As the first step toward putting together designs for drug trials in children, the FDA's Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee (ODAC) questioned Abbvie Inc. about the epidermal growth factor receptor (EGFR) inhibitor ABT-414, an antibody-drug conjugate for glioblastoma multiforme (GBM), and sought input from Eisai Inc. regarding Lenvima (lenvatinib), the vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) inhibitor that was approved by the FDA in February for differentiated thyroid cancer.

It was not a voting meeting, but one to help developers understand the concerns of U.S. regulators with regard to pediatric studies, so that both sides know better how the experiments might be put together.

ODAC panelists liked North Chicago-based Abbvie's plan to conduct a "nested" phase I trial, including the pediatric patients in an experiment testing ABT-414 in adults, but advised against adding temozolomide to the kids' drug regimen and recommended careful monitoring of ocular toxicity with the compound, which pairs monoclonal antibody depatuxizumab with chemotherapy monomethyl auristatin phenylalanine.

Abbvie, last Saturday at the annual Scientific Meeting and Education Day of the Society for Neuro-Oncology in Miami, disclosed interim results from a phase I trial with ABT-414 in patients with GBM showing that in those with measurable disease and EGFR amplification, four of 12 patients (33 percent) achieved an objective response, including two with complete responses. Results were presented from a three-arm trial that evaluated ABT-414 as a monotherapy, in combination with chemo, or in combination with radiation and chemo.

But common adverse events in all three arms included fatigue, blurred vision, nausea, photophobia, constipation, increased aspartate aminotransferase, increased alanine aminotransferase, keratitis, thrombocytopenia, dry eye, eye pain and foreign-body sensation in the eye. Among the grade 3/4 adverse events were keratitis, lymphopenia and thrombocytopenia. Dose-limiting toxicities occurred at multiple doses and affected the eye (in the form of keratitis) and liver, Abbvie said.

At the panel meeting, consumer representative Pamela Havlock wanted to know about the overall treatment plan for pediatrics, as well as how the "expectations of family" would be handled, and any "supportive care that happens between doses" for the young patients, given the side effects they could face.

Kyle Holen, senior project leader in oncology development for Abbvie, said the company "envisions[s] treating children similar to how adults are treated. They would stay on treatment for as long as the patient may be benefiting. If there aren't severe toxicities and it seems like the tumor's under control, then they can stay on treatment until the point where the patient, family or investigator decides it's no longer of benefit. Hopefully that would be a long time." Giving aid to the at-home caregivers, he said, "is not something we've spent enough time on, but I think we need to develop educational and support material specifically for families – information about how to administer eye drops in children, things like that. We have a couple of ophthalmologists we've talked to, and I think they may be of help." Questioned further about heading off problems caused by treatment, he said, "The only thing we do as a prophylactic measure is the steroid eye drops. We have not recommended routine anti-emetics, because nausea although it's reported in our studies hasn't been a significant problem, and oftentimes it's hard to tease out if that's from the disease or from the drug."

WHAT'S THE TARGET, AGAIN?

Deborah Armstrong, professor of oncology at the Johns Hopkins University School of Medicine in Baltimore, suggested "a little more lax eligibility criteria" in the pediatric trial, allowing for maybe two prior chemo therapies in those subjects rather than one as in the adult population tested, maybe with more-stringent performance status criteria making up for it. "I just think it would be a cleaner study," she said. "You might capture more patients."

Holen said Abbvie "want[s] to be as flexible and open as possible with our eligibility criteria, because of the rarity of this diagnosis – EGFR amplification. We don't want to lose patients just because they happen to have only one prior therapy, or three prior or more. So we've eliminated any mention of prior therapies from our eligibility. We've in fact even eliminated performance status. We may get more variety, in terms of the population [that is] under study, but I think we can adequately assess ABT-414 toxicity, particularly because the toxicity is so unique," with the ocular toxicity being the only dose-limiting effect, he said.

Other ideas involved keeping track of pharmacokinetics so that pediatrics would not be underdosed, which was seen as more of a possibility than overdosing. The main age group to be studied would be 6 to 12, though committee members proposed including children even younger.

In October, a randomized, double-blind, placebo-controlled, parallel assignment, safety/efficacy phase IIb/III study in GBM and gliosarcoma began in the U.S., with plans for Brazil and Mexico. The trial is expected to complete in 2020. Developed by Abbvie with components in-licensed from Greenwich, Conn.-based Life Science Pharmaceuticals Inc. and Seattle Genetics Inc., of Bothell, Wash., ABT-414 is also in trials for squamous cell tumors, including non-small-cell lung cancer.

Taken up in the second part of the meeting, tyrosine kinase inhibitor (TKI) Lenvima also is in the works for renal cell carcinoma, and the FDA has granted breakthrough therapy designation. Dimitris Voliotis, vice president of clinical research in oncology for Woodcliff Lake, N.J.-based Eisai, walked panelists through the available data and fielded questions from the subcommittee.

Toxicity worries had to do with bone-growth abnormalities, the thyroid gland and heart function, along with gastrointestinal effects and weight loss. Voliotis said he couldn't comment on possible effects in children since no data are available, but he spoke about the diarrhea side effect. "We did not have to discontinue a single patient in the trial with monotherapy in thyroid cancer," he said. "With the appropriate dose management, we were able to keep patients on study drug. The same effect we also saw in the combination trial [a phase II renal cell cancer experiment adding the mammalian target of rapamycin inhibitor Afinitor (everolimus, Novartis AG)]. We had about 19-20 percent grade 3 diarrhea, and only one patient had to be discontinued permanently," and "once patients get back on drug, we were able to keep them on drug," he said.

Mark Kieran, director of pediatric neuro-oncology at the Dana-Farber Cancer Institute and Boston Children's Hospital, said he was "still trying to get my head around exactly what the target is," pointing out that Lenvima "seems to have multiple targets simultaneously [beyond VEGF and FGF]. How does one really know what you're going after, in terms of how one chooses intelligently the right patient to go into this trial?" Voliotis called Kieran's "the million-dollar question. At this point, in the absence of a biomarker, we would simply go after tumor types where it has been shown that those types of drugs have a particular effect," he said, such as thyroid, renal cell and hepatocellular carcinoma. "We are going to further look into tumor types primarily, rather than isolating individual patient populations across different tumor types," he said.

Kieran pressed on, saying he was taken aback also by the relatively benign profile of Lenvima by itself and in the combo trial, since other TKIs as VEGF inhibitors have carried "very significant rates" of severe hypertension and diarrhea, events that "really brought many of those studies to their knees. You compared [Lenvima] to sorafenib [Nexavar, Bayer Healthcare Pharmaceuticals Inc.] We could debate exactly what [Nexavar] is. [But] if you compared [Lenvima] to some of the more traditional targeted small-molecule inhibitors of VEGF, I guess I'm surprised you're not seeing the kinds of toxicities that one would expect, which again raises the question of whether we're sure about the target." The same would be true for Afinitor, used in the combo trial, since ordinarily the drug would bring on hypercholesterolemia, he said. But Voliotis said high cholesterol did, in fact, turn up in the combo trial as researchers anticipated. "I think, at the end of the day, [the differences] really depend on the particular on-target profile" of Lenvima, he said. "This is a unique drug, in that it targets VEGF and FGF in a way that other TKIs like sorafenib don't do."