447PDPHASE IB STUDY OF PLX3397, A CSF1R INHIBITOR, AND PACLITAXEL IN PATIENTS WITH ADVANCED SOLID TUMORS

ABSTRACT Aim: CSF1R kinase regulates the recruitment of macrophages to tumors and osteoclast differentiation leading to bone lysis. PLX3397 (PLX), a small molecule CSF1R inhibitor, blocked paclitaxel (TAX) -induced macrophage infiltration in mouse tumor models, resulting in slower tumor growth and reduction of metastases. We conducted a phase Ib study of PLX combined with TAX in patients (pts) with advanced solid tumors. Methods: This trial has 2 parts: to explore safety of escalating doses of PLX with weekly 80 mg/m2 TAX to find a recommended Phase 2 dose (RP2D) of PLX, and to determine efficacy and safety of PLX dosed orally twice daily at the RP2D combined with weekly TAX. PLX dose started at 600 mg/day, escalating in increments of ≤ 50% using a standard 3 + 3 design. Endpoints also include pharmacokinetics (PK) and correlation of PLX biomarkers with clinical activity. Results: 36 pts received study drugs and 35 pts reported treatment-emergent adverse events (AEs) including anemia, fatigue, decreased appetite, diarrhea, nausea, AST increase, and alopecia. Grade 3-4 AEs were recorded in 28 (anemia, lymphopenia, hypertension, neutropenia), none clearly related to PLX. Treatment was discontinued in 3 (8%) pts due to AEs. No dose limiting toxicity (DLT) emerged after allowing growth factors for neutropenia. 15 pts have enrolled at the PLX RP2D of 1600 mg/day. Of 23 efficacy evaluable pts (600 mg - 1600 mg), 4 had PR (2 breast,1 squamous cell, 1 bladder cancer), 10 had SD, 9 had PD. Neither PLX or TAX affected PK of the other drug. Two biomarkers were evaluated: in all pts plasma CSF-1 levels increased (range: 1.6 to 53-fold) and CD14dim/CD16+ monocyte levels decreased (57% to 100%), indicating blockade of CSF1R signaling. Conclusions: Combining PLX with TAX was generally well-tolerated. No DLT was observed and RP2D for PLX was 1600mg/day. Biomarkers suggest that PLX blocked CSF1R signaling, predicting a strong impact on the macrophage tumor microenvironment. Enrollment at the R2PD is ongoing, with plans to combine PLX and TAX in the I-SPY2 adaptive neoadjuvant trial to assess efficacy in biologic subsets of breast cancer. Disclosure: H.S. Rugo, N. Sharma and R. Wesolowski: I have research funding from Plexxikon Inc.; B.L. West, A. Marimuthu and D.A. Karlin: I am an employee of Plexxikon Inc.; L.M. Coussens: I have research funding from the Komen Foundation. All other authors have declared no conflicts of interest.