Dacarbazine with or without oblimersen (a Bcl-2 antisense oligonucleotide) in chemotherapy-naive patients with advanced melanoma and low-normal serum lactate dehydrogenase: 'The AGENDA trial'.

Abstract

In a previous large randomized, open-label study, retrospective subset analysis revealed that the addition of the Bcl-2 antisense oligonucleotide oblimersen to dacarbazine (Dac) significantly improved overall survival, progression-free survival, and the response rate in chemotherapy-naive patients with advanced melanoma and normal baseline serum lactate dehydrogenase (LDH) levels. To confirm and expand on this observation, we conducted a prospective double-blind, placebo-controlled study to determine whether oblimersen augmented the efficacy of Dac in advanced melanoma patients with low-normal baseline LDH levels. A total of 314 chemotherapy-naive patients were randomly assigned to receive Dac (1000 mg/m(2)) preceded by a 5-day continuous intravenous infusion of either oblimersen sodium (7 mg/kg/day) or placebo every 21 days for less than eight cycles. Co-primary efficacy endpoints were overall survival and progression-free survival. Response and progression of the disease were assessed by independent blinded review of computed tomography scan images. No difference in overall nor progression-free survival was observed between the Dac-oblimersen and Dac-placebo groups. Although the overall (17.2 vs. 12.1%) and durable (10.8 vs. 7.6%) response rates numerically favored Dac-oblimersen over Dac-placebo, they did not differ significantly (P=0.19 and 0.32, respectively). The incidence of hematologic adverse events, particularly thrombocytopenia and neutropenia, was higher in the Dac-oblimersen group than in the Dac-placebo group. Withdrawals from the study because of treatment-related adverse events were low (i.e. <2.5%) in both groups. The addition of oblimersen to Dac did not significantly improve overall survival nor progression-free survival in patients with advanced melanoma and low-normal levels of LDH at baseline.

• Authors: Agop Y Bedikian, Claus Garbe, Robert Conry, Celeste Lebbe, Jean J Grob, Genasense Melanoma Study Group
• Journal: Melanoma research (Melanoma Res) Vol. 24 Issue 3 Pg. 237-43 (Jun 2014) ISSN: 1473-5636 [Electronic] England
• PMID: 24667300 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Antineoplastic Agents, Alkylating
• Oligonucleotides, Antisense
• Proto-Oncogene Proteins c-bcl-2
• Thionucleotides
• Dacarbazine
• oblimersen

Topics

• Aged
• Antineoplastic Agents, Alkylating (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Dacarbazine (administration & dosage)
• Disease-Free Survival
• Double-Blind Method
• Drug Administration Schedule
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Infusions, Intravenous
• Male
• Melanoma (diagnostic imaging, drug therapy, genetics, metabolism, mortality)
• Middle Aged
• Oligonucleotides, Antisense (administration & dosage)
• Prospective Studies
• Proto-Oncogene Proteins c-bcl-2 (genetics)
• Skin Neoplasms (diagnostic imaging, drug therapy, genetics, mortality)
• Thionucleotides (administration & dosage)
• Time Factors
• Tomography, X-Ray Computed
• Treatment Outcome