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Phase 1 study of M2698, a p70S6K/AKT dual inhibitor, in patients with advanced cancer
Apostolia-Maria Tsimberidou1, Jamie V Shaw2, Dejan Juric3
1Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Boulevard, Houston, TX, 77030, USA. atsimber@mdanderson.org.
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.
Insights
M2698, a dual inhibitor of p70S6K/AKT, showed tolerability in advanced cancer patients. Combination therapy with M2698 demonstrated antitumor activity in advanced breast cancer, suggesting potential to overcome treatment resistance.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- The PI3K/AKT/mTOR (PAM) pathway is crucial in regulating tumor therapy resistance.
- M2698 is an oral dual inhibitor targeting p70S6K and AKT within the PAM pathway.
- This study investigated M2698 in patients with advanced cancer who had exhausted standard treatment options.
Purpose of the Study:
- To evaluate the safety and tolerability of M2698 in patients with advanced cancer.
- To determine the recommended Phase 2 doses for M2698 monotherapy and in combination with trastuzumab or tamoxifen.
- To assess the preliminary antitumor activity of M2698, alone and in combination, in heavily pretreated patients.
Main Methods:
- M2698 was administered as monotherapy (dose escalation and food effect cohorts) and in combination with trastuzumab or tamoxifen.
- 101 patients were enrolled across the different treatment arms.
- Pharmacodynamic assessments included dose- and concentration-dependent inhibition of pS6 levels in peripheral blood mononuclear cells and tumor tissue.
Main Results:
- M2698 was generally well-tolerated, with common adverse events including gastrointestinal issues, fatigue, and abnormal dreams.
- Recommended Phase 2 doses were established for M2698 monotherapy (240 mg QD) and combinations (160 mg QD or 160 mg QD/240 mg intermittent).
- While monotherapy showed stable disease in 27.4% of patients, partial responses were observed in two breast cancer patients treated with M2698 in combination, with one achieving a progression-free survival of 31 months.
Conclusions:
- M2698 was well-tolerated in patients with advanced cancer.
- M2698, in combination with trastuzumab or tamoxifen, exhibited antitumor activity in advanced breast cancer.
- These findings suggest M2698's potential to overcome treatment resistance in specific patient populations.
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