oblimersen and Skin-Neoplasms

Merkel cell carcinoma is an aggressive neuroendocrine tumor with a high incidence of local recurrence, regional nodal and distant metastasis, and a high mortality rate. It has been linked to a polyomavirus in addition to immune suppression. Traditionally, treatment options have been limited to surgery and radiation therapy. Better understanding of the molecular pathways of infection and carcinogenesis has provided potential molecular targets and potential immunotherapies which are discussed in this review.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Benzamides; Biomarkers; Carcinoma, Merkel Cell; CD56 Antigen; Electrochemotherapy; Hepatitis A Virus Cellular Receptor 2; Humans; Imatinib Mesylate; Immunotherapy; Immunotherapy, Adoptive; Indazoles; Inhibitor of Apoptosis Proteins; Interferons; Interleukin-12; Interleukin-2; Ipilimumab; Lymphatic Metastasis; Membrane Proteins; Merkel cell polyomavirus; Oligonucleotides, Antisense; Piperazines; Polyomavirus Infections; Prognosis; Programmed Cell Death 1 Receptor; Pyrimidines; Receptors, Somatomedin; Skin Neoplasms; Somatostatin; Sulfonamides; Survivin; Thionucleotides; TOR Serine-Threonine Kinases

Oblimersen (Genasense is a Bcl-2 antisense compound that selectively targets Bcl-2 RNA for degradation by RNase H and thereby decreases Bcl-2 protein production. Bcl-2 protein plays a major role in preventing apoptosis and has been linked to chemotherapy resistance in melanoma. Preclinical studies with oblimersen in melanoma cell lines and xenograft models of melanoma have demonstrated downregulation of Bcl-2 protein, induction of apoptosis and enhanced tumor response when combined with chemotherapy. Results of a Phase I/II study have shown that reducing Bcl-2 with oblimersen coincident with the administration of dacarbazine may amplify apoptosis and improve therapeutic outcome. A subsequent Phase III trial showed that the addition of oblimersen to dacarbazine significantly improved multiple clinical outcomes relative to dacarbazine alone based on an intent-to-treat analysis of progression-free survival and response rate (overall, complete and durable), as well as overall survival in patients with normal lactate dehydrogenase. This article reviews the biochemistry, pharmacodynamics and pharmacokinetics, safety and efficacy data related to oblimersen in melanoma.

Topics: Antineoplastic Agents, Alkylating; Humans; Melanoma; Oligonucleotides, Antisense; Proto-Oncogene Proteins c-bcl-2; Skin Neoplasms; Thionucleotides

The results of treatment for metastatic melanoma remain disappointing. Single-agent chemotherapy produces response rates ranging from 8% to 15%, and combination chemotherapy, from 10% to 30%. However, these responses are usually not durable. Immunotherapy, particularly high-dose interleukin (IL)-2 (Proleukin), has also shown a low response rate of approximately 15%, although it is often long-lasting. In fact, a small but finite cure rate of about 5% has been reported with high-dose IL-2. Phase II studies of the combination of cisplatin-based chemotherapy with IL-2 and interferon-alfa, referred to as biochemotherapy, have shown overall response rates ranging from 40% to 60%, with durable complete remissions in approximately 8% to 10% of patients. Although the results of the phase II single-institution studies were encouraging, phase III multicenter studies have reported conflicting results, which overall have been predominantly negative. Various factors probably explain these discrepancies including different biochemotherapy regimens, patient selection, and, most importantly, "physician selection." Novel strategies are clearly needed, and the most encouraging ones for the near future include high-dose IL-2 in combination with adoptive transfer of selected tumor-reactive T cells after nonmyeloablative regimens, BRAF inhibitors in combination with chemotherapy, and the combination of chemotherapeutic agents and biochemotherapy with oblimersen sodium (Genasense).

Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Dacarbazine; Humans; Immunotherapy; Interleukin-2; Melanoma; Multicenter Studies as Topic; Neoplasm Staging; Prognosis; Randomized Controlled Trials as Topic; Skin Neoplasms; Survival Analysis; Temozolomide; Thionucleotides; Treatment Outcome

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.

Topics: Aged; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Dacarbazine; Disease-Free Survival; Double-Blind Method; Drug Administration Schedule; Female; Gene Expression Regulation, Neoplastic; Humans; Infusions, Intravenous; Male; Melanoma; Middle Aged; Oligonucleotides, Antisense; Prospective Studies; Proto-Oncogene Proteins c-bcl-2; Skin Neoplasms; Thionucleotides; Time Factors; Tomography, X-Ray Computed; Treatment Outcome

The combination of oblimersen, a bcl-2 antisense oligonucleotide, and dacarbazine lead to superior progression-free survival in advanced melanoma patients. Albumin-bound paclitaxel (nab-paclitaxel) has single-agent activity in melanoma.. In a phase I trial, chemotherapy-naïve patients with metastatic melanoma and normal LDH levels were enrolled on 3 cohorts. The treatment regimen consisted of 56-day cycles of oblimersen (7 mg/kg/day continuous IV infusion on day 1-7 and 22-28 in cohort 1 and 2; 900 mg fixed dose, twice weekly in weeks 1-2, 4-5 for cohort 3), temozolomide (75 mg/m(2), days 1-42), and nab-paclitaxel (175 mg/m(2) in cohort 1 and 3, 260 mg/m(2) in cohort 2 on day 7 and 28). Apoptosis markers were tested in pre- and post-treatment specimens of a subset of patients.. Six grade 3 events (neutropenia, renal insufficiency, hyponatremia, elevated creatinine, allergic reaction, and neuropathy) and 2 grade 4 events (neutropenia and thrombocytopenia) were seen in 32 patients. The objective response rate was 40.6% (2 complete responses and 11 partial responses) and 11 patients had stable disease, for a disease control rate of 75%.. The combination of oblimersen, temozolomide, and nab-paclitaxel was well tolerated and demonstrated encouraging activity in patients with advanced melanoma.

Topics: Adult; Aged; Albumin-Bound Paclitaxel; Albumins; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Dacarbazine; Humans; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Oligonucleotides, Antisense; Paclitaxel; Skin Neoplasms; Temozolomide; Thionucleotides; Treatment Outcome

Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine malignancy of the skin. Preclinical studies have identified up-regulation of the critical antiapoptosis gene bcl-2 in MCC. We conducted a multicenter phase II trial of the novel bcl-2 antisense agent (G3139, Genasense) in patients with advanced MCC.. Twelve patients (9 men, 3 women) with histologically confirmed metastatic or regionally recurrent MCC were enrolled. Ten patients (83%) had received prior chemotherapy. Eight patients (67%) had Karnofsky performance status of 90 to 100. Patients received continuous IV infusion of G3139 (7 mg/kg/d) via central venous access in an outpatient setting for 14 days, followed by a 7-day rest period. Response was assessed at 6-week intervals. Patients were allowed to continue therapy until unacceptable toxicity or disease progression.. No objective responses were observed. The best response was stable disease in 3 patients and progressive disease in 9 patients. A median of 4 doses per patient (total 46 doses) was administered. Dose delays and/or reductions were required in 6 patients. One patient developed grade 4 lymphopenia. One patient developed grade 3 renal failure characterized by grade 3-elevated creatinine and grade 4 hyperkalemia. Other grade 3 events included cytopenia (n = 5), aspartate aminotransferase/alanine aminotranferease elevation (n = 3), hypophosphatemia (n = 2), and pain (n = 1). The most frequent grade 1 to 2 toxicities were elevated creatinine, ALT elevation, hypokalemia, lymphopenia, and fatigue.. Bcl-2 antisense therapy (G3139) was well tolerated among patients with advanced MCC. Although probable antitumor activity was documented in 1 patient, no objective responses per Response Evaluation Criteria in Solid Tumors criteria were observed.

Topics: Aged; Carcinoma, Merkel Cell; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Oligonucleotides, Antisense; Prognosis; Skin Neoplasms; Survival Rate; Thionucleotides

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 [1.1xupper limit of normal (ULN)]. Each stratification factor was assessed for an interaction with treatment on survival and an interaction was detected only for LDH.. Baseline LDH values in Study GM301 treatment groups were combined and analysed using cutoffs above and below 1xULN. 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.. 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.. In designing studies, LDH should be considered, regardless of tumour size or disease site.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Dacarbazine; Follow-Up Studies; Humans; L-Lactate Dehydrogenase; Liver Neoplasms; Melanoma; Prognosis; Skin Neoplasms; Survival Analysis; Thionucleotides; Treatment Outcome

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.. 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.. 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.. 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.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Combined Modality Therapy; Dacarbazine; Disease Progression; Drug Resistance, Neoplasm; Female; Humans; L-Lactate Dehydrogenase; Male; Melanoma; Middle Aged; Oligonucleotides, Antisense; Proto-Oncogene Proteins c-bcl-2; Skin Neoplasms; Survival Analysis; Thionucleotides; Treatment Outcome

New medications and combination treatment strategies for patients with metastatic melanoma are discussed.. Bcl-2 is an inhibitor of apoptosis that is overexpressed in approximately 80% of melanoma cell lines and is believed to contribute to the development of resistance to cytotoxic chemotherapy in patients with melanoma. Oblimersen, an antisense oligonucleotide that stops the translation of Bcl-2 mRNA to protein, significantly improved progression-free survival when administered in combination with dacarbazine. Overall survival was significantly improved in patients with low levels of serum lactate dehydrogenase (LDH), but not in patients with elevated LDH. RAF proteins are a family of serine/threonine kinases that regulate many aspects of cellular function. RAF mutations occur in 70% of melanoma cell lines. Although RAF kinases are thought to be important in the pathogenesis of melanoma, RAF inhibition with sorafenib has not significantly improved survival in patients with advanced disease. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a naturally occurring inhibitor of T-cell function that prevents the complete activation of T cells upon exposure to antigens by antigen-presenting cells. Two monoclonal antibodies to CTLA-4 (tremelimumab and ipilimumab) have been developed to promote T-cell activation in melanoma and other types of cancer. Phase I and phase II clinical trials of these agents in patients with metastatic melanoma have demonstrated promising effects on tumor progression, with objective response rates of approximately 20% and sustained responses in some patients. Several vaccines have been developed to stimulate immune system responses against melanoma. Despite promising early findings with polyvalent melanoma vaccine and with vaccine containing heat shock proteins, results with these agents in larger clinical trials have been disappointing.. Ongoing clinical trials continue to evaluate these and other novel approaches to the treatment of metastatic melanoma.

Topics: Antibodies, Monoclonal; Antigens, CD; Antineoplastic Agents; Benzenesulfonates; Cancer Vaccines; Clinical Trials as Topic; CTLA-4 Antigen; Humans; Melanoma; Niacinamide; Phenylurea Compounds; Pyridines; raf Kinases; Skin Neoplasms; Sorafenib; Thionucleotides

Advanced melanoma resists all current therapies, and metastases in the liver are particularly problematic. Prevalent resistance factors include elevated glutathione (GSH) and increased expression of bcl-2 in melanoma cells. GSH has pleiotropic effects promoting cell growth and broad resistance to therapy, whereas Bcl-2 inhibits the activation of apoptosis and contributes to elevation of GSH. This study determined the in vivo efficacy of combination therapies administered while GSH and Bcl-2 were individually and simultaneously decreased in metastatic melanoma lesions.. Highly metastatic murine B16 melanoma (B16M-F10) cells have elevated levels of both GSH and Bcl-2. B16M-F10 cells were injected i.v. to establish metastatic lesions in vivo. GSH was decreased using an L-glutamine--enriched diet and administration of verapamil and acivicin, whereas Bcl-2 was reduced using oligodeoxynucleotide G3139. Paclitaxel, X-rays, tumor necrosis factor-alpha, and IFN-gamma were administered as a combination therapy.. Metastatic cells were isolated from liver to confirm the depletion of GSH and Bcl-2 in vivo. Reduction of Bcl-2 and GSH, combined with partial therapies, decreased the number and volume of invasive B16M-F10 foci in liver by up to 99% (P<0.01). The full combination of paclitaxel, X-rays, and cytokines eliminated B16M-F10 cells from liver and all other systemic disease, leading to long-term survival (>120 days) without recurrence in 90% of mice receiving the full therapy. Toxicity was manageable; the mice recovered quickly, and hematology and clinical chemistry data were representative of accepted clinical toxicities.. Our results suggest a new strategy to induce regression of late-stage metastatic melanoma.

Topics: Animals; Antineoplastic Agents, Phytogenic; Combined Modality Therapy; Glutamine; Glutathione; Melanoma, Experimental; Mice; Neoplasm Metastasis; Paclitaxel; Proto-Oncogene Proteins c-bcl-2; Skin Neoplasms; Thionucleotides; Treatment Outcome; Tumor Necrosis Factor-alpha; X-Rays

Topics: Combined Modality Therapy; Dacarbazine; Extracellular Signal-Regulated MAP Kinases; Humans; Melanoma; Oligonucleotides, Antisense; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Skin Neoplasms; Thionucleotides

Topics: Antineoplastic Combined Chemotherapy Protocols; Dacarbazine; Drug Approval; Humans; Melanoma; Oligonucleotides, Antisense; Randomized Controlled Trials as Topic; Skin Neoplasms; Thionucleotides; United States; United States Food and Drug Administration

Topics: Cancer Vaccines; Humans; Melanoma; Neoplasm Metastasis; Oligonucleotides, Antisense; Prognosis; Skin Neoplasms; Survival; Thionucleotides

Inhibition of the function of Bcl-2 protein has been postulated to sensitize cells to cytotoxic chemotherapy. G3139 (Genasense) is a phosphorothioate anti-Bcl-2 antisense oligonucleotide, but its mechanism of action is uncertain. The aim of the present work is to investigate inhibition of Bcl-2 expression in 518A2 melanoma cells, the cell line on which recent phase II and phase III clinical trials employing this agent were based.. We down-regulated the expression of Bcl-2 protein by two different strategies in these cells: one employing G3139 and controls, and the other using a small interfering RNA approach. Cell viability after treatment with oligonucleotides or small interfering RNA and cytotoxic agents including gemcitibine, DDP, docetaxel, and thapsigargin was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. A 518A2 melanoma cell line stably overexpressing Bcl-2 protein was constructed and treated with either these cytotoxic agents or G3139.. The cytotoxic effects of either G3139 or small interfering RNA treatment of 518A2 melanoma cells are Bcl-2 independent. In addition, in the Bcl-2-overexpressing cells, only a modest increment in chemoresistance was observed, and treatment with G3139 not only did not down-regulate Bcl-2 expression but produced essentially identical toxicity as was observed in the wild-type or mock-transfected cells.. Our results suggest that the mechanism whereby G3139 produces drug-induced cytotoxicity in the 518A2 melanoma line is not dependent on levels of Bcl-2. These findings emphasize the nonsequence specific effects of this phosphorothioate oligonucleotide and call into question the validity of Bcl-2 as a target in this cell line.

Topics: Antineoplastic Agents; Apoptosis; Cisplatin; Deoxycytidine; Docetaxel; Down-Regulation; Drug Resistance, Neoplasm; Enzyme Inhibitors; Gemcitabine; Humans; Melanoma; Oligonucleotides, Antisense; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; RNA, Small Interfering; Skin Neoplasms; Taxoids; Thapsigargin; Thionucleotides; Tumor Cells, Cultured