At yesterday's ODAC meeting, the committee recommended in a 9-3 vote that the company conduct controlled trials in elderly AML patients with a comparative therapy:
"In the absence of a randomized trial, we don't have an
evidence-based justification that alternative standard therapy
wouldn't be better."
Panel member Thomas Fleming, a
statistician at the University of Washington in Seattle.
The drug is already approved for the treatment of ALL in children and is used off-label to treat adult AML. According to Genzyme, in a press release:
is conducting a randomized Phase 3 trial comparing clofarabine in
combination with cytarabine to cytarabine alone in relapsed and
refractory adult AML patients 55 years old or older. The trial
continues to exceed patient accrual expectations, and results are
expected in 2011. Clofarabine is also being investigated in clinical
trials by most of the leading AML experts and major cooperative
leukemia investigation groups in the United States and Europe."
This is a very similar situation to the one that J&J found themselves in a few years ago with tipifarnib who also did not perform a randomised trial and in both cases, the FDA and ODAC felt that many patients could have received standard induction chemotherapy. This sets back the approval process since the FDA are unlikely to disagree with the panel having raised the questions themselves in their pre-briefing document.
September 1st was a bad day for AML therapies because in the afternoon session, the committee voted unanimously 13-0 not to approve Vion's Onrigin (larumustine), also for elderly (>60yo) patients with AML, principally for the same reasons, ie whether a single arm trial was sufficient, but in this case, safety concerns were also raised.
Although this patient population has a very poor prognosis, the remission rates seen with Onrigin were in the order of 32%, which is very respectable. Unfortunately, 14% of patients died within a month of treatment, raising concerns about it's tolerability. Vion claimed that this was not different from other therapies used to treat the disease, although ultimately this argument falls on it's sword with the lack of comaparative data to support the case.
The FDA's characterisation of the Onrigin data was startling negative:
"Use of laromustine in these studies was associated with both infusional toxicity (headache, nausea, dizziness, vomiting, hypotension, and dizziness) as well as typical post-infusional toxicity seen with myelosuppressive chemotherapy. However, during the conduct of the phase 2 studies and the phase 3 trial, laromustine use was associated with a unique and sometimes fatal pulmonary toxicity resembling nitrosourea pulmonary toxicity and requiring mechanical ventilation for some patients just achieving leukemia remission. Safety data review revealed that pulmonary toxicity was in the top 3 causes of Grade 3, 4 and 5 Treatment Emergent Adverse Events (TEAEs) as well as Serious Adverse Events (SAEs)."
Overall, the response from the FDA and ODAC panels sends a strong message that comparative trials are needed for approval in this patient setting.
It will be interesting to see what the panel makes of the NHL data from Gloucester's romidepsin in CTCL and Allos Therapeutic's pralatrexate in PTCL today. More on that later.