Phase 1 Study Of Rg7155, A Novel Anti-Csfir Antibody, In Patients With Locally Advanced Pigmented Villonodular Synovitis (Pvns).

10504^ Background: PVNS, also known as tenosynovial giant cell tumor (TGCT), is a rare disease mainly affecting young adults. This neoplastic disease is driven in most cases by a t(1;2) translocation resulting in fusion of COL6A3 and M-CSF genes encoding for colony-stimulating factor 1 (CSF1). The bulk tumor mass consists of CSF1 receptor (CSF1R) positive cells. RG7155 is a monoclonal antibody that potently inhibits the dimerization of CSF1R. Methods: In this dose-escalation and –extension phase I study, we treated patients with locally advanced PVNS, who were not amenable to surgical treatment. Primary objectives were to assess safety, tolerability, pharmaco-kinetics and -dynamics. Clinical activity was evaluated using FDG-PET (at 4 weeks after treatment start; EORTC criteria) and MRI (at 6 weeks; RECIST 1.1). Pre- and on-treatment biopsies of tumor and surrogate skin tissue as well as peripheral blood PD markers were analyzed. Results: Between September 2012 and October 2013, 11 PVNS patients (median age 38 (range 18-64)) were treated at three French institutions at four different dose levels (q2w). Three patients had previously been treated with nilotinib and imatinib, respectively. Seven patients had undergone previous surgeries. RG7155 induced a sustained increase of CSF1 associated with a decrease of CD14+CD16+ monocytes in peripheral blood in all 10 evaluable patients. RG7155 led to striking reductions of CSF1R+ and CD163+ macrophages in tumor tissue associated with rapid onset of objective clinical responses in 7/9 patients (78%; partial metabolic response at 4 weeks; FDG-PET) and 7/10 patients (70%; PR at 6 weeks; MRI). All patients showed tumor shrinkage associated with symptomatic improvement. 9/10 patients remained clinically progression-free with a longest follow-up of 17 months. RG7155 was well tolerated with only two patients experiencing grade 3 adverse events (periorbital edema; mucositis). Conclusions: RG7155 treatment induced rapid clinical responses in the vast majority of PVNS patients associated with profound reduction of CSF1R+ and CD163+ macrophages in tumor tissue. Clinical trial information: NCT01494688. Clinical trial information: NCT01494688.