447PD - Phase Ib study of PLX3397, a CSF1R inhibitor, and paclitaxel in patients with advanced solid tumors

Date 28 September 2014
Event ESMO 2014
Session Developmental therapeutics
Topics Anticancer Agents
Clinical Research
Translational Research
Basic Scientific Principles
Basic Principles in the Management and Treatment (of cancer)
Biological Therapy
Presenter Hope Rugo
Citation Annals of Oncology (2014) 25 (suppl_4): iv146-iv164. 10.1093/annonc/mdu331
Authors H.S. Rugo1, N. Sharma2, L. Reebel3, M.B. Rodal4, A. Peck5, B.L. West6, A. Marimuthu7, D.A. Karlin8, A. Dowlati2, M.H. Le9, L.M. Coussens10, R. Wesolowski11
  • 1M_med-hmon-core-onco-gen, UCSF Helen Diller Family Comprehensive Cancer Center, 94115 - San Francisco/US
  • 2Department Of Medicine-hematology And Oncology, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, 14263 - Cleveland/US
  • 3Internal Medicine, The Ohio State University, 43212 - Columbus/US
  • 4Department Of Medicine-hematology And Oncology, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, 44106 - Cleveland/US
  • 5M_hdf Comprehensive Cancer Ctr, UCSF Helen Diller Family Comprehensive Cancer Center, 94115 - San Francisco/US
  • 6Translatioinal Pharmacology, Plexxikon Inc, 94710 - Berkeley/US
  • 7Nonclinical Chemistry, Plexxikon Inc, 94147 - Berkeley/US
  • 8Clinical Development, Plexxikon Inc, 9710 - Berkeley/US
  • 9Clinical Development, Calithera Biosciences, Inc., 94080 - South San Francisco/US
  • 10Knight Cancer Institute, Oregon Health and Science University, 97239 - Portland/US
  • 11Internal Medicine, The Ohio State University, 43210 - Columbus/US



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.


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.


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.


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.


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.