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Phase 1 study of M2698, a p70S6K/AKT dual inhibitor, in patients with advanced cancer

Posted on 2021-08-19 - 04:36
Abstract Background The PI3K/AKT/mTOR (PAM) pathway is a key regulator of tumor therapy resistance. We investigated M2698, an oral p70S6K/AKT dual inhibitor, in patients with advanced cancer who failed standard therapies. Methods M2698 was administered as monotherapy (escalation, 15–380 mg daily; food effect cohort, 240–320 mg daily) and combined with trastuzumab or tamoxifen. Results Overall, 101 patients were treated (M2698, n = 62; M2698/trastuzumab, n = 13; M2698/tamoxifen, n = 26). Patients were predominantly aged < 65 years, were female, had performance status 1 and were heavily pretreated. There was a dose- and concentration-dependent inhibition of pS6 levels in peripheral blood mononuclear cells and tumor tissue. M2698 was well tolerated; the most common treatment-emergent adverse events were gastrointestinal, abnormal dreams and fatigue (serious, attributed to M2698: monotherapy, 8.1%; M2698/trastuzumab, 7.7%; M2698/tamoxifen, 11.5% of patients). The recommended phase 2 doses of M2698 were 240 mg QD (monotherapy), 160 mg QD (M2698/trastuzumab) and 160 mg QD/240 mg intermittent regimen (M2698/tamoxifen). In the monotherapy cohort, 27.4% of patients had stable disease at 12 weeks; no objective response was noted. The median progression-free survival (PFS) durations in patients with PAM pathway alterations with and without confounding markers (KRAS, EGFR, AKT2) were 1.4 months and 2.8 months, respectively. Two patients with breast cancer (M2698/trastuzumab, n = 1; M2698/tamoxifen, n = 1) had partial response; their PFS durations were 31 months and 2.7 months, respectively. Conclusions M2698 was well tolerated. Combined with trastuzumab or tamoxifen, M2698 demonstrated antitumor activity in patients with advanced breast cancer resistant to multiple standard therapies, suggesting that it could overcome treatment resistance. Trial registration ClinicalTrials.gov, NCT01971515. Registered October 23, 2013.

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Journal of Hematology & Oncology

AUTHORS (15)

Apostolia-Maria Tsimberidou
Jamie V. Shaw
Dejan Juric
Claire Verschraegen
Amy M. Weise
John Sarantopoulos
Gilberto Lopes
John Nemunaitis
Monica Mita
Haeseong Park
Barbara Ellers-Lenz
Hui Tian
Wenyuan Xiong
Remigiusz Kaleta
Razelle Kurzrock
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