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FDA Grants Pexidartinib Breakthrough Status for Tenosynovial Giant Cell Tumor

Silas Inman @silasinman
Published: Monday, Nov 02, 2015

Mahmoud Ghazzi

Mahmoud Ghazzi, MD, PhD

The FDA has granted a breakthrough therapy designation to pexidartinib (formerly PLX3397) as a potential therapy for patients with tenosynovial giant cell tumor (TGCT) for which surgical removal is contraindicated, according to a statement from the companies codeveloping the drug, Daiichi Sankyo and Plexxikon.

The designation was based on findings from a phase I study, which were published in The New England Journal of Medicine. In an expansion cohort of the study, the objective response rate with pexidartinib was 52.2% (95% CI, 32-73). At this time, there are not currently any therapies approved specifically for TGCT.

"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," Mahmoud Ghazzi, MD, PhD, Executive Vice President and Global Head of Development for Daiichi Sankyo, said in a statement.

Pexidartinib is an oral small molecule inhibitor of the CSF1 receptor and Kit kinases, which regulate key components of the tumor and its microenvironment. The CSF1 gene is elevated in most TGCTs. In the two part phase I study on which the new designation was based, 41 patients were treated with pexidartinib in a dose escalation cohort with an additional 23 patients enrolled in an extension study.

The mean duration of treatment for patients in the dose escalation arm was 70.7 days (range, 3-575). In patients who completed at least 1 cycle of pexidartinib (n = 35), the stable disease rate was 23% and there was 1 patient with a partial response (3%). Overall, this portion of the study identified a 1000 mg/day dose of pexidartinib for future study.

In the extension arm, which utilized the 1000 mg/day dose, the mean age of patients was 46 years. The most common site of disease was the knee. Eighteen patients had undergone previous surgery and 4 had received prior therapy with imatinib or nilotinib. The median duration of treatment with pexidartinib was 8 months.

Overall, 30.4% of patients treated with pexidartinib had stable disease, for a disease control rate of 83% (95% CI, 67-98). At the time of the analysis, the median progression-free survival had not been reached, with 17 patients remaining on the study, 7 of which had received pexidartinib for longer than 12 months.

The authors of the study noted that responses seen with pexidartinib were significantly better than traditionally experienced by patients treated with imatinib. In previous studies, imatinib has demonstrated an objective response rate of 19%. 

"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."

In the expansion arm, dose reductions were required for 61% of patients, with 30% requiring a temporary treatment withdrawal. The most common reason for dose alteration was fatigue.

The most common pexidartinib-related all-grade adverse events (AEs) were changes in hair color (74%), fatigue (65%), nausea (39%), dysgeusia (26%), and periorbital edema (26%). The most frequent grade ≥3 AEs were hyponatremia (9%), elevated aspartate aminotransferase or alanine aminotransferase level or both (9%), fatigue (4%), diarrhea (4%), anemia (4%), and neutropenia 4%.

"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.

The pivotal phase III ENLIVEN trial is currently enrolling participants with TGCT. In the study, pexidartinib is being compared with placebo. The trial plans to enroll 126 participants, with an estimated completion date of March 2018 (NCT02371369).


Tap WD, Wainberg ZA, Anthony SP, et al. Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor. N Engl J Med. 2015;373:428-437.



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