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Phase Ib study of the combination of pexidartinib (PLX3397), a CSF-1R inhibitor, and paclitaxel in patients with advanced solid tumors

Phase Ib study of the combination of pexidartinib (PLX3397), a CSF-1R inhibitor, and paclitaxel in patients with advanced solid tumors

Authors :
Robert Wesolowski
Neelesh Sharma
Laura Reebel
Mary Beth Rodal
Alexandra Peck
Brian L. West
Adhirai Marimuthu
Paul Severson
David A. Karlin
Afshin Dowlati
Mai H. Le
Lisa M. Coussens
Hope S. Rugo
Source :
Therapeutic Advances in Medical Oncology, Vol 11 (2019)
Publication Year :
2019
Publisher :
SAGE Publishing, 2019.

Abstract

Purpose: To evaluate the safety, recommended phase II dose (RP2D) and efficacy of pexidartinib, a colony stimulating factor receptor 1 (CSF-1R) inhibitor, in combination with weekly paclitaxel in patients with advanced solid tumors. Patients and Methods: In part 1 of this phase Ib study, 24 patients with advanced solid tumors received escalating doses of pexidartinib with weekly paclitaxel (80 mg/m 2 ). Pexidartinib was administered at 600 mg/day in cohort 1. For subsequent cohorts, the dose was increased by ⩽50% using a standard 3+3 design. In part 2, 30 patients with metastatic solid tumors were enrolled to examine safety, tolerability and efficacy of the RP2D. Pharmacokinetics and biomarkers were also assessed. Results: A total of 51 patients reported ≥1 adverse event(s) (AEs) that were at least possibly related to either study drug. Grade 3–4 AEs, including anemia (26%), neutropenia (22%), lymphopenia (19%), fatigue (15%), and hypertension (11%), were recorded in 38 patients (70%). In part 1, no maximum tolerated dose was achieved and 1600 mg/day was determined to be the RP2D. Of 38 patients evaluable for efficacy, 1 (3%) had complete response, 5 (13%) partial response, 13 (34%) stable disease, and 17 (45%) progressive disease. No drug–drug interactions were found. Plasma CSF-1 levels increased 1.6- to 53-fold, and CD14dim/CD16+ monocyte levels decreased by 57–100%. Conclusions: The combination of pexidartinib and paclitaxel was generally well tolerated. RP2D for pexidartinib was 1600 mg/day. Pexidartinib blocked CSF-1R signaling, indicating potential for mitigating macrophage tumor infiltration.

Details

Language :
English
ISSN :
17588359
Volume :
11
Database :
Directory of Open Access Journals
Journal :
Therapeutic Advances in Medical Oncology
Publication Type :
Academic Journal
Accession number :
edsdoj.26e5bc3db4084f12bdaf56d54e8bff23
Document Type :
article
Full Text :
https://doi.org/10.1177/1758835919854238