title: 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.affiliation: aDepartment of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas bDivision of Hematology/Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA cDermatology Polyclinic, Saint Louis Hospital, Paris dDepartment of Dermatology, Aix-Marseille University, Marseille, France eDepartment of Dermatology, University Medical Centre, Tubingen, Germany.
authors.forename: Agop Y
authors.initials: AY
authors.lastname: Bedikian
authors.forename: Claus
authors.initials: C
authors.lastname: Garbe
authors.forename: Robert
authors.initials: R
authors.lastname: Conry
authors.forename: Celeste
authors.initials: C
authors.lastname: Lebbe
authors.forename: Jean J
authors.initials: JJ
authors.lastname: Grob
mesh_terms: D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003606:Dacarbazine / Q000008:administration & dosage; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008545:Melanoma / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D008875:Middle Aged; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage; D011446:Prospective Studies; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D012878:Skin Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D013873:Thionucleotides / Q000008:administration & dosage; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
chemical_list: D018906:Antineoplastic Agents, Alkylating; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D013873:Thionucleotides; D003606:Dacarbazine; C408162:oblimersen