Back to Search
Start Over
Phase I dose-escalation trial of the oral investigational Hedgehog signaling pathway inhibitor TAK-441 in patients with advanced solid tumors.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2015 Mar 01; Vol. 21 (5), pp. 1002-9. Date of Electronic Publication: 2014 Dec 12. - Publication Year :
- 2015
-
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.<br />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.<br />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).<br />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.<br /> (©2014 American Association for Cancer Research.)
- Subjects :
- Administration, Oral
Adult
Aged
Aged, 80 and over
Antineoplastic Agents administration & dosage
Antineoplastic Agents adverse effects
Antineoplastic Agents pharmacokinetics
Disease Progression
Female
Gene Expression
Humans
Male
Middle Aged
Molecular Targeted Therapy
Neoplasm Staging
Neoplasms diagnosis
Neoplasms genetics
Pyridines administration & dosage
Pyridines adverse effects
Pyridines pharmacokinetics
Pyrroles administration & dosage
Pyrroles adverse effects
Pyrroles pharmacokinetics
RNA, Messenger genetics
Retreatment
Transcription Factors genetics
Treatment Outcome
Zinc Finger Protein GLI1
Antineoplastic Agents therapeutic use
Hedgehog Proteins metabolism
Neoplasms drug therapy
Neoplasms metabolism
Pyridines therapeutic use
Pyrroles therapeutic use
Signal Transduction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 21
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 25501576
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-14-1234