377P - Phase 1 study of investigational oral mTORC1/2 inhibitor TAK-228 (MLN0128): Tolerability and food effects of a milled formulation in patients (pts)...

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Clinical research
Basic Scientific Principles
Presenter Kathleen Moore
Citation Annals of Oncology (2016) 27 (6): 114-135. 10.1093/annonc/mdw368
Authors K.N. Moore1, T.M. Bauer2, G. Falchook3, C. Patel4, R. Neuwirth5, A. Enke6, F. Zohren7, M.R. Patel8
  • 1Department Of Obstetrics & Gynecology, University of Oklahoma, 73104 - Oklahoma City/US
  • 2Drug Development Unit, Sarah Cannon Research Institute/Tennessee Oncology, 37205 - Nashville/US
  • 3Drug Development, Sarah Cannon Research Institute at HealthONE, 80219 - Denver/US
  • 4Clinical Pharmacology, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, 02139 - Cambridge/US
  • 5Global Statistics, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, 02139 - Cambridge/US
  • 6Oncology Clinical Research, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, 02139 - Cambridge/US
  • 7Early Clinical Research & Development, Oncology Therapeutic Area Unit, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, 02139 - Cambridge/US
  • 8Drug Development Unit, Florida Cancer Specialists/Sarah Cannon Research Institute, 34232 - Sarasota/US

Abstract

Background

The mTOR signaling pathway is frequently dysregulated in human cancers. TAK-228 is an investigational, orally available, highly selective mTOR inhibitor. Larger scale manufacturing of TAK-228 required a formulation change from unmilled to milled drug substance. Here we present safety, tolerability, and preliminary efficacy, as well as pharmacokinetics (PK) under fed and fasted conditions, of milled TAK-228.

Methods

Escalation cohorts of eligible pts (aged ≥18 y with advanced nonhematologic malignancies) were concurrently enrolled into 3 arms: once daily (QD), once weekly (QW), and three days each week plus weekly paclitaxel 80 mg/m2 (QDx3QW + P). Starting doses of milled TAK-228 were 4 mg QD, 20 mg QW and 6 mg QDx3QW + P, representing a one-dose-level reduction compared to the previously established recommended phase 2 doses of unmilled TAK-228. The effect of food on milled TAK-228 PK was evaluated in 14 of 16 pts in the QD arm enrolled into a designated PK run-in cohort; the PK of milled TAK-228 was assessed in all pts.

Results

At data cut-off (March 11, 2016), 61 pts (median age 64 y [28–88]) were enrolled and formed the safety-population, n = 58 the response-population, and n = 53 the PK-population. The safety and preliminary efficacy results are presented (Table). Preliminary PK comparisons of 4 mg milled TAK-228 QD under fed (n = 14) and fasted (n = 13) conditions reported a clinically meaningful 38% reduction in Cmax and a delay in absorption with food (median Tmax 6 h [fed] vs 2 h [fasted]), with no meaningful change in total AUC.

Single-agent QD Arm TAK-228 QD (N = 19) 3 mg (n = 11) / 4 mg (n = 8) Single-agent QW Arm TAK-228 QW (N = 20) 20 mg (n = 7) / 30 mg (n = 13) Combination Arm TAK-228 QDx3QW + P (N = 22) 6 mg (n = 15) / 4 mg (n = 7)
Dose limiting toxicity (DLT)-evaluable population, n 10 / 6 6 / 13 12 / 6
DLTs 1 pt at 3 mg (Grade [Gr] 3 thrombocytopenia); 3 pts at 4 mg (Gr 3 fatigue; Gr 3 fatigue, rash, decreased appetite; Gr 3 rash) 1 pt at 30 mg (Gr 3 drug reaction) 1 pt at 6 mg (Gr 3 fatigue, dehydration)
Maximum tolerated dose (MTD) 3 mg QD 30 mg QW 6 mg QDx3QW + P
Safety population, n 17 20 22
Treatment-related adverse events (>20% all grades) Fatigue (47%), pruritus (41%), rash (41%), decreased appetite (24%), diarrhea (24%), nausea (24%) Nausea (45%), vomiting (45%), fatigue (35%), diarrhea (30%) Diarrhea (64%), decreased appetite (41%), fatigue (41%), nausea (36%), vomiting (32%), stomatitis (27%), asthenia (23%)
Response, n (tumor type) 2 partial responses (PR) (kidney, uterus); 4 stable disease (SD) >90 d (2 fallopian tube, colon, ovary) 2 SD >90 d (head/neck, gall bladder) 1 complete response (breast); 2 PR (urinary bladder, uterus); 3 SD >90 d (rectal, ovary, stomach)

Conclusions

Safety was established for milled TAK-228 at the MTDs of 3 mg QD, 30 mg QW and 6 mg QDx3QW + P, lower doses than the MTDs identified for unmilled TAK-228. PK data suggest that a relevant food effect might be attributable for the observed difference in tolerability. Preliminary efficacy seen with milled TAK-228 is encouraging.

Clinical trial identification

NCT02412722 (Clinical Trial Protocol MLN0128-1004 Amendment 2, 14 May 2015)

Legal entity responsible for the study

Millennium Pharmaceuticals, Inc.

Funding

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

Disclosure

K.N. Moore: Advisory boards/honoraria: Advaxis, AstraZeneca, Amgen, Clovis, Immunogen, Merrimack, VBL Therapeutics. G. Falchook: Corporate-sponsored research: Millennium Pharmaceuticals, Inc. (research funding for clinical trials; travel reimbursement to present trial results at ESGO 2013). C. Patel, F. Zohren: Employment: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited; Stock ownership: Takeda Pharmaceutical Company Limited. R. Neuwirth, A. Enke: Employment: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. All other authors have declared no conflicts of interest.