TY - JOUR
T1 - Phase 1 study of M2698, a p70S6K/AKT dual inhibitor, in patients with advanced cancer
AU - Tsimberidou, Apostolia Maria
AU - Shaw, Jamie V.
AU - Juric, Dejan
AU - Verschraegen, Claire
AU - Weise, Amy M.
AU - Sarantopoulos, John
AU - Lopes, Gilberto
AU - Nemunaitis, John
AU - Mita, Monica
AU - Park, Haeseong
AU - Ellers-Lenz, Barbara
AU - Tian, Hui
AU - Xiong, Wenyuan
AU - Kaleta, Remigiusz
AU - Kurzrock, Razelle
N1 - Funding Information:
This research was sponsored by Merck KGaA, Darmstadt, Germany. Support was also provided in part by the National Institutes of Health/National Cancer Institute under award number P30CA016672. Supported in part by donor funds from Jamie’s Hope, Mr. and Mrs. Zane W. Arrott, and Mr. and Mrs. Steven McKenzie for Dr. Tsimberidou’s Personalized Medicine Program. Supported in part by Institute for Drug Development, Cancer Therapy and Research Center at University of Texas Health Science Center San Antonio; San Antonio, TX under Cancer Center Support Grant P30CA054174. Employees of the sponsor (Merck KGaA, Darmstadt, Germany) were involved in study design; acquisition, analysis and interpretation of data; and contributed in part to the writing of the report in collaboration with study investigators.
Funding Information:
The authors would like to thank the patients and their families, investigators, co-investigators, and the study teams at each of the participating centers, and at Merck Healthcare KGaA, Darmstadt, Germany. In addition, we thank Anja Victor and Christine Hicking of Merck KGaA, Darmstadt, Germany, for their statistical input, Ursula Hering of Merck KGaA, Darmstadt, Germany, for her safety input, and Henry Vo of MD Anderson Cancer Center, Houston, Texas, for editorial support. Medical writing assistance was provided by Helen Swainston and Duncan Fisher, Bioscript Science, Macclesfield, UK, and funded by Merck Healthcare KGaA, Darmstadt, Germany.
Funding Information:
The authors would like to thank the patients and their families, investigators, co-investigators, and the study teams at each of the participating centers, and at Merck Healthcare KGaA, Darmstadt, Germany. In addition, we thank Anja Victor and Christine Hicking of Merck KGaA, Darmstadt, Germany, for their statistical input, Ursula Hering of Merck KGaA, Darmstadt, Germany, for her safety input, and Henry Vo of MD Anderson Cancer Center, Houston, Texas, for editorial support. Medical writing assistance was provided by Helen Swainston and Duncan Fisher, Bioscript Science, Macclesfield, UK, and funded by Merck Healthcare KGaA, Darmstadt, Germany.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
KW - AKT
KW - Advanced cancer
KW - Clinical trial
KW - M2698
KW - PI3K
KW - Phase I
KW - Targeted therapy
KW - p70S6K
UR - http://www.scopus.com/inward/record.url?scp=85112781061&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85112781061&partnerID=8YFLogxK
U2 - 10.1186/s13045-021-01132-z
DO - 10.1186/s13045-021-01132-z
M3 - Article
C2 - 34407844
AN - SCOPUS:85112781061
SN - 1756-8722
VL - 14
JO - Journal of Hematology and Oncology
JF - Journal of Hematology and Oncology
IS - 1
M1 - 127
ER -