ORLANDOEncouraging preliminary clinical results have paved the way
for phase II trials of a novel oral therapy for multiple myeloma. The study,
under the leadership of Paul G. Richardson, MD, instructor in medicine, Harvard
Medical School, evaluated the safety and efficacy of the immunomodulatory drug
(IMiD) CC5013, a thalidomide derivative. He presented the findings at the 43rd
annual meeting of the American Society of Hematology (abstract 3225).
Dr. Richardson said that preclinical data showed substantial antiangiogenic
activity and cytokine-related antimyeloma effects for the new agent. CC5013
directly induces apoptosis or G1 growth arrest in myeloma cell line and patient
myeloma cells that are resistant to melphalan (Alkeran), doxorubicin, and
dexamethasone. "In mice treated with the IMiD, there is a marked
prolongation in their survival leading to eradication of the myeloma," Dr.
Richardson said. "Moreover, this agent has a favorable safety profile in
normal human volunteers."
The phase I dose-escalation study enrolled 26 patients at Dana-Farber Cancer
Institute who had relapsed or relapsed, refractory disease. Of these patients,
65% had received prior thalidomide (Thalomid) and 60% had undergone autologous
stem cell transplantation.
At least 3 patients were treated with daily doses of CC5013 at each of four
dose levels ranging from 5 mg to 50 mg daily given for 4 weeks. Patients
tolerating the drug and without disease progression were permitted to continue
on therapy beyond 4 weeks as part of an extension phase for up to 1 year and
beyond. When treatment extended beyond 4 weeks, dose reduction and G-CSF (Neupogen)
support were permitted, Dr. Richardson said.
Median duration of treatment is currently 2 months, and, to date, 11
patients continue to receive treatment.
The results of this pilot study confirmed that CC5013 is active and well
tolerated. Data showed a 25% or greater reduction in paraprotein in 15 of 24
patients (63%) who have received at least 4 weeks of therapy.
"Stable disease or better was noted in 79% of these high-risk patients
who had either relapsed or relapsed and were not responding to other therapies,
Dr. Richardson said. Responses were seen at lower dose levels,
although the majority of responses occurred at doses higher than 5 mg/d and between 25 and 50 mg/d.