Include Patients With Brain Tumors in Phase 1 Trials

Fran Lowry

August 24, 2011

August 24, 2011 — Leaders in the field of neuro-oncology have joined forces to plead for the inclusion of patients with brain tumors in phase 1 trials in oncology.

Led by Patrick Y. Wen, from Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, Massachusetts, the group of 16 brain tumor experts from across the United States claim that, although the inclusion of patients with primary brain tumors in phase 1 studies might modestly increase the complexity of those studies, it would be of benefit to both patients and pharmaceutical companies.

Dr. Patrick Y. Wen

Their article appears in the August 20 issue of the Journal of Clinical Oncology.

"Excluding patients with primary brain tumors from phase 1 studies results in a significant handicap in the identification of drugs that may be particularly active in these tumor types," Dr. Wen and his colleagues write.

The traditional reasons for excluding these patients have become obsolete in this era of targeted therapies, they argue.

Banned for the Wrong Reasons

Patients with brain tumors have been excluded from phase 1 trials for several reasons. For one, these patients were treated with cytochrome P450 enzyme-inducing antiepileptic drugs, such as phenytoin and carbamazepine, which slowed or increased the metabolism of the agents being studied.

This often necessitated a separate phase 1 study for these patients, with dosing that was often 2 to 3 times higher than in patients not receiving enzyme-inducing antiepileptic drugs.

Another reason was the perception that patients with brain tumors were in worse physical condition and had a short life expectancy, and were therefore likely to increase any adverse events associated with the study drug.

Other reasons include the belief that patients with primary brain tumors were at increased risk for brain hemorrhage, that the neurologic signs and symptoms from their tumor would become confused with drug-related neurotoxicity, and that drugs under study might be unable to cross the blood-brain barrier.

Another "unspoken" reason was the discomfort felt by some oncologists with regard to caring for patients with primary brain tumors.

Most of these reasons for excluding patients with brain tumors from phase 1 trials are no longer valid, the authors state.

"The trend is to move towards doing trials based on molecular targets. If you are doing that, there's no reason to exclude brain tumors if they have the molecular target and the drug gets in," Dr. Wen told Medscape Medical News. "Many years ago people thought brain tumors were a completely different category of tumors with a lot of complexity and many of those issues really don’t exist anymore."

Losing the fear of including patients with brain tumors in phase 1 trials will lead to faster development of more effective therapies for brain tumor patients, Dr. Wen said.

He also pointed out that brain metastases are an important problem in many cancers. "Pharmaceutical companies do care about brain metastases from melanoma, HER2 breast cancer, and other cancers. Getting more experience with their drugs in patients with various types of brain tumors is to the advantage of everybody, to the patients and to the companies."

Kudos for the Authors

"I applaud them for what they say," David Korones, MD, professor of pediatrics, oncology and neurology at the James P. Wilmot Cancer Center, University of Rochester Medical Center, New York, told Medscape Medical News.

Dr. David Korones

"There is significance to this article for a number of reasons. One is the specific issue they address, which is that patients with brain tumors should have the same availability of phase 1 trials as anybody else with cancer," Dr. Korones said. "They also bring out a broader issue, which is that patients with brain tumors need to be brought into the mainstream of oncology."

Historically, patients with brain tumors have not been a part of mainstream oncology because their treatment generally consisted of radiology and surgery.

"Chemotherapy wasn’t used that much, and perhaps as a consequence, oncologists in general don’t feel comfortable taking care of patients with brain tumors. I think this is just a bias, through nobody’s fault, but more through a fault of the system," he said.

The objections to the inclusion of patients with brain tumors in phase 1 trials are based on false premises, Dr. Korones said.

Brain Tumor Patients Are Not Weaker

"Patients with brain tumors are not sicker than patients with other types of cancer. Certainly, they can get quite sick, and can get complications that patients with other types of tumors do not, but there are patients with other types of tumors that get complications that people with brain tumors wouldn’t. Also, as the authors point out, many patients with brain tumors are younger and otherwise healthier, so to say that they’re a more fragile population is not true," he said.

The issue of seizure drugs interfering with study drugs is no longer valid, Dr. Korones pointed out. "There are new seizure drugs that do not interfere with chemotherapy, so that is just not an issue any more."

Also, study after study shows that patients with brain tumors are not at increased risk of bleeding in their brain.

The one legitimate reason to consider exclusion of patients with brain tumors is if the phase 1 study is investigating a drug that clearly does not cross the blood-brain barrier.

"In that case it might make sense to consider them in a different category, but as the authors point out, even that is not a sure thing because sometimes we think things don’t get across the blood-brain barrier, and yet they work," Dr. Korones said.

Phase 1 Data Important

The goal of a phase 1 study is to determine the highest and safest dose of a new drug. But often, such a trial will also yield important preliminary data, Dr. Korones said.

"There is the example of temozolomide, as the authors cite in their article. The phase 1 trials of this drug included patients with all types of cancer, including brain tumors. They achieved their objective of finding the right dose, but in so doing, they noticed that the handful of patients with brain tumors actually did better than anyone believed. So they studied it further and found that it was quite effective in brain tumor patients. If those patients had been excluded, that would never have happened and we wouldn’t have discovered the utility of temozolomide for brain tumors," he noted.

Dr. Wen and Dr. Korones have reported no relevant financial relationships. The other authors of the article report financial relationships with the following: Pharmacyclics, Roche, Amgen, Merck, sanofi-aventis, Allergan, Epizyme, PharmaMar, GlaxoSmithKline, Peregrine Pharmaceuticals, Onyx Pharmaceuticals, Genentech, TomoTherapy, Novartis, Diffusion Pharmaceuticals, Tau Pharmaceuticals, Medimmune, Gilead, Human Genome Sciences, Exelixis, Rigel Pharmaceuticals, Seattle Genetics, Agios, Eli Lilly, Pfizer, Millenium, Schering-Plough, Daiichi.

J Clin Oncol. 2011;29:3211-3213. Full text


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