my personal edition > oncology other > news


  E-Mail this DGDispatch to a colleague

DGDispatch

Thalidomide + Celecoxib May Enhance Irinotecan's Antitumour Activity: Presented at AACR-NCI-EORTC

By Paula Moyer

BOSTON, MA -- November 24, 2003 -- Added to irinotecan, a combination of thalidomide and celecoxib is well tolerated, and may enhance the inhibition of nuclear factor-kappaB (NF-kappaB), according to findings presented here November 19^th at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.

"The findings warrant further study," said Kevin G. Panico, MD, clinical oncology fellow, Arthur G. James Comprehensive Cancer Hospital and Research Institute, Ohio State University, Columbus, United States. "We want to confirm the validity of this combination of therapy."

NF-kappaB is a transcription factor that prior research says plays a role in the development of resistance to irinotecan. The investigators were interested in the thalidomide and celecoxib combination because thalidomide and cyclooxygenase-2 (COX-2) inhibitors had been shown reduce NF-kappaB activation. Therefore, the investigators wanted to see if the combination could increase the efficacy of irinotecan.

In this phase I trial, 36 patients with various solid tumours first received treatment with irinotecan and thalidomide, and then afterward with a treatment that added celecoxib to the cocktail. The irinotecan dosage consisted of 125 mg/m² on Days 1 and 8 every 3 weeks. The patients received thalidomide at 2 different doses, with 11 patients at a dose of 200 mg/daily and 13 patients at a dose of 400 mg/daily. In the second part of the study, 12 patients received treatment consisting of irinotecan, thalidomide 400 mg, and celecoxib, 400 mg twice daily.

To evaluate the pharmacokinetic interactions, the investigators started thalidomide and celecoxib on Day 3 of the treatment cycle. They then measured the pharmacokinetics on Days1-3, 12-14, and 22-24. At this time the investigators also obtained levels of tumour necrosis factor alpha (TNF-alpha), beta-fibroblast growth factor (betaFGF), and NF-kappaB activation in blood mononuclear cells. Patients were restricted from taking CYP450 enzyme-inducing or -inhibiting agents.

In the group of patients receiving 200 mg thalidomide, 6 patients experienced grades 2-3 diarrhoea; 4 patients had grades 3-4 myelosuppression; 4 patients had paresthesias; and 4 patients had fatigue. In the group at 400 mg thalidomide, 3 patients had grades 2-3 diarrhoea; 1 patient had at least grade 3 myelosuppression; 2 patients had paresthesias; and 3 patients had fatigue. The investigators documented 3 episodes of thrombosis, which consisted of 2 cases of pulmonary embolism and 1 of deep venous thrombosis.

The team noted that thalidomide did not affect irinotecan pharmacokinetics either positively or negatively.

Dr. Panico and his co-investigators documented antitumour activity in 2 patients, 1 who had non-small cell lung cancer and the other of whom had cholangiocarcinoma. Prolonged disease stabilisation, for a duration of at least 4 months, occurred in 8 patients. In this patient group, 14 experienced a progression of their disease and 8 patients discontinued during the first course due to either withdrawal of consent or toxicity.

Patients' mean betaFGF and TNF-alpha levels were unchanged from baseline through the first 2 cohorts; however, the investigators observed wide variability in NF-kappaB activation among patients in all groups. NF-kappaB activation changes were higher in non-responding patients in contrast to those who either responded or were stabilised (P = .02).


[Study Title: Phase I and Pharmacobiological Study of Thalidomide and Celecoxib as Modulators of Irinotecan's Anti-Cancer Activity. Abstract B248]

E-Mail this DGDispatch to a colleague

To print, use this version