Online supplementary materialsfor:

TAK-228 (formerly MLN0128), an investigational dual TORC1/2 inhibitor plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies

H. A. Burris III1,2, C. D. Kurkjian1,3, L. Hart1,4, S. Pant1,3*, P. B. Murphy1,2, S. F. Jones1, R. Neuwirth5, C. G. Patel5, F. Zohren5, J. R. Infante1,2

1Sarah Cannon Research Institute, Nashville, Tennessee, USA

2Tennessee Oncology PLLC, Nashville, Tennessee, USA

3Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

4Florida Cancer Specialists, Fort Myers, Florida, USA

5Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited

*Current affiliation: The University of TexasMD Anderson Cancer Center, Houston, Texas, USA

Supplementary Results

Table S1Summary of treatment exposure and termination data by dosing schedule

Dose escalation phase / Expansion phase
N = 20 / Total
N = 67
QDx3d QW
N = 29 / QDx5d QW
N = 10 / QW
N = 8 / Subtotal
N = 47
Median cycles entered, n (range) / 3 (1–22) / 2 (1–14) / 2 (1–4) / 2 (1–22) / 3 (1–19) / n/a
Median treatment duration, weeks (range) / 8.6 (0.4–87.4) / 5.5 (1.1–65.4) / 6.2 (1.3–15.3) / 7.1 (0.4–87.4) / 7.5 (0.6–61.6) / n/a
Median cumulative TAK-228 dose, mg (range) / 180.0 (21–1308) / 164.5 (7–1925) / 170.0 (40–480) / 180.0 (7–1925) / 189.0 (24–1728) / n/a
Median planned TAK-228 dose received, % (range) / 68.3 (25–100) / 72.8 (5–100) / 67.4 (25–100) / 70 (5–100) / 75.0 (25–100) / n/a
Median planned paclitaxel dose received, % (range) / 66.5 (32.5–100.1) / 75.6 (33.3–101.8) / 66.6 (33.1–101.6) / 66.7 (32.5–101.8) / 85.3 (33.0–101.9) / n/a
Primary reason for TAK-228 termination, n (%)
Disease progression / 13 (45) / 6 (60) / 5 (63) / 24 (51) / 11 (55) / 35 (52)
AE / 10 (34) / 1 (10) / 1 (13) / 12 (26) / 2 (10) / 14 (21)
Subject decision / 6 (21) / 3 (30) / 2 (25) / 11 (23) / 5 (25) / 16 (24)

AE adverse event,n/a not applicable, QD once daily,QW once weekly.

Table S2Safety profile of TAK-228 and paclitaxel/trastuzumab by dosing schedule

Dose escalation phase / Expansion phase
N = 20 / Total
N = 67
Patients, n (%) / QDx3d QW
N = 29 / QDx5d QW
N = 10 / QW
N = 8 / Subtotal
N = 47
Any AE / 29 (100) / 10 (100) / 8 (100) / 47 (100) / 20 (100) / 67 (100)
Any study drug-related AE / 28 (97) / 10 (100) / 8 (100) / 46 (98) / 19 (95) / 65 (97)
Any serious AE / 12 (41) / 6 (60) / 5 (63) / 23 (49) / 6 (30) / 29 (43)
Any study drug-related serious AE / 5 (17) / 3 (30) / 1 (13) / 9 (19) / 1 (5) / 10 (15)
Any AE leading to TAK-228 discontinuation / 10 (34) / 1 (10) / 1 (13) / 12 (26) / 2 (10) / 14 (21)
Any AE leading to paclitaxel discontinuation / 11 (38) / 1 (10) / 1 (13) / 13 (28) / 3 (15) / 16 (24)
Any AE leading to trastuzumab discontinuation / n/a / n/a / n/a / n/a / 0 / 0
Any AE leading to TAK-228 dose modification/interruption / 18 (62) / 10 (100) / 5 (63) / 33 (70) / 14 (70) / 47 (70)
Any AE leading to paclitaxel dose modification/interruption / 19 (66) / 9 (90) / 6 (75) / 34 (72) / 13 (65) / 47 (70)
Any AE leading to trastuzumab dose modification/interruption / n/a / n/a / n/a / n/a / 2 (10) / 2 (3)
On study deaths / 2 (7) / 2 (20) / 2 (25) / 6 (13) / 3 (15) / 9 (13)

AE adverse event, n/anot applicable,QD once daily,QW once weekly.

Appendix p. 1