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Paul B Chapman

Publications and source records attributed to Paul B Chapman.

At least 19 recordsLinked to original sources
PubMed2006

Phase II study of temozolomide plus pegylated interferon-alpha-2b for metastatic melanoma.

BACKGROUND: Temozolomide and interferon-alpha-2b (IFN-alpha-2b) are both active in melanoma. Therefore, the efficacy and safety of temozolomide in combination with pegylated IFN-alpha-2b in patients with metastatic melanoma without brain metastases was investigated. METHODS: Patients with histologically confirmed, unresectable, American Joint Committee on Cancer Stage IV melanoma were enrolled in an open-label, Phase II study. The primary endpoints were tumor response and safety. Patients received temozolomide (75 mg/m2/dayx6 weeks with a 2-week break between cycles) plus concomitant subcutaneous pegylated IFN-alpha-2b (0.5 microg/kg/wk, continuously). Treatment was continued until unacceptable toxicity or disease progression occurred. RESULTS: Thirty-five patients (median age, 55 years) with Stage IV melanoma and a median of 3 metastatic sites were enrolled and received a median of 1 cycle (i.e., 8 weeks) of therapy (range, 0-6 cycles). Eleven patients (31%) (95% confidence interval, 16% to 47%) had an objective tumor response, including 3 with clinical complete response durations of 6 months, 20 months, and 32+ months and 8 with partial responses. Three patients with a partial or mixed response were subsequently rendered free of clinically detectable disease with surgery. The median survival was 12 months with a median follow-up among survivors of 16 months. No patient developed brain metastases while receiving study treatment. Treatment was generally well tolerated. Hematologic toxicity consisted mainly of lymphopenia and leukopenia (National Cancer Institute Common Toxicity Criteria Grades 1-3); no Grade 4 hematologic toxicity was observed. CONCLUSIONS: The combination of temozolomide plus pegylated IFN-alpha-2b had antitumor activity and was well tolerated in patients with metastatic melanoma. Therefore, further study is warranted.

Adult↗
PubMed2006

Immunotherapy of melanoma.

Melanoma has been widely studied as a target for immunotherapy because it has been considered more susceptible to immune attack than other tumors and because of the relative ease with which melanoma cells can be adapted to in vitro culture. The availability of hundreds of melanoma cell lines for study has led to the identification of tumor antigens and the development of monoclonal antibodies and T cells against these antigens, revolutionizing the understanding of how the immune system sees and reacts to cancer. This article reviews the recent clinical results of trials exploring different immunotherapy strategies against melanoma.

Antibodies, Neoplasm↗
PubMed2005

Variates of survival in metastatic uveal melanoma.

PURPOSE: The course and outcome of metastatic uveal melanoma are not well described. We evaluated the survival of our patients with metastatic uveal melanoma, described factors that correlated with survival, and evaluated the influence of screening tests on time of detection and survival. PATIENTS AND METHODS: All patients with metastatic uveal melanoma seen at Memorial Sloan-Kettering Cancer Center between 1994 and 2004 were identified from our database. We recorded date of initial diagnosis, date of metastatic disease, date of last follow-up, site of the first metastasis, how the first metastasis was discovered, treatment, and outcome of therapy. RESULTS: The estimated median survival of the 119 patients analyzed was 12.5 months; 22% of patients were alive at 4 years. Five variates correlated independently with prolonged survival: Lung/soft tissue as only site of first metastasis, treatment with surgery or intrahepatic therapy, female sex, age younger than 60, and a longer interval from initial diagnosis to metastatic disease. Discovering metastatic disease in asymptomatic patients did not correlate with overall survival; 89% of patients had a single organ as the site of first metastasis. Although liver was the most common site, 39.5% of patients had nonliver sites, most commonly lung, as the first site of metastasis. CONCLUSION: A substantial subset of patients with metastatic uveal melanoma survive more than 4 years with metastatic disease. Data on variates of survival and site of first metastasis may guide strategies for screening patients, although our data failed to show a survival advantage in discovering asymptomatic metastatic disease.

Adult↗
PubMed2005

Phase III study of adjuvant vaccination with Bec2/bacille Calmette-Guerin in responding patients with limited-disease small-cell lung cancer (European Organisation for Research and Treatment of Cancer 08971-08971B; Silva Study).

PURPOSE: Bec2 is an anti-idiotypic antibody that mimics GD3, a ganglioside that is expressed on the surface of tumor cells and is of neuroectodermal origin. We assessed whether Bec2/bacille Calmette-Guerin (BCG) vaccination prolongs survival in patients with limited-disease small-cell lung cancer (SCLC) after a major response to chemotherapy and chest radiation. PATIENTS AND METHODS: Patients were randomly assigned to receive five vaccinations of Bec2 (2.5 mg)/BCG vaccine or follow-up. Vaccination was given over a 10-week period. The sample size was targeted to detect an increase in median survival of 40% after random assignment, and stratification was by performance status, response, and institution. Quality of life was assessed by using the European Organisation for Research and Treatment of Cancer instrument. Humoral response was assessed in patients who received vaccination. RESULTS: A total of 515 patients were randomly assigned. The primary toxicities of vaccination were transient skin ulcerations and mild flu-like symptoms. There was no improvement in survival, progression-free survival, or quality of life in the vaccination arm. Median survival from randomization was 16.4 and 14.3 months in the observation and vaccination arms (P = .28), respectively. Among vaccinated patients, a trend toward prolonged survival was observed in those (one third) who developed a humoral response (P = .085). Multivariate analysis showed a positive impact on survival by prior treatment with concomitant chemoradiotherapy, prophylactic cranial irradiation, female sex, low lactate dehydrogenase, and normal platelets. CONCLUSION: Vaccination with Bec2/BCG has no impact on outcome of patients with limited-disease SCLC responding to combined-modality treatment. Vaccination strategies in SCLC may still be warranted using vaccines that produce a better immunologic response.

Adjuvants, Immunologic↗
PubMed2005

Temozolomide plus thalidomide in patients with brain metastases from melanoma: a phase II study.

BACKGROUND: Temozolomide plus thalidomide is a promising oral combination regimen for the treatment of metastatic melanoma. The current Phase II study examined the efficacy and safety of this combination in chemotherapy-naive patients with brain metastases. METHODS: Patients with histologically confirmed metastatic melanoma and measurable brain metastases received temozolomide (75 mg/m2 per day for 6 weeks with a 2-week break between cycles) plus concomitant thalidomide (200 mg/day escalating to 400 mg/day for patients < 70 years or 100 mg/day escalating to 250 mg/day for patients > or = 70 years). The primary end point was tumor response in the brain assessed every 8 weeks. RESULTS: Twenty-six patients with a median age of 60 years were treated. All patients had progressive brain metastases: 16 were symptomatic and 25 had extensive extracranial metastases. Eight patients had received whole-brain radiotherapy, 4 had received stereotactic radiotherapy, and 8 had received craniotomy with resection of hemorrhagic lesions. Fifteen patients completed > or = 1 cycle (median, 1 cycle; range, 0-4 cycles), and 11 discontinued treatment before completing 1 cycle (7 for intracranial hemorrhage, 2 for pulmonary embolism, 1 for deep vein thrombosis, and 1 for Grade 3 rash). Of 15 patients assessable for response, 3 had a complete or partial response (12% intent to treat) and 7 had minor response or stable disease in the brain. However, 5 of these 10 patients had disease progression at extracranial sites. The median survival period was 5 months for all 26 patients and 6 months for the 15 assessable patients. CONCLUSIONS: Temozolomide plus thalidomide was an active oral regimen for patients with brain metastases from malignant melanoma.

Adult↗
PubMed2005

Helping melanoma patients decide whether to choose adjuvant high-dose interferon-alpha2b.

High-dose interferon-alpha2b is a U.S. Food and Drug Administration-approved adjuvant treatment for stage III melanoma, and yet, because of its limited efficacy and well-known toxicity, it is not universally accepted by patients and oncologists. In this paper, we evaluate the benefits and risks of adjuvant high-dose interferon-alpha2b and try to provide a framework to help oncologists guide patients trying to decide whether to undergo adjuvant high-dose interferon therapy.

Decision Making↗
PubMed2004

Clinical significance of BRAF mutations in metastatic melanoma.

Forty to eighty percent of melanoma tumors have activating mutations in BRAF although the clinical importance of these mutations is not clear. We previously reported an analysis of BRAF mutations in metastatic melanoma samples from 68 patients. In this study, we correlated patient baseline characteristics, prognostic factors, and/or clinical outcomes with the presence of BRAF mutations. No significant differences were observed in age, gender, location of primary melanoma, stage at the diagnosis, and depth of primary tumor between patients with and without BRAF mutations. Melanomas harboring BRAF mutations were more likely to metastasize to liver (P = 0.02) and to metastasize to multiple organs (P = 0.048). Neither time to progression to stage IV nor overall survival were associated with BRAF mutations. In conclusion, we observed no significant differences in clinical characteristics or outcomes between melanomas with or without BRAF mutations. Although there was an increased frequency of liver metastasis and tendency to metastasize to multiple organs in tumors with BRAF mutations, there was no detectable effect on survival. Future prospective studies should include analysis of whether BRAF mutations in melanoma tumors correlate with an increased tendency to metastasize to liver or to multiple organs.

Journal Article↗
PubMed2004

A phase II trial comparing five dose levels of BEC2 anti-idiotypic monoclonal antibody vaccine that mimics GD3 ganglioside.

In previous studies, we showed that immunization with 2.5 mg of BEC2, an anti-idiotypic MAb that mimics GD3 ganglioside, can induce antibodies against GD3 in approximately 25% of patients. In this trial, 50 melanoma patients at high risk for recurrence were randomly assigned to one of the five BEC2 dose levels (2.5 microg-10mg) to determine if lower or higher BEC2 doses are more immunogenic. We also tested whether prolonged booster immunizations can enhance the anti-GD3 antibody response. All patients developed detectable IgG against BEC2 except for one patient at the lowest BEC2 dose level. Six patients developed detectable antibody responses to GD3, all of them at the lower three dose levels of BEC2. We conclude that high doses of BEC2 are not necessary to induce anti-GD3 antibody responses and that lower doses may be more immunogenic than the 2.5 mg dose used in previous BEC2 trials. Prolonged booster immunizations did not induce or maintain antibody responses.

Adjuvants, Immunologic↗
PubMed2004

Sequential immunization of melanoma patients with GD3 ganglioside vaccine and anti-idiotypic monoclonal antibody that mimics GD3 ganglioside.

GD3 ganglioside is an attractive target for immunotherapy of melanoma because it is abundantly expressed on all melanomas but not expressed on most normal tissues. Although GD3 has proven to be one of the least immunogenic gangliosides, our recent studies showed that anti-GD3 antibodies can be induced in patients immunized either with GD3-lactone-KLH (GD3-L-KLH) plus QS-21 adjuvant or with BEC2 anti-idiotypic monoclonal antibody vaccine, which mimics GD3, plus Bacillus Calmette-Guérin. We compared the immunogenicity of these two vaccines and tested whether one vaccine could prime an antibody response to the other. This is the first clinical trial immunizing patients with both antigen and anti-idiotypic monoclonal antibody vaccine. Twenty-four melanoma patients were randomized to be immunized with either BEC2 followed by GD3-L-KLH or in the opposite order. Our prior study suggested that a 25-microg dose of BEC2 was more immunogenic than our standard dose of 2.5 mg and therefore was used in this trial. Overall, 10 of 24 patients (42%) developed anti-GD3 antibodies detectable by ELISA, five in each cohort. All antibody responses were in response to the GD3-L-KLH vaccine. We found no evidence of priming by either vaccine. Antibody responses did not correlate with survival outcomes. Cellular responses were detected by enzyme-linked immunospot against BEC2, Bacillus Calmette-Guérin, and KLH, but not against GD3. We confirmed that GD3-L-KLH vaccine induces anti-GD3 antibodies, but we were unable to confirm our previous finding that a 25-microg dose of BEC2 is immunogenic. Future multivalent ganglioside vaccines should include the GD3-L-KLH vaccine.

Adolescent↗
PubMed2004

Selective CD4+ lymphopenia in melanoma patients treated with temozolomide: a toxicity with therapeutic implications.

PURPOSE: Standard schedule temozolomide (TMZ; daily for 5 days every 4 weeks) is often used in melanoma patients, but phase III data show that it is no more effective than standard dacarbazine. Extended TMZ dosing regimens may be superior by delivering the drug continuously at a higher dose over time. Using an extended dosing schedule, we noted a high incidence of lymphopenia and occasional opportunistic infections (OIs). Here we report our retrospective experience in the first 97 patients. MATERIALS AND METHODS: TMZ was administered at 75 mg/m(2)/d orally for 6 weeks every 8 weeks, although nine patients were treated continuously without a break. Seventeen patients were treated with TMZ alone; 73 patients received TMZ with thalidomide; seven patients received TMZ with low-dose interferon alfa. RESULTS: Median duration of TMZ treatment was 113 days; 29% received > or = 24 weeks of therapy. Lymphopenia was seen in 60% of patients (absolute lymphocyte count < 800/microL) with a median of 101 days to lymphopenia. TMZ did not cause significant neutropenia or thrombocytopenia. Lymphopenia was not more common in patients treated concomitantly with thalidomide. In all patients analyzed for lymphocyte subsets, lymphopenia induced by TMZ affected the CD4(+) compartment preferentially. There were two documented OIs (Pneumocystis and Aspergillus pneumonia) as well as other infections indicative of T-cell dysfunction in another 21 patients. CONCLUSION: TMZ at this dose and schedule results in CD4(+) lymphopenia in a majority of patients that can result in OIs. Pneumocystis pneumonia prophylaxis should be considered for patients who develop sustained lymphopenia on TMZ.

Adult↗
PubMed2003

Consistent antibody response against ganglioside GD2 induced in patients with melanoma by a GD2 lactone-keyhole limpet hemocyanin conjugate vaccine plus immunological adjuvant QS-21.

PURPOSE: Melanomas, sarcomas, and neuroblastomas abundantly express the ganglioside GD2 on the cell surface where it is susceptible to immune attack by antibodies. Overexpression of GD2 on these tumors is striking, as is the frequency of clinical responses after treatment of neuroblastoma with monoclonal antibodies against GD2. In addition, preclinical models have demonstrated the ability of a GD2-keyhole limpet hemocyanin (KLH) conjugate vaccine to induce antibodies that eliminate micrometastases. However, vaccination of patients with GD2-KLH has previously failed to induce a consistent relevant antibody response. We test here whether the use of GD2 lactone-KLH can overcome the low immunogenicity of GD2-KLH. EXPERIMENTAL DESIGN: Eighteen patients with melanoma were vaccinated s.c. in the adjuvant setting on weeks 0, 1, 2, 3, 10, and 24. Groups of 6 patients were entered at three dose levels (3, 10, or 30 micro g) of GD2 lactone (GD2L) in vaccines containing GD2L-KLH plus the immunological adjuvant QS-21. Blood was drawn at regular intervals to assess the antibody response. RESULTS: The vaccine was well tolerated. The majority of patients in all three dose levels produced anti-GD2 antibodies detectable by ELISA assay. Specificity for GD2 was also confirmed by immune thin-layer chromatography. Although there was no statistical difference in terms of titers between the three groups, patients at the 30- micro g dose level had higher titers and longer lasting antibody responses overall by ELISA (median IgM/IgG peak titer 1:640/1:80) and generated the strongest cell surface reactivity by fluorescence-activated cell sorting (median IgM peak percentage positive cells/mean fluorescence intensity for pre- and postvaccination sera is 10%/63 and 70%/135). Patients vaccinated with the 30- micro g GD2 dose also had the most potent complement dependent cytotoxicity using human complement, with 5 of 6 patients showing strong cell surface reactivity by fluorescence-activated cell sorting and >30% cytotoxicity by chromium release with a serum dilution of 1/100. CONCLUSIONS: GD2L-KLH conjugate vaccine plus adjuvant QS-21 induces antibodies against GD2 that bind to the cell surface and induce complement-dependent cytotoxicity in the majority of patients with melanoma.

Adjuvants, Immunologic↗
PubMed2003

Phase II study of temozolomide plus thalidomide for the treatment of metastatic melanoma.

PURPOSE: To further investigate the efficacy and safety of temozolomide plus thalidomide in patients with metastatic melanoma without brain metastases. PATIENTS AND METHODS: Patients with histologically confirmed advanced-stage metastatic melanoma were enrolled in an open-label, phase II study. The primary end point was response rate. Patients received temozolomide (75 mg/m2/d x 6 weeks with a 2-week rest between cycles) plus concomitant thalidomide (200 mg/d with dose escalation to 400 mg/d for patients < 70 years old, or 100 mg/d with dose escalation to 250 mg/d for patients >/= 70 years old). Treatment was continued until unacceptable toxicity or disease progression occurred. RESULTS: Thirty-eight patients (median age, 62 years) with stage IV (three patients with M1a, eight with M1b, and 26 with M1c) or stage IIIc (one patient) melanoma and a median of four metastatic sites were enrolled, and received a median of two cycles of therapy. Twelve patients (32%) had an objective tumor response, including one with an ongoing complete response of 25+ months' duration and 11 with partial responses. Five patients achieving partial response with a more than 90% reduction of disease were converted to a complete response with surgery. Treatment was generally well tolerated. Median survival was 9.5 months (95% confidence interval, 6.05 to 19.38 months), with a median follow-up among survivors of 24.3 months. CONCLUSION: The combination of temozolomide plus thalidomide seems to be a promising and well-tolerated oral regimen for metastatic melanoma that merits further study.

Adult↗
PubMed2003

Cross-presentation of disialoganglioside GD3 to natural killer T cells.

GD3, a ganglioside expressed on human melanoma, can be recognized by the humoral immune system. In this paper, we demonstrate that immunizing mice with the human melanoma cell line SK-MEL-28 (GD3+ GM2- CD1-) or with syngeneic APCs loaded with GD3 can induce a GD3-reactive natural killer T (NKT) cell response. GD3-reactive NKT cells were detected among splenocytes of immunized mice at frequencies of approximately 1:2000 both by ELISPOT and GD3-loaded mouse CD1d tetramer analysis. GD3-reactive NKT cells did not react with GM2, a closely related ganglioside, and were not detectable in unimmunized mice. GD3-reactive NKT cells initially produced IL-4 and IFN-gamma followed by IL-10. They were CD1d restricted in that reactivity was abrogated when APCs were blocked with anti-CD1d monoclonal antibody before being loaded with GD3 or when APCs from CD1d knockout mice were used. Because SK-MEL-28 does not express any isoform of human CD1, GD3 must be cross-presented by murine APCs in vivo. This is the first analysis of a natural ligand for mouse NKT cells and the first definitive paper of cross-presentation to NKT cells. This could be a mechanism for NKT cell recognition of tumor gangliosides in CD1- tumors.

Amino Acid Sequence↗
PubMed2003

Phase I trial of high dose paracetamol and carmustine in patients with metastatic melanoma.

Reduced glutathione (GSH) production by tumour cells has been proposed as a mechanism for resistance to alkylating agents. High levels of paracetamol can deplete intracellular GSH. We conducted a phase I trial of high dose paracetamol and carmustine (BCNU) in patients with advanced malignant melanoma to determine the optimal biological dose and the maximum tolerated dose (MTD) with the goal of increasing sensitivity to BCNU by GSH depletion. Groups of three to five patients received escalating doses of paracetamol (10, 15 or 20 g/m(2)) every 3 weeks. Every other cycle, BCNU (10 mg/m(2)) was given 6.5 h after administration of paracetamol and 45 min before a 20 h infusion of N-acetylcysteine. Once the MTD for paracetamol had been determined, the dose of BCNU was sequentially escalated in subsequent cohorts to 150 mg/m(2). GSH levels were measured in peripheral blood mononuclear cells (PBMCs) and, when available, in tumour biopsies. The MTD of paracetamol was 15 g/m(2). The dose of BCNU was safely escalated to 150 mg/m(2). The most common toxicity was grade II nausea/vomiting. At 15 g/m(2), peak paracetamol levels (median 253 microg/ml) were reached between 1 and 4 h. No changes in GSH levels in PBMCs were seen. There were two partial responses, including a dramatic decrease in hepatic metastases. Treatment of melanoma patients with paracetamol (15 g/m(2)) every 3 weeks and BCNU (150 mg/m(2)) every 6 weeks is safe. The observation of two partial responses has led to a phase II study to evaluate treatment with high dose paracetamol alone or in combination with BCNU.

Acetaminophen↗