925TiP - A phase 2 study of investigational TORC1/2 inhibitor TAK-228 and TAK-228 plus investigational PI3Kα-selective inhibitor TAK-117 vs everolimus in ad...

Date 10 September 2017
Event ESMO 2017 Congress
Session Poster display session
Topics Cytotoxic agents
Clinical research
Renal Cell Cancer
Genitourinary Cancers
Personalised/Precision medicine
Basic Scientific Principles
Basic Principles in the Management and Treatment (of cancer)
Biological therapy
Presenter Toni Choueiri
Citation Annals of Oncology (2017) 28 (suppl_5): v295-v329. 10.1093/annonc/mdx371
Authors T.K. Choueiri1, C. Porta2, C. Suarez Rodriguez3, R. Alter4, P. Czaykowski5, I. Duran6, M. Gross-Goupil7, E. Kalinka-Warzocha8, B. Melichar9, C. Patel10, R. Neuwirth11, A. Enke10, F. Zohren12, T. Powles13
  • 1Medical Oncology, Dana-Farber Cancer Institute, 02215-5450 - Boston/US
  • 2Medical Oncology, I.R.C.C.S. San Matteo University Hospital Foundation, Pavia/IT
  • 3Medical Oncology, Vall d'Hebron University Hospital, 08035 - Barcelona/ES
  • 4Head And Neck & Urologic Oncology, Hackensack University Medical Center, Hackensack/US
  • 5Medical Oncology And Hematology, CancerCare Manitoba, Manitoba/CA
  • 6Medical Oncology, Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad, Seville/ES
  • 7Medical Oncology, CHU Bordeaux Hopital St. André, 33000 - Bordeaux/FR
  • 8Clinic Of Oncologic Surgery And Breast Cancer, Polish Mother's Memorial Hospital - Research Institute, Lodz/PL
  • 9Medical Oncology, Lekarska fakulta Univerzity Palackeho a Fakultní nemocnice, 77520 - Olomouc/CZ
  • 10Quantitative Clinical Pharmacology, Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge/US
  • 11Medical Oncology, Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge/US
  • 12Oncology Clinical Research, Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge/US
  • 13Oncology, St. Bartholomew's Hospital, EC1A 7BE - London/GB



VEGF-targeted therapies are the cornerstone of first and subsequent lines of therapy in ccRCC; however, resistance develops almost invariably. Another proven therapeutic intervention in ccRCC is treatment with the allosteric mTOR inhibitor everolimus, which only partially inhibits TORC1 and thus results in increased phosphorylation of Akt and paradoxical hyperactive signalling. TAK-228, a highly selective ATP-competitive TORC1 and TORC2 inhibitor, has shown promising antitumor activity and acceptable safety in ccRCC. In a pooled analysis of 2 prior studies of 41 patients (pts) with ccRCC, TAK-228 treatment resulted in 1 CR, 5 PR and 21 pts with SD; 13 pts who achieved ≥SD had prior treatment with a rapalog. The median duration of overall response was 250 d (range, 55–1614). The most common AEs were fatigue, nausea and hyperglycemia. Also, combination of TAK-228 with TAK-117, a selective inhibitor of PI3Kα, has shown more complete and prolonged inhibition of TORC1 and TORC2. This phase 2, open-label, randomized study will evaluate the efficacy and safety of TAK-228 and TAK-228+TAK-117 vs everolimus in pts with advanced or metastatic ccRCC that have progressed on or after VEGF-targeted therapy (NCT02724020).

Trial design

189 pts will be randomized 1:1:1 to TAK-228 30 mg once-weekly on d1, 8, 15, 22 with a light meal; TAK-228 4 mg once-daily (QD) + TAK-117 200 mg QD on d1–3, 8–10, 15–17, 22–24 on an empty stomach; or everolimus 10 mg QD, in 28-d cycles. Pts will be stratified by number of prior therapy lines and IMDC risk category. Pts with histologically confirmed advanced/metastatic ccRCC, ≥1 prior line of VEGF-targeted therapy with PD, KPS ≥70%, and adequate organ function, but no CNS metastasis or prior therapy with agents that target PI3K, AKT, or mTOR are eligible. Pts in the everolimus arm who progress may crossover. An interim futility analysis will be conducted after 30 pts in each arm have received 2 treatment cycles. Primary endpoint is PFS. Secondary endpoints are OS, TTP, ORR, CBR, safety, and QoL. As of January 24, 2017, 54 pts have been screened.

Clinical trial identification


Legal entity responsible for the study

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


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


T.K. Choueiri: Advisory board member: AstraZeneca, Bayer, BMS, Cerulean, Eisai, Foundation Medicine Inc., Genetech, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, Prometheus Labs Inc, Roche, Eisai; Research funding: AstraZeneca, BMS, Exelixis, Genentech, GSK, Merck, Novartis, Peloton, Pfizer, Roche, Tracon, Eisai (all institutional); Travel expenses, including accommodations: for advisory boards C. Porta: Consultant and/or Speaker for Novartis, Bristol-Myers Squib, Ipsen, Pfizer, Jannsen, Eisai, EUSA, Peloton; received research grant from Pfizer. R. Alter: Advisory boards: Astellas, Teva Speakers bureau: AstraZeneca, Astellas, Eisai, Novartis, Sanofi, Merck, Pfizer, Janssen, Bayer, Exelixis, Amgen, Bristol-Myers Squibb, Genetech. I. Duran: Consulting/Advisory role: Roche/Genentech, Ipsen, Sanofi, Bristol-Myers Squib, MSD, Janssen. Ad board: Roche/Genentech, Ipsen. Travel/accommodation/expenses: Astellas, Janssen, Roche/Genentech. Research funding: Astellas, Roche/Genentech. C. Patel: Employment: Takeda Pharmaceuticals, Inc. Stock/ownership: Takeda Pharmaceuticals, Inc. Patents/royalties: Takeda Pharmaceuticals, Inc. Travel/accommodation/expenses: Takeda Pharmaceuticals, Inc. R. Neuwirth, A. Enke: Employment: Millennium Pharmaceuticals, Inc. F. Zohren: Employment: Takeda Pharmaceuticals, Inc. T. Powles: Research funding: AstraZeneca, Roche. Honoraria: Roche, AstraZeneca, Bristol-Myers Squib, Novartis, Pfizer. All other authors have declared no conflicts of interest.