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Biomedical subjects

Paul B Chapman

Publications and source records attributed to Paul B Chapman.

27 records · Page 2Linked to original sources
PubMed2003

Vaccinating against GD3 ganglioside using BEC2 anti-idiotypic monoclonal antibody.

GD3, a ganglioside expressed on tumors of neuroectodermal origin such as melanoma and small-cell lung carcinoma (SCLC), is an attractive vaccine target but is poorly immunogenic. Our group has pursued several strategies designed to immunize patients against GD3 including using BEC2, an anti-idiotypic monoclonal antibody that mimics GD3. Pilot trials in melanoma and SCLC indicate that BEC2 can induce an anti-GD3 antibody response in a subset of patients and also suggests that immunization with BEC2 is associated with improved survival. A phase III trial is underway in SCLC patients to determine the effects of BEC2 on overall survival.

Animals↗
PubMed2002

Temozolomide plus thalidomide in patients with advanced melanoma: results of a dose-finding trial.

PURPOSE: To establish a safe and tolerated regimen of an oral cytotoxic agent, temozolomide, and a cytostatic agent, thalidomide, in patients with unresectable stage III or IV malignant melanoma. PATIENTS AND METHODS: Patients with unresectable stage III or IV melanoma without brain metastases were entered successively onto four treatment cohorts: level 1, temozolomide 50 mg/m(2)/d for 6 weeks followed by a 4-week break; levels 2, 3, and 4, temozolomide 75 mg/m(2)/d for 6 weeks followed, respectively, by breaks of 4, 3, and 2 weeks. Thalidomide was started at 200 mg/d, and escalated to a maximum dose of 400 mg/d. Safety was assessed at weeks 2 and 4 and every 4 weeks thereafter; tumor response was evaluated every 8 to 10 weeks. RESULTS: Twelve patients were enrolled, three on each cohort. Therapy was generally well tolerated on all of the treatment schedules. Thalidomide at a dose of 400 mg/d was well tolerated in patients younger than 70, and 200 mg/d was well tolerated in older patients. The most common adverse events were grade 2 or 3 constipation and neuropathy, which were attributed to thalidomide. Five major responses (one complete, four partial) were documented, all at dose levels 2 to 4. Three of the five responding patients were in the over-70 age group. The median duration of response was 6 months (range, 4 to 17+ months), and the median overall survival was 12.3 months (range, 4 to 19+ months). CONCLUSION: The combination of temozolomide and thalidomide was well tolerated and had antitumor activity in patients with advanced melanoma, including elderly patients over 70 years old.

Aged↗
PubMed2002

An optimal two-stage phase II design utilizing complete and partial response information separately.

Phase II clinical trials in oncology are performed to evaluate the therapeutic efficacy of a new treatment regimen. A common measure of efficacy for these trials is the proportion of patients who obtain a response measured by tumor shrinkage. It is standard practice to classify this response into the following categories: (1) complete response (CR); (2) partial response (PR); (3) stable disease; and (4) progression of disease. Tumor response is then treated as a binary variable whereby patients who achieve either a CR or a PR are considered responders and all others nonresponders. A two-stage design that allows for early termination of the trial if the treatment shows little efficacy such as Gehan or Simon gives equal weight to a CR and a PR. However, a CR, defined as complete disappearance of the tumor, is more likely than a PR to signal an important antitumor effect and result in a survival advantage. We argue that CRs and PRs should be considered separately, and hence we propose a two-stage design with a multilevel endpoint (i.e., CR, PR, and nonresponders). This design is an extension of Simon's optimal two-stage design and is based on a trinomial model. For most scenarios the proposed design results in an improvement in expected sample size compared to Simon's optimal design. Design optimization was performed by a direct search based on enumerating exact trinomial probabilities. Sample size tables are provided for parameter sets commonly used in the oncologic setting. Software is available by contacting the authors.

Clinical Trials, Phase II as Topic↗
PubMed2002

Serum levels of melanoma-inhibiting activity do not predict relapse in melanoma patients.

Melanoma-inhibiting activity (MIA) is a 107 amino-acid protein secreted from melanoma cells and frequently detectable at high concentration in the serum of patients with advanced melanoma. Early studies suggested that MIA may be a useful serum tumor-marker for detection of recurrent or progressive disease. We evaluated the sensitivity of serum MIA levels in predicting the risk of relapse in patients with American Joint Committee on Cancer (AJCC) Stage II, III, and IV melanoma. MIA was measured by ELISA in serum from 39 patients with AJCC Stage II, III and IV disease at a single time-point 1 month to 5 years after they were rendered free of disease. Twenty-three of the 39 patients recurred, with a median follow-up of 4.5 months. Only four of the 23 patients who recurred had shown elevated MIA values (17% sensitivity). Of the 16 patients who remain free of disease (median follow-up 3.5 years, range 11 months to 6.3 years), one patient had an elevated MIA. There was no significant difference in the proportion of patients with elevated serum MIA between the patients who recurred and those who remained free of disease. In this series, serum MIA was not a sensitive marker for relapse in patients who were clinically free of disease after treatment.

Adult↗
PubMed2002

T-cell responses against tyrosinase 368-376(370D) peptide in HLA*A0201+ melanoma patients: randomized trial comparing incomplete Freund's adjuvant, granulocyte macrophage colony-stimulating factor, and QS-21 as immunological adjuvants.

We conducted a randomized trial in HLA*A0201+ patientswith American Joint Committee on Cancer stage III or IV melanoma immunized with tyrosinase 368-376(370D) peptide and gp100 209-217(210M) peptide to compare the potency of three different adjuvants. Patients received 3 monthly immunizations with 500 microg of each peptide either with incomplete Freund's adjuvant (IFA), QS-21, or granulocyte macrophage colony-stimulating factor (GM-CSF). The primary end point was induction of IFN-gamma release by CD8+ T cells against tyrosinase and gp100 peptides measured by enzyme-linked immunospot assays without in vitro prestimulation measured pretreatment, 2 and 8 weeks after the third vaccination. Four of 9 and 4 of 8 patients immunized using QS-21 and GM-CSF, respectively, developed increased frequencies of CD8+ T cells against tyrosinase 370D peptide compared with 0 of 9 patients immunized using IFA (P = 0.045). T-cell responses against a gp100-related peptide showed similar results, but their relevance to T-cell reactivity against native gp100 209-217 is uncertain. These results show that: (a) QS-21 and GM-CSF are superior to IFA as immunological adjuvants for vaccination against tyrosinase 370D peptide; and (b) with appropriate adjuvants, increased frequencies of peptide-specific T cells after vaccination can be detected by enzyme-linked immunospot without prolonged prestimulation in vitro.

Adult↗
PubMedDate not supplied

Phase 2 study of the g209-2M melanoma peptide vaccine and low-dose interleukin-2 in advanced melanoma: Cancer and Leukemia Group B 509901.

High-dose interleukin-2 (IL-2) is the only approved immunologic therapy for advanced melanoma, but response rates are low and significant toxicities limit treatment to otherwise healthy patients. g209-2M is a nanopeptide engineered to mimic an epitope of the gp100 melanocyte differentiation protein that is recognized in a human leukocyte antigen (HLA)-restricted manner by melanoma tumor-infiltrating lymphocytes in some patients. Previous reports indicated that administration of the g209-2M peptide could induce g209-reactive circulating T cells in patients with melanoma and that the combination of g209-2M and high-dose IL-2 might be a more active treatment than high-dose IL-2 alone. Low-dose IL-2 is not active but has significant biologic effects, and because of a different toxicity profile, it can be offered to most patients. The primary objective of this cooperative group phase 2 study was to determine the activity of the combination of g209-2M and low-dose IL-2 in advanced melanoma. Twenty-six HLA appropriate patients with advanced melanoma received subcutaneous g209-2M peptide once every 3 weeks and subcutaneous IL-2 (5 million IU/m) daily for 5 days during the first and second weeks. Patients were monitored for tumor response, toxicity, and induction of g209-reactive circulating T cells. There were no objective responses. There were no toxic deaths and no grade 4 toxicities. More than half of the patients experienced some grade 2 toxicity and one quarter experienced grade 3 toxicity. There was no convincing evidence by enzyme-linked immunospot or tetramer analysis of induction of g209-reactive circulating T cells. The combination of g209-2M and low-dose IL-2 is safe and tolerable but inactive against advanced melanoma. Absence of evidence of immunization raises concerns for peptide-based immunization strategies with concurrent IL-2.

Adult↗