Phase I dose-escalation trial of the oral investigational Hedgehog signaling pathway inhibitor TAK-441 in patients with advanced solid tumors

Jonathan Goldman, S. Gail Eckhardt, Mitesh J Borad, Kelly K. Curtis, Manuel Hidalgo, Emiliano Calvo, David P. Ryan, Lori J. Wirth, Asit Parikh, James Partyka, Helene Faessel, Esha Gangolli, Sally Stewart, Lee S. Rosen, Daniel W. Bowles

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Abstract

Purpose: This first-in-human study assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity of single and multiple doses of TAK-441, an investigational inhibitor of the Hedgehog signaling pathway. Experimental Design: Patients with advanced, solid tumors received daily oral TAK-441 (50-1, 600 mg/day); daily dose was doubled in each subsequent cohort until the maximum tolerated/ feasible dose (MTD/MFD) was reached. Blood was collected to evaluate TAK-441 plasma concentrations. Skin biopsies were obtained to evaluate suppression of the Hedgehog-regulated gene Gli1. Results: Thirty-four patients were enrolled (median age 59). The most common diagnoses were colorectal cancer (26%), basal cell carcinoma (BCC, 21%), and pancreatic cancer (9%). The MFD of 1, 600 mg/day (based on tablet size and strength) was considered the MTD. Dose-limiting toxicities included muscle spasms and fatigue. Grade ≥3 treatment-emergent adverse events, regardless of causality, occurred in 15 patients (44%), of which hyponatremia (n =4) and fatigue (n =3) were most common. Oral absorption was fairly rapid; median Tmax was 2.0 to 4.0 hours after a single dose. Mean elimination half-life was 13.5 to 22.6 hours. Systemic exposure of TAK-441 based on the area under the plasma concentration-time curve was linear across the dose range. Gli1 expression in skin biopsies was strongly inhibited at all dose levels. Best response was partial response (1 patient with BCC) and stable disease (7 patients with various solid tumors). Conclusions: TAK-441 was generally well tolerated up to MFD of 1, 600 mg/day, with preliminary antitumor activity. Further study of TAK-441 may be appropriate in populations selected for tumors with ligand-dependent or independent Hedgehog signaling. Clin Cancer Res; 21(5); 1002-9.

Original languageEnglish (US)
Pages (from-to)1002-1009
Number of pages8
JournalClinical Cancer Research
Volume21
Issue number5
DOIs
StatePublished - Mar 1 2015

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Neoplasms
Biopsy
Muscle Fatigue
Skin
Maximum Tolerated Dose
Hyponatremia
Basal Cell Carcinoma
Spasm
Pancreatic Neoplasms
Causality
Tablets
Fatigue
Half-Life
TAK-441
Colorectal Neoplasms
Research Design
Pharmacokinetics
Ligands
Safety
Population

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Phase I dose-escalation trial of the oral investigational Hedgehog signaling pathway inhibitor TAK-441 in patients with advanced solid tumors. / Goldman, Jonathan; Eckhardt, S. Gail; Borad, Mitesh J; Curtis, Kelly K.; Hidalgo, Manuel; Calvo, Emiliano; Ryan, David P.; Wirth, Lori J.; Parikh, Asit; Partyka, James; Faessel, Helene; Gangolli, Esha; Stewart, Sally; Rosen, Lee S.; Bowles, Daniel W.

In: Clinical Cancer Research, Vol. 21, No. 5, 01.03.2015, p. 1002-1009.

Research output: Contribution to journalArticle

Goldman, J, Eckhardt, SG, Borad, MJ, Curtis, KK, Hidalgo, M, Calvo, E, Ryan, DP, Wirth, LJ, Parikh, A, Partyka, J, Faessel, H, Gangolli, E, Stewart, S, Rosen, LS & Bowles, DW 2015, 'Phase I dose-escalation trial of the oral investigational Hedgehog signaling pathway inhibitor TAK-441 in patients with advanced solid tumors', Clinical Cancer Research, vol. 21, no. 5, pp. 1002-1009. https://doi.org/10.1158/1078-0432.CCR-14-1234
Goldman, Jonathan ; Eckhardt, S. Gail ; Borad, Mitesh J ; Curtis, Kelly K. ; Hidalgo, Manuel ; Calvo, Emiliano ; Ryan, David P. ; Wirth, Lori J. ; Parikh, Asit ; Partyka, James ; Faessel, Helene ; Gangolli, Esha ; Stewart, Sally ; Rosen, Lee S. ; Bowles, Daniel W. / Phase I dose-escalation trial of the oral investigational Hedgehog signaling pathway inhibitor TAK-441 in patients with advanced solid tumors. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 5. pp. 1002-1009.
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abstract = "Purpose: This first-in-human study assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity of single and multiple doses of TAK-441, an investigational inhibitor of the Hedgehog signaling pathway. Experimental Design: Patients with advanced, solid tumors received daily oral TAK-441 (50-1, 600 mg/day); daily dose was doubled in each subsequent cohort until the maximum tolerated/ feasible dose (MTD/MFD) was reached. Blood was collected to evaluate TAK-441 plasma concentrations. Skin biopsies were obtained to evaluate suppression of the Hedgehog-regulated gene Gli1. Results: Thirty-four patients were enrolled (median age 59). The most common diagnoses were colorectal cancer (26{\%}), basal cell carcinoma (BCC, 21{\%}), and pancreatic cancer (9{\%}). The MFD of 1, 600 mg/day (based on tablet size and strength) was considered the MTD. Dose-limiting toxicities included muscle spasms and fatigue. Grade ≥3 treatment-emergent adverse events, regardless of causality, occurred in 15 patients (44{\%}), of which hyponatremia (n =4) and fatigue (n =3) were most common. Oral absorption was fairly rapid; median Tmax was 2.0 to 4.0 hours after a single dose. Mean elimination half-life was 13.5 to 22.6 hours. Systemic exposure of TAK-441 based on the area under the plasma concentration-time curve was linear across the dose range. Gli1 expression in skin biopsies was strongly inhibited at all dose levels. Best response was partial response (1 patient with BCC) and stable disease (7 patients with various solid tumors). Conclusions: TAK-441 was generally well tolerated up to MFD of 1, 600 mg/day, with preliminary antitumor activity. Further study of TAK-441 may be appropriate in populations selected for tumors with ligand-dependent or independent Hedgehog signaling. Clin Cancer Res; 21(5); 1002-9.",
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AU - Goldman, Jonathan

AU - Eckhardt, S. Gail

AU - Borad, Mitesh J

AU - Curtis, Kelly K.

AU - Hidalgo, Manuel

AU - Calvo, Emiliano

AU - Ryan, David P.

AU - Wirth, Lori J.

AU - Parikh, Asit

AU - Partyka, James

AU - Faessel, Helene

AU - Gangolli, Esha

AU - Stewart, Sally

AU - Rosen, Lee S.

AU - Bowles, Daniel W.

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N2 - Purpose: This first-in-human study assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity of single and multiple doses of TAK-441, an investigational inhibitor of the Hedgehog signaling pathway. Experimental Design: Patients with advanced, solid tumors received daily oral TAK-441 (50-1, 600 mg/day); daily dose was doubled in each subsequent cohort until the maximum tolerated/ feasible dose (MTD/MFD) was reached. Blood was collected to evaluate TAK-441 plasma concentrations. Skin biopsies were obtained to evaluate suppression of the Hedgehog-regulated gene Gli1. Results: Thirty-four patients were enrolled (median age 59). The most common diagnoses were colorectal cancer (26%), basal cell carcinoma (BCC, 21%), and pancreatic cancer (9%). The MFD of 1, 600 mg/day (based on tablet size and strength) was considered the MTD. Dose-limiting toxicities included muscle spasms and fatigue. Grade ≥3 treatment-emergent adverse events, regardless of causality, occurred in 15 patients (44%), of which hyponatremia (n =4) and fatigue (n =3) were most common. Oral absorption was fairly rapid; median Tmax was 2.0 to 4.0 hours after a single dose. Mean elimination half-life was 13.5 to 22.6 hours. Systemic exposure of TAK-441 based on the area under the plasma concentration-time curve was linear across the dose range. Gli1 expression in skin biopsies was strongly inhibited at all dose levels. Best response was partial response (1 patient with BCC) and stable disease (7 patients with various solid tumors). Conclusions: TAK-441 was generally well tolerated up to MFD of 1, 600 mg/day, with preliminary antitumor activity. Further study of TAK-441 may be appropriate in populations selected for tumors with ligand-dependent or independent Hedgehog signaling. Clin Cancer Res; 21(5); 1002-9.

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