A phase I study of thalidomide, capecitabine and temozolomide in advanced cancer

Aim: To develop a novel oral antiangiogenic and immunomodulatory chemotherapy regimen against advanced cancers. Methods: Patients were enrolled in cohorts of three or six in a standard phase I design. Thalidomide 100 mg was kept stable for all cohorts. If well tolerated after one week, capecitabine and temozolomide (TCT) fixed-dose were given daily without rest and escalated one at a time until dose limiting toxicity (DLT) occurred. If no DLT occurred within 28 days (1 cycle), the subsequent group was enrolled into the next dose level. Results: Twenty-three adult patients with objective documentation of progressive metastatic cancer after a median of two therapies (range 0-4) received TCT in this study. Based on DLT within the first 28 days, the MTD of daily TCT therapy was thalidomide 100 mg, capecitabine 2000 mg and temozolomide 100 mg. With long-term treatment, majority of the patients required dose interruptions due to fatigue, hand-foot syndrome, and neutropenia. A dose level consisting of daily thalidomide and three-weeks-on one-week-off capecitabine and temozolomide was implemented and administered to six patients without DLT. Out of 23 subjects, four (17%) achieved a partial response (renal, gastric, prostate 2), and four patients (17%) had stable disease (renal, colon, pancreas 2), adding to a clinical benefit of 34%. Conclusions: TCT is an effective palliative oral chemo-immunotherapy for patients with advanced cancer. The recommended dose for phase II trial is thalidomide 100 mg daily without a break, capecitabine 2000 mg and temozolomide 100 mg daily three-weeks-on and one-week-off.