Summary People with tenosynovial giant-cell tumor, a rare, debilitating joint disease also known as pigmented villonodular synovitis, currently have few options for treatment if surgery is not successful. A new targeted therapy developed by MSK researchers could offer them hope for relief. Highlights Tenosynovial giant-cell tumor most commonly affects people in their 30s and 40s.

The disease is also known as pigmented villonodular synovitis.

An experimental medication called PLX3397 was shown to shrink many of these tumors.

The drug is now being offered in a larger, multicenter clinical trial.

For people with tenosynovial giant-cell tumor (TGCT) — a rare, debilitating joint disorder also known as pigmented villonodular synovitis (PVNS) that most commonly affects those in their 30s and 40s — treatment options have long been slim. But a team of Memorial Sloan Kettering investigators recently advanced a promising new option to combat these damaging tumors.

The researchers studied a new oral medication known as PLX3397 in a small group of patients with the disease. Results from this early-stage clinical trial, published today in the New England Journal of Medicine, found that the drug induced significant tumor shrinkage in about half of patients, with most additional patients experiencing stable disease (meaning their tumors stopped growing).

These findings were so promising that the investigators are now launching an international, multicenter trial of the drug involving more than 120 patients.

“This study really drives home the power of precision medicine,” says MSK medical oncologist William Tap, who led the early-stage trial. The treatment specifically targets the underlying cause of the disease.

This study really drives home the power of precision medicine. William Tap medical oncologist

A Destructive Tumor

While not technically considered a malignancy because it usually does not metastasize to other parts of the body, diffuse TGCT is an extremely destructive tumor that often comes back after initial surgical treatment. It’s difficult to remove with surgery because of its invasive nature, and it can cause significant pain, swelling, stiffness, and decreased range of motion in the affected joint (most commonly the knee).

The tumor is caused by a translocation (rearrangement) involving the gene CSF1. Last year, an earlier report from the same study presented at the American Society of Clinical Oncology annual meeting showed that PLX3397 was effective in addressing the ramifications of an abundance of CSF1 protein in tumors. This protein attracts a large number of macrophages and other inflammatory cells, which in turn destroy the joint over time.

PLX3397 targets a protein called CSF1.

“One thing that’s interesting is that only a small percentage of cells in TGCTs are actually neoplastic, meaning they carry the CSF1 abnormality,” Dr. Tap notes. “But the interaction between the protein that results from the mutated gene and the formation of the tumor is clear: When we use this drug to block the protein interaction, the inflammation is significantly reduced.”

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Advancing the Research

Based on the early results, the team was able to determine the optimum dose of PLX3397 — one that would be effective yet minimize side effects — and extended the phase I study to additional patients at the recommended dose. They found that responses to treatment occurred within four months of when patients started taking the pill and lasted more than eight months. Some patients have been taking the drug for close to two years and are still doing well, Dr. Tap adds, although these data were not reported in the current study.

Some patients have been taking the drug for close to two years and are still doing well.

Because the drug proved effective and the side effects were minimal, the researchers were able to skip the traditional phase II trial (which is designed to review safety and efficacy) and go right to a pivotal phase III trial, in which the effect of PLX3397 will be evaluated in large groups of patients.

That study, which currently is enrolling patients, will randomize participants to receive either PLX3397 or a placebo, but those who get the placebo will be able to cross over to the other arm of the study.

“This research is opening a new door in drug development,” Dr. Tap concludes. “It’s leading to an understanding of how to apply effective drugs to neoplastic conditions that are not necessarily deadly malignancies, but that very much affect a person’s quality of life.”

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