New pivotal trial needed for Vion's leukaemia drug Onrigin
This article was originally published in Scrip
A new Phase III trial of Vion Pharmaceuticals' lead oncology drug candidate Onrigin (laromustine; formerly cloretazine) in acute myeloid leukaemia (AML) will be needed after the US FDA told the company that an ongoing, independently sponsored Phase III trial would not suffice for the chemotherapy drug's approval.
Vion, which in December filed a voluntary petition for relief under Chapter 11 of the United States Bankruptcy Code, said that a new Phase III trial would need to be conducted "at significant additional time and expense". It will evaluate whether to file another special protocol assessment (SPA) for an alternative randomised Phase III trial within the next two weeks, it said.
The Connecticut-based biotech company previously announced that it lacked sufficient funds to conduct a new randomised study and would have to curtail or cease operations if it was unable to obtain additional financing, sell assets or restructure its operations.
Vion has retained the services of Roth Capital Partners, LLC to assist with the sale of the company and/or its key assets during the Chapter 11 proceeding.
In December, the FDA in a complete response letter refused on the basis of single-arm Phase II studies to approve Onrigin in elderly patients with acute myeloid leukaemia (AML), and called for a randomised study designed to demonstrate a clear survival benefit and an acceptable safety profile in a well-characterised patient population (scripnews.com December 15th, 2009).
Vion subsequently filed an SPA with the FDA, looking for the agency to evaluate the Phase III randomised trial HOVON AML 92 sponsored by the Dutch-Belgian Cooperative Group for Hematology Oncology (HOVON). However, the company has now said that the FDA raised concerns with the design, including the primary endpoint and study regimen of the trial, and therefore a new Phase III trial will be needed.
The HOVON trial is assessing laromustine in combination with standard remission-induction chemotherapy in patients aged 18-65 years with previously untreated AML or myelodysplasia (MDS).
The first part of the two-part trial is a dose selection, evaluating laromustine at three possible dose levels in combination with standard induction chemotherapy, while the second part is evaluating efficacy at the selected feasible dose level in terms of event-free survival, again in combination with standard induction chemotherapy versus induction chemotherapy alone.
troubled history
The FDA's complete response letter followed the recommendations of its oncologic drugs advisory panel, which in September cited pulmonary safety concerns and efficacy questions and concluded that a randomised controlled trial was needed for approval (scripnews.com, September 2nd, 2009).
Vion's proposed indication was remission induction therapy for patients aged 60 years or older with de novo, poor-risk AML. This is a patient population for whom standard induction therapy with cytarabine and an anthracycline is unlikely to work owing to tolerability and efficacy issues, the company has said.
At the panel meeting, the FDA said the survival results were confounded because patients who achieved remission with laromustine induction also received cytarabine for consolidation, making laromustine's role unclear. Additionally, 29% of responders had age and ECOG performance status as their only risk factors, and they may have qualified for standard induction therapy. Pulmonary toxicity was among the top three causes of early death and serious adverse events.
Pulmonary adverse events were also seen in an earlier Phase III, randomised study (CLI-037) in patients 18 and older with relapsed AML. There was a more than three-fold increase in death, from 13% in the cytarabine arm to 40% in the laromustine combination group. Deaths were due primarily to infections and pulmonary toxicities. Vion said the clinical hold which was placed on the trial was lifted in January 2008 after drug doses in the study were lowered.
An advisory board convened by Vion found that laromustine causes direct injury to the lungs.
In the pivotal Phase II 85-patient trial in patients aged 60 years or older with de novo, poor-risk AML, 28% of patients achieved complete remissions (complete remission or complete remission without platelet recovery). In more than one third of those achieving remission, response lasted less than 90 days. Median leukaemia-free survival was 174 days, and median overall survival was 98 days.
Standard induction therapy for AML comprises cytarabine and an anthracycline, and produces a complete remission in 50-70% of patients in large trials. However, poor-risk elderly patients have a much lower rate of complete remission, and only about a third of these patients even receive chemotherapy, Vion says. It has said that Onrigin, while also an alkylating agent, would offer a better benefit-risk profile than the combination chemotherapy regimen.