTORC1/mTORC2 inhibitor MLN0128 was recently reported to exhibit no activity in lymphoma. 14 These results suggest that most cancers, including lymphoma, likely use multiple signaling pathways to ensure robust translation, and therefore are able to bypass translational downregulation caused by mTOR inhibitors. As an example, casein kinase-1 e (CK1e) activates mRNA translation through phosphorylating 4E-BP1 at residues distinct from those responsive to mTOR.…”

“…[8][9][10] In keeping with these data, mTORC1 and dual mTORC1/mTORC2 inhibitors have been found to cause varied degrees of inhibition of 4E-BP1 phosphorylation and translation initiation for tumor-promoting genes. [11][12][13][14][15][16][17] However, the therapeutic effects of mTOR inhibition in c-Myc-driven cancer remain poorly understood.…”

The PI3K Pathway in Human Disease

“…First, it likely contributes to common long-term side effects of rapamycin or rapalog treatment, namely mucositis and pneumonitis. Mucositis is also one of the main dose-limiting toxicities of the TORKi compounds (Table S1) AZD2014 (Basu et al, 2015) and CC-223 (Bendell et al, 2015a), and occurred frequently in a phase I trial of TAK-228 (Ghobrial et al, 2016). Mucositis was reported in phase I studies of pan-PI3K inhibitor buparlisib (BKM120) (Bendell et al, 2012; Ragon et al, 2017) and the dual PI3K/mTOR inhibitor BEZ235 (Bendell et al, 2015b; Carlo et al, 2016).…”

Catalytic mammalian target of rapamycin inhibitors as antineoplastic agents

“…Apart from hematologic malignancies, there is strong evidence of INK128 activity in cell lines and xenograft models from several tumors, underscoring the potential importance of this agent in clinical oncology [68][69][70][71][72][73]. Preliminary results are available from a phase I dose escalation study of INK128 in patients with relapsed/refractory MM, Waldenström macroglobulinemia (WM) and non-Hodgkin lymphoma [74]. Thirty-seven patients were enrolled and treated with six dose levels of INK128 (either daily or daily 3 days on and 4 days off in 28-day cycles).…”

“…Some 27% of patients discontinued the drug due to adverse events, while 43% of patients experienced grade 3 or 4 adverse events, the most common of which included thrombocytopenia, fatigue, mucositis and neutropenia. Of the 27 patients evaluable for response, one patient with MM achieved a minor response, while 13 patients with MM and two with WM had stable disease [74]. Several other clinical investigations of INK128 are ongoing in both hematologic and solid malignancies.…”