ALBERT

Description: Introduction JNJ-40346527 is a selective inhibitor of the colony stimulating factor-1 receptor (CSF-1R) tyrosine kinase. It impairs macrophage recruitment in animal models and reduces viability of Hodgkin lymphoma (HL) cell lines in vitro. Therefore, JNJ-40346527 has two potential targets in HL tumors: tumor associated macrophages and HL cancer cells. This study investigates JNJ-40346527 as a treatment for relapsed or refractory classical HL. Methods The patient population included men and women aged 18 years of age or older with a histopathologically confirmed initial diagnosis of classical HL and who have disease that has relapsed or is refractory after at least 1 appropriate therapy. Patients were assigned to sequential cohorts of oral daily dose of JNJ-40346527 (150, 300, 450, 600 mg QD, and 150 mg BID). Each treatment cycle consisted of 21 days. Dosing was continuous until progressive disease, toxicity or any other reason. Upon completion of 1 cycle (21 days of dosing, this may include any delays occurring during cycle 1) of each dose cohort, a review of all available study data was done by the study evaluation team (SET). The SET consists of the principal investigators (or their designees), the sponsor's medical monitors, and the sponsor's clinical pharmacologist. All (serious) adverse events, occurrence of dose limiting toxicities, pharmacokinetics and overall response rate were considered by the SET before deciding to go to the next dose level. Disease evaluations were done at baseline, end of cycle 2, end of cycle 6, and thereafter at the discretion of the investigator, and included CT/MRI and PET scan. Overall response was based upon both modalities. During the first cycle, pharmacokinetic (PK), and pharmacodynamic (PD) analysis of blood samples was performed on days 1, 7, 14 and 21 and at various timepoints during the day. PD included total and phosphorylated CSF-1R after CSF-1 stimulation. The primary endpoint for dose escalation phase was to establish the recommended phase 2 dose. Secondary endpoints included safety, overall response rate, PK, and PD. Results In this ongoing phase 1 study, 21 patients ([150 mg: 3; 300 mg: 5; 450 mg: 3, 600 mg: 3] QD, and 150 mg: 7 BID) were enrolled, 10 men/11 women, median age 40 (range, 19–75) years, and median number of prior systemic therapies were 6 (range, 3–12); 12/21 pts underwent 〉5 prior systemic therapies and 18/21 pts received autologous stem cell transplant. In addition, 15/21 patients underwent radiotherapy and 3/21 patients had HL related surgery. No dose limiting toxicities were observed. Maximum tolerated dose has not been established yet. As of 01 June 2013, 6 patients are ongoing in the study. Best overall response seen is 1 patient with a complete response, ongoing in the study for 10 months, and 10 patients showing stable disease, varying from 1.5–8 months. A first disease evaluation is still pending for 2 patients. A total of 15 patients discontinued treatment, 13 patients due to progression of disease, 1 patient by investigator decision (increased PET activity), and 1 patient due to treatment-emergent adverse events (TEAEs, lung embolism noted at C1D1, which was a pre-existing event at study entry). Median number of cycles received was 3.5 (range, 1–15). Most common (≥20% of patients) possibly drug-related TEAEs (per investigator assessment) were nausea, headache and vomiting. Serious TEAEs were recorded for 4 patients, none of them related to treatment as per investigator assessment. Preliminary PK analysis showed that JNJ-40346527 exposure increased in a near dose-proportional manner over the dose range of 150–450 mg QD but plateaued out at 600 mg QD. Serum trough levels were within the projected pharmacologically active concentration range at a dose as low as 150 mg QD. Preliminary PD analysis confirmed target engagement and showed 〉80% inhibition of CSF-1R phosphorylation at 4 hours post dosing in peripheral blood mononuclear cells stimulated with CSF-1. Conclusion Preliminary results indicate that JNJ-40346527 was well-tolerated and may be effective for the treatment of Hodgkin lymphoma. Disclosures: von Tresckow: Novartis: honoraria for acting as a consultant: Consultancy; Takeda Pharma GmbH: reimbursement of congress, travel, and accommodation costs and honoraria for preparation of scientific educational events: Honoraria. Morschhauser: Janssen Research & Development : Honoraria. Ribrag: Bayer: Research Funding; takeda: Membership on an entity’s Board of Directors or advisory committees; Janssen Research & Development: Membership on an entity’s Board of Directors or advisory committees; Servier: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Chien: Janssen Research & Development: Employment, Equity Ownership. Seetharam: Janssen Research & Development: Employment, Equity Ownership. Aquino: Janssen Research & Development: Employment. Kotoulek: Janssen Research & Development: Employment. Khan: Janssen Research & Development: Employment, Equity Ownership. de Boer: Janssen Biologics B.V.: Employment, Equity Ownership. Engert: Millennium, Takeda: Consultancy, Honoraria, Research Funding.