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Poster display

2453 - Phase 1b/2 safety and efficacy of TAK-228 (MLN0128), plus exemestane (E) or fulvestrant (F) in postmenopausal women with ER + /HER2- metastatic breast cancer (MBC)

Date

10 Oct 2016

Session

Poster display

Presenters

Jennifer Diamond

Citation

Annals of Oncology (2016) 27 (6): 68-99. 10.1093/annonc/mdw365

Authors

J. Diamond1, V.F. Borges1, P. Kabos2, E. Krill-Jackson3, R. Graham4, A. Hoffman5, B. Lim6, D.A. Richards7, M.A. Salkeni8, S. Wilks9, C. Patel10, R. Neuwirth11, M. Kneissl12, F. Zohren13

Author affiliations

  • 1 Medical Oncology, University of Colorado Cancer Center, 80045 - Aurora/US
  • 2 Medicine, University of Colorado Cancer Center, 80045 - Aurora/US
  • 3 Tbc, Mount Sinai Medical Center, 33140 - Miami Beach/US
  • 4 Hematology And Oncology, UT-Erlanger Medical Center, 37403 - Chattanooga/US
  • 5 Medical Oncology, Eastchester Center for Cancer Care / BRANY, 10469 - Bronx/US
  • 6 Department Of Breast Medical Oncology, MD Anderson Cancer Center, 77030 - Houston/US
  • 7 Tbd, Texas Oncology – Tyler, 75702 - Tyler/US
  • 8 Department Of Medicine, Section Of Hematology/oncology, West Virginia University, 26506 - Morgantown/US
  • 9 Tbd, Cancer Care Network of South Texas – SAT&BC, 78217 - San Antonio/US
  • 10 Clinical Pharmacology, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, 02139 - Cambridge/US
  • 11 Statistics, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, 02139 - Cambridge/US
  • 12 Oncology Clinical Research, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, 02139 - Cambridge/US
  • 13 Early Clinical Research & Development, Oncology Therapeutic Area Unit, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, 02139 - Cambridge/US
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Resources

Abstract 2453

Background

TAK-228, an investigational, oral, highly selective, ATP-competitive inhibitor of TORC1/2, may mitigate feedback activation within the PI3K/AKT/mTOR pathway. This represents a potential cause of resistance to TORC1 selective inhibitors. Thus TORC1/2 inhibition may restore sensitivity to endocrine therapies in patients (pts) who have progressed on such agents plus everolimus. We report the recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), and preliminary efficacy of TAK-228 + E or F.

Methods

Postmenopausal (≥1 y) women ≥18 y with advanced or MBC following everolimus + E or F were eligible. Phase 1b: part 1, unmilled TAK-228 5 mg continuously once-daily (QD) + E 25 mg QD or F 500 mg monthly; part 2, milled TAK-228 3 or 4 mg QD + E or F. Modified 3 + 3 dose escalation rules were applied, and pts were treated until disease progression.

Results

N = 24 were enrolled into phase 1b (median age 58.5 y [33–75]; median prior lines of therapy/chemotherapy 5 [1–10]/1 [0–2]). In part 1 (n = 12), pts received 5 mg unmilled TAK-228 QD + E or F (each n = 6). No dose-limiting toxicities (DLT) were seen, with no apparent differences in tolerability between the two groups. In part 2 (n = 12), 6 pts received 3 mg milled TAK-228 QD and no DLTs were seen. Another 6 pts received 4 mg milled TAK-228 QD; 1 pt treated with TAK-228 + E had DLTs of grade 3 nausea and diarrhea. The most common grade ≥3 drug-related adverse events (≥2 pts) were: diarrhea (13%) and increased ALT, fatigue, hyperglycemia, nausea, rash and stomatitis (each 8%). PK data suggest there was a dose related increase in total systemic exposure from 3 to 5 mg TAK-228, with no readily apparent difference between milled and unmilled TAK-228. Five pts (21%) had an overall response (1 complete response [CR], 4 partial responses [PRs]), and 12 (50%) had stable disease (SD). The overall response rate was 21% (7% E vs 44% F) and the disease control rate (CR + PR + SD) was 71% (60% E vs 89% F). The median duration of clinical benefit was 6 mos for TAK-228 + E vs 10 mos for TAK-228 + F.

Conclusions

Safety was established for milled TAK-228 at the RP2D of 4 mg QD + E or F. The encouraging preliminary efficacy warrants further evaluation in the phase 2 portion.

Clinical trial identification

NCT02049957 (Clinical Trial Protocol C31001 Amendment 4; October 22, 2015)

Legal entity responsible for the study

Millennium Pharmaceuticals, Inc.

Funding

Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited

Disclosure

C. Patel: Employment: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited; Stock ownership: Takeda Pharmaceutical Company Limited.

R. Neuwirth: Employment: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. M. Kneissl: Employment: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. F. Zohren: Employment: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited; Stock ownership: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. All other authors have declared no conflicts of interest.

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