MSK at ASCO

On Cancer: Study Suggests Targeted Drug Is a Potential Therapy for Rare Joint Disorder PVNS

By Media Staff  |  Thursday, May 15, 2014
Pictured: William Tap William Tap, Chief of the Sarcoma Medical Oncology Service

This is the first in a series of posts about new research Memorial Sloan Kettering investigators are presenting at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO) — one of the largest educational and scientific events in the international oncology community — which will take place from May 30 through June 3 in Chicago.

New research from Memorial Sloan Kettering investigators is shedding light on a potential therapy for pigmented villonodular synovitis (PVNS), a rare and destructive joint disorder that affects approximately 600 young and middle-aged adults in the United States each year.

Patients with PVNS experience an inflammation and overgrowth of the synovium, or joint lining, which results in swelling, pain, and reduced mobility in the affected joint. The knee is the most common site involved, followed by the hip. Advanced cases of PVNS can be extremely debilitating.

Now a study led by medical oncologist William Tap, Chief of the Sarcoma Medical Oncology Service, suggests that a drug blocking a protein known to promote PVNS could alleviate these symptoms and improve quality of life.

A Tumor, But Not a Cancer

While the overgrowth of the joint lining may be referred to as a tumor, PVNS is not considered a cancer because the growth usually remains within a single joint and is not known to cause death.

Such tumors are removed surgically, and some patients receive radiation as well. In some cases the disease may recur after treatment, requiring additional surgery or a joint replacement. Eventually, PVNS may advance to the point that it is no longer operable, and the tumor will begin to further invade the joint, wrapping around bones, tendons, and ligaments.

There are no drugs approved to treat PVNS once it has progressed, and patients with advanced forms of the disease have few treatment options, among them amputation.

A Single Genetic Driver

Research has shown that a protein called colony stimulating factor 1 (CSF1) kinase is a driving force in the development and growth of advanced PVNS.

PVNS tumors express high levels of CSF1 because the tumor cells carry a specific genetic abnormality. This attracts an abundance of white blood cells called macrophages that overexpress a receptor for CSF1 . The influx of macrophages causes the inflammation and overgrowth of the joint lining, which can destroy the joint over time.

Armed with this knowledge, Memorial Sloan Kettering researchers organized a phase I clinical trial to test whether a novel drug called PLX3397, a tyrosine kinase inhibitor that potently inhibits the CSF1 receptor kinase, could safely slow the growth of PVNS.

The Right Drug for the Right Molecular Abnormality

Among 14 patients with advanced PVNS, 11 responded to the drug, while three others had stable disease. The average reduction in tumor size among the 14 patients was 61 percent, and all experienced rapid, marked improvements in symptoms. Side effects from the drug were minimal.

“By taking this drug that potently inhibits a single genetic process, several patients with advanced PVNS appeared to experience, in a relatively short amount of time, relief from pain and stiffness as well as marked improvement in joint function, all with minimal side effects,” says Dr. Tap, who led the trial and will present the findings at the ASCO meeting on Sunday, June 1.

“This study demonstrates the powerful clinical benefit of matching the right drug to the right molecular abnormality, and further spurs excitement over the potential of precision medicine,” he adds.

The drug is moving to an international phase III clinical trial, which Dr. Tap is helping to organize.

This research was supported by Plexxikon.

Comments

As I understand it "Cartilage undergoes a normal cycle of breakdown and repair, but in the condition of osteoarthritis, the cartilage is not replaced effectively, and ultimately the joint lining wears thin." so do you think CSF1 can be used to treat osteoarthritis?

Regards,
JDM

John, we consulted with Dr. Tap and he responded that he is "unaware of any preclinical data or rationale for PLX3397 use in osteoarthritis." Thanks for reaching out.

I wasn't thinking that PLX3397 could treat osteoarthritis. Since CSF1 is the reason for the linings overgrowth I thought it might treat osteoarthritis (which is a thinning of the lining) . . .

Regards,
JDM

Not to Dr. Tap's knowledge, John.

I just was diagnosed with a recurrence of PVNS after 9 years. Originally it was localized, but now it is diffuse. I was wondering how to potentialyl qualify for the phase III trial.

Daniel, we reached out to Dr. Tap, and he says: "The Phase III trial is still some time away, but the Current trial is still open if interested. There are several sites across the country depending on where he lives. We would also be happy to see him in clinic." You can learn more about the current trial here: http://clinicaltrials.gov/ct2/show/NCT01004861?term=pvns&rank=3

That is wonderful news. I live in Minneapolis, but grew up in NY and my father is a physician in NYC and Westchester so the NY location is best for me. I am waiting to hear from the PVNS specialist at the University of MN and will discuss my intention to attend Dr. Tap's clinic. I will call Dr. Tap's offices within the next few days to set up an appointment. I am truly grateful for modern medicine and Dr. Tap's generous offer to see me.

Hi, I am a 44 years old Swede with diffuse PVNS. I got my hip replaced 2010 in a private clinic in Switzerland but then had to make a new replacement one year later, after loosing the stem and a lot of other complications. They told it was PVNS after the first operation but that "it was not there" by the second operation. However they missed the giant mass that had grown outside the hip in between the ilias and psoas muscle. This I found out half a year ago after having problems with bowels and strong sudden hip pain then and then. The size of the tumor is 18*7*8 cm and the biopsy test showed, as I understood it, that it was mostly blood, no malignancy. I wonder if I can take part in the tests of the new drug?

Dear Gunnar, thank you for reaching out to us. There are several trial sites across the United States. You can learn more here: http://clinicaltrials.gov/ct2/show/NCT01004861?term=pvns&rank=3

Hi, I am 37 years old and I from Brazil.
I am very interested in this new study on this drug would be able to do with our tumors stop growing and even recede, so to be able to lead a more normal life.
Is there any joint work with Brazil? How I could be part of this study? Next week I'm traveling to Vegas and going to Miami in December. Please do not hesitate to warn me as if there is the possibility of being part of a study group.
Thank you very much.
Veronica

Veronica, thank you for your comment. We suggest you contact our International Center (1-212-639-4900) or go to (http://www.mskcc.org/cancer-care/international-patients) if you are interested in learning about any trials that may exist for PVNS.

I'm too active. I played a lot of tennis, at this time I can not play tennis at the knee but do gymnastics and pilates and sometimes I ride. You think you have to stop exercising due to this problem SVNP? I have several tumors behind the right knee, one being 10 x 3cm.
I would be a big help to people who are studying this disease can guide me on how to continue my life without aggravating the disease, since little is known about this problem globally.
From already thank you very much for everything.
Veronica

Hi, I have had pvns in my ankle joint for 13 years... My feeling is that it has regrown after a partial synevectomy 3 years ago. Are there any hospitals in Boston that are participating in the research and if so who? Thank you for your work! Much needed as this is a painful and debilitating condition.

Dan, for more information about the trial, including a list of hospitals that are participating, you can go to http://clinicaltrials.gov/ct2/show/NCT01004861?term=pvns&rank=3. It appears there are two hospitals in Boston that are currently recruiting for this study. Thank you for your comment.

Hi Dr. Tap. I am a patient of Dr. Wagner's at Dana Faber. I have extremely diffuse / radiation resistant PVNS. Gleevec has prevented me from amputation and more surgeries, however damage and pain continues in my left knee and distal quadricep. More importantly and very unfortunately because I have a another unrelated chronic illness, Gleevec tends to interact with some potential drug therapy options I very much need to try. I would like to be able to take medication that has less side effects on the liver like Gleevec.

Thus, my question is related to the potentially know drug interactions of PLX3397? I image your case studies, and future drug trials will be elevating such drug interactions... If you could provide me a list of the most statistically significant interactions, I would really appreciate it.

Thank you for your consideration.
Cheers,
Eric

Eric, we reached out to Dr. Tap and he is trying to get some information for you. We will follow up with you at the email address you provided when we hear back from him. Thank you for your comment.

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