[G3139 -- PII with dexamethasone & thalidomide in relapsed MM]
>>JCO Early Release, published online ahead of print May 2 2005
Journal of Clinical Oncology, 10.1200/JCO.2005.14.381 This Article
Received January 31, 2005
Accepted March 16, 2005
Phase II Study of G3139, a Bcl-2 Antisense Oligonucleotide, in Combination With Dexamethasone and Thalidomide in Relapsed Multiple Myeloma Patients
Ashraf Z. Badros *, Olga Goloubeva , Aaron P. Rapoport , Bashi Ratterree , Natalie Gahres , Barry Meisenberg , Naoko Takebe , Meyer Heyman , James Zwiebel , Howard Streicher , Christopher D. Gocke , Dragana Tomic , Jodi A. Flaws , Bin Zhang , and Robert G. Fenton
From the Greenebaum Cancer Center and Departments of Pathology and Epidemiology and Preventive Medicine, University of Maryland, Baltimore; and Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD.
* To whom correspondence should be addressed. E-mail: abadros@umm.edu
Purpose: Bcl-2 regulates the mitochondrial apoptosis pathway that promotes chemotherapy resistance. Bcl-2 antisense oligonucleotide, G3139, targets Bcl-2 mRNA.
Patients and Methods: G3139 was administered (3 to 7 mg/kg/d for 7 days) by continuous intravenous infusion. On day 4, patients started thalidomide (100 to 400 mg as tolerated) and dexamethasone (40 mg daily for 4 days) on 21-day cycles for three cycles. Stable and responding patients continued on 35-day cycles for 2 years.
Results: Thirty-three patients (median age, 60 years; range, 28 to 76 years) received 220 cycles. Patients received a median of three prior regimens including thalidomide (n = 15) and stem-cell transplantation (n = 31). The regimen was well tolerated; the median number of cycles per patient was eight (range, one to 16+ cycles). Toxicities included reversible increase in creatinine, thrombocytopenia, neutropenia, fatigue, anorexia, constipation, fever, neuropathy, edema, electrolyte disturbances, and hyperglycemia. Fifty-five percent of patients had objective responses, including two complete responses (CRs), four near CRs (positive immunofixation), and 12 partial responses; six patients had minimal responses (MRs). Of patients who received prior thalidomide, seven had objective responses, and three had MRs. The median duration of response was 13 months, and estimated progression-free and overall survival times were 12 and 17.4 months, respectively. Responding patients had significant increase in polyclonal immunoglobulin M (P = .005), indicating innate immune system activation. Western blot analysis of Bcl-2 protein isolated from myeloma cells before and after G3139 demonstrated a decrease of Bcl-2 levels in three of seven patients compared with six of nine patients using reverse transcriptase polymerase chain reaction.
Conclusion: G3139, dexamethasone, and thalidomide are well tolerated and result in encouraging clinical responses in relapsed multiple myeloma patients.<<
Not sure if this combo beats others. Thalidomide is coming under renewed scrutiny, too.
Cheers, Tuck |
