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

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.

Population Pharmacokinetic Analysis of Pexidartinib in Healthy Subjects and Patients With Tenosynovial Giant Cell Tumor or Other Solid Tumors

“…The analysis showed that the estimated exposure values for patients receiving pexidartinib 400 mg twice daily increased following multiple daily dosing, with accumulation ratios of 3.6 and 4.6 for pexidartinib and ZAAD, respectively. These results are in line with published phase 1 results evaluating pexidartinib in predominantly White patients 15 and Asian patients 16 with solid tumors. In the assessment of the effect of covariates on pexidartinib, small effect of study population was noted, with healthy subjects having 26% higher CL/F and 21% lower AUC 0-24,ss compared to patients with TGCT.…”

Pexidartinib: First Approval

“…Oral pexidartinib in combination with paclitaxel was of clinical benefit (i.e. produced a complete response, partial response or stable disease) in 50% of patients with advanced solid tumors (n = 38 evaluable) in a first-in-human phase Ib trial (NCT01525602); one patient (with peritoneal carcinoma) had a complete response and five patients (with breast, rectal, bladder or ovarian cancer) had partial responses [6]. In part one of the study (a dose-escalation component), pexidartinib 1600 mg per day was selected as the recommended phase II dose [6].…”

“…Pexidartinib (TURALIO™) is a novel, orally available small molecule tyrosine kinase inhibitor (TKI) with potent and selective activity against the colony-stimulating factor 1 (CSF1) receptor [1][2][3]. CSF1, expressed in high levels in several types of solid tumors, facilitates the differentiation of monocytes into tumor-associated macrophages (TAMs) and the survival of TAMs within the tumor microenvironment [4][5][6]. TAMs in turn have immunosuppressive effects and promote tumor growth and metastases [4,6].…”

“…CSF1, expressed in high levels in several types of solid tumors, facilitates the differentiation of monocytes into tumor-associated macrophages (TAMs) and the survival of TAMs within the tumor microenvironment [4][5][6]. TAMs in turn have immunosuppressive effects and promote tumor growth and metastases [4,6]. Pexidartinib also inhibits KIT proto-oncogene receptor tyrosine kinase (KIT) and FMS-like tyrosine kinase 3 harboring an internal tandem duplication mutation (FLT3-ITD) [2,3,7,8].…”

Current Strategies to Target Tumor-Associated-Macrophages to Improve Anti-Tumor Immune Responses

“…In animal models, emactuzumab, a humanized mAb targeting CSF-1R, resulted in decreased TAM numbers in the tumor and increased CD8+/CD4+ T cell ratio [87]. The evaluation of this mAb alone or in combination with paclitaxel in patients with advanced solid tumors revealed an important reduction of TAMs in the TME and a good safety profile, but so far, no clinically relevant improved outcomes [88,89]. Similar mAbs targeting CSF-1R are currently being investigated in clinical trials as monotherapy or in combination with ICB for advanced solid tumors and with cyclophosphamide in patients with ovarian cancer (Table 1).…”