Drug Shows Efficacy in Neoplastic Joint Disorder

Based on preliminary results of a phase I study, the experimental oral tyrosine kinase inhibitor PLX3397 (Plexxikon; Berkeley, CA) appears remarkably active against the rare neoplastic joint disorder pigmented villonodular synovitis (PVNS). Thus far, about three quarters of the evaluable patients in the study—patients who had no other treatment options—have had their tumors rapidly shrink by at least half.

The trial's findings were presented by William Tap, MD, chief of the sarcoma medical oncology service at Memorial Sloan Kettering Cancer Center in New York, NY, at a press conference highlighting research that will be discussed at the American Society of Clinical Oncology's Annual Meeting, to be held May 30–June 3 in Chicago, IL.

Every year, about 600 people in the United States are diagnosed with PVNS, a synovial tumor of joints and tendon sheaths that typically affects the knees and hips. The tumors are known to express high levels of CSF1, “which causes a reactive inflammatory proliferation in the joint by attracting CSF1R-expressing cells, such as monocytes, macrophages, and osteoclasts,” Tap explained. The physiologic implications, he continued, include collagen scarring, bone destruction, and repeated joint bleeds, which can lead to joint swelling, pain and stiffness, decreased range of motion, functional impairment, significant narcotic use, and disability.

Because no drugs are approved by the FDA for the treatment of PVNS, surgery is the standard of care, Tap noted. Unfortunately, PVNS recurs in some patients, necessitating additional surgical procedures, such as joint replacement and amputation.

Tap's team hypothesized that PLX3397, which inhibits CSFR1, KIT, and FLT3 kinases, might stem the accumulation of macrophages and other inflammatory cells in joints and reduce the size of tumors.

The researchers enrolled 23 patients in the single-arm trial, all of whom had advanced PVNS tumors. Most of the patients had undergone multiple surgeries, and some had received radiation and/or systemic targeted therapies prescribed for other conditions, such as imatinib (Gleevec; Novartis) or nilotinib (Tasigna; Novartis). They took 1,000 mg of PLX3397 a day until the disease progressed or they could no longer tolerate the drug.

Of the 14 patients who have been evaluated so far, 11 (79%) saw their tumor volume decrease by at least 50%, with an average reduction in tumor volume of 61%. They also experienced substantial improvement in symptoms, Tap said. The other three patients had stable disease. The most common side effects included changes in hair color, fatigue, nausea, swelling around the eyes, abnormal taste, diarrhea, vomiting, and decreased appetite.

“With medications like this, you do have a chance to really affect the course of an individual's life,” said Tap.

Plexxikon aims to launch a larger, phase III study of PLX3397 in patients with PVNS. The drug was deemed an Orphan Drug by the FDA in February, a designation that would provide 7 years of additional marketing exclusivity if it is approved.