A first-in-human, Phase I, dose-escalation study of TAK-117, A selective PI3Ka isoform inhibitor, in patients with advanced solid malignancies

Dejan Juric, Johann S. De Bono, Patricia M. LoRusso, John Nemunaitis, Elisabeth I. Heath, Eunice L. Kwak, Teresa Macarulla Mercade, Elena Geuna, Maria Jose De Miguel-Luken, Chirag Patel, Keisuke Kuida, Serap Sankoh, Eric H. Westin, Fabian Zohren, Yaping Shou, Josep Tabernero

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Purpose: To evaluate the safety, MTD, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of TAK-117 (MLN1117/INK1117), an investigational PI3Ka-selective inhibitor, in patients with advanced solid tumors. Experimental Design: Seventy-one patients received oral TAK-117 once daily [100-300 mg (n = 24)] or 3 days per week [Monday-Wednesday-Friday (MWF), 200-1, 200 mg (n = 27); Monday-Tuesday-Wednesday (MTuW), 200-900 mg (n = 20)], in 21-day cycles. Dose escalation proceeded via a 3 + 3 design. Results: TAK-117 once-daily dosing was associated with doselimiting grade ≥3 alanine/aspartate aminotransferase (ALT/AST) elevations, resulting in a narrow range of tolerable doses (100-150 mg once daily). With MWF/MTuW dosing, no dose-limiting ALT/AST elevations occurred until the MTD of 900 mg; total weekly dose was 2.6-fold that of 150 mg once daily. Drug-related grade ≥3 adverse events occurred in 25%/22%/35% (including hyperglycemia in 0%/7%/15%) of once-daily/MWF/MTuW patients. TAK-117 (100-1, 200 mg) exhibited moderately fast oral absorption, a generally dose proportional increase in exposure, and plasma half-life of approximately 11 hours. Total weekly exposures with 900 mg MWF/MTuW dosing were approximately 4 times greater than with 150 mg once daily. Skin pS6 expression was suppressed at ≥200 mg. There were 3/1/0 partial responses (once daily/MWF/MTuW) and 5/7/5 patients had stable disease lasting ≥3 months (all PIK3CA mutated). Conclusions: Intermittent dosing of TAK-117 had an acceptable safety profile and enabled higher doses and total weekly exposures versus once-daily dosing. Although the potential for TAK-117 as single-agent therapy appears limited, further evaluation in combination approaches for advanced solid tumors is warranted.

Original languageEnglish
Pages (from-to)5015-5023
Number of pages9
JournalClinical Cancer Research
Volume23
Issue number17
DOIs
Publication statusPublished - Sep 1 2017

Fingerprint

Protein Isoforms
Neoplasms
Safety
Aspartate Aminotransferases
Alanine Transaminase
Hyperglycemia
Half-Life
Research Design
Pharmacokinetics
Skin
Pharmaceutical Preparations
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A first-in-human, Phase I, dose-escalation study of TAK-117, A selective PI3Ka isoform inhibitor, in patients with advanced solid malignancies. / Juric, Dejan; De Bono, Johann S.; LoRusso, Patricia M.; Nemunaitis, John; Heath, Elisabeth I.; Kwak, Eunice L.; Mercade, Teresa Macarulla; Geuna, Elena; De Miguel-Luken, Maria Jose; Patel, Chirag; Kuida, Keisuke; Sankoh, Serap; Westin, Eric H.; Zohren, Fabian; Shou, Yaping; Tabernero, Josep.

In: Clinical Cancer Research, Vol. 23, No. 17, 01.09.2017, p. 5015-5023.

Research output: Contribution to journalArticle

Juric, D, De Bono, JS, LoRusso, PM, Nemunaitis, J, Heath, EI, Kwak, EL, Mercade, TM, Geuna, E, De Miguel-Luken, MJ, Patel, C, Kuida, K, Sankoh, S, Westin, EH, Zohren, F, Shou, Y & Tabernero, J 2017, 'A first-in-human, Phase I, dose-escalation study of TAK-117, A selective PI3Ka isoform inhibitor, in patients with advanced solid malignancies', Clinical Cancer Research, vol. 23, no. 17, pp. 5015-5023. https://doi.org/10.1158/1078-0432.CCR-16-2888
Juric, Dejan ; De Bono, Johann S. ; LoRusso, Patricia M. ; Nemunaitis, John ; Heath, Elisabeth I. ; Kwak, Eunice L. ; Mercade, Teresa Macarulla ; Geuna, Elena ; De Miguel-Luken, Maria Jose ; Patel, Chirag ; Kuida, Keisuke ; Sankoh, Serap ; Westin, Eric H. ; Zohren, Fabian ; Shou, Yaping ; Tabernero, Josep. / A first-in-human, Phase I, dose-escalation study of TAK-117, A selective PI3Ka isoform inhibitor, in patients with advanced solid malignancies. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 17. pp. 5015-5023.
@article{579e49e482d448ffad831ff0bb6a87e6,
title = "A first-in-human, Phase I, dose-escalation study of TAK-117, A selective PI3Ka isoform inhibitor, in patients with advanced solid malignancies",
abstract = "Purpose: To evaluate the safety, MTD, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of TAK-117 (MLN1117/INK1117), an investigational PI3Ka-selective inhibitor, in patients with advanced solid tumors. Experimental Design: Seventy-one patients received oral TAK-117 once daily [100-300 mg (n = 24)] or 3 days per week [Monday-Wednesday-Friday (MWF), 200-1, 200 mg (n = 27); Monday-Tuesday-Wednesday (MTuW), 200-900 mg (n = 20)], in 21-day cycles. Dose escalation proceeded via a 3 + 3 design. Results: TAK-117 once-daily dosing was associated with doselimiting grade ≥3 alanine/aspartate aminotransferase (ALT/AST) elevations, resulting in a narrow range of tolerable doses (100-150 mg once daily). With MWF/MTuW dosing, no dose-limiting ALT/AST elevations occurred until the MTD of 900 mg; total weekly dose was 2.6-fold that of 150 mg once daily. Drug-related grade ≥3 adverse events occurred in 25{\%}/22{\%}/35{\%} (including hyperglycemia in 0{\%}/7{\%}/15{\%}) of once-daily/MWF/MTuW patients. TAK-117 (100-1, 200 mg) exhibited moderately fast oral absorption, a generally dose proportional increase in exposure, and plasma half-life of approximately 11 hours. Total weekly exposures with 900 mg MWF/MTuW dosing were approximately 4 times greater than with 150 mg once daily. Skin pS6 expression was suppressed at ≥200 mg. There were 3/1/0 partial responses (once daily/MWF/MTuW) and 5/7/5 patients had stable disease lasting ≥3 months (all PIK3CA mutated). Conclusions: Intermittent dosing of TAK-117 had an acceptable safety profile and enabled higher doses and total weekly exposures versus once-daily dosing. Although the potential for TAK-117 as single-agent therapy appears limited, further evaluation in combination approaches for advanced solid tumors is warranted.",
author = "Dejan Juric and {De Bono}, {Johann S.} and LoRusso, {Patricia M.} and John Nemunaitis and Heath, {Elisabeth I.} and Kwak, {Eunice L.} and Mercade, {Teresa Macarulla} and Elena Geuna and {De Miguel-Luken}, {Maria Jose} and Chirag Patel and Keisuke Kuida and Serap Sankoh and Westin, {Eric H.} and Fabian Zohren and Yaping Shou and Josep Tabernero",
year = "2017",
month = "9",
day = "1",
doi = "10.1158/1078-0432.CCR-16-2888",
language = "English",
volume = "23",
pages = "5015--5023",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "17",

}

TY - JOUR

T1 - A first-in-human, Phase I, dose-escalation study of TAK-117, A selective PI3Ka isoform inhibitor, in patients with advanced solid malignancies

AU - Juric, Dejan

AU - De Bono, Johann S.

AU - LoRusso, Patricia M.

AU - Nemunaitis, John

AU - Heath, Elisabeth I.

AU - Kwak, Eunice L.

AU - Mercade, Teresa Macarulla

AU - Geuna, Elena

AU - De Miguel-Luken, Maria Jose

AU - Patel, Chirag

AU - Kuida, Keisuke

AU - Sankoh, Serap

AU - Westin, Eric H.

AU - Zohren, Fabian

AU - Shou, Yaping

AU - Tabernero, Josep

PY - 2017/9/1

Y1 - 2017/9/1

N2 - Purpose: To evaluate the safety, MTD, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of TAK-117 (MLN1117/INK1117), an investigational PI3Ka-selective inhibitor, in patients with advanced solid tumors. Experimental Design: Seventy-one patients received oral TAK-117 once daily [100-300 mg (n = 24)] or 3 days per week [Monday-Wednesday-Friday (MWF), 200-1, 200 mg (n = 27); Monday-Tuesday-Wednesday (MTuW), 200-900 mg (n = 20)], in 21-day cycles. Dose escalation proceeded via a 3 + 3 design. Results: TAK-117 once-daily dosing was associated with doselimiting grade ≥3 alanine/aspartate aminotransferase (ALT/AST) elevations, resulting in a narrow range of tolerable doses (100-150 mg once daily). With MWF/MTuW dosing, no dose-limiting ALT/AST elevations occurred until the MTD of 900 mg; total weekly dose was 2.6-fold that of 150 mg once daily. Drug-related grade ≥3 adverse events occurred in 25%/22%/35% (including hyperglycemia in 0%/7%/15%) of once-daily/MWF/MTuW patients. TAK-117 (100-1, 200 mg) exhibited moderately fast oral absorption, a generally dose proportional increase in exposure, and plasma half-life of approximately 11 hours. Total weekly exposures with 900 mg MWF/MTuW dosing were approximately 4 times greater than with 150 mg once daily. Skin pS6 expression was suppressed at ≥200 mg. There were 3/1/0 partial responses (once daily/MWF/MTuW) and 5/7/5 patients had stable disease lasting ≥3 months (all PIK3CA mutated). Conclusions: Intermittent dosing of TAK-117 had an acceptable safety profile and enabled higher doses and total weekly exposures versus once-daily dosing. Although the potential for TAK-117 as single-agent therapy appears limited, further evaluation in combination approaches for advanced solid tumors is warranted.

AB - Purpose: To evaluate the safety, MTD, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of TAK-117 (MLN1117/INK1117), an investigational PI3Ka-selective inhibitor, in patients with advanced solid tumors. Experimental Design: Seventy-one patients received oral TAK-117 once daily [100-300 mg (n = 24)] or 3 days per week [Monday-Wednesday-Friday (MWF), 200-1, 200 mg (n = 27); Monday-Tuesday-Wednesday (MTuW), 200-900 mg (n = 20)], in 21-day cycles. Dose escalation proceeded via a 3 + 3 design. Results: TAK-117 once-daily dosing was associated with doselimiting grade ≥3 alanine/aspartate aminotransferase (ALT/AST) elevations, resulting in a narrow range of tolerable doses (100-150 mg once daily). With MWF/MTuW dosing, no dose-limiting ALT/AST elevations occurred until the MTD of 900 mg; total weekly dose was 2.6-fold that of 150 mg once daily. Drug-related grade ≥3 adverse events occurred in 25%/22%/35% (including hyperglycemia in 0%/7%/15%) of once-daily/MWF/MTuW patients. TAK-117 (100-1, 200 mg) exhibited moderately fast oral absorption, a generally dose proportional increase in exposure, and plasma half-life of approximately 11 hours. Total weekly exposures with 900 mg MWF/MTuW dosing were approximately 4 times greater than with 150 mg once daily. Skin pS6 expression was suppressed at ≥200 mg. There were 3/1/0 partial responses (once daily/MWF/MTuW) and 5/7/5 patients had stable disease lasting ≥3 months (all PIK3CA mutated). Conclusions: Intermittent dosing of TAK-117 had an acceptable safety profile and enabled higher doses and total weekly exposures versus once-daily dosing. Although the potential for TAK-117 as single-agent therapy appears limited, further evaluation in combination approaches for advanced solid tumors is warranted.

UR - http://www.scopus.com/inward/record.url?scp=85026509256&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85026509256&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-16-2888

DO - 10.1158/1078-0432.CCR-16-2888

M3 - Article

AN - SCOPUS:85026509256

VL - 23

SP - 5015

EP - 5023

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 17

ER -