Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder cancer

Abstract

Background This Phase 1 dose-escalation/expansion study assessed safety/tolerability of sapanisertib, an oral, highly selective inhibitor of mTORC1/mTORC2, in advanced solid tumours. Methods Eligible patients received increasing sapanisertib doses once daily (QD; 31 patients), once weekly (QW; 30 patients), QD for 3 days on/4 days off QW (QD × 3dQW; 33 patients) or QD for 5 days on/2 days off QW (QD × 5dQW; 22 patients). In expansion cohorts, 82 patients with renal cell carcinoma (RCC), endometrial or bladder cancer received sapanisertib 5 mg QD (39 patients), 40 mg QW (26 patients) or 30 mg QW (17 patients). Results Maximum tolerated doses of sapanisertib were 6 mg QD, 40 mg QW, 9 mg QD × 3dQW and 7 mg QD × 5dQW. Frequent dose-limiting toxicities (DLTs) included hyperglycaemia, maculo-papular rash (QD), asthenia and stomatitis (QD × 3dQW/QD × 5dQW); expansion phase doses of 5 mg QD and 30 mg QW were selected based on tolerability beyond the DLT evaluation period. One patient with RCC achieved complete response; nine experienced partial responses (RCC: seven patients; carcinoid tumour/endometrial cancer: one patient each). Sapanisertib pharmacokinetics were time-linear and supported multiple dosing. Pharmacodynamic findings demonstrated treatment-related reductions in TORC1/2 biomarkers. Conclusions Sapanisertib demonstrated a manageable safety profile, with preliminary antitumour activity observed in RCC and endometrial cancer. Clinical trial registration ClinicalTrials.gov, NCT01058707.

Sapanisertib Plus Exemestane or Fulvestrant in Women with Hormone Receptor–Positive/HER2-Negative Advanced or Metastatic Breast Cancer

“…24). In addition to our observations in patients with breast cancer, sapanisertib has demonstrated a manageable safety profile and broader activity in a phase I study in patients with other advanced solid tumors (25), which supports further clinical development. Furthermore, evidence of sapanisertib activity has been reported in a patientderived xenograft model of everolimus-resistant pancreatic neuroendocrine tumors (26), suggesting that further development of sapanisertib for everolimus-resistant cancers is warranted.…”

Alternative approaches to target Myc for cancer treatment

“…MLN0128, a next-generation inhibitor of mTOR after rapamycin and its analogs, is extensively evaluated in clinical trials from phase 1 to phase 2. 38,39 Phosphorylation of 4EBP1 by mTORC1, a poised status for the initiation of mRNA translation, is potently inhibited by MLN0128. 40 More importantly, tumor burden of Eµ-Myc transgenic mouse model is reduced.…”

The effectiveness of monotherapy with PI3K/AKT/mTOR pathway inhibitors in ovarian cancer: A meta-analysis

“…However, several of the included studies did not specify therapy response for ovarian cancer patients, for which we contacted the authors to retrieve additional data. Eventually, we were unable to obtain sufficient response data of the ovarian cancer patients of four studies [20][21][22][23], resulting in the inclusion of 19 studies to conduct the meta-analysis [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42].…”

“…The included studies involved a total of 233 ovarian cancer patients. The sample size of individual studies ranged from five to 54 ovarian cancer patients treated with PI3K/AKT/mTOR inhibitors (Table 1) [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42]. Nine phase I and six phase II studies were included, as well as one phase I/IIA study.…”