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Originally published as JCO Early Release 10.1200/JCO.2006.06.0483 on September 11 2006 © 2006 American Society of Clinical Oncology. Bcl-2 Antisense (oblimersen sodium) Plus Dacarbazine in Patients With Advanced Melanoma: The Oblimersen Melanoma Study Group
From the University of Texas M.D. Anderson Cancer Center, Houston, TX; Sydney Cancer Centre and Sydney Melanoma Unit, Sydney, Australia; Division of General Dermatology, Medical University of Vienna, Vienna, Austria; University of Alabama at Birmingham, Hematology/Oncology, Birmingham, AL; Royal Marsden Hospital, London, United Kingdom; Klinik fur Dermatologie, Venerologie, und Allergologie mit Asthmapoliklinik, Charité Universitätsmedizin Berlin, Berlin, Germany; New York University School of Medicine, New York, NY; H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Arizona Cancer Center, Tucson, AZ; Newcastle Mater Misericordiae Hospital, Waratah, Australia; University of Pittsburgh Cancer Institute, Pittsburgh, PA; and Tufts-New England Medical Center, Boston, MA Address reprint requests to Frank G. Haluska, MD, PhD, Tufts-New England Medical Center, 750 Washington St, Box 6626, Boston, MA 02111; e-mail: FHaluska{at}tufts-nemc.org
PURPOSE: Chemotherapy resistance in melanoma has been linked to antiapoptotic effects mediated by Bcl-2 protein. We evaluated whether targeting Bcl-2 using an antisense oligonucleotide (oblimersen sodium) could improve the efficacy of systemic chemotherapy in patients with advanced melanoma. PATIENTS AND METHODS: We randomly assigned chemotherapy-naïve patients with advanced melanoma to treatment with dacarbazine (1,000 mg/m2) alone or preceded by a 5-day continuous intravenous infusion of oblimersen sodium (7 mg/kg/d) every 3 weeks for up to eight cycles. Patients were stratified by Eastern Cooperative Oncology Group performance status, liver metastases, disease site, and serum lactate dehydrogenase (LDH). The primary efficacy end point was overall survival. RESULTS: Among 771 patients randomly assigned, the addition of oblimersen to dacarbazine yielded a trend toward improved survival at 24-month minimum follow-up (median, 9.0 v 7.8 months; P = .077) and significant increases in progression-free survival (median, 2.6 v 1.6 months; P < .001), overall response (13.5% v 7.5%; P = .007), complete response (2.8% v 0.8%), and durable response (7.3% v 3.6%; P = .03). A significant interaction between baseline serum LDH and treatment was observed; oblimersen significantly increased survival in patients whose baseline serum LDH was not elevated (median overall survival, 11.4 v 9.7 months; P = .02). Neutropenia and thrombocytopenia were increased in the oblimersen-dacarbazine group; however, there was no increase in serious infections or bleeding events. CONCLUSION: The addition of oblimersen to dacarbazine significantly improved multiple clinical outcomes in patients with advanced melanoma and increased overall survival in patients without an elevated baseline serum LDH.
Melanoma is an increasingly common disease.1 Although localized disease is frequently curable by surgical excision, metastatic melanoma is inherently resistant to most systemic treatments, and survival of patients with advanced disease has not improved in more than 30 years.2,3 Cytotoxic chemotherapy triggers cancer cell death by activating an apoptotic cascade that is initiated by mitochondrial release of cytochrome C and activation of caspase 9. Drug resistance in melanoma has been partially attributed to overexpression of Bcl-2, an antiapoptotic protein that blocks the release of cytochrome C.4 Experimental transfection of cells with Bcl-2 confers a multidrug resistant phenotype in both hematologic and solid tumor cells.5 Conversely, pharmacologic reduction or targeted inactivation of Bcl-2 amplifies anticancer responses to chemotherapy in multiple in vivo models.6,7 Antisense is a pharmacologic strategy that decreases expression of specific proteins by blocking their translation from mRNA. Oblimersen sodium (Genasense; Genta International Inc, Berkeley Heights, NJ) is an 18-base phosphorothioate antisense oligonucleotide that binds the first six codons of the bcl-2 mRNA open-reading frame and mediates RNA cleavage by RNase H. Oblimersen has been shown to downregulate Bcl-2 protein and increase chemotherapy-induced apoptosis in human cancer xenografts.6,7 Dacarbazine is the most commonly used therapy for metastatic melanoma. Response to dacarbazine has generally ranged from approximately 10% to 20%2,3; however, recent studies have yielded lower response rates,8,9 and complete responses are rare.2,3,8-10 Compared with dacarbazine alone, no single agent or combination of agents has yielded a significant improvement in durable or complete responses10-13 or in overall survival in a randomized trial.8,10,13 Results of a dose-ranging study suggested that oblimersen might improve response to dacarbazine and overall survival in patients with advanced melanoma without increasing toxicity.14 In that study, oblimersen decreased Bcl-2 protein in serial biopsies of superficial melanoma lesions by a median of approximately 40%. We conducted this randomized, controlled trial to examine whether pretreatment with oblimersen could improve the efficacy of dacarbazine in patients with advanced melanoma and report findings after all patients had been followed for a minimum of 24 months from randomization. The primary efficacy end point was overall survival.
Patients Adult patients with histologically confirmed advanced melanoma (stage 4 or unresectable stage 3) and measurable disease were eligible if they had not received cytotoxic chemotherapy. Prior adjuvant or therapeutic use of cytokine and biologic agents and vaccines was allowed. Other inclusion requirements were Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2; minimum 4 weeks and recovery from major prior surgery or other therapy; serum creatinine 1.5x the upper limit of normal (ULN) or less or 24-hour creatinine clearance at least 50 mL/min; serum bilirubin 1.5x ULN or lower; AST, ALT, and alkaline phosphatase 2.5x ULN or lower; serum albumin at least 2.5 g/dL (25 g/L); prothrombin and partial thromboplastin times 1.5x ULN or lower; absolute neutrophil count (ANC) at least 1,500 cells/mm3; platelet count at least 100,000/mm3; and hemoglobin at least 8 g/dL (80 g/L). Exclusion criteria included prior cytotoxic chemotherapy; prior radiotherapy or intratumor injection therapy to target lesions, unless progression was documented or measurable disease was apparent outside the treated area; history of brain metastases or leptomeningeal disease; significant medical conditions other than cancer; organ allograft; HIV infection; history of other cancer except adequately treated basal or squamous cell carcinoma or cervical carcinoma in situ for which the patient had been disease free for at least 5 years; metastases confined to bone; primary ocular or mucosal melanoma; concomitant anticoagulant therapy; experimental therapy within 3 weeks preceding baseline evaluation; known hypersensitivity to phosphorothioate-containing oligonucleotides or dacarbazine; pregnancy; and lactation. The protocol and amendments were reviewed and approved by institutional review boards before patient enrollment; written informed consent was obtained from all patients.
Stratification, Random Assignment, and Treatment Patients received dacarbazine (1,000 mg/m2 intravenously for 60 minutes) or oblimersen (7 mg/kg/d by continuous intravenous infusion for 5 days) followed by the same dacarbazine dose. In the absence of progressive disease, treatment was repeated every 3 weeks for up to eight cycles. Stable or responding patients in the oblimersen arm were eligible to continue oblimersen plus dacarbazine in an extension protocol for eight additional cycles. Patients receiving dacarbazine alone were given the option to continue dacarbazine beyond the initial eight courses, but were not permitted to cross over to oblimersen-dacarbazine treatment. Dacarbazine was delayed for grade 4 neutropenia or grade 3 neutropenia with fever or systemic infection until the severity was grade 1 or lower; subsequent dacarbazine doses were reduced by 25%. Delays of 1 week were specified for grade 3 to 4 nonhematologic toxicity (except hypersensitivity and alopecia), with 25% dose reduction for recovery to grade 2 and no reduction for recovery to grade 1 or lower. Patients with dose-limiting toxicity causing a 2-week delay or recurrent grade 3 to 4 toxicity despite two consecutive dacarbazine dose reductions were removed from the study.
Antiemetics were to be administered before dacarbazine; antipyretics, antihistamines, and corticosteroids were allowed for fever, chills, rash, and hypersensitivity reactions. Granulocyte colony-stimulating factor was allowed after the first cycle for grade 3 to 4 neutropenia more than 5 days in duration, or febrile neutropenia (ANC < 1.0 x 109/L with temperature
Evaluations Hematology and biochemistry tests were repeated approximately 14 days after dacarbazine administration. Repeat physical examination and documentation of performance status and adverse events were performed on the day of or 1 day before dacarbazine and at treatment completion. Target lesions were formally re-evaluated by physical exam and radiologic studies every two cycles. After treatment completion, patients were examined and radiologically evaluated every 2 months for at least 24 months from date of random assignment or until disease progression. Response Evaluation Criteria in Solid Tumors (RECIST) were employed to calculate response according to a standard algorithm.15 Complete response was defined as disappearance of all target lesions and nonmeasurable disease. Partial response was defined as a decrease of at least 30% from baseline in sum LD. Progression was defined as an increase of at least 20% in sum LD as compared with the smallest value observed since baseline. Durable response was defined as complete or partial response lasting at least 6 months. All responses required confirmation by a second measurement within a minimum of 3 weeks. An independent panel blinded to treatment assignment reviewed all radiologic responses. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria (version 2.0).16
End Points and Statistical Analysis
The primary analysis for overall survival used the log-rank test. A 2-year survival curve was presented based on Kaplan-Meier estimates for each treatment group. The hazard ratio and 95% CI were estimated by using an unadjusted Cox proportional hazards model. Progression-free survival was similarly analyzed. Response rates were compared by The prospective analysis plan provided for analysis after 508 deaths had occurred. After that analysis (which occurred after all patients had been followed for a minimum of 6 months from date of random assignment), patients continued to be followed as specified in the protocol to further assess overall survival. An analysis was performed when all patients had been followed for the prespecified minimum period of 24 months. The primary analysis was conducted by Parexel International (Waltham, MA).
To assess whether findings would change if the groups were not balanced at baseline, the Cox proportional hazards regression model was used with the terms of treatment and the following baseline factors, which were prognostic for survival in metastatic melanoma based on multivariate analyses of large patient populations17: LDH, site of metastases, ECOG performance status (0 v
Patient Population and Treatment Between July 2000 and February 2003, 771 patients were randomly assigned (386 and 385 to the oblimersen-dacarbazine and dacarbazine groups, respectively) and included in intent-to-treat analyses. The groups were well balanced at baseline (Table 1). Fifteen patients (3.9%) in the oblimersen-dacarbazine group and 25 patients (6.5%) in the dacarbazine group did not initiate treatment; the remaining 731 patients initiated at least one cycle of therapy. Both the number of cycles and the dose of dacarbazine delivered were similar in the two groups (Table 1).
Overall Survival With 24 months of minimum follow-up, median survival in the oblimersen-dacarbazine group was 9.0 months compared with 7.8 months in the dacarbazine group (hazard ratio = 0.87; 95% CI, 0.75 to 1.01; P = .077; Fig 1A). Data were censored for only 14 patients before the cutoff date for this analysis.
Overall Response The overall response rate (complete plus partial responses) was 13.5% for patients treated with oblimersen-dacarbazine and 7.5% for patients who received dacarbazine (P = .007; Table 2). Complete responses were biopsy proven in two patients who had residual radiologic abnormalities in the oblimersen-dacarbazine group. The proportion of patients with durable responses (  6 months) was significantly higher in the oblimersen-dacarbazine group (7.3% v 3.6%; P = .03). Eleven patients (2.8%) achieved a complete response in the oblimersen-dacarbazine group compared with three patients (0.8%) in the dacarbazine group. Of the 11 oblimersen-treated patients with complete response, nine were alive after 24 months of follow-up, with survival ranging from 24 months to more than 36 months from date of random assignment. The other two patients survived 19 and 22 months. Notably, among these 11 oblimersen-treated patients, six remained alive and free of disease, including four patients who were followed for at least 36 months. In the dacarbazine group, one of the three patients with complete response died at 20 months; the remaining two patients were alive and disease-free at 28 months and 29 months. Review of radiologic images with appropriate medical history by an expert panel blinded to treatment assignment yielded a concordance rate of more than 90% (data not shown).
Progression-Free Survival Median progression-free survival was significantly longer in the oblimersen-dacarbazine group compared with the dacarbazine group (2.6 v 1.6 months, respectively; hazard ratio = 0.75; P < .001; Fig 1B). Multiple sensitivity analyses were conducted to evaluate the impact of missing data and possible differences in interval assessments. Results consistently favored the oblimersen-dacarbazine combination, affirming the robustness of the increase in progression-free survival (data not shown).
Effect of Serum LDH
Among patients with elevated LDH, no significant differences between treatment groups were demonstrated (Figs 3A and 3B), confirming that baseline LDH value is an appropriate parameter for the selection of patients most likely to benefit from oblimersen-dacarbazine treatment.
Safety and Tolerability The majority of patients in both groups experienced at least one adverse event; 67% of patients treated with oblimersen-dacarbazine and 43% of patients treated with dacarbazine experienced at least one grade 3 to 4 event (Table 4). The proportion of patients who discontinued treatment because of a treatment-related adverse event was 6.2% in the oblimersen-dacarbazine group and 2.2% in the dacarbazine group.
The most important adverse events were neutropenia and thrombocytopenia. Grade 3 to 4 neutropenia with infection occurred in 16 patients (4.3%) treated with oblimersen-dacarbazine, compared with 10 patients (2.8%) treated with dacarbazine. There was an increased incidence of bleeding events in the oblimersen-dacarbazine group (13.7% v 9.2% for dacarbazine alone). These events consisted primarily of grade 1 to 2 epistaxis or hematuria. In contrast, more grade 3 to 4 bleeding events (primarily GI events) occurred in the dacarbazine group (3.1% v 2.2% for oblimersen-dacarbazine). Catheter-related events, including such adverse events as venous thrombosis, infection, and device blockage or breakage, occurred in 19.1% of patients in the oblimersen-dacarbazine group and 8.6% of patients in the dacarbazine group. Safety findings in patients with normal LDH suggest an enhanced risk/benefit ratio based on lower rates of adverse events with an outcome of death, adverse events resulting in treatment discontinuation, and serious adverse events than observed in all treated patients.
This trial is the largest randomized study ever conducted in advanced melanoma. The timing of the primary survival analysis (ie, after all patients had been followed for a minimum of 6 months from date of random assignment) was event driven, at which time 535 events were included in the analysis. Median overall survival was 9.0 months in the oblimersen-dacarbazine group and, consistent with the literature,9,18,19 7.8 months in the dacarbazine group. Median follow-up time among patients who were alive at last contact was 9.5 months. At 24-month minimum follow-up, analysis of overall survival in the intent-to-treat population showed a log-rank P value of .077. The issue of a potential penalty in statistical significance because of multiple analyses is relevant here. However, because the secondary end points were significant at the prospectively defined initial analysis and the primary end point is qualitatively unchanged, application of a penalty would not alter the conclusions of the study. Progression-free survival analysis showed that half the patients had progressed after approximately two cycles of therapy. It is not surprising that patients with a poor prognosis in either arm did not receive the planned treatment and did not have a longer survival than observed. Notably, the addition of oblimersen to dacarbazine provided clinically meaningful benefit at 6-month minimum follow-up based on secondary efficacy end points that were mature, including progression-free survival (P = .0003) and response rate (P = .02). At 24-month minimum follow-up, the addition of oblimersen significantly increased progression-free survival and overall, durable, and complete responses compared to dacarbazine alone. The independent contribution of serum LDH as a biomarker for poor prognosis in advanced melanoma is well recognized.17 We confirmed the adverse prognosis associated with elevated serum LDH, as well as the interaction of this factor with treatment effect. Our analysis showed a survival benefit in patients who had normal LDH at baseline—about two thirds of our patients—a proportion that comprises a group larger than that in any prior randomized trial in advanced melanoma. These findings suggest that serum LDH can be used to identify patients who are unlikely to benefit from oblimersen-dacarbazine treatment, and support the use of LDH as a key stratification factor in future randomized trials. Bcl-2 expression, which was not assessed in this study, is increased in early stages of disease. Targeting bcl-2 may not be effective in patients with elevated LDH; the presence of this finding suggests tumor burden may be high, possibly resulting in poor drug infusion into the tumor, or drug resistance may be caused by mechanisms other than Bcl-2 expression. Oblimersen increased the incidence of neutropenia and thrombocytopenia. However, the incidence of grade 3 to 4 neutropenia (21%) and thrombocytopenia (16%) with oblimersen-dacarbazine was substantially lower compared with other drugs or regimens in patients with advanced melanoma8,10,20; oblimersen-associated thrombocytopenia did not cause an increase in serious bleeding events, and the incidence of neutropenic infection was low. Given the route of administration of oblimersen, it is not surprising that the incidence of catheter-related events was increased in the oblimersen-dacarbazine group. Other, more convenient routes of administration and/or regimens for oblimersen, including daily subcutaneous injections and short intravenous infusions, are being studied. Pretreatment with oblimersen did not compromise the ability to deliver full doses of dacarbazine. In summary, the use of oblimersen with dacarbazine can safely improve multiple outcomes in patients with advanced melanoma, particularly those with normal baseline LDH. It is likely that survival can be further improved by appropriate patient selection in future trials. These trials should examine patients with less advanced disease in whom Bcl-2 expression has been confirmed and employ drug regimens with higher antitumor response rates than dacarbazine.
Oblimersen Melanoma Study Group: N. Abramson; P. Altmeyer; R. Anderson; S. Anthony; M. Arias; R. Asbury; E. Bayliss; J.C. Becker; A. Bedikian; R. Belt; J. Bernstein; W. Berry; D.W. Blayney; A. Blidaru; P.D. Boasberg; E.C. Borden; J. Cantrell; S. Chakrabarti; E. Chimielowska; E.W. Cochran; G. Cohen; R. Conry; J. Cox; W.E. Davis; R. DeConti; A.B. Deisseroth; L.V. Demidov; V.T. DeVita; N. DiBella; J.J.P. Dutcher; J.R. Eckardt; M.S. Ernstoff; W. Ferri; R.L. Fine; R. Fiore; T. Fisher; J. Fleagle; M.R. Flores; P. Flynn; L. Frase; G.P. Frennette; D. Friedland; P. Fritsch; R. Ganick; N. Ghilezan; C. Ghosh; J. Glaspy; W.L. Gluck; R. Gonzales; R.H. Good; V.A. Gorbounova; D. Gordon; M. Gore; G. Guzley; B.W. Hancock; L.L. Hart; J. Harvey Jr; A. Hauschild; T.A. Hensing; P. Hersey; E.M. Hersh; J. Hopkins; L.F. Hutchins; D. Irwin; N.A. Iscoe; J. Jassem; B. Jansen; A.M.T. Jones; D. Jones; R.G. Just; A. Kalisiak; K. Katato; R. Kefford; P.S. Kennedy; P. Khandelwal; J.J. Kirshner; R.J. Klasa; H.M. Kluger; D.H. Lawson; C.W.K. Lee; S. Legha; D. Loesch; R.C. Lohmann; J. Lopez; P. Lorigan; J. Lubinski; J. Lutzky; A. Mackiewicz; S. Madajewicz; G.M. Manikhas; B. Marek; M. Marples; R. Marschke; T. Marsland; H. McCoy; K. McIntyre; M. Middleton; D.M. Miller; W.H. Miller; M. Millward; M. Modiano; V.M. Moiseyenko; C. Neumann; S.J. O'Day; M. Olsen; K. Olson; M. O'Rourke; G. Parker; R.S. Paulson; A.C. Pavlick; A.L. Pecora; H. Pehamberger; T.M. Petrella; R. Pluenneke; E.T. Quan; I. Quirt; R. Raju; D. Richards; P. Richards; M. Roberts; K.D. Sabbath; J. Sandbach; T. Sato; M. Savin; D. Schadendorf; L.M. Schuchter; J. Schulz; L.S. Sender; J. Shaw; M.G.B. Smylie; P. Soyer; W. Sterry; J. Stone; J.W. Sullivan; F. Swan; C.A. Szczylik; J. Thachil; N. Thatcher; D.B. Thomson; G.A. Van Hazel; S.A. Volk; D. Waterhouse; R. Weinstein; N.W.R. Wickham; M. Wiesenfeld; K.S. Wilson; M. Yoffe; V. Young.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-$99,999 (C)
We are indebted to the patients who participated in this trial and to their families. The following individuals provided advice and expertise: biostatistics—Janet Wittes, PhD, Biostatistical Services, LLC (Bethesda, MD); Robert Makuch, PhD, Yale University (New Haven, CT); data monitoring—Parexel International Inc (Waltham, MA).
published online ahead of print at www.jco.org on September 11, 2006. Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005. Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test. The interaction of 
1.1x ULN] v elevated [> 1.1x ULN]; P = .03). Multivariate analyses that adjusted for baseline prognostic factors confirmed an interaction between treatment and LDH (
) in metastatic melanoma. Clin Oncol (R Coll Radiol) 13:458-465, 2001
