Thalidomide Studied in a Variety of Cancers and Metabolic Disorders

April 1, 2001

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

At the Chemotherapy Foundation Symposium XVIIIin New York City, researchers from the ArkansasCancer Research Center, Cedars-Sinai Medical Center, M. D. Anderson, and theNational Cancer Institute presented updated clinical trial data on the safetyand potential activity of thalidomide (Thalomid) in the treatment of a varietyof cancers and immune disorders. According to the published abstracts, the datawere consistent with previously published results on the potential activity ofthalidomide in hematologic cancers such as multiple myeloma and solid-tumorcancers such as colorectal cancer and prostate cancer.

The session on angiogenesis treatments included discussionsrelating to the use of thalidomide in the treatment of multiple myeloma, primaryamyloidosis, colorectal cancer, and acute myeloid leukemia. Bart Barlogie, MD,PhD, director of the Arkansas Cancer Research Center, evaluated the potentialuse of thalidomide as a single agent and as part of combination chemotherapy forpatients with multiple myeloma.

As a single agent, thalidomide was found to induce greater than25% reductions in paraproteins with concurrent improvements in bone marrowhistology 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 rateat 18 months, with a 30% event-free survival. "These results in multiplemyeloma are consistent with the clinical results we have observedpreviously," said Dr. Barlogie. Major side effects seen were constipation,weakness, somnolence, and tingling/numbness in 10% of patients who received a400-mg dose of thalidomide.

In addition to the single-agent study, Dr. Barlogie discussed anongoing investigation of thalidomide as part of several combination therapyregimens for multiple myeloma patients. According to Dr. Barlogie, more than 300patients have been enrolled in these clinical investigations.

Potential Use in Primary Amyloidosis

Dr. James Berenson of Cedars-Sinai Medical Center is leading theresearch on the potential activity of thalidomide in patients with primaryamyloidosis. Primary amyloidosis affects about 2,000 new adult patients annuallyand approximately 10% of patients who have multiple myeloma develop amyloidosis.

Dr. Berenson’s team treated six patients with primaryamyloidosis and renal organ involvement for 3 to 7 months with escalating dosesof thalidomide (100 to 400 mg). In addition to thalidomide, oral steroids(either prednisone or dexamethasone) were administered to four patients.

Marked improvement was seen in five patients, including recoveryof macroglossia with speech impairment, joint symptoms, and gastrointestinalproblems, and four patients also experienced improved renal involvement withmarked decrease in edema and reduction or discontinuation of diuretic use.Therapy with the combination of thalidomide and a steroid continues in fourpatients.

Side effects observed included somnolence (n = 4), numbness andparesthesias (n = 3), tremor and rash (n = l), and constipation (n = 1). Dr.Berenson’s group suggested that this preliminary research points to thepotential activity of thalidomide in combination with steroids, in patients withprimary amyloidosis.

Metastatic Colorectal Cancer

Dr. Rangaswamy Govindarajan, assistant professor of medicine atthe University of Arkansas for Medical Sciences, evaluated the combination ofthalidomide with irinotecan (CPT-11, Camptosar) in metastatic colorectal cancer.Of 17 patients currently enrolled in the trial, 11 experienced a reduction insevere (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, andgrade 2 bradycardia in 18%, 9%, and 9% of the patients, respectively. A phase IItrial is currently ongoing.

Acute Myeloid Leukemia

Dr. Jorge Cortes of M. D. Anderson Cancer Center initiated atrial to assess the impact of angiogenesis inhibiting agents in combination withchemotherapy for acute myeloid leukemia. Acute myeloid leukemia is associatedwith elevated levels of vascular endothelial growth factor (VEGF) plasma levels,increased expression of VEGF receptors, and significant increase in bone marrowvascularity.

Dr. Cortes reported on a trial evaluating thalidomide incombination chemotherapy treatment with cytarabine and liposomal daunorubicinfor patients with refractory acute myeloid leukemia. Of nine patients, threeexperienced a transient decrease in blasts, and one had a complete response.Based on these results, Dr. Cortes’ group suggested that additional studiesare warranted.

"On the basis of these trials, we plan to continue ourextensive clinical study program to evaluate the potential role of thalidomidein cancers," said Sol J. Barer, PhD, president and COO of CelgeneCorporation.

Androgen-Independent Prostate Cancer

As part of the session on prostate cancer, Dr. William Figg ofthe National Cancer Institute presented data on an open-label randomized trialevaluating the effects of thalidomide treatment in 63 patients withandrogen-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 200mg/d, escalating to 1,200 mg/d).

A reduction in prostate-specific antigen (PSA) was reported in58% 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 onbone scan criteria, two patients in the low-dose arm also had a partialresponse. Dr. Figg’s group said that these data may suggest that thalidomideaffects PSA levels and may also have an impact on tumor metabolism and metabolicvolume as measured by positron-emission tomography scan.

Among the side effects seen were symptoms of peripheralneuropathy in four patients receiving thalidomide for more than 9 months.Constipation and fatigue were also observed. Dr. Figg’s group is currentlyconducting two phase II trials to assess the effects of thalidomide incombination chemotherapy for patients with prostate cancer.