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

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.

• Authors: 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
• Journal: Journal of hematology & oncology (J Hematol Oncol) Vol. 14 Issue 1 Pg. 127 (08 18 2021) ISSN: 1756-8722 [Electronic] England
• PMID: 34407844 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-akt
• Ribosomal Protein S6 Kinases, 70-kDa

Topics

• Aged
• Aged, 80 and over
• Antineoplastic Agents (adverse effects, blood, therapeutic use)
• Female
• Humans
• Male
• Middle Aged
• Neoplasms (drug therapy)
• Protein Kinase Inhibitors (adverse effects, blood, therapeutic use)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
• Ribosomal Protein S6 Kinases, 70-kDa (antagonists & inhibitors)
• Treatment Outcome