Roxanne Nelson

May 15, 2014

A new targeted therapy has demonstrated "profound activity" in the treatment of pigmented villonodular synovitis (PVNS). This rare joint proliferative neoplasm involves the synovium of joints or tendons.

An experimental compound, known as PLX3397 (under development by Plexxikon) could offer the first drug treatment for these patients.

The results are preliminary, but so far 11 of 14 evaluable patients have responded to the drug. They experienced a mean reduction in tumor volume of 61%, and rapid and substantial improvements in symptoms.

The responses were dramatic and sustained, said lead author William D. Tap, MD, chief of the Sarcoma Medical Oncology Service at the Memorial Sloan-Kettering Cancer Center in New York City. He was speaking during a press briefing held in advance of 2014 Annual Meeting of the American Society of Clinical Oncology® (ASCO).

"Eleven of the patients had a partial response, for an overall response rate of 79%," Dr. Tap reported. The drug was well tolerated.

"Patients on PLX3397 also demonstrated marked clinical improvement, as assessed by the treating physician," he added. "The majority of patients had improvements in pain, stiffness, and the ability to perform their activities in daily living."

No FDA-Approved Treatment

PVNS is the result of a clonal neoplastic process related to the translocation of t(1;2) in the COL6A3–CSF1 fusion gene.

"This results in overexpression of CSF1 in synovium, which causes a reactive inflammatory proliferation in the joint by attracting CSF1R-expressing cells, such as monocytes, macrophages, osteoclasts," Dr. Tap explained.

The result is collagen scarring, bone destruction, and repeated joint bleeds. It typically affects the hip or knee, and usually occurs in younger individuals. For the patient, it can manifest as pain, decreased range of motion, stiffness, functional impairment, narcotic use, and disability.

Even though it is characterized by an overgrowth of abnormal cells, PVNS is not considered to be a cancer because it usually does not spread to other parts of the body, Dr. Tap noted.

There is currently no treatment approved by the US Food and Drug Administration (FDA). Although the majority of patients do well with surgical treatment, PVNS generally recurs, necessitating additional surgery or joint replacement. It eventually advances to the point where the condition is no longer operable.

PLX3397 might be a therapeutic option for patients who have exhausted standard treatment. It is a novel oral tyrosine kinase inhibitor that blocks several molecular targets, including CSF1 receptor, Kit, and Flt3 kinases.

Well Tolerated

In their phase 1 ongoing multicenter trial, Dr. Tap and his colleagues wanted to find out whether blocking a clonal neoplastic process driven by a single genetic event with the highly targeted therapy (PLX3397) would produce a therapeutic result.

Patients with advanced disease and tumors in the knees, ankles, feet, or elbows were enrolled into an expansion cohort, and received daily oral PLX3397 1000 mg (600 mg in the morning, 400 mg in the evening) in 28-day cycles.

Every 2 cycles, a blinded central musculoskeletal radiologist used MRI results to assess tumor volume score (TVS), which was developed specifically for PVNS.

The tool, based on the modified Whole-Organ MRI score commonly used in arthritis, calculates tumor volume as a percentage of the entire synovium.

Partial response was defined as a decrease in TVS of at least 50% from baseline. Progressive disease was defined as an increase in TVS of at least 30% from the lowest score.

Patients remained on therapy until disease progression or intolerability. The majority of the participants had already undergone multiple surgeries, and some had received radiation and/or other systemic targeted treatments, such as imatinib (Gleevec) or nilotinib.

To date, 23 patients have enrolled in the study. Dr. Tap presented results from the 14 patients who were evaluable at the April cutoff date. Median exposure to PLX3397 was 244 days (range, 15 to 585 days).

The agent was generally well tolerated. Common treatment-related adverse events (>20%) included hair color changes, fatigue, nausea, swelling around the eyes, abnormal taste, diarrhea, vomiting, and decreased appetite. Events of grade 3 or higher included hyponatremia and elevated liver enzymes in 2 patients each, and anemia, fatigue, diarrhea, and neutropenia in 1 patient each.

Patient Returns to Work

Dr. Tap presented a brief case study to illustrate the benefit of PLX3397.

Before entering the trial, the patient was walking with a cane, unable to straighten her knee, taking significant narcotics for pain relief, and unable to work. Her physicians were considering amputation.

"After only 4 months on PLX3397, she is now walking unassisted, has increased range of motion, is off of narcotics, and has returned to work," Dr. Tap reported.

PLX3397 is a very promising novel treatment for patients with advanced PVNS, he explained, and a phase 3 study is planned.

"It's exciting that by targeting this abnormality, and specifically the colony-stimulating factor 1 receptor, the promise of a novel therapeutic for a disease that was untreatable with drugs has been demonstrated," said ASCO president Clifford A. Hudis, MD, FACP.

Even though the numbers are modest, 11 patients appear to have had a marked response. "We will have to see how durable this is and how it fits into the overall management of these patients," Dr. Hudis noted.

This study was funded by Plexxikon. Dr. Tap and several coauthors report financial relationships with Plexxikon and other companies.

2014 Annual Meeting of the American Society of Clinical Oncology. Abstract 10503. To be presented June 1, 2014.

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