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 Drug Development
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.