Stable Cancer Patients Phase I Dosing Could Be Extended If Benefit Shown

A Phase I trial participant should be allowed to continue receiving an investigational oncology compound beyond the duration of animal safety data if he has stable disease and he and his physician agree that this represents a benefit from therapy, FDA's Oncologic Drugs Advisory Committee said March 13.

The committee voted unanimously that trial participants should be allowed to continue receiving investigational therapy beyond the duration of preclinical safety data if patients and their physicians determine that there is clinical benefit.

FDA convened the panel to discuss preclinical toxicology requirements for biologics. One of the agency's key questions was whether Phase I patients whose disease has stabilized should be allowed to continue therapy beyond the amount of time the drug has been tested in animals.

[Editor's note: To ¹ watch a webcast or order a video/DVD of this meeting, visit FDAAdvisoryCommittee.com.]

FDA usually requests one-to-one duration of animal safety data to patient treatment, with extensions of therapy allowed on an ad hoc basis.

The question of preclinical safety data is not as pressing for patients exhibiting tumor response as they are generally allowed to continue therapy. FDA was interested in what the committee thought of stable disease, since the clinical benefit is not as clear.

Committee member Bruce Cheson (Georgetown University Hospital) said that continuing therapy "is a decision between the physician and the patient."

"If you call it stable disease with clinical benefit versus stable disease without clinical benefit, then a patient who is having stable disease with clinical benefit should be allowed to continue the drug, whatever the status of the preclinical data," he explained.

FDA and panel members agreed that one of the key challenges is defining stable disease.

Cheson said a better definition of stable disease needs to be developed. "There are patients who enter trials with very large tumor masses, very symptomatic from their disease and if that doesn't change that is still stable disease by current response criteria, but that is not somebody I would want to continue treating with a particular agent," Cheson noted.

Biogen Idec Senior VP-Preclinical & Clinical Development Sciences James Green suggested that stable disease may be an indication that drugs such as targeted therapies are working even without significant tumor regression.

"With some of these agents stable disease may be in fact just binding to the receptor, lighting up the expected pathway, the patient essentially showing no signs of toxicity and there is a potential hope of benefit," Green said.

Committee consultant Susan Bates (National Institutes of Health) pointed to Bayer/Onyx' Nexavar (sorafenib) as an example of a therapy providing clinical benefit without tumor response. FDA cleared Nexavar in December for kidney cancer based on a statistically significant benefit on progression-free survival (² (Also see "Bayer/Onyx Nexavar Approved For Broad Advanced Kidney Cancer Indication" - Pink Sheet, 2 Jan, 2006.), p. 8).

With Nexavar, "you can see patients who did have clinical benefit when they didn't achieve a [partial response], so there is a group of patients who have minimal response that you are impacting the biology of their disease," she said.

However, Bates noted that "if you are going to give an agent that is essentially inactive to an indolent disease population, you do run the risk of a publication coming out later saying 'yes we have stable disease in 40% of our patient population,' when you in fact had no impact on the biology of the disease."

For this reason, she suggested that patients deemed as having stable disease only be allowed to continue therapy if the investigational compound has been shown to be hitting its target.

Some committee members suggested that more information about continuing therapy in the absence of preclinical safety data could be included in informed consent documents for trial participants.

The original consent could state, "you may be one of the lucky ones who is treated for some length of time and we may get to a point where we have very little knowledge of whether that is good, bad or indifferent or what side effects are pursuant to that," committee chair Silvana Martino (University of Southern California) said.

FDA's questions for the committee suggested that patients could be asked to sign an additional consent form if they continued therapy beyond the duration of preclinical safety data.

Committee member Michael Perry (University of Missouri) said that suggestion "really rankles, particularly coming from a government agency. Those of us who have to deal with the [institutional review board] know that signing the consent form is not the same as obtaining consent, which is an ongoing process and it is not a simple legal document," he said.

FDA also asked committee members how much preclinical safety data should be required in advance of initiation of Phase I trials for biologic products.

The current standard for small molecules is 28-day repeat dosing data, FDA said. However, biologics often require longer duration data because of their long half-lives and, consequently, greater accumulation in the body.

FDA said three-month animal toxicity data would be sufficient for the vast majority of biologics. However, FDA and committee members agreed that requiring three-month animal toxicity data in advance of initiation of Phase I trials could delay entry of new products to market.

Requiring three-month safety data before the initiation of Phase I trials could lead to "significant delays in the development of therapeutics," Office of Oncology Drug Products Director Richard Pazdur maintained.

Instead, most panel members supported a "rolling" approach to requiring animal toxicity data. Under the system, sponsors would be required to conduct three-month trials, but only 28-day data would be required to initiate a Phase I study.

Sponsors would need "to start with 28-day toxicity data, but to continue the three-month testing in the event that new information could change the ongoing trial," committee member Gregory Reaman (George Washington University) explained.

Biogen Idec's Green said requiring longer preclinical trials could become a financial barrier to smaller companies bringing compounds to market. He said that extending animal toxicity trials two months would add 20%, or approximately $600,000-$700,000, to the cost of conducting such a trial.

Green noted that the cost of producing additional drug could be greater than the additional costs of conducting a trial. "You can actually go through millions of dollars of drug and some small companies just don't have that capability early on," he explained.