CHICAGO, IL—“Early, dramatic, and sustained reduction in tumor mass.”

That is the result of a pilot study in patients with advanced pigmented villonodular synovitis (PVNS) following treatment with the novel agent PLX3397, William D. Tap, MD, of Memorial Sloan Kettering Cancer Center, New York, NY, concluded at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting.

The study hypothesized, “can we help patients with a highly targeted therapy that blocks the CSF1R pathway in this clonal neoplastic process frequently initiated by a single genetic event?”

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That therapy is the novel oral small molecule PLX3397, a potent inhibitor of colony-stimulating factor 1 (CSF1) receptor kinase activity.

PVNS, a rare synovial tumor, occurs when the genetic translocation t(1;2) CSF1:COL6A3 causes overexpression of CSF1 and reactive inflammatory proliferation of CSF1R-expressing cells (i.e., macrophages, osteoclasts, mast cells), resulting in collagen scarring, bone destruction, and repeat joint bleeds. Patients experience joint swelling, pain, decreased range of motion, stiffness, functional impairment, narcotic use, and disability.

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The goals of the study were to evaluate early efficacy signal, both clinical and radiographic; investigate potential ways to measure efficacy signals accurately; and understand application of a selective inhibitor in a neoplastic disease that is not necessarily a cancer, Dr. Tap outlined.

Patients with advanced PVNS were enrolled into an expansion cohort of an ongoing multicenter phase 1 clinical trial and given PLX3397 1,000mg/day (600 mg in the morning and 400 mg in the evening) in 28-day cycles. Every two cycles, patients underwent MRI assessment by a central musculoskeletal radiologist blinded to chronology using a novel tumor volume score (TVS) that calculated tumor volume as a percentage of the entire synovium. Partial response was defined as a 50% or higher decrease in TVS compared with screening, while progressive disease was defined as a 30%or higher increase in TVS relative to a patient’s lowest score.

The 23 patients enrolled had advanced PVNS with tumors in the knee (15 patients, or 65%), ankle (2 patients; 9%), foot (2 patients; 9%), hip (2 patients, 9%), elbow (1 patient, 4%), forearm (1 patient, 4%), or metastatic (1 patient, 4%). The majority of the patients were female (57%); mean age was 46 years (range, 22-80 years); 83% were white; 18 patients had undergone previous surgery; and four patients had previous tyrosine kinase inhibitor (TKI) use.

Of the 21 patients in the efficacy population, 14 were evaluable by MRI as of the April 2014 data cutoff. Median exposure to PLX3397 was 256 days (range, 21-585 days).

Median progression-free survival has not been reached. Of 20 patients evaluable by RECIST (Response Evaluation Criteria In Solid Tumors), 12 had a partial response (PR), for an overall response rate (ORR) of 60%. An additional seven patients (35%) had stable disease (SD), for a disease control rate of 95%. One patient (5%) had progressive disease.

“If we look specifically at the 14 patients that were evaluable for TVS, what we saw is a rapid and sustained tumor size reduction in the majority of the cases,” Dr. Tap said, which occurred within the first 4 months and was sustained over time. “This is critical data, in my opinion, as we move forward and figure out how to apply some of these drugs clinically.”