Experimental Drug Targets Rare Joint Disorder

MRI image of a tumor behind the knee.

An MRI image shows a tumor (measured by green lines) behind the knee.

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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This study was funded by Plexxikon Inc., the company that makes PLX3397.


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My 27 yr old son was diagnosed with PVNS of his left knee in August of 2014. He had surgery to remove his interior and anterior synovium. He saw his surgeon today, November 3, 2015 and the PVNS has returned. He's in constant pain. I would like some information on this trial medication.

Jacqueline, we’re sorry to hear about your son. If he would like to participate in the PVNS trial at MSK, he can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. If he is not able to come to New York for treatment, we recommend he go to www.clinicaltrials.gov to find other centers that are offering new treatments for PVNS. Thank you for your comment.

I just had my 3rd surgery on my left knee. The PVNS are diffused. How can someone get on this trial medication.

Hi I was just diagnosed with PVNS. I am in south jersey. 48 year old male. No treatment yet but heard of William Tap. I am going to try and make an appointment with him.

Hi, I am very interested in learning more about this drug trial for pvns. I had surgery to remove pvns from my knee 5 years ago, and recently have been diagnosed with a reoccurrence. Hopeful that this drug has been found effective will be available soon. My only option currently is surgery.
Thank you,

Good evening,

l have been diagnosed with R knee Diffuse Type Pigmented Villonodullar Synovitis and l would like to know if you have Ongoing, currently recreuiting clinical trials in Pretoria South Africa. l am 23 years of age, diagnosis based on contrast and plain MRI, no biopsy. Please connect me to the right people.

Dear Tatenda, we’re sorry to hear about your diagnosis. We recommend you go to www.clinicaltrials.gov. This is an international database of clinical trials. You may be able to find something in South Africa. You might also want to contact the company that makes this drug. You can find their website here: http://www.daiichisankyo.com/contact/index.html

Thank you for your comment, and best wishes to you.

My 5 year old Daughter has just had her 2nd MRI showing that the PVNS now affects 6 joints. Both elbows,knees and ankles. Is this Trial including children?

Dear Amy, we’re very sorry to hear about your daughter’s diagnosis. Dr. Tap said he is not aware of any trials for pediatric patients, but that it’s unusual for this condition to be diagnosed in someone so young, and so extensively. If you are interested in coming to MSK for a second opinion, you can call 800-525-2225 or go to https://www.mskcc.org/pediatrics/cancer-care/about for more information.

Thank you for your comment, and best wishes to you.

Hi this is great news and I have been following the testing of this drug closely.

I was diagnosed with localised P.V.N.S (knee) in 2012 then aged 40. I had my first surgery 2 years later but the tumour could not removed due to nerve damage risks.

In the first few years of the disease the pain was terrible and constant requiring morphine at times. After surgery it improved but within less than 2 years the pain and limited mobility began to increase again so I was walking with a stick.

I'm happy to say that for the last year my condition has improved significantly without any further medical intervention simply by making lifestyle changes. I have found that limiting use of the joint (no running at all and limiting walking, and definitely no impact sports/stress exercise that uses joints) makes a considerable difference and I no longer take painkillers, use a stick or have problems sleeping.

Whether this will continue who knows? I have been told by the NHS here in UK I'm eventually going to need a second and subsequent bouts of surgery to remove the knee lining growth and eventually the tumor. The long-term prognosis I got too (assuming no medications available in UK) was a knee replacement op by the time I'm in my early to mid 50's.

Dear Paul, we’re happy to hear that you’re doing well. Thank you for sharing your story, and best wishes to you.

I had 3 scopes on my knee before finally having a total knee replacement in 2016 and the age of 40. The pain came back quickly. My doctor believes the PVNS is back in the knee with the replacement, as well as in my other knee. I am in constant pain. It hurts to stand up. It hurts to talk. It hurts to sleep. I a 43 years old, and I am in a deep depression that this is what my life is now. If I hurt this much at 43, I don't even want to know what 50 will be like.


We are sorry to hear you are going through this. If you would like to consult with an MSK expert, you can request an appointment online or call 800-525-2225 for more information. Thank you for your comment, and best wishes to you.