Idec should establish a centralized monitoring program to assess Zevalin biodistribution images, FDA Oncologic Drugs Advisory Committee Chair Stacy Nerenstone, MD, Helen & Harry Gray Cancer Center, suggested during the Sept. 11 review of the radioimmunotherapy.

Several committee members agreed that the biodistribution images called for as a part of the Zevalin (ibritumomab tiuxetan) regimen would be useful in assessing cumulative doses for future radiotherapy.

"But," Nerenstone said, "someone has to be keeping a record of what's going on because...if nobody is looking at these results in a centralized way, we're not going to have any idea at the end of the day what to do."

The committee recommended approval of Zevalin for use in non-Hodgkin's lymphoma patients who are refractory to Idec/Genentech's Rituxan (rituximab).

The committee also suggested that an accelerated approval could be appropriate for use in patients who have not failed Rituxan (¹ Also see "Idec Zevalin Clears Cmte.: Non-Refractory Use May Be Accelerated Approval" - Pink Sheet, 17 September, 2001.).

The proposed Zevalin regimen consists of administration of 250 mg/m2 rituximab, immediately followed by indium-111 labeled Zevalin for imaging. Seven to nine days after the imaging dose, patients receive 250 mg/m2 Rituxan followed by .4 mCi/kg yttrium-90 labeled Zevalin for therapy.

Idec modified the Zevalin regimen to include the imaging step after FDA requested the change in a "complete review" letter in May (² Also see "Idec Zevalin" - Pink Sheet, 14 May, 2001.).

"Biodistribution of the indium-labeled antibodies is assessed by obtaining [gamma camera] images at 2-24 hours, 48-72 [hours], with an optional third image at 90-120 hours," Idec VP-Medical Affairs Christine White, MD, explained.

Committee Chair Nerenstone suggested "central monitoring of these images to know at what point it's no longer needed," noting that the cost and complexity of imaging could be significant. "We're not allowed to consider cost in our evaluation, but certainly we can look at difficulty in giving this medication, especially with imaging."

Center for Biologics Evaluation & Research Division of Clinical Trial Design & Analysis Acting Branch Chief George Mills pointed out that although "we've had a lot of multi-center experience" with Zevalin, "we've not gotten out into community hospitals and part of the concern we have...is that the ability to prepare the indium label" may be more challenging in a community setting.

The purpose of the imaging step is to provide "a visual evaluation of the Zevalin biodistribution," Idec Director-Oncology Bryan Leigh, MD, explained.

"We've been asked by the FDA to include this as a safety measure that may detect unexpected areas of high radioactivity uptake that may indicate that the patients [should] not proceed to the yttrium-labeled Zevalin," Leigh said.

Zevalin labeling will include criteria for evaluating the biodistribution images, Idec's White said.

"Potential things that might indicate that the patient should not proceed with treatment might be if the blood pool is not visualized on the first image...[which] may indicate the patient has an unknown [human-antimouse antibody] causing rapid clearance," Leigh said.

In addition, "if there was increased uptake in [the] kidneys or bladder, it may identify urinary tract obstruction."

Altered biodistribution was not observed during the Zevalin clinical trials, causing several committee members to question the necessity of retaining the imaging step in clinical practice.

"I think it was a really good thing to [assess biodistribution] in the initial studies, and dosimetry was useful," committee consultant Edward Sausville, MD, National Cancer Institute, said. "It's just that one would have to carefully consider what level of complexity it adds to actual use potentially."

Currently, there is inadequate safety data in patients who received Rituxan alone without radiolabeled material to support deletion of the biodistribution assessment, FDA said. The agency asked the committee for advice on what data could be collected to support eliminating the imaging step.

"My suggestion is that you convene a group, a panel of imaging experts who are used to looking at dosimetry," Nerenstone said.

She suggested the panel could recommend limits on acceptable levels of abnormal biodistribution for future studies involving radioimmunotherapies. "This is going to be a concern of more than just one application," Nerenstone noted.

Idec's White said that the company "would be prepared to further collect data on imaging as time went on to see how useful it is as we get into a larger and larger patient population."

During the Zevalin studies, the "radiation-absorbed dose to normal organs was acceptable in all patients," White said. "There was no correlation between hematologic toxicity and dosimetry parameters or pharmacokinetic parameters."

However, several committee members recommended additional study of the level of 90-yttrium radiation being absorbed by patients' organs, especially the testes, which had a median radiation absorbed dose of 950 cGy.

White noted that in response to this concern, "some of [Idec's] planned and newly-begun investigator-initiated IND trials [will] look at baseline sperm counts and androgen levels and look again after Zevalin to see if there are any biological effect."

Idec plans to market Zevalin in two kits: an imaging kit for use with indium and a therapeutic kit for use with yttrium. "The kit components include ibritumomab tiuxetan, a 50 mM sodium acetate solution, formulation buffer and a reaction vial," FDA Product Reviewer Marjorie Shapiro, PhD, said.

"There are some outstanding manufacturing issues that need to be resolved," Shapiro noted.

Idec said its manufacturing facilities require pre-approval inspections, which it anticipates will be complete prior to approval; the user fee action date for Zevalin is Jan. 8.

"It strikes me that if you're taking a radioactive isotope from one vendor and a monoclonal antibody from Idec, getting these to places that may not be as experienced as your investigative sites represents a challenge for stability as well as preparation," committee member Douglas Blayney, MD, Wilshire Oncology Medical Group, suggested.

A single-point distribution system will be established for shipping the Zevalin kits and the yttrium isotope. A separate order will need to be placed for the indium directly from an approved source.

Both radiolabeled forms of Zevalin will be compounded - about a five minute process - on-site at the nuclear pharmacy.

Idec has experience with 533 radioincorporations, "and 98% of the doses...exceeded the 95% release specification," White said. Zevalin remains "stable for eight hours after it is radioincorporated and that is, of course, within the timeframe it would be used."

The committee questioned how patients' prior external beam radiation therapy might affect their treatment with Zevalin.

"We feel that there is inadequate data to assess the safety of additive localize radiation effects on external beam radiation therapy and Zevalin therapy," FDA Medical Reviewer Phillippe Bishop, MD, said.

"With regard to patients who have had previous external beam radiation therapy, our only guideline, which would be in the package insert, would be not to include patients who have had radiation therapy for more than 25% of their active marrow," White said.

"With regard to soft-tissue radiation therapy, we will include in the package insert an actual table of the mean, median and also the range of radiation absorbed doses...so that a patient that received external beam could have his radiation oncologist be aware of that information."

One other issue that Idec will need to resolve relates to patent rights surrounding radioimmunotherapy. The company is in litigation with Corixa and partner GlaxoSmithKline over patents infringement (³ Also see "Idec, GSK, Corixa Discussing Licensing Of Radioimmunotherapy Patents" - Pink Sheet, 24 September, 2001.).

Idec Zevalin May Need Central Monitoring Of Bio-Images, FDA Cmte. Suggests

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