Experimental Giant Cell Tumor Drug Gets Breakthrough Therapy Designation

There are currently no approved treatments for tenosynovial giant cell tumors.

Hope is on the horizon for patients with a form of cancer that currently has no approved therapeutic options available.

The FDA this week granted breakthrough therapy designation to pexidartinib for the treatment of tenosynovial giant cell tumor (TGCT) in which surgical removal is contraindicated. The drug is being codeveloped Daiichi Sankyo and Plexxikon.

The breakthrough designation followed a phase 1 study published in The New England Journal of Medicine. An expansion cohort showed an objective response rate from pexidartinib of 52.2% (95% CI, 32-73).

"We are pleased that the FDA recognizes the unmet need for the treatment of TGCT and we look forward to working closely with the agency on the expedited development of this potential non-surgical treatment for patients with TGCT," said Mahmoud Ghazzi, MD, PhD, executive vice president and global head of Development for Daiichi Sankyo.

The oral small molecule inhibitor of the CSF1 gene receptor and Kit kinases regulates key components of the tumor and its microenvironment.

The 2-part phase 1 study enrolled 41 patients who were administered pexidartinib in a dose escalation cohort along with 23 patients as part of an extension study.

The mean treatment duration in the dose escalation arm of the study was 70.7 days.

Patients who completed at least 1 cycle of pexidartinib (n = 35) showed a stable disease rate of 23%, with 1 patient who had a partial response.

Patients in the extension arm had a mean age of 46 years and received a 1000 mg/day dose of pexidartinib, with 18 of the patients already having received surgery, while 4 patients were previously treated with imatinib or nilotinib.

The median treatment duration time with pexidartinib in this arm was 8 months.

In this patient group, 30.4% of individuals treated with pexidartinib showed stable disease with a disease control rate of 83% (95% CI, 67-98).

Median progression-free survival was not reached at the time of the analysis, as 17 patients remained enrolled in the study, 7 of whom received pexidartinib for more than 1 year.

Results of treatment with pexidartinib were significantly better than patients treated with imatinib typically experience, with an objective response rate of 19%, the study noted.

"The responses seen in our ongoing phase I study provided initial proof-of-concept that selective CSF-1R inhibition with pexidartinib may safely and effectively reduce tumor burden in patients with TGCT, providing the rationale to move directly into a phase III clinical trial," said Gideon Bollag, PhD, chief executive officer of Plexxikon. "This breakthrough therapy designation represents another significant milestone in our commitment to develop novel targeted agents that address unmet medical needs in rare conditions such as TGCT."

Dose reductions in the expansion arm were needed for 61% of patients. Thirty percent required temporary treatment withdrawal, with fatigue noted as the most common reason for dose alteration.

All-grade adverse events associated with pexidartinib included hair color changes (74%), fatigue (65%), nausea (39%), dysgeusia (26%), and periorbital edema (26%).

An ongoing phase 3 trial is currently enrolling patients with TGCT to compare pexidartinib with placebo. The estimated completion date for this trial is March 2018.

"Surgery is the primary treatment for TGCT, but for patients with a diffuse form of the condition, the tumor is more difficult to remove and has a high rate of recurrence, resulting in multiple complicated surgeries and even amputation in some patients," Ghazzi said.