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 Gocke, Dragana Tomic, Jodi A. Flaws, Bin Zhang, Robert G. Fenton

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4089-4099
Number of pages11
JournalJournal of Clinical Oncology
Volume23
Issue number18
DOIs
StatePublished - 2005
Externally publishedYes

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Thalidomide
Antisense Oligonucleotides
Multiple Myeloma
Dexamethasone
oblimersen
Myeloma Proteins
Anorexia
Stem Cell Transplantation
Constipation
Neutropenia
Reverse Transcriptase Polymerase Chain Reaction
Intravenous Infusions
Hyperglycemia
Thrombocytopenia
Electrolytes
Disease-Free Survival
Fatigue
Immunoglobulin M
Immune System
Edema

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Phase II study of G3139, a Bcl-2 antisense oligonucleotide, in combination with dexamethasone and thalidomide in relapsed multiple myeloma patients. / Badros, Ashraf Z.; Goloubeva, Olga; Rapoport, Aaron P.; Ratterree, Bashi; Gahres, Natalie; Meisenberg, Barry; Takebe, Naoko; Heyman, Meyer; Zwiebel, James; Streicher, Howard; Gocke, Christopher; Tomic, Dragana; Flaws, Jodi A.; Zhang, Bin; Fenton, Robert G.

In: Journal of Clinical Oncology, Vol. 23, No. 18, 2005, p. 4089-4099.

Research output: Contribution to journalArticle

Badros, AZ, Goloubeva, O, Rapoport, AP, Ratterree, B, Gahres, N, Meisenberg, B, Takebe, N, Heyman, M, Zwiebel, J, Streicher, H, Gocke, C, Tomic, D, Flaws, JA, Zhang, B & Fenton, RG 2005, 'Phase II study of G3139, a Bcl-2 antisense oligonucleotide, in combination with dexamethasone and thalidomide in relapsed multiple myeloma patients', Journal of Clinical Oncology, vol. 23, no. 18, pp. 4089-4099. https://doi.org/10.1200/JCO.2005.14.381
Badros, Ashraf Z. ; Goloubeva, Olga ; Rapoport, Aaron P. ; Ratterree, Bashi ; Gahres, Natalie ; Meisenberg, Barry ; Takebe, Naoko ; Heyman, Meyer ; Zwiebel, James ; Streicher, Howard ; Gocke, Christopher ; Tomic, Dragana ; Flaws, Jodi A. ; Zhang, Bin ; Fenton, Robert G. / Phase II study of G3139, a Bcl-2 antisense oligonucleotide, in combination with dexamethasone and thalidomide in relapsed multiple myeloma patients. In: Journal of Clinical Oncology. 2005 ; Vol. 23, No. 18. pp. 4089-4099.
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abstract = "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.",
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T1 - Phase II study of G3139, a Bcl-2 antisense oligonucleotide, in combination with dexamethasone and thalidomide in relapsed multiple myeloma patients

AU - Badros, Ashraf Z.

AU - Goloubeva, Olga

AU - Rapoport, Aaron P.

AU - Ratterree, Bashi

AU - Gahres, Natalie

AU - Meisenberg, Barry

AU - Takebe, Naoko

AU - Heyman, Meyer

AU - Zwiebel, James

AU - Streicher, Howard

AU - Gocke, Christopher

AU - Tomic, Dragana

AU - Flaws, Jodi A.

AU - Zhang, Bin

AU - Fenton, Robert G.

PY - 2005

Y1 - 2005

N2 - 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.

AB - 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.

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