Peter F. Lebowitz, MD, PhD
The FDA has granted a priority review to trabectedin (Yondelis) to treat patients with advanced soft tissue sarcoma, including liposarcoma and leiomyosarcoma subtypes, who have previously received chemotherapy that included an anthracycline.
The priority designation was announced by the company developing trabectedin, Janssen Research & Development, which submitted a New Drug Application (NDA) to the FDA on November 24, 2014. Under the expedited program, the FDA will make its final approval decision within 6 months.
“We are excited the FDA has granted priority review for Yondelis, as it is an important step forward in making this therapy available to physicians and those living with this aggressive disease,” said Peter F. Lebowitz, MD, PhD, global oncology head at Janssen, in a statement.
The investigational antitumor agent trabectedin was originally derived from the sea squirt, Ecteinascidia turbinate
, and is now manufactured synthetically.
Janssen’s NDA for the drug is based on the open-label, multicenter, phase III ET743-SAR-3007 trial, which is comparing trabectedin with dacarbazine in over 500 patients with liposarcoma and leiomyosarcoma who previously received anthracycline and ifosfamide or an anthracycline followed by one additional line of chemotherapy. The protocol required patients to have an ECOG performance status of 0 or 1.
The study has completed accrual and is randomizing patients in a 2:1 ratio to 1.5 mg/m2 of trabectedin or 1.0 g/m2 of dacarbazine once every 3 weeks until disease progression or unacceptable toxicity. Trabectedin will be administered through a catheter as an IV infusion over 24 hours and patients will receive dacarbazine as a 20- to 120-minute infusion.
The primary outcome measure of the trial is overall survival (OS). Secondary outcome measures include progression-free survival (PFS), objective response rate, time to progression, duration of response, and safety.
At this point, no data for the phase III study are available, with Janssen noting in a statement that it intends to present the results “at a future date.”
Results were previously published for a phase II study of trabectedin combined with dexamethasone in pretreated patients with recurrent advanced soft tissue sarcoma (Invest New Drugs.
Among 35 evaluable patients, 18 patients had stable disease and 1 patient had a partial response. Median OS and PFS were 10.2 months and 2.1 months, respectively.
Twenty-one patients had grade 3/4 neutropenia, with transient asymptomatic grade 3/4 AST and ALT elevation experienced by 23 and 27 patients, respectively. In most cases, grade 3/4 toxicities were successfully managed through dose reductions. Drug-related toxicities were linked to four deaths among patients receiving trabectedin.
A study presented at the 2014 ASCO Annual Meeting looked specifically at the impact of grade 3/4 AST and ALT increases on outcomes with trabectedin in patients with soft tissue sarcoma (J Clin Oncol
32:5s, 2014 [suppl; abstr 10572]). According to the researchers, 40% of patients with soft tissue sarcoma who receive trabectedin experience a transient increase in liver enzymes.
The study assessed data from 113 patients with advanced soft tissue sarcoma who had previously received at least one anthracycline-containing regimen. The patients were receiving 1.5 mg/m2 of IV trabectedin administered over 24 hours.
Grade 3/4 ALT increases were experienced by 45 patients in the first two cycles, with 68 patients not experiencing the side effect. There was not a statistically significant difference in the hazard ratios for PFS and OS when comparing these two patient subgroups (HR = 0.791, P =
0.309; and HR = 0.930, P =
In their conclusion, the authors wrote, “These results should discourage the premature discontinuation of the drug due to the increase in liver enzymes.”
During the FDA's priority review period, patients with soft tissue sarcoma who are unlikely to benefit from available therapies and who cannot participate in a clinical trial can apply to receive trabectedin through an FDA expanded access program (NCT00210665).
“Today, we are one step closer to our goal of making another treatment option available for people living with advanced soft tissue sarcoma,” said Denise Reinke, President and CEO of Sarcoma Alliance for Research through Collaboration, in a statement when Janssen filed it’s New Drug Application. “People living with this type of cancer are in urgent need of new options to help treat their disease, and we welcome new medicines that may help make a difference in their lives.”