Phase Ib study of the combination of pexidartinib (PLX3397), a CSF-1R inhibitor, and paclitaxel in patients with advanced solid tumors. (June 2019)

• Record Type: Journal Article
• Authors: Wesolowski, Robert; Sharma, Neelesh; Reebel, Laura; Rodal, Mary Beth; Peck, Alexandra; West, Brian L.; Marimuthu, Adhirai; Severson, Paul; Karlin, David A.; Dowlati, Afshin; Le, Mai H.; Coussens, Lisa M.; Rugo, Hope S.
• Is Part Of: Therapeutic advances in medical oncology. Volume 11(2019)
• Publication Date: 2019-06
• Subjects: advanced solid tumors -- colony stimulating factor receptor 1 inhibitor -- paclitaxel -- phase I trials -- tumor associated macrophages; Oncology -- Periodicals; Cancer -- Treatment -- Periodicals; 616.994005
• DOI: 10.1177/1758835919854238
• Languages: English
• ISSNs: 1758-8340

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.