Pharmacokinetics and pharmacodynamics of an anti-CSF1 receptor antibody in the intra-articular treatment of tenosynovial giant cell tumor.

CSF1R-targeted pharmacotherapy is a viable treatment approach for TGCT but may be associated with pharmacologic side effects when given systemically. As a first study of its kind, intra-articular (IA) administration of an anti-CSF1R antibody (AMB-05X) into the knee of normal monkeys and TGCT patients was characterized. Following favorable results of 5 mg/kg IA dosing in monkeys, a multi-center, single-arm, Phase 2a trial was undertaken. IA AMB-05X was administered to the affected knee at 150 mg (N = 8) or 90 mg (N = 3) every 2 weeks for 12-weeks. Safety and tolerability, and efficacy (tumor response assessed on MRI and patient reported outcomes (PROs)), PK, PD, and anti-drug antibody (ADA) were evaluated. IA injection to monkeys was well-tolerated and AMB-05X knee synovial fluid levels were greater than that in serum with a similar half-life. In the clinical trial, most common low-grade treatment-emergent adverse events (TEAEs) were edema (55 %), fatigue (46 %), arthralgia (36 %), rash (36 %) and pruritus or hypertension (27 %). These events were lower in the 90 mg cohort compared to the 150 mg cohort. Q2W dosing resulted in accumulation of high synovial vs systemic AMB-05X (PK) and CSF1 (PD) levels. Objective tumor response by RECISTv1.1 was 36 % overall, while Modified RECIST was 45 %. PROs were significantly improved at 10-12 weeks. ADA was 0 %. Favorable PK, PD, efficacy, and safety/tolerability of intra-articular administration of an anti-CSF1R mAb for TGCT was validated. These results support further development of this novel treatment approach.