Abstract PR-1: AGENDA: Results of a randomized, double-blind phase III trial of dacarbazine with or without Bcl-2 targeted therapy (oblimersen) in a biomarker-defined patient population with advanced melanoma
Authors: Lebbe Celeste , Bedikian Agop Y. , Grob Jean-Jacques , Robert Caroline , Dreno Brigitte , Agarwala Sanjiv S. , Garbe Claus 
Published: June 2012

Abstract
Background: Oblimersen (OBL) is an 18-mer phosphorothioate DNA antisense oligonucleotide that targets the first 6 codons of an open reading frame in bcl-2 mRNA. OBL downregulates Bcl-2 protein, increases apoptosis, and enhances the activity of multiple anticancer agents in preclinical models. A randomized trial in patients with advanced melanoma showed OBL plus dacarbazine (DTIC) significantly increased progression-free survival (PFS) plus overall, durable, and complete response rates. Moreover, there was a trend for increased overall survival (OS) (p=0.077). There were no unexpected adverse reactions to OBL. Many of the frequently occurring adverse events with the OBL-DTIC regimen were similar to those commonly associated with DTIC. Further analysis revealed a significant treatment interaction with baseline levels of serum lactate dehydrogenase (LDH), a prospective stratification factor that has been negatively correlated with OS in advanced melanoma. This trial - and an independent analysis of an EORTC study - showed that this negative correlation extended into the upper limit of the normal range (ULN). Patients with low-normal LDH (≤0.8 × ULN) had distinctly superior survival when OBL was added to DTIC, compared with patients who received DTIC alone (median 12.3 vs. 9.9 months, respectively; p&lt;0.001; hazard ratio=0.64). We have now completed a new trial (AGENDA) that employed the LDH biomarker to confirm that finding using this highly targeted therapy.
Methods: Inclusion criteria in this phase 3 multinational study included: no prior chemotherapy; measurable disease; LDH ≤0.8 × ULN; and ECOG performance status ×1. Patients were stratified by disease site and geographic region and were randomized to receive DTIC (1000 mg/m2 IV) preceded by a 5-day continuous IV infusion of either OBL (7 mg/kg/d) or placebo. Treatment was given for 8 cycles absent progression; responding patients and those with stable disease could receive 8 additional cycles. Disease was assessed every 42 days, at the end of treatment, and every 2 months thereafter for up to 2 years. Co-primary endpoints were PFS and OS. PFS will be assessed 6 months after completion of accrual when approximately 243 events have been observed. OS will be assessed after 2 years. Secondary endpoints include overall and durable response rates, duration of response, and safety.
Results: Accrual was completed in March 2009; 314 patients were randomized. Demographics of patients in the 2 treatment groups combined show a median age of 58 years; 38% female gender; and 25% with liver metastases, 51% with other visceral disease, and 24% with skin/soft tissue/nodal disease.
Conclusions: AGENDA will be unblinded in Oct. 2009. Primary PFS results, response rates, and safety findings will be presented.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):PR-1.