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Agop Y. Bedikian - One of the best experts on this subject based on the ideXlab platform.
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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
Melanoma Research, 2014Co-Authors: Agop Y. Bedikian, Claus Garbe, Robert M Conry, Celeste Lebbe, Jean Jacques GrobAbstract: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.
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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'.
Melanoma research, 2014Co-Authors: Agop Y. Bedikian, Claus Garbe, Robert M Conry, Celeste Lebbe, Jean Jacques GrobAbstract: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.
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Survival in a phase III, randomized, double-blind study of dacarbazine with or without Oblimersen (Bcl-2 antisense) in patients with advanced melanoma and low-normal serum lactate dehydrogenase (LDH; AGENDA).
Journal of Clinical Oncology, 2011Co-Authors: Agop Y. Bedikian, Sanjiv S. Agarwala, Claus Garbe, C. Lebbé, C. Robert, T. Cousin, J.-j. GrobAbstract:8531 Background: Oblimersen (OBL) is a Bcl-2 targeted phosphorothioate antisense that enhances antitumor activity of alkylating agents in preclinical studies. A prior phase III study of dacarbazine...
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LDH correlation with survival in advanced melanoma from two large, randomised trials (Oblimersen GM301 and EORTC 18951)
European journal of cancer (Oxford England : 1990), 2009Co-Authors: Sanjiv S. Agarwala, Cy A. Stein, Ulrich Keilholz, Erard Gilles, Agop Y. Bedikian, Richard Kay, Loretta M. Itri, Stefan Suciu, Alexander M.m. EggermontAbstract:Purpose: In a randomised study (GM301; dacarbazine with/without Oblimersen), patients with advanced melanoma were stratified based on performance status, metastatic site and lactate dehydrogenase (LDH). Progression-free survival and response and durable response rates showed a highly significant difference favouring dacarbazine-Oblimersen and a nearly significant survival difference. All efficacy parameters significantly favoured dacarbazine-Oblimersen in patients with normal baseline LDH [
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ldh correlation with survival in advanced melanoma from two large randomised trials Oblimersen gm301 and eortc 18951
43rd Annual Meeting of the American-Society-of-Clinical-Oncology, 2009Co-Authors: Sanjiv S. Agarwala, Cy A. Stein, Ulrich Keilholz, Erard Gilles, Agop Y. Bedikian, Richard Kay, Loretta M. Itri, Stefan Suciu, Alexander M.m. EggermontAbstract:Purpose: In a randomised study (GM301; dacarbazine with/without Oblimersen), patients with advanced melanoma were stratified based on performance status, metastatic site and lactate dehydrogenase (LDH). Progression-free survival and response and durable response rates showed a highly significant difference favouring dacarbazine-Oblimersen and a nearly significant survival difference. All efficacy parameters significantly favoured dacarbazine-Oblimersen in patients with normal baseline LDH [<= 1.1 x upper limit of normal (ULN)]. Each stratification factor was assessed for an interaction with treatment on survival and an interaction was detected only for LDH. Experimental design: Baseline LDH values in Study GM301 treatment groups were combined and analysed using cutoffs above and below 1 x ULN. Baseline LDH in EORTC study 18951 (dacarbazine, cisplatin, interferon-alfa-2b with/without interleukin-2 in advanced melanoma) was independently analysed using the same approach. In Study GM301, the relation between treatment effect and LDH, treatment effect and tumour size, LDH and tumour size and LDH and disease site were determined. Results: In Study GM301 (N = 760) and Study 18951 (N = 325), LDH was within the upper range of normal for a large number of patients. This was not exhibited in the general population, suggesting such values may be elevated rather than normal in melanoma. A highly ordered and monotonic relationship was apparent between LDH and survival: survival worsened as LDH became more elevated, even when LDH remained within normal range. LDH and tumour size were poorly correlated; elevated LDH was not associated with any one disease site. LDH was highly predictive of Oblimersen effect. Conclusion: In designing studies, LDH should be considered, regardless of tumour size or disease site. (C) 2009 Elsevier Ltd. All rights reserved.
Stanley R. Frankel - One of the best experts on this subject based on the ideXlab platform.
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The Combination of the Proteasome Inhibitor Bortezomib and the Bcl-2 Antisense Molecule Oblimersen Sensitizes Human B-Cell Lymphomas to Cyclophosphamide
Clinical cancer research : an official journal of the American Association for Cancer Research, 2006Co-Authors: Owen A. O'connor, Emily A. Smith, Lorraine E. Toner, Julie Teruya-feldstein, Stanley R. Frankel, Mark Rolfe, Xiaohui Wei, Shujun Liu, Guido Marcucci, Kenneth K. ChanAbstract:Purpose: To determine whether the combination of the proteasome inhibitor bortezomib and the bcl-2 antisense molecule Oblimersen can sensitize human lymphoma to cyclophosphamide. Experimental Design: Cytotoxicity assays were conducted to determine if there was any additive or synergistic interaction between the combinations of bortezomib, Oblimersen, and cyclophosphamide using a standard trypan blue exclusion assay. Based on these experiments, in vivo experiments in severe combined immunodeficiency beige mice were done using human lymphoma xenografts in which different schedules were explored. Bcl-2 and Oblimersen levels were determined in treated tumors, some of which were resected at the end of the in vivo experiment and evaluated pathologically. Results: The results suggest that the combination of bortezomib and Oblimersen seem to interact in at least an additive fashion, and that the addition of cyclophosphamide to this drug combination can markedly improve tumor cell kill. In addition, it seems that these drug combinations may be schedule-dependent, with a requirement for Oblimersen pretreatment. Animals treated with the triplet drug combination in a schedule-dependent manner experienced pathologic complete regression of disease, which was not observed in other treatment cohorts. The addition of bortezomib also seemed to increase the levels of intracellular Oblimersen, which resulted in a marked reduction in Bcl-2. Histologic studies confirmed marked necrosis and caspase-3 activation only in the cohort receiving all three drugs. Conclusion: The use of Bcl-2-directed therapy and a proteasome inhibitor sensitizes human lymphoma cells to cytotoxic drugs like cyclophosphamide. This combination may offer new opportunities for integrating novel targeted therapies with conventional chemotherapy.
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Phase 2 Study of Oblimersen Sodium (G3139; Bcl-2 Antisense; Genasense®) Plus Gemtuzumab Ozogamcin (Mylotarg®) in Elderly Patients with Relapsed Acute Myeloid Leukemia (AML).
Blood, 2004Co-Authors: Joseph O. Moore, Karen Seiter, Jonathan E. Kolitz, Wendy Stock, Stanley R. FrankelAbstract:Patients with relapsed AML over the age of 60 have a poor prognosis. Gemtuzumab ozogamicin (GO) has been approved for older pts in first relapse, although many pts who attain complete remission (CR) do not fully recover normal platelet count (so-called CRp). In vitro studies have shown that Oblimersen down-regulates Bcl-2 in AML cells and enhances apoptotic cell death induced by GO. We conducted a Phase 2 study to evaluate the safety and efficacy of GO combined with Oblimersen for older pts with AML. Eligibility requirements included: age ≥ 60 yrs; AML in 1st relapse; ≥ 3 mos 1st CR duration; ≥ 25% CD33-positive AML cells. Pts received Oblimersen at a dose of 7 mg/kg/d for 7 days by CIV beginning on days 1 and 15; GO was given at a dose of 9 mg/m2 IV over 2 hrs on days 4 and 18. A total of 48 pts were enrolled (ITT population), all of whom received at least 1 dose of Oblimersen; 9 pts failed to receive the required 2 doses of GO (per-protocol population, n=39). The median age was 67 (range, 59 to 88 yrs). Duration of 1st CR: 12 mos: 12 pts (25%). No. of prior regimens: 1 (17 pts, 35%); 2 or 3 (26 pts, 54%); ≥ 4 (5 pts, 10%). Among treated pts, 79% completed 21 days of protocol therapy. Overall, 12 pts achieved a major response, either CR (n=5) or CRp (n=7), for an ITT response rate of 25% and a per-protocol response rate of 31%. The median time to remission was 52 days. Ten of the 12 responders survived > 6 mos, whereas only 6 non-responders survived ≥ 6 mos. Serious adverse events for the Oblimersen/GO combination were qualitatively similar to those reported for GO alone and included among other reactions: Grade 3-4 febrile neutropenia (42%) or thrombocytopenia 33%; nausea; fever; rigors, and dyspnea. Treatment-emergent adverse reactions led to discontinuation of protocol therapy in 10 pts (21%). The most common serious adverse event was febrile neutropenia (25%). One pt (2.1%) died during treatment (sepsis) and 16 pts (33%) died within 30 days of last study medication (infection, bleeding, respiratory failure, progressive AML, and other disease-related complications). No episodes of VOD were observed. Oblimersen can be safely combined with GO; however, pts enrolled in this study appear to have had more unfavorable characteristics at entry compared with prior studies using GO alone in pts with relapsed AML. Therefore, assessment of an incremental benefit from the addition of Oblimersen will require a randomized trial.
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Randomized Multicenter Phase 3 Trial of High-Dose Dexamethasone (dex) with or without Oblimersen Sodium (G3139; Bcl-2 antisense; Genasense) for Patients with Advanced Multiple Myeloma (MM).
Blood, 2004Co-Authors: Asher A. Chanan-khan, Ruben Niesvizky, Raymond J. Hohl, Todd M. Zimmerman, Neal P. Christiansen, Gary J. Schiller, Sandra Smith, Stanley R. FrankelAbstract:Over-expression of Bcl-2 has been linked to acquired dex resistance in MM cells. Conversely, reduction of Bcl-2 using Oblimersen has been shown to enhance dex-induced apoptosis in MM cell lines and in fresh MM cells in culture (Liu et al., Blood101:4105, 2003). Preliminary non-randomized clinical studies have suggested that Oblimersen may potentiate the activity of VAD and dex/thalidomide in patients (pts) with resistant MM. We have conducted a randomized, multinational, Phase 3 trial of pts with advanced MM using dex given with or without Oblimersen. Eligibility requirements included: relapsed or refractory MM; measurable M-protein in serum or urine; ≤ 6 prior regimens; ECOG PS ≤ 3; serum Cr ≤ 1.5 mg/dL; ANC > 1,000/ml; plts ≥ 50,000/ml. Exclusions: previous allogeneic transplant; other significant medical disease. Pts were stratified according to number of prior treatments (1 or 2 vs. ≥ 3 regimens), prior autologous stem cell transplant (yes/no), and primary resistance to vs. relapse from primary treatment. All pts received dex 40 mg p.o. x 4 days during weeks 1, 2 and 3. Pts randomized to Oblimersen received 7 mg/kg/d x 7 days by IV infusion, beginning 3 days before dex treatment during the 1st and 3rd weeks, and during all subsequent dex cycles. Beginning on week 5, additional 4-day dex cycles were repeated in stable or responding pts every 3 weeks, for a maximum of 12 months. All pts received prophylactic H-2 antagonists, TMP/SMZ, and a bisphosphonate. Response assessments were conducted prior to each treatment cycle. The primary endpoint of the study was to compare time-to-disease progression between the 2 treatment groups. Secondary endpoint comparisons included overall survival, event-free survival at 6 months, overall response rates, response duration, clinical benefit, and safety. A total of 224 pts were randomized into the study. All pts have completed > 12 mos follow-up, and final results of this trial will be presented.
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Oblimersen sodium genasense bcl 2 antisense oligonucleotide a rational therapeutic to enhance apoptosis in therapy of lung cancer
Clinical Cancer Research, 2004Co-Authors: Roy S Herbst, Stanley R. FrankelAbstract:Bcl-2 protein inhibits apoptosis and confers resistance to treatment with traditional cytotoxic chemotherapy, radiotherapy, and monoclonal antibodies. Oblimersen sodium is an antisense oligonucleotide compound designed to specifically bind to human bcl-2 mRNA, resulting in catalytic degradation of bcl-2 mRNA and subsequent decrease in bcl-2 protein translation. Both small cell and non-small cell lung cancer show baseline and inducible expression of bcl-2, which may contribute to resistance to therapy. Preclinical studies have shown that combining bcl-2 antisense with chemotherapy improves antitumor response, increases apoptosis of tumor cells, and increases survival. Preliminary data from a large international randomized trial in melanoma show a trend toward increased survival and significantly improved response rates and response duration when Oblimersen is added to dacarbazine. Phase I studies in small cell lung cancer patients demonstrate that Oblimersen can be combined with paclitaxel or carboplatin and etoposide. The combination of docetaxel and Oblimersen has been shown to be feasible in Phase I studies and is currently undergoing evaluation in comparison with docetaxel alone as first-line salvage therapy in patients refractory or relapsed after one prior chemotherapy regimen. Enhancement of the efficacy of anticancer treatments with Oblimersen bcl-2 antisense therapy represents a promising new apoptosis-modulating strategy.
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Oblimersen sodium (G3139 Bcl-2 antisense oligonucleotide) therapy in Waldenstrom's macroglobulinemia: a targeted approach to enhance apoptosis.
Seminars in oncology, 2003Co-Authors: Stanley R. FrankelAbstract:The components of the apoptotic pathway are targets for anticancer therapy. Bcl-2 protein inhibits apoptosis and confers resistance to treatment with traditional cytotoxic chemotherapy, radiotherapy, and monoclonal antibodies. Oblimersen sodium (G3139, Genasense, Genta Inc, Berkeley Heights, NJ) is an antisense oligonucleotide compound designed to specifically bind to the first six codons of the human bcl-2 mRNA sequence, resulting in degradation of bcl-2 mRNA and subsequent decrease in Bcl-2 protein translation. Oblimersen is the first oligonucleotide to demonstrate proof of principle of an antisense effect in human tumors by the documented downregulation of the target Bcl-2 protein. A growing body of preclinical and clinical evidence suggests that Oblimersen synergizes with many cytotoxic and biologic/immunotherapeutic agents against a variety of hematologic malignancies and solid tumors. Randomized clinical trials are currently underway to evaluate the efficacy and tolerability of Oblimersen in combination with cytotoxic chemotherapy in chronic lymphocytic leukemia (CLL), multiple myeloma (MM), malignant melanoma, and non-small cell lung cancer. In addition, nonrandomized trials are underway to evaluate Oblimersen in non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), and hormone-refractory prostate cancer. Preclinical data support the clinical evaluation of Oblimersen in additional tumor types, including chronic myelogenous leukemia, and breast, small cell lung, gastric, colon, bladder (CML), and Merkel cell cancers. Enhancement of the efficacy of anticancer treatments with Oblimersen Bcl-2 antisense therapy represents a promising new apoptosis-modulating strategy, and ongoing clinical trials will test this therapeutic approach.
Asher A. Chanan-khan - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetic evaluation of Oblimersen sodium for the treatment of chronic lymphocytic leukemia
Expert opinion on drug metabolism & toxicology, 2011Co-Authors: Pooja Advani, Aneel Paulus, Ayesha Masood, Taimur Sher, Asher A. Chanan-khanAbstract:Introduction: Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the western hemisphere. Developing new therapies remains a priority as present treatment options do not offer a cure. BCL-2 overexpression in CLL is associated with aggressive disease features and resists chemotherapy. Oblimersen sodium (G3139) is a phosphorothioate oligonucleotide antisense drug targeting the BCL-2 mRNA and is the first antisense to reach advanced clinical testing in oncology. Preclinical evaluation has demonstrated good antineoplastic effect in B-cell cancers; several clinical trials have confirmed its safety and efficacy both alone and in combination with other therapeutics. Areas covered: This review focuses on the chemistry, pharmacodynamics, pharmacokinetics and clinical evaluation of Oblimersen in CLL. PubMed and MEDLINE searches assisted in data collection. Expert opinion: Bcl-2 is an important target in CLL. Antisense therapy is a novel approach to target oncoproteins; this can be beneficial i...
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Phase III randomised study of dexamethasone with or without Oblimersen sodium for patients with advanced multiple myeloma
Leukemia & lymphoma, 2009Co-Authors: Asher A. Chanan-khan, Ruben Niesvizky, Raymond J. Hohl, Todd M. Zimmerman, Neal P. Christiansen, Gary J. Schiller, Natalie S. Callander, John Lister, Martin M. Oken, Sundar JagannathAbstract:Upregulation of the Bcl-2 antiapoptotic protein is reported to be associated with aggressive clinical course in multiple myeloma. Oblimersen sodium is a bcl-2 antisense oligonucleotide complementary to the first six codons of the open-reading frame of bcl-2 mRNA that can decrease transcription of Bcl-2 protein and increase myeloma cell susceptibility to cytotoxic agents. In this phase III randomised trial, we investigated in patients with relapsed/refractory myeloma whether addition of Oblimersen to dexamethasone improved clinical outcomes vs. dexamethasone alone. Two hundred and twenty-four patients were randomised to receive either Oblimersen/dexamethasone (N = 110) or dexamethasone alone (N = 114). The primary endpoint was time to tumor progression (TTP). Final results of this study demonstrated no significant differences between the two groups in TTP or objective response rate. The Oblimersen/dexamethasone regimen was generally well tolerated with fatigue, fever and nausea, the most common adverse eve...
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“Complete” Remission in Chronic Lymphocytic Leukemia (CLL) Is Strongly Affected by the Use of CT Scanning: Results from a Prospective Randomized Trial of Fludarabine Plus Cyclophosphamide (Flu/Cy) with or without Genasense (Oblimersen) in Patients wi
Blood, 2006Co-Authors: Peter Maslak, James Caravelli, Asher A. Chanan-khanAbstract:Literature in CLL has emphasized the importance of patient evaluation with measures of minimal residual disease (MRD) by flow cytometry, FISH, or RT-PCR after complete remission (CR). However, the widely used National Cancer Institute-Working Group (NCI-WG) criteria for response in CLL do not mandate the use of CT scanning or ultrasound (US) for the evaluation of patients with abdominal lymphadenopathy. Recently, the German CLL Study Group reported that the CR rate in chemonaive patients treated with fludarabine (Flu) alone or in combination with cyclophosphamide (Flu/Cy) was reduced by almost one-third when patients were routinely scanned using CT/US (Eichhorst et al, Blood 2006). We recently completed a randomized trial in patients with relapsed/refractory CLL, which afforded an opportunity to examine the impact of CT/US on residual disease in this setting. Methods: Patients were randomized to treatment with Flu/Cy with or without Oblimersen. The primary objective was to determine the proportion of patients who achieved CR or nodular partial response (nPR) using NCI-WG criteria. Response and progression were independently assessed by blinded expert review of clinical data, radiology, and bone marrow histopathology. The protocol required that patients with abnormalities on CT/US at study entry must have a repeat CT/US in order to document CR/nPR. CT/US followup was not required in pts who did not respond by other clinical criteria. Results: At entry, 92 of 120 pts (77%) on the Oblimersen arm and 97 of 121 pts (80%) on the Flu/Cy arm had baseline CT/US. These baseline scans were abnormal in 88 (73%) and 90 (74%) of pts in each group, respectively. Followup of patients with an initially abnormal scan showed that repeat assessments (i.e., one or more followup CT/US) were similar in each group: 71 pts (59%) in the Oblimersen group and 66 (55%) of pts in the Flu/Cy group. The number of followup CT/US (mean = 3; range = 1–14 for both groups), as well as the time between followup scans was also balanced in pts receiving Oblimersen (mean = 113 days; median = 97, range = 9–324) or Flu/Cy (mean = 125 days; median = 121, range 5–327). The addition of Oblimersen to Flu/Cy significantly increased the proportion of pts who achieved a confirmed CR/nPR (17% vs. 7%) when CT/US was required. To estimate the incidence of CR/nPR when CT was omitted, we assumed that marrow biopsy of pts with a histologically unconfirmed CR/nPR would have shown CR/nPR. With that assumption, the estimated incidence of CR/nPR (ie, absent the requirement for CT/US) increased to 25% and 14% for pts treated with Oblimersen and Flu/Cy, respectively. Conclusion: CT or US appear to be widely used by clinicians who treat CLL. Our results confirm and extend prior data that suggest the routine use of CT or US reduces the CR or CR/nPR rates by approximately 30% in both treatment-naive and previously treated pts with CLL. These data argue that lack of mandatory abdominal CT/US routinely results in an overestimation of CR/nPR incidence, and that evaluation of MRD is potentially meaningful only in the context of confirmed elimination of gross residual disease.
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Clinical characterization of first cycle reactions in patients with chronic lymphocytic leukemia treated with Oblimersen
Journal of Clinical Oncology, 2006Co-Authors: Kathryn S. Kolibaba, Joseph O. Moore, Asher A. Chanan-khan, G. Bociek, Thomas E. Boyd, Susan O'brienAbstract:16514 Background: Serious adverse reactions during the first treatment cycle characterize many drugs used for chronic lymphocytic leukemia (CLL), including rituximab, alemtuzumab, flavopiridol, lenalidomide, and Oblimersen. Termed cytokine release reactions (CRRs), these events have occurred more commonly in pts with bulky disease and elevated leukocyte counts, and some have been fatal. Rapid increases in serum levels of tumor necrosis factor-α, interleukin-6, interleukin-2, interferon-γ, and other cytokines may result in symptoms including fever, chills, nausea, vomiting, hypotension, and dyspnea. Ex vivo treatment of CLL cells with Oblimersen induce release of vasoactive interleukin-8. First cycle reactions, including tumor lysis syndrome (TLS), proved dose-limiting in a phase 1–2 trial of Oblimersen in pts with relapsed or refractory CLL. To characterize these reactions, we evaluated data from this single-agent study and from a phase 3 randomized clinical trial of Oblimersen with fludarabine and cyclop...
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Pooled safety analysis of Oblimersen alone or with fludarabine and cyclophosphamide in patients with advanced chronic lymphocytic leukemia
Journal of Clinical Oncology, 2006Co-Authors: Benjamin Koziner, Joseph O. Moore, Thomas E. Boyd, Susan O'brien, Loree Larratt, Asher A. Chanan-khanAbstract:6611 Background: Bcl-2 is an antiapoptotic protein linked to chemotherapy resistance and poor prognosis in chronic lymphocytic leukemia (CLL) patients (pts). Oblimersen (Obl), an anti-Bcl-2 oligonucleotide, has been shown to enhance apoptosis induced by fludarabine (Flu) + cyclophosphamide (Cy) in pts with relapsed CLL. We combined safety results from 2 CLL clinical trials to determine the relative effect of Obl on treatment-emergent adverse events (TEAEs) in Obl+Flu+Cy therapy. Methods: This analysis included 30 pts who received Obl 3mg/kg/d alone by continuous IV on days 5–7 and 230 pts who received Flu 25mg/m2/d + Cy 250mg/m2/d on days 5–7, every 28th day, either with (n=115) or without (n=115) Obl 3mg/kg/d on days 1–7. Mean number of cycles initiated were 3.3, 3.6, and 4.0 for Obl, Obl+Flu+Cy, and Flu+Cy, respectively. Results: The most frequent (>2% patients) grade 4 TEAEs were mainly hematologic: neutropenia (Obl alone, 0.0%; Flu+Cy, 11.3%; Obl+Flu+Cy 7.0%), thrombocytopenia (3.3%, 1.7%, 4.3%), anem...
Anthony W. Tolcher - One of the best experts on this subject based on the ideXlab platform.
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Safety and pharmacokinetics of Oblimersen administered as a weekly 2-hour intravenous infusion
Molecular Cancer Therapeutics, 2007Co-Authors: Anthony W. Tolcher, Amita Patnaik, Erard Gilles, Bob D Brown, Thomas Julian, Kyriakos P. Papadopoulos, M. Goldston, Theresa Mays, A. Qureshi, Chris H. TakimotoAbstract:A166 Background: Oblimersen (Genasense®), an investigational antisense oligonucleotide anticancer agent that decreases levels of the antiapoptotic protein Bcl-2, has a short plasma half-life (t1/2 50 µg/mL) have exceeded 10-fold the reported Css of CIVI schedules. There was no change in metabolism or plasma clearance with increasing doses. Large inter-patient variability was observed; however, intra-patient variability was low as indicated by a coefficient of variation of
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Oblimersen can be administered by subcutaneous (SC) and brief intravenous (IV) infusion: Clinical pharmacokinetics and pharmacodynamics (PK/PD) in patients with advanced cancer
Journal of Clinical Oncology, 2007Co-Authors: Chia Chi Lin, Amita Patnaik, Bob D Brown, Kyri Papadopoulos, K. K. Sankhala, C. H. Takimoto, Jordi Rodon, T. N. Julian, Anthony W. TolcherAbstract:14083 Background: Oblimersen (OBL) is a phosphorothioate oligodeoxynucleotide that decreases Bcl-2 protein levels. OBL has been administered by continuous intravenous infusion (CIVI) in most clinic...
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A Phase II, Pharmacokinetic, and Biological Correlative Study of Oblimersen Sodium and Docetaxel in Patients with Hormone-Refractory Prostate Cancer
Clinical cancer research : an official journal of the American Association for Cancer Research, 2005Co-Authors: Anthony W. Tolcher, John G. Kuhn, Garry Schwartz, Amita Patnaik, K. Berg, Kim N. Chi, Martin E. Gleave, Chris H. Takimoto, Ian M. Thompson, Susan D’aloisioAbstract:Purpose: To determine the antitumor activity and safety of Oblimersen sodium, a phosphorothioate antisense oligonucleotide directed to the bcl-2 mRNA, with docetaxel in patients with hormone-refractory prostate cancer (HRPC) and to determine if relevant pharmacokinetic and pharmacodynamic variables of Oblimersen or docetaxel influence response to this therapy. Experimental Design: Patients with HRPC were treated with Oblimersen sodium by continuous i.v. infusion on days 1 to 8 with docetaxel given i.v. over 1 hour on day 6 every 3 weeks. Plasma samples were analyzed to characterize the pharmacokinetic variables of both Oblimersen and docetaxel, and paired collections of peripheral blood mononuclear cells were collected to determine Bcl-2 protein expression pretreatment and post-treatment. Results: Twenty-eight patients received 173 courses of Oblimersen (7 mg/kg/d continuous i.v. infusion on days 1-8) and docetaxel (75 mg/m 2 i.v. on day 6). Prostate-specific antigen responses were observed in 14 of 27 (52%) patients, whereas 4 of 12 (33%) patients with bidimensionally measurable disease had objective responses. The mean Oblimersen steady-state concentration ( C ss ) was a significant determinant of antitumor activity; mean C ss values were higher in responders compared with nonresponders (6.24 ± 1.68 versus 4.27 ± 1.22; P = 0.008). The median survival of all patients was 19.8 months. Bcl-2 protein expression decreased a median of 49.9% in peripheral blood mononuclear cells post-treatment, but the individual incremental change did not correlate with either Oblimersen C ss or response. Conclusions: Oblimersen combined with docetaxel is an active combination in HRPC patients demonstrating both an encouraging response rate and an overall median survival. The absence of severe toxicities at this recommended dose, evidence of Bcl-2 protein inhibition, and encouraging antitumor activity in HPRC patients warrant further clinical evaluation of this combination, including studies to optimize Oblimersen C ss .
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Predictive Biomarkers of Response to Bc1-2 Biomodulation by G3139 and Docetaxel in Hormone-Refractory Prostate Cancer
2005Co-Authors: Anthony W. TolcherAbstract:Abstract : The specific aims of this grant are to demonstrate (1) that bcl-2 overexpression in prostate cancer specimens is a predictive biomarker for enhanced responsiveness to G3139 (Oblimersen), and antisense oligonucleotide targeting Bcl-2, and docetaxel; (2) that the degree of bcl-2 downregulation in normal tissue surrogate (peripheral blood mononuclear cells MNC), will predict prostate cancer responsiveness to Oblimersen and docetaxel; and (3) whether the pharmacokinetic parameters of Oblimersen and docetaxel are predictive of bcl-2 biomodualtion and antitumor activity, respectively. Oblimersen steady-state concentrations are a predictive determinant of PSA response to the combination of Oblimersen and docetaxel in patients with hormone-refractory prostate cancer. Although the majority of patients had marked decrements in Bcl-2 protein expression in MNCs following treatment with Oblimersen, there was no relationship between the decrement in bcl-2 expression in MNC and response to therapy or Oblimmersen Css. Bcl-2, Bax and Bcl-X expression in the patient's original tumor block specimens was not predictive of response to therapy with Oblimersen and docetaxel. Oblimersen Css is a significant predictor of PSA response to therapy with this combination. Oblimersen at the current recommended dose of 7 mg/kg/day in solid tumor studies may provide inadequate Css for a significant proportion of patients treated that may lead to suboptimal effectiveness in some clinical studies.
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Targeting Bcl-2 protein expression in solid tumors and hematologic malignancies with antisense oligonucleotides.
Clinical advances in hematology & oncology : H&O, 2005Co-Authors: Anthony W. TolcherAbstract:This review article focuses on the intrinsic (mitochondrial) pathway of apoptosis, the function of the Bcl-2 protein family that regulates this pathway, the background of the antisense oligonucleotide Oblimersen, which targets Bcl-2 protein synthesis, and the implications for this agent in hematologic malignancies.
Christian R Noe - One of the best experts on this subject based on the ideXlab platform.
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Off‐Target Effects Related to the Phosphorothioate Modification of Nucleic Acids
ChemMedChem, 2010Co-Authors: Johannes Winkler, Martina Stessl, Jennifer Amartey, Christian R NoeAbstract:Phosphorothioate antisense oligonucleotides have been widely used in clinical studies for rational sequence-specific gene silencing. However, several sequence-unspecific off-target effects have been recently described for this compound class. In contrast to siRNA-mediated knockdown of the same gene, the bcl-2-targeted Oblimersen (Genasense, G3139) downregulates a number of proteins involved in apoptotic resistance and several glycolytic enzymes in 607B human melanoma cells. Regardless of their target, phosphorothioate-modified antisense and siRNA compounds, but not oligonucleotides with a phosphodiester backbone, resulted in a similar impact on the proteome. Unspecifically downregulated proteins include cancer markers involved in apoptotic resistance and endoplasmatic reticulum (ER) stress such as the 78 kDa glucose regulated protein (GRP 78), protein disulfide isomerase A3 (PDIA3, GRP 58), calumenin, and galectin-1, as well as the glycolytic enzymes triose phosphate isomerase, glyceraldehyde phosphodehydrogenase, and phosphoglycerate mutase. The depletion of the glycolytic enzymes is reflected by a decrease in L-lactate production, indicating a partial reversal of the Warburg effect. Compared with other phosphorothioate oligonucleotides, Oblimersen generally led to a more pronounced effect both in terms of the number of influenced proteins and the extent of downregulation, suggesting a synergistic effect of Bcl-2 downregulation.
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a proteomic study reveals unspecific apoptosis induction and reduction of glycolytic enzymes by the phosphorothioate antisense oligonucleotide Oblimersen in human melanoma cells
Journal of Proteomics, 2009Co-Authors: Martina Stessl, Martina Marchettideschmann, Johannes Winkler, Bodo Lachmann, Gunter Allmaier, Christian R NoeAbstract:The question of specificity and the elucidation of the exact molecular mechanism of action of post-transcriptional gene silencing agents are two major challenges for their establishment as therapeutics. A proteomic off-target effect study (2-DE with MS) in combination with DIGE comparing the phosphorothioate antisense oligonucleotide Oblimersen (Genasense, G3139) to a Bcl-2-targeting siRNA-sequence on human melanoma cells showed that additional off-target effects contribute to the apoptotic effect of Oblimersen. When both oligonucleotides were transfected with lipofectamine 2000, only Oblimersen increased apoptosis as determined by annexin staining and caspase activity measurement. In contrast to the highly specific siRNA, the expression level of a number of proteins was found to be altered after Oblimersen treatment. Several proteins linked to apoptosis and stress response, among those galectin-1, cofilin-1, GRP78, HSP60, nucleophosmin, and peroxiredoxins, were identified and found to be down-regulated after Oblimersen treatment. A down-regulation of enolase-1 and three other glycolytic enzymes indicates a reversion of the cancer-related Warburg effect. The observed effects may be caused by a phosphorothioate mediated blockage of the mitochondrial voltage dependent anion channel (VDAC).
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Oligonucleotides Conjugated to Short Lysine Chains
Bioconjugate chemistry, 2005Co-Authors: Johannes Winkler, Ernst Urban, Christian R NoeAbstract:A new method for synthesizing oligonucleotide peptide conjugates by an in-line approach is presented. A phosphorothioate oligonucleotide with the sequence of bcl-2 targeted Oblimersen by employing a modified 2'-amino-2'-desoxy-uridine nucleotide bearing a succinyl linker at the 2' position was prepared. The carboxyl group was protected for solid-phase synthesis as the benzyl ester. Ester cleavage was afforded by a phase transfer reaction using palladium nanoparticles as catalyst and cyclohexadiene as hydrogen donor. Short tails of up to three lysyl residues were conjugated to the oligonucleotide by an inverse stepwise peptide synthesis. The conjugates were characterized by HPLC, mass spectrometry, and circular dichroism. Influence of lysyl tails on CD spectra were minimal. Melting profiles revealed only minimal destabilizing effects on duplexes by conjugation of peptides.
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A novel concept for ligand attachment to oligonucleotides via a 2′‐succinyl linker
Nucleic acids research, 2004Co-Authors: Johannes Winkler, Hubert Pehamberger, Ernst Urban, Doris Losert, Volker Wacheck, Christian R NoeAbstract:Conjugation of ligands to antisense oligonucleotides is a promising approach for enhancing their effects. In this report, a new method for synthesizing oligonucleotide conjugates is described. 2'-Amino-2'-deoxy-5'-dimethoxytrityl-uridine was select ively acylated with a succinic acid linker at the 2' position. This compound was incorporated at the 3' end of an oligonucleotide corresponding to the sequence of Oblimersen. The carboxyl group was protected for oligonucleotide synthesis as a benzyl ester, which could be selectively cleaved at the solid phase by a catalytic phase transfer reaction using palladium nanoparticles as catalyst. An oligonucleotide-fluorescein conjugate was prepared by condensation of aminofluorescein. Circular dichroism spectroscopic experiments showed a B-DNA type structure. The melting temperature of the duplex was only slightly lower than that of Oblimersen. Biological activity measured by western blotting resulted in a Bcl-2 target downregulation nearly identical to that of control Oblimersen on human melanoma cells, proving that this method is attractive for the binding of ligands located in the minor groove.
