Vanderbilt-Ingram Cancer Center (VICC) investigators and colleagues at several major medical centers have been testing a new targeted therapy that is showing promise for the treatment of a rare tumor that forms in and around joint cavities.
The study was published in the July 30 issue of The New England Journal of Medicine.
Tenosynovial giant-cell tumors, also known as pigmented villonodular synovitis (PVNS), are rare, locally aggressive tumors that develop in the lining of joints, including knees, hips, shoulders, elbows, ankles and feet. These tumors, which feature painful inflammation, often grow and destroy the joint, leading to joint replacement surgery or even amputation. There is no approved systemic therapy.
The newly designed drug, PLX3397, is a tyrosine kinase inhibitor that blocks interaction between the colony-stimulating factor1 (CSF1) gene and the gene receptor (CSF1R). Expression of the CSF1 gene is elevated in most cases of tenosynovial giant-cell tumor.
The multicenter clinical trial, led by William Tap, M.D., at Memorial Sloan Kettering Cancer Center, New York, included a Phase 1 dose escalation study to establish a safe dose of PLX3397. Igor Puzanov, M.D., associate professor of Medicine and associate director of Phase 1 Drug Development, led VICC’s Phase 1 portion of the trial in patients with solid tumors.
Forty-one patients enrolled in the dose-escalation study and 35 patients completed this portion of the study. Patients received MRI imaging at the time of enrollment and every two months to assess the status of their tumors.
The mean duration of treatment with PLX3397, which is given in capsule form, was 70.7 days. Eight of the patients had stable disease and one had a partial response.
A multicenter extension study with 23 patients was conducted to test the safety and efficacy of PLX3397 in patients with tenosynovial giant-cell tumors. Most of the patients had tumors in the knee. Vicki Keedy, M.D., assistant professor of Medicine and clinical director of the Sarcoma Program, led VICC’s effort.
In the extension study, 12 of the 23 patients had a partial response for an overall response rate of 52 percent, and seven of the 23 had stable disease. The total rate of disease control (complete response, partial response or stable disease) was 83 percent. Only one patient who already had metastatic disease had disease progression. The median duration of treatment was eight months at the time of data cutoff.
The investigators found that patients generally had a large reduction in tumor burden within the first four months of treatment that persisted over time. The mean decrease in tumor volume score was 61 percent.
Side effects from the therapy included changes in hair color, fatigue and nausea. An elevation in liver enzymes also occurred in half of patients.
Based on this research and a previous study, the authors said it appears tenosynovial giant-cell tumor can be added to the “growing list of oncogene-driven neoplasms that respond to drugs targeting the oncogenic driver.”
Patients often develop resistance to targeted therapies and the authors said it will be important to determine if resistance occurs with this new drug, along with the mechanisms that cause treatment resistance.
Plans are underway for additional trials of the new therapy.
Collaborators participating in the study include investigators from Weill Cornell Medical College, New York; University of California Los Angeles Medical Center; Stanford University School of Medicine, California; Evergreen Hematology and Oncology, Spokane, Washington; University of Pennsylvania School of Medicine, Philadelphia; Rocky Mountain Cancer Centers, Denver; Dana-Farber Cancer Institute and Massachusetts General Hospital, Boston; Virginia G. Piper at Scottsdale Healthcare-Translational Genomics Research Institute, Scottsdale, Arizona; Spire Sciences, Boca Raton, Florida, and Plexxikon, Berkeley, California.
Plexxikon provided funding for the study.
