At the Chemotherapy Foundation Symposium XVIII in New York City, researchers from the Arkansas Cancer Research Center, Cedars-Sinai Medical Center, M. D. Anderson, and the National Cancer Institute presented updated clinical trial data on the safety and potential activity of thalidomide(Drug information on thalidomide) (Thalomid) in the treatment of a variety of cancers and immune disorders. According to the published abstracts, the data were consistent with previously published results on the potential activity of thalidomide in hematologic cancers such as multiple myeloma and solid-tumor cancers such as colorectal cancer and prostate cancer.
The session on angiogenesis treatments included discussions relating to the use of thalidomide in the treatment of multiple myeloma, primary amyloidosis, colorectal cancer, and acute myeloid leukemia. Bart Barlogie, MD, PhD, director of the Arkansas Cancer Research Center, evaluated the potential use of thalidomide as a single agent and as part of combination chemotherapy for patients with multiple myeloma.
As a single agent, thalidomide was found to induce greater than 25% reductions in paraproteins with concurrent improvements in bone marrow histology in as much as one-third of patients with refractory disease. Moreover, in this high-risk patient group, there was a 55% overall patient survival rate at 18 months, with a 30% event-free survival. "These results in multiple myeloma are consistent with the clinical results we have observed previously," said Dr. Barlogie. Major side effects seen were constipation, weakness, somnolence, and tingling/numbness in 10% of patients who received a 400-mg dose of thalidomide.
In addition to the single-agent study, Dr. Barlogie discussed an ongoing investigation of thalidomide as part of several combination therapy regimens for multiple myeloma patients. According to Dr. Barlogie, more than 300 patients have been enrolled in these clinical investigations.
Potential Use in Primary Amyloidosis
Dr. James Berenson of Cedars-Sinai Medical Center is leading the research on the potential activity of thalidomide in patients with primary amyloidosis. Primary amyloidosis affects about 2,000 new adult patients annually and approximately 10% of patients who have multiple myeloma develop amyloidosis.
Dr. Berenson’s team treated six patients with primary amyloidosis and renal organ involvement for 3 to 7 months with escalating doses of thalidomide (100 to 400 mg). In addition to thalidomide, oral steroids (either prednisone or dexamethasone(Drug information on dexamethasone)) were administered to four patients.
Marked improvement was seen in five patients, including recovery of macroglossia with speech impairment, joint symptoms, and gastrointestinal problems, and four patients also experienced improved renal involvement with marked decrease in edema and reduction or discontinuation of diuretic use. Therapy with the combination of thalidomide and a steroid continues in four patients.
Side effects observed included somnolence (n = 4), numbness and paresthesias (n = 3), tremor and rash (n = l), and constipation (n = 1). Dr. Berenson’s group suggested that this preliminary research points to the potential activity of thalidomide in combination with steroids, in patients with primary amyloidosis.
Metastatic Colorectal Cancer
Dr. Rangaswamy Govindarajan, assistant professor of medicine at the University of Arkansas for Medical Sciences, evaluated the combination of thalidomide with irinotecan(Drug information on irinotecan) (CPT-11, Camptosar) in metastatic colorectal cancer. Of 17 patients currently enrolled in the trial, 11 experienced a reduction in severe (grade 3 to 4) gastrointestinal side effects (ie, nausea, vomiting, diarrhea, abdominal pain) generally associated with irinotecan treatment. Significant side effects included grade 3 constipation, grade 3 skin rash, and grade 2 bradycardia in 18%, 9%, and 9% of the patients, respectively. A phase II trial is currently ongoing.
Acute Myeloid Leukemia
Dr. Jorge Cortes of M. D. Anderson Cancer Center initiated a trial to assess the impact of angiogenesis inhibiting agents in combination with chemotherapy for acute myeloid leukemia. Acute myeloid leukemia is associated with elevated levels of vascular endothelial growth factor (VEGF) plasma levels, increased expression of VEGF receptors, and significant increase in bone marrow vascularity.
Dr. Cortes reported on a trial evaluating thalidomide in combination chemotherapy treatment with cytarabine and liposomal daunorubicin(Drug information on daunorubicin) for patients with refractory acute myeloid leukemia. Of nine patients, three experienced a transient decrease in blasts, and one had a complete response. Based on these results, Dr. Cortes’ group suggested that additional studies are warranted.
"On the basis of these trials, we plan to continue our extensive clinical study program to evaluate the potential role of thalidomide in cancers," said Sol J. Barer, PhD, president and COO of Celgene Corporation.
Androgen-Independent Prostate Cancer
As part of the session on prostate cancer, Dr. William Figg of the National Cancer Institute presented data on an open-label randomized trial evaluating the effects of thalidomide treatment in 63 patients with androgen-independent prostate cancer. Patients were randomized to a low-dose arm (50 patients taking 200 mg/d) or a high-dose arm (13 patients started at 200 mg/d, escalating to 1,200 mg/d).
A reduction in prostate-specific antigen (PSA) was reported in 58% of patients in the low-dose arm and 68% of patients in the high-dose arm, while 18% of patients in the low-dose arm had a 50% reduction in PSA. Based on bone scan criteria, two patients in the low-dose arm also had a partial response. Dr. Figg’s group said that these data may suggest that thalidomide affects PSA levels and may also have an impact on tumor metabolism and metabolic volume as measured by positron-emission tomography scan.
Among the side effects seen were symptoms of peripheral neuropathy in four patients receiving thalidomide for more than 9 months. Constipation and fatigue were also observed. Dr. Figg’s group is currently conducting two phase II trials to assess the effects of thalidomide in combination chemotherapy for patients with prostate cancer.