Non-Hodgkin's lymphoma initial studies may use historical controls -- FDA advisory committee.

NON-HODGKIN's LYMPHOMA AGENT INITIAL STUDIES: HISTORICAL CONTROLS ACCEPTABLE to determine whether response rates reflect meaningful clinical benefit over existing therapies, members of FDA's Biological Response Modifiers Advisory Committee agreed at an Oct. 21 meeting. The committee discussed clinical trial issues for drugs and biologics being developed for non-Hodgkin's lymphoma in the context of FDA's oncologics initiative.

For agents being used to treat NHL, "a randomized trial is still doable, and...that should be the goal against standard treatment," but "initial studies...might have to be comparing [the new agent] to historical controls," said temporary committee member and Oncology Drugs Advisory Committee member Janice Dutcher, MD, Montefiore Medical Center. Committee member Ellin Berman, MD, Memorial Sloan-Kettering Cancer Center, agreed that "it is not always feasible to perform a prospective randomized trial. I would argue that historical controls could be used...and that it would be possible to derive meaningful benefit."

Randomized trials for non-Hodgkin's lymphoma agents could be done post-marketing, Dutcher told FDA representatives, "depending on the drama of the benefit" of the new agent.

The committee also discussed relevant surrogate endpoints for NHL studies. While "there is not extensive data" on the use of polymerase chain reaction negativity for the bcl-2 translocation as a surrogate marker for low-grade NHL, the use of PCR is "very impressive," committee guest Jeffrey Cossman, MD, Georgetown University Medical Center, said. "I think these are valid tests and...should be considered because you'll get data much earlier," but "they are not stand-alone tests."

The committee agreed that patients with recurrent disease need not have failed anthracycline-containing regimens to have their responses to a new agent show meaningful benefit.

"Particularly for low-grade lymphomas," Vose said, "failure in anthracycline isn't necessarily the final thing. I think there are many patients who have failed multiple other therapies...for low-grade lymphoma, and they, too, could be well-benefitted." Committee member Carole Miller, MD, Johns Hopkins Oncology Center, observed that it is "not just the number of [prior] regimens, but the total duration of therapy" that is important.

The results of clinical trials for NHL in narrowly defined populations would be "difficult to generalize" across risk populations, Vose contended, as "the efficacy is going to be different in different populations." Dutcher said that she "would not like to shut the door" on generalizing studies across populations, adding that "agent-dependent, population-dependent, toxicity-dependent factors" can influence how widely generalizable studies may be.

The committee did not address the issue of specific response criteria for response in non-Hodgkin's lymphoma. Idec Senior VP-Medical & Regulatory Affairs Antonio Grillo-Lopez, MD, reported during the open public hearing that his company, which is developing two monoclonal antibodies for NHL, convened an expert panel to compile objective response criteria for low-grade or follicular lymphoma studies.

Grillo-Lopez said Idec has submitted the criteria to FDA, and expects that the National Cancer Institute will call a spring meeting for representatives of cooperative groups to discuss the development of standard criteria for non-Hodgkin's lymphoma studies.

The Idec expert panel defined the required criteria for a "complete response" classification as having: no evidence of disease; all nodes visualized from CT scan would be 1x1 cm or smaller; response continuing for 28 or more days; liver and spleen of normal size; and negative bone marrow, Grillo-Lopez said. The panel's criteria for "partial response" were: the sum of products of perpendicular diameters (SPD) must increase by 50% or more from baseline; no new lesions; and response for 28 or more days. "Stable disease" was defined by the panel as either a less-than-50% decrease in SPD from baseline, or less-than-50% increase in SPD from baseline with no new lesions.