Panel Recommends Thalidomide Approval For Leprosy, Studies in Cancer Are Reported

BETHESDA, Md—Thalidomide could be increasingly used off-label to treat several cancers and other diseases if the Food and Drug Administration takes the advice of an advisory committee and, for the first time, approves the agent for marketing in the United States.

The FDA’s Dermatologic and Dental Drugs Advisory Committee has recommended that the agency approve thalidomide (manufactured by New Jersey-based Celgene Corporation) for the treatment of erythema nodosum leprosum (ENL) in leprosy patients, with tight restrictions on distribution.

Shortly after the committee’s action, the National Institutes of Health hosted a scheduled two-day conference on thalidomide sponsored by the NIH, the FDA, and the Centers for Disease Control and Prevention. Sessions examined the drug’s history, risks (severe birth defects and peripheral neuropathy), ethical issues, and therapeutic potential in a number of diseases, including four types of malignancies—recurrent high-grade gliomas, metastatic breast cancer, androgen-independent prostate cancer, and Kaposi’s sarcoma (KS).

Resurgence of Interest

Thalidomide was widely prescribed outside the United States in the 1950s and early 1960s for insomnia and morning sickness. It was taken off the market after being identified as a teratogen responsible for 10,000 to 12,000 serious and often fatal birth defects. However, a small group of researchers continued to explore the drug in laboratories in the United States and abroad.

In 1964, Kenneth B. Olson, MD, and his colleagues published findings from an NCI thalidomide study of 21 patients with 14 different cancers. They found no tumor regression, but noted “significant palliation” in seven patients and urged further study, noting that “there was possible arrest of particularly rapid growth of tumor in two cases.”

The current excitement for use in cancer, however, stems from a paper published in 1994, by Robert D’Amato, MD, M. Judah Folkman, MD, and coworkers at Harvard Medical School. This study showed that thalidomide inhibited angiogenesis in a rabbit cornea assay. Given the importance of angiogenesis to tumor growth, “this excited everyone,” commented Said Baidas, MD, assistant professor of medicine, Georgetown University School of Medicine.

“Angiogenesis has become a very attractive new target in cancer,” added Howard A. Fine, MD, director of the neuro-oncology center at the Dana-Farber Cancer Institute. However, any antiangiogenesis drug would need to be taken for long periods, making an oral form highly desirable. Dr. Fine suggested that thalidomide’s excellent oral bioavailability and minimal side effects in most patients make it an appealing candidate for study.

Thalidomide is just emerging as an experimental cancer drug. Four studies reported at the NIH conference found some encouraging early results, but researchers caution that most were too preliminary to draw meaningful conclusions.

High-Grade Gliomas

Dr. Fine reported on a multicenter study of 39 patients with recurrent high-grade gliomas. Thirty-eight were available for toxicity evaluation and 32 for response assessment. “Gliomas are among the most angiogenic tumors,” he said, adding that their “biologic aggressiveness correlates with the degree of microvascularity.”

Patients began on 800 mg of thalidomide daily, moved to 1,000 mg two weeks later, and then to 1,200 mg after another two weeks.

Two of 32 patients had a partial response (reduction greater than 50%). Two others had minimal responses (between 25% and 50% reduction); 12 remained stable for two months or more; 16 progressed. The few responses occurred in patients with small-volume recurrences.

“Something is going on in a subpopulation of these patients,” Dr. Fine said. “Thalidomide does appear to have antiglioma activity; however, we don’t know for a fact that antiangiogenesis is the mechanism.”

Almost all patients experienced some sedation—and six reached grade 3 somnolence—but this improved with time, even as patients moved to higher doses of the drug. Four participants developed grade 1 or 2 anemia; four had grade 1 and one had grade 3 neutropenia. Four patients suffered seizures, not uncommon in brain tumors. Three had had previous episodes, and there was no evidence that any of the seizures resulted from thalidomide use. “The drug was very well tolerated,” Dr. Fine said.

An ongoing phase II study at the National Cancer Institute is examining thalidomide administered for up to 52 week in HIV-infected individuals with cutaneous Kaposi’s sarcoma, a very vascular tumor. Nine patients have been enrolled to date, all male and all with evidence of disease progression in the two months prior to entering the trial. Participants start at 200 mg/day “with escalation every two weeks, as tolerated, to a maximum of 1,000 mg/day,” said Robert Yarchoan, MD, chief of NCI’s HIV and AIDS Malignancy Branch.

No complete responses occurred, and two of the nine patients progressed. However, four patients had partial responses, defined as a greater than 50% decrease in tumor parameters, sustained for at least four weeks. Three patients remained stable; one of these progressed after 26 weeks, but two had not progressed at 42 and 35 weeks, respectively. CD4 counts rose in only one patient, and the NCI researchers saw little neuropathy, “which was quite heartening,” Dr. Yarchoan said.

Another NCI team is evaluating two thalidomide dosing regimens, 200 mg/day vs 1,200 mg/day, in treating androgen-independent prostate cancer. Currently, nine patients (median age, 65) are entered on the low-dose arm and 10 patients (median age, 68) on the high-dose arm. The researchers expect enrollment will reach 28 patients, evenly divided between the two arms, said NCI senior investigator William D. Figg, PharmD.

The group has established that thalidomide itself does not lower prostate-specific antigen (PSA) levels, and, in fact, the drug appears to “upregulate” the antigen. This is an important piece of knowledge, since PSA readings are used in evaluating patient responses to treatments.

Toxicity has been low, with constipation the leading complaint, followed by sedation. “We have not had any grade 4 toxicity and only a couple of grade 3s,” Dr. Figg said.

Dr. Baidas leads a study of thalidomide in metastatic breast cancer at Georgetown that so far has enrolled six patients out of an anticipated 28 participants. Patients will be divided equally into two groups: a low-dose arm receiving 200 mg/day and a high-dose regimen of 800 mg/day escalated up to 1,200 mg/day. No response data are yet available, Dr. Baidas said, but one patient in the high-dose group dropped out of the study after four weeks because of morning dizziness. Constipation is the most common side effect, he said.

As researchers considered the findings reported at the meeting on possible future uses of thalidomide, they also had the words of attorney Frank C. Woodside III, MD, JD, of Dinsmore & Shohl in Cincinnati, to ponder: “There will be birth defects, and there will be lawsuits.”