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Kerstin Trunzer,
Anna C Pavlick,
Lynn Schuchter,
Rene Gonzalez,
Grant A McArthur,
Thomas E Hutson,
Stergios J Moschos,
Keith T Flaherty,
Kevin B Kim,
Jeffrey S Weber, [......],
Mark Kockx,
Olivia Spleiss,
Annette Schell-Steven,
Houston N Gilbert,
Louise Cockey,
Gideon Bollag,
Richard J Lee,
Andrew K Joe,
Jeffrey A Sosman,
Antoni Ribas
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ABSTRACT: PURPOSETo assess pharmacodynamic effects and intrinsic and acquired resistance mechanisms of the BRAF inhibitor vemurafenib in BRAF(V600)-mutant melanoma, leading to an understanding of the mechanism of action of vemurafenib and ultimately to optimization of metastatic melanoma therapy. METHODS
In the phase II clinical study NP22657 (BRIM-2), patients received oral doses of vemurafenib (960 mg twice per day). Serial biopsies were collected to study changes in mitogen-activated protein kinase (MAPK) signaling, cell-cycle progression, and factors causing intrinsic or acquired resistance by immunohistochemistry, DNA sequencing, or somatic mutation profiling.ResultsVemurafenib inhibited MAPK signaling and cell-cycle progression. An association between the decrease in extracellular signal-related kinase (ERK) phosphorylation and objective response was observed in paired biopsies (n = 22; P = .013). Low expression of phosphatase and tensin homolog showed a modest association with lower response. Baseline mutations in MEK1(P124) coexisting with BRAF(V600) were noted in seven of 92 samples; their presence did not preclude objective tumor responses. Acquired resistance to vemurafenib associated with reactivation of MAPK signaling as observed by elevated ERK1/2 phosphorylation levels in progressive lesions and the appearance of secondary NRAS(Q61) mutations or MEK1(Q56P) or MEK1(E203K) mutations. These two activating MEK1 mutations had not previously been observed in vivo in biopsies of progressive melanoma tumors. CONCLUSION
Vemurafenib inhibits tumor proliferation and oncogenic BRAF signaling through the MAPK pathway. Acquired resistance results primarily from MAPK reactivation driven by the appearance of secondary mutations in NRAS and MEK1 in subsets of patients. The data suggest that inhibition downstream of BRAF should help to overcome acquired resistance.
Journal of Clinical Oncology 04/2013; · 18.37 Impact Factor
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Edward L Jones,
Teresa S Jones,
Nathan W Pearlman,
Dexiang Gao,
Robert Stovall,
Csaba Gajdos,
Nicole Kounalakis,
Rene Gonzalez, Karl D Lewis,
William A Robinson,
Martin D McCarter
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ABSTRACT: OBJECTIVE To analyze the predictors and patterns of recurrence of melanoma in patients with a negative sentinel lymph node biopsy result. DESIGN Retrospective chart review of a prospectively created database of patients with cutaneous melanoma. SETTING Tertiary university hospital. PATIENTS A total of 515 patients with melanoma underwent a sentinel lymph node biopsy without evidence of metastatic disease between 1996 and 2008. MAIN OUTCOME MEASURES Time to recurrence and overall survival. RESULTS Of 515 patients, 83 (16%) had a recurrence of melanoma at a median of 23 months during a median follow-up of 61 months (range, 1-154 months). Of these 83 patients, 21 had melanoma that metastasized in the studied nodal basin for an in-basin false-negative rate of 4.0%. Patients with recurrence had deeper primary lesions (mean thickness, 2.7 vs 1.8 mm; P < .001) that were more likely to be ulcerated (32.5% vs 13.5%; P < .001) than those without recurrence. The primary melanoma of patients with recurrence was more likely to be located in the head and neck region compared with all other locations combined (31.8% vs 11.7%; P < .001). Median survival following a recurrence was 21 months (range, 1-106 months). Favorable characteristics associated with lower risk of recurrence included younger age at diagnosis (mean, 49 vs 57 years) and female sex (9% vs 27% for males; P < .001). CONCLUSION Overall, recurrence of melanoma (16%) after a negative sentinel lymph node biopsy result was similar to that in previously reported studies with an in-basin false-negative rate of 4.0%. Lesions of the head and neck, the presence of ulceration, increasing Breslow thickness, older age, and male sex are associated with increased risk of recurrence, despite a negative sentinel lymph node biopsy result.
JAMA surgery. 01/2013;
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Kevin B Kim,
Richard Kefford,
Anna C Pavlick,
Jeffrey R Infante,
Antoni Ribas,
Jeffrey A Sosman,
Leslie A Fecher,
Michael Millward,
Grant A McArthur,
Patrick Hwu,
Rene Gonzalez,
Patrick A Ott,
Georgina V Long,
Olivia S Gardner,
Daniele Ouellet,
Yanmei Xu,
Douglas J Demarini,
Ngocdiep T Le,
Kiran Patel, Karl D Lewis
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ABSTRACT: PURPOSEBRAF mutations promote melanoma cell proliferation and survival primarily through activation of MEK. The purpose of this study was to determine the response rate (RR) for the selective, allosteric MEK1/MEK2 inhibitor trametinib (GSK1120212), in patients with metastatic BRAF-mutant melanoma. PATIENTS AND METHODS
This was an open-label, two-stage, phase II study with two cohorts. Patients with metastatic BRAF-mutant melanoma previously treated with a BRAF inhibitor (cohort A) or treated with chemotherapy and/or immunotherapy (BRAF-inhibitor naive; cohort B) were enrolled. Patients received 2 mg of trametinib orally once daily.ResultsIn cohort A (n = 40), there were no confirmed objective responses and 11 patients (28%) with stable disease (SD); the median progression-free survival (PFS) was 1.8 months. In cohort B (n = 57), there was one (2%) complete response, 13 (23%) partial responses (PRs), and 29 patients (51%) with SD (confirmed RR, 25%); the median PFS was 4.0 months. One patient each with BRAF K601E and BRAF V600R had prolonged PR. The most frequent treatment-related adverse events for all patients were skin-related toxicity, nausea, peripheral edema, diarrhea, pruritis, and fatigue. No cutaneous squamous cell carcinoma was observed. CONCLUSION
Trametinib was well tolerated. Significant clinical activity was observed in BRAF-inhibitor-naive patients previously treated with chemotherapy and/or immunotherapy. Minimal clinical activity was observed as sequential therapy in patients previously treated with a BRAF inhibitor. Together, these data suggest that BRAF-inhibitor resistance mechanisms likely confer resistance to MEK-inhibitor monotherapy. These data support further evaluation of trametinib in BRAF-inhibitor-naive BRAF-mutant melanoma, including rarer forms of BRAF-mutant melanoma.
Journal of Clinical Oncology 12/2012; · 18.37 Impact Factor
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Yuchun Luo,
Lixia Z Ellis,
Katiuscia Dallaglio,
Moe Takeda,
William A Robinson,
Steven E Robinson,
Weimin Liu, Karl D Lewis,
Martin D McCarter,
Rene Gonzalez,
David A Norris,
Dennis R Roop,
Richard A Spritz,
Natalie G Ahn,
Mayumi Fujita
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ABSTRACT: Side population (SP) cells are identified as cells capable of excluding the fluorescent Hoechst dye and anticancer drugs, and it represents hematopoietic stem cells and chemoresistant cells from several solid tumors. In this study, we confirmed the presence of SP cells in tumors from melanoma patients. Melanoma SP cells overexpressed ATP-binding-cassette (ABC) transporters, ABCB1 and ABCB5. We generated a direct in vivo xenograft model, and demonstrated that SP cells were resistant to paclitaxel, a substrate of ABCB1, both in vitro and in vivo. However, melanoma SP cells were also resistant to temozolomide, which is not a substrate for ABC transporters, through IL-8 upregulation. In addition, gene profiling studies identified three signaling pathways (NF-κB, α6-β4-integrin, and IL-1) as differentially upregulated in melanoma SP cells, and there was a significant increase of PCDHB11 and decrease of FUK and TBX2 in these cells. Therefore, we provide evidence that SP is an enriched source of chemoresistant cells in human melanomas, and suggest that the selected genes and signaling pathways of SP cells may be a potential target for effective melanoma therapies. To our knowledge, this is a previously unreported study to isolate SP cells from melanoma patients and to investigate the gene expression profiling of these cells.
Journal of Investigative Dermatology 05/2012; 132(10):2440-50. · 6.31 Impact Factor
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Jeffrey A Sosman,
Kevin B Kim,
Lynn Schuchter,
Rene Gonzalez,
Anna C Pavlick,
Jeffrey S Weber,
Grant A McArthur,
Thomas E Hutson,
Stergios J Moschos,
Keith T Flaherty, [......],
Ravi K Amaravadi,
Bartosz Chmielowski,
H Jeffrey Lawrence,
Yu Shyr,
Fei Ye,
Jiang Li,
Keith B Nolop,
Richard J Lee,
Andrew K Joe,
Antoni Ribas
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ABSTRACT: Approximately 50% of melanomas harbor activating (V600) mutations in the serine-threonine protein kinase B-RAF (BRAF). The oral BRAF inhibitor vemurafenib (PLX4032) frequently produced tumor regressions in patients with BRAF V600-mutant metastatic melanoma in a phase 1 trial and improved overall survival in a phase 3 trial.
We designed a multicenter phase 2 trial of vemurafenib in patients with previously treated BRAF V600-mutant metastatic melanoma to investigate the efficacy of vemurafenib with respect to overall response rate (percentage of treated patients with a tumor response), duration of response, and overall survival. The primary end point was the overall response rate as ascertained by the independent review committee; overall survival was a secondary end point.
A total of 132 patients had a median follow-up of 12.9 months (range, 0.6 to 20.1). The confirmed overall response rate was 53% (95% confidence interval [CI], 44 to 62; 6% with a complete response and 47% with a partial response), the median duration of response was 6.7 months (95% CI, 5.6 to 8.6), and the median progression-free survival was 6.8 months (95% CI, 5.6 to 8.1). Primary progression was observed in only 14% of patients. Some patients had a response after receiving vemurafenib for more than 6 months. The median overall survival was 15.9 months (95% CI, 11.6 to 18.3). The most common adverse events were grade 1 or 2 arthralgia, rash, photosensitivity, fatigue, and alopecia. Cutaneous squamous-cell carcinomas (the majority, keratoacanthoma type) were diagnosed in 26% of patients.
Vemurafenib induces clinical responses in more than half of patients with previously treated BRAF V600-mutant metastatic melanoma. In this study with a long follow-up, the median overall survival was approximately 16 months. (Funded by Hoffmann-La Roche; ClinicalTrials.gov number, NCT00949702.).
New England Journal of Medicine 02/2012; 366(8):707-14. · 53.30 Impact Factor
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ABSTRACT: Melanoma is a malignancy that is highly curable in the early stages but has devastating consequences in later stages due to lack of response to traditional treatments. Improved understanding of the basic science of tumorigenesis has helped lead to novel targeted therapies which are producing beneficial results in patients with melanoma. Enhancement of the immune system by blockade of the cytotoxic T-lymphocyte associated antigen-4 by the monoclonal antibody ipilimumab is now approved by the United States Food and Drug Administration (FDA) for use in patients with unresectable melanoma. The approval of this drug was based on the first ever data in melanoma showing an improvement in overall survival. New advances in targeting components of the mitogen-activated protein kinase pathway are showing impressive responses in clinical trials in most patients harboring activating mutations in BRAF. Thus, this is a new era in the management of melanoma and we review the recent progress made in treating patients with advanced disease.
rapeutic Advances in Medical Oncology, The 09/2011; 3(5):245-51.
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European journal of dermatology: EJD 08/2011; 21(4):642-3. · 2.53 Impact Factor
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ABSTRACT: INTRODUCTION: Stage III melanoma, also referred to as regional metastatic melanoma, has five-year survival rates ranging between 40% and 78%. In order to reduce the likelihood of recurrence in this high-risk population, patients undergo resection of primary tumors and all involved nodal basins. Systemic therapy is being pursued in an effort to improve outcome data, but the best strategy has yet to be defined. Interferon alpha-2b remains to date the most promising approach available. Toxicities and intensive intravenous administration, unfortunately, are major concerns. An alternative is the use of interferon in its pegylated subcutaneous form. The aim of this research was to review the evidence for the use of pegylated interferon alpha-2b in Stage III malignant melanoma. EVIDENCE REVIEW: ECOG 1684 was the pivotal trial that first demonstrated a statistically significant benefit in relapse-free and overall survival for adjuvant interferon alpha-2b in high-risk melanoma. Other larger studies, such as ECOG 1690, confirmed a relapse-free survival benefit but did not achieve statistical significance for overall survival. The first study of the pegylated form of interferon alpha-2b in Stage III melanoma, EORTC 18991, is reviewed here. This trial showed a statistically significant improvement in relapse-free survival but not overall survival. Encouraging data of potential equivalent efficacy, easier administration, and fewer Grade 3 and 4 adverse reactions compared with high-dose intravenous interferon raises the question of its potential role in Stage III melanoma in the adjuvant setting.
Core Evidence 01/2010; 5:39-48.
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ABSTRACT: The development of vitiligo has been associated with an improved clinical response in melanoma patients.
We report a case of vitiligo associated with a novel antisurvivin drug and review the literature to determine the pathogenesis of vitiligo occurring during melanoma treatment.
A 78-year-old man with stage IV malignant melanoma developed vitiligo after the first therapeutic cycle of a novel antisurvivin drug. Although his vitiligo remained static, his melanoma continued to progress and he died in 8 months. A review of the literature demonstrates a relationship between vitiligo development and improved clinical response in many melanoma cases treated with immunotherapy; however, the relationship may depend on the type of treatment.
Understanding complex immune responses in vitiliginous skin and melanoma sites is important in order to interpret the development of vitiligo occurring during melanoma treatment.
International journal of dermatology 05/2009; 48(4):426-30. · 1.18 Impact Factor
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ABSTRACT: Growth factors that stimulate angiogenesis are vital in tumor development and maintenance. Inhibitors of angiogenesis are emerging as key elements in anticancer treatments, and now antibodies and small molecule kinase inhibitors are approved in the treatment of a variety of solid tumors. These have shown modest but statistically significant benefit in colon, breast and lung cancers. PI-88 has a novel mechanism of action compared to the drugs on the market today. By inhibiting heparanase, PI-88 blocks angiogenesis on several different cellular and biological levels. Promising results from Phase I/II trials are being seen with PI-88 in a variety of tumor types including melanoma and hepatocellular carcinoma. However, the development of antibody-induced thrombocytopenia has limited its use in some patients.
Expert Opinion on Investigational Drugs 12/2008; 17(11):1769-76. · 5.27 Impact Factor
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ABSTRACT: Melanoma often elicits a profound immune response, and this response has been exploited by various immune therapies. These immunotherapies ultimately fail, however, and advanced melanoma is uniformly fatal, suggesting the development of an immune escape mechanism. In this study, markers of immune escape including regulatory T cells (T(regs)), dendritic cells (DCs), and TGF-beta were evaluated in 14 Stage IV melanoma patients and correlated with survival.
Peripheral blood mononuclear cells were isolated from Stage IV melanoma patients and analyzed for T(regs) and DCs by flow cytometry using fluorescent CD3, CD4, CD25, Lin, HLA-DR, CD11c, and CD123 antibodies. Serum TGF-beta levels were evaluated by ELISA from these patients. Clinical data were extracted from the patients' medical records.
Stage IV melanoma patients with shorter survival (less than 24 mo) had a significantly higher proportion of T(regs) than those with longer survival (15% versus 8%, respectively, P = 0.004). The numbers of DCs and the serum TGF-beta levels were not significantly different in these two groups. There was an inverse relationship between the percentage of T(regs) and survival, although this did not reach statistical significance (r = -0.35, P = 0.22). There was also an inverse relationship between peripheral T(regs) and DCs. When patients were divided into groups of greater than or less than 7% T(regs), the number of total DCs was higher in the patients with fewer T(regs) than in those with more T(regs), but this did not reach statistical significance (16,535 versus 12,126 total DCs/mL, P = 0.52).
In Stage IV melanoma patients, a high percentage of T(regs) appears to be associated with shorter survival. The inverse relationship of the number of DCs and T(regs) in these patients may provide an insight to the origin of this observation.
Journal of Surgical Research 07/2008; 154(1):13-20. · 2.25 Impact Factor
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Karl D Lewis,
William A Robinson,
Michael J Millward,
Alex Powell,
Timothy J Price,
Damien B Thomson,
Euan T Walpole,
Andrew M Haydon,
Brian R Creese,
Kaye L Roberts,
John R Zalcberg,
Rene Gonzalez
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ABSTRACT: Treatment options for advanced melanoma are limited. PI-88, a potent inhibitor of heparanase, demonstrates anitangiogenic properties and has shown activity against melanoma in phase I studies. This was an open-label, multicenter, phase II study of PI-88 in patients with advanced melanoma. Patients received a fixed-dose of 250 mg/day given subcutaneously for four consecutive days followed by three drug-free days per week in a 28-day cycle. A total of 44 patients were enrolled in the intent to treat population, with 59.1% having received previous therapy. The median time to progression and overall survival was 1.7 months and 9 months, respectively. Forty-one patients are included in the efficacy analysis. One (2.4%) patient achieved a partial response, six (14.6%) patients had stable disease as best response, and 30 (73.2%) had progressive disease. At the end of six cycles of treatment, three of the 41 evaluable patients had non-progressive disease. Treatment was generally well tolerated. Injection site bruising occurred in 45% of patients. Serious bleeding did occur in two patients and three patients developed a positive anti-platelet antibody test during the study. One of these four patients experienced an associated thrombosis. In patients with advanced melanoma, PI-88 demonstrates an overall survival and time to progression similar to standard chemotherapy. Although the current study did not meet the primary end-point of progression free survival of >or=20%, there is some evidence of activity and further investigation is warranted.
Investigational New Drugs 02/2008; 26(1):89-94. · 3.36 Impact Factor
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Karl D Lewis,
William A Robinson,
Martin McCarter,
Nathan Pearlman,
Steven J O'Day,
Clay Anderson,
Thomas T Amatruda,
Anna Baron,
Chan Zeng,
Maude Becker,
Susan Dollarhide,
Karen Matijevich,
Rene Gonzalez
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ABSTRACT: To determine the relapse-free survival, overall survival, and response rate of patients with stage III melanoma treated with neoadjuvant biochemotherapy in a multicenter setting.
Patients with pathologically proven stage III melanoma, either via clinical detection or sentinel lymph node positivity, were eligible for enrollment. Patients received two cycles of preoperative biochemotherapy followed by complete regional lymphadenectomy and two postoperative courses of biochemotherapy. The biochemotherapy regimen consisted of the following: cisplatin 20 mg/m2 on days 1 to 4, dacarbazine 800 mg/m2 on day 1 only, vinblastine 1.6 mg/m2 on days 1 to 4, interleukin-2 total dose of 36 MU/m2 during 4 days, and interferon alfa 5 MU/m2 on days 1 to 5. Growth factor support was administered with each cycle.
Ninety-two patients were eligible for the study. At a median follow-up of 40.4 months, relapse-free survival and overall survival are 64% and 78%, respectively. There was a lower relapse rate and improved survival for patients with a positive sentinel lymph node compared with patients with clinically detected lymph nodes, although this difference did not reach statistical significance. Of the 50 patients with measurable disease, the overall response rate was 26%. Toxicity of the biochemotherapy was high but generally manageable.
The current study has expanded the preliminary evidence on neoadjuvant biochemotherapy for stage III melanoma.
Journal of Clinical Oncology 08/2006; 24(19):3157-63. · 18.37 Impact Factor
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Oncology (Williston Park, N.Y.) 07/2006; 20(7):763-70. · 1.03 Impact Factor
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ABSTRACT: Metastatic melanoma continues to be a very difficult disease to treat. Options are limited and often have very little impact on the course of the disease. The objective of the current study was to evaluate the efficacy and safety of continuously administered Apomine (SR-45023A), a novel bisphosphonate, in patients with previously treated metastatic malignant melanoma. Adult patients with previously treated metastatic melanoma received Apomine 100 mg orally, twice daily (total dose 200 mg per day) continuously for 28 days (defined as a cycle). Treatment was continued until disease progression or unacceptable toxicity. A total of 42 patients received at least one dose of Apomine. Stable disease was achieved in 2 patients (5%). No complete or partial responses were observed. Progression free survival of at least 16 weeks was observed in 6 patients (14%). The median overall survival was 6.1 months (95% CI, 4.9-9.4 months). Time to treatment failure was 1.7 months (95% CI, 1.6-1.8 months) with Apomine therapy. By cycle 2, Apomine concentrations reached steady-state. Apomine was well tolerated with only 37% of patients experiencing any drug-related event. Abdominal pain was the most frequent adverse event occurring in 26% of patients. In conclusion, Apomine, at the current dose studied, failed to produce a 30% progression free survival rate at 16 weeks considered to be a meaningful benefit for further development.
Investigational New Drugs 02/2006; 24(1):89-94. · 3.36 Impact Factor
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ABSTRACT: Metastatic malignant melanoma remains a very difficult disease to treat. Previous phase II studies using biochemotherapy (combination of platinum-containing chemotherapy with IL-2 and IFNalpha) have shown response rates of about 50%. However, a site of frequent relapse is in the central nervous system (CNS). Temozolomide is an oral alkylating agent that has equivalent activity to dacarbazine, but it has the advantage of CNS penetration. We report the results of a phase II study using a novel biochemotherapy regimen containing temozolomide, cisplatin, decrescendo IL-2, IFNalpha, and GM-CSF in the treatment of stage IV melanoma. Seventy-one patients with histologically confirmed metastatic melanoma were enrolled between June 1998 and October 1999. Prior chemotherapy or IL-2 was not permitted. The median age was 54 years (range 22-72). Twenty-one patients (30%) had a history of treated brain metastases. Patients received temozolomide 150 mg/m2 orally days 1-5, cisplatin 30 mg/m2 IV days 1-3, IFNalpha 5 MU/m2 SQ on days 1-5, and IL-2 was administered in a decrescendo fashion according to the following schedule: day 1: 18 MU/m2 continuous IV infusion over 6 hours; day 2: 18 MU/m2 continuous IV infusion over 12 hours; day 3: 9 MU/m2 subcutaneously q12 hours; day 4: 4.5 MU/m2 subcutaneously x 1. Patients were also given GM-CSF 250 microg subcutaneously days 6-25. The cycles were repeated every 4 weeks. Partial responses were seen in 10 of the 71 patients (14%) with a median duration of response of 9.4 months. There were no complete responses. The median survival for all patients was 8.6 months. Further studies of this novel biochemotherapy regimen are not indicated. Other schedules that incorporate temozolomide and/or GM-CSF and further studies to define the optimal method of delivering IL-2 should be pursued.
Cancer Investigation 02/2005; 23(4):303-8. · 1.85 Impact Factor
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ABSTRACT: Since the discovery of DNA and the subsequent recognition that genetic defects (either inherited or acquired) can be responsible for various disease states, the concept of gene therapy has been extremely appealing. However, despite intensive work in this field of medicine, gene therapy has yet to make a major impact on the treatment of patients. Many technical challenges exist that must be overcome before gene therapy can be put into widespread practice. The gene delivery system (vector) encounters extracellular and intracellular barriers, must be nontoxic and nonimmunogenic, and must allow sufficient expression of the gene of interest. Many vectors have been created in attempts to overcome these problems; however, the ideal expression vector for use in humans has yet to be identified. Both inherited and acquired diseases may potentially benefit from gene therapy. X-linked severe combined immunodeficiency-X1 is an inherited disease in which gene therapy is not only being actively pursued as a potentially curative treatment, but some exciting progress has been made in recent years. In addition, acquired diseases, such as cancer, often have defined genetic alterations and, thus, are potential candidates for treatment with gene therapy. For example, malignant melanoma, a tumor that is notoriously chemoresistant, may avoid immune recognition by progressive loss of cell surface MHC class I molecules. Allovectin-7® is a DNA plasmid containing the gene encoding human MHC class I HLA-B7. Early phase I/II studies of Allovectin-7® in patients with metastatic melanoma have shown some encouraging results. It is one of many examples of how gene therapy may affect cancer treatment in the near future.
American Journal of Cancer 12/2004; 4(3):137-144.
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Oncology (Williston Park, N.Y.) 07/2004; 18(7):794-9. · 1.03 Impact Factor
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Karl D Lewis,
William A Robinson,
Michael J Millward,
Alex Powell,
Timothy J Price,
Damien B Thomson,
Euan T Walpole,
Andrew M Haydon,
Brian R. Creese,
Kaye L. Roberts,
John R Zalcberg,
Rene Gonzalex
[show abstract]
[hide abstract]
ABSTRACT: Treatment options for advanced melanoma are limited. PI-88, a potent inhibitor of heparanase, demonstrates anitangiogenic properties and has shown activity against melanoma in phase I studies. This was an open-label, multicenter, phase II study of PI-88 in patients with advanced melanoma. Patients received a fixed-dose of 250 mg/day given subcutaneously for four consecutive days followed by three drug-free days per week in a 28-day cycle. A total of 44 patients were enrolled in the intent to treat population, with 59.1% having received previous therapy. The median time to progression and overall survival was 1.7 months and 9 months, respectively. Forty-one patients are included in the efficacy analysis. One (2.4%) patient achieved a partial response, six (14.6%) patients had stable disease as best response, and 30 (73.2%) had progressive disease. At the end of six cycles of treatment, three of the 41 evaluable patients had non-progressive disease. Treatment was generally well tolerated. Injection site bruising occurred in 45% of patients. Serious bleeding did occur in two patients and three patients developed a positive anti-platelet antibody test during the study. One of these four patients experienced an associated thrombosis. In patients with advanced melanoma, PI-88 demonstrates an overall survival and time to progression similar to standard chemotherapy. Although the current study did not meet the primary end-point of progression free survival of >/=20%, there is some evidence of activity and further investigation is warranted.
