Interferon alfa-2a for melanoma metastases.
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Chemotherapy, Adjuvant↗
Biomedical subjects
Marc S Ernstoff
Publications and source records attributed to Marc S Ernstoff.
The pharmacokinetics of the bispecific antibody MDX-H210 when combined with interferon gamma-1b in a multiple-dose phase I study in patients with advanced cancer.
INTRODUCTION: MDX-H210 is a Fab'xFab' bispecific antibody (BsAb) constructed chemically by crosslinking Fab' mAb 520C9 (anti-HER-2/neu) and humanized Fab' mAbH22 (anti-CD64). STUDY DESIGN AND OBJECTIVES: This was a phase I dose-escalation study of intravenous MDX-H210 (1-70 mg/m(2)) combined with subcutaneous IFN-gamma, 50 microg/m(2) given 24 h before the BsAb, both drugs being given three times a week for 3 weeks. The major objectives of the study were to define the safety, tolerability and pharmacokinetics of MDX-H210 when given with IFN-gamma on this schedule. RESULTS: The study group comprised 23 patients (19 female, 4 male; median age 51.5 years, range 25-72 years) with advanced HER-2/neu-positive cancers (19 breast, 3 prostate and 1 lung). Inspection of the log plasma MDX-H210 concentrations-time data for both days 1 and 17 of treatment revealed monoexponential decay in the majority of patients with adequate concentration-time data points. The MDX-H210 T(1/2) ranged from 2.9 to 21.9 h. The MDX-H210 C(max) on day 1 (means+/-SD) increased from 0.30+/-0.22 microg/ml at the 1-mg/m(2) dose tier to 86.91+/-6.46 microg/ml at 70 mg/m(2). Equivalent day-17 values were 0.27+/-0.30 microg/ml increasing to 147.85+/-40.23 microg/ml. The MDX-H210 T(max) occurred at or after the end of the infusion for all treatments. The mean MDX-H210 total body clearance (Cl) was in the range 0.01-0.34 ml/min per kg and the mean MDX-H210 apparent volume of distribution at steady-state (Vd(ss)) in the range 20-170 ml/kg, compatible with distribution primarily limited to the intravascular space. MDX-H210 T(1/2) increased with dose (ANOVA P=0.001) and Cl decreased with dose (ANOVA P=0.006). There were no significant changes in MDX-H210 C(max), AUC, Cl or Vd(ss) between day 1 and day 17. CONCLUSIONS: MDX-H210 pharmacokinetics appeared saturable over the dose range 1-70 mg/m(2), and there was no significant change in MDXH210 pharmacokinetics over the course of the study, or evidence of excessive accumulation of MDX-H210 on this multiple dosing schedule. When MDX-H210 was combined with IFN-gamma, the estimated MDX-H210 pharmacokinetic parameters were similar to the published data for single-agent MDX-H210.
Adult↗
Alteration of chromosome 9p21 and/or p16 in benign and dysplastic nevi suggests a role in early melanoma progression (United States).
OBJECTIVE: The importance of p16 alterations in the pathogenesis of dysplastic nevi and sporadic melanoma remains controversial. The goal of this work was to discover if p16/9p21 alterations occur early in precursor lesions as well as related sporadic melanomas. METHODS: DNA was microdissected from 44 cutaneous melanomas, 14 dysplastic nevi, and six nevi without atypia as part of a study of melanoma. Alteration of the p16 region on 9p21 was measured by loss of heterozygosity (LOH) analysis as well as detection of homozygous deletions for p16 exon 2. RESULTS: This analysis revealed that LOH in 9p21 directly surrounding p16 occurred in approximately 40% (17/44) of melanoma tumors representing all Clark levels. LOH was also discovered in 64% (9/14) of dysplastic nevi, and 50% (3/6) of benign nevi. Homozygous deletion of p16 was found in 29% (4/14) of dysplastic nevi but never in benign nevi. CONCLUSIONS: These studies reveal that LOH and homozygous deletion can affect 9p21 and the p16 locus early in putative precursor lesions of melanoma, even prior to the establishment of cytologically evident aberrant histology. Comparison of alterations in nevi and melanomas from the same individual revealed a pattern of progressive but heterogeneous events suggesting that systemic processes may affect this region of 9p21 at various times during melanoma progression.
Adult↗
Expressive disclosure and health outcomes in a prostate cancer population.
OBJECTIVE: This pilot study explored the feasibility and the efficacy of a brief, well-defined psychosocial intervention (expressive disclosure) in improving behavioral, medical, immunological, and emotional health outcomes in men with diagnosed prostate cancer. METHOD: Thirty prostate cancer patients receiving outpatient oncology care were randomized into experimental (disclosure) and control (non-disclosure) groups. All had been previously treated by surgery or radiation within the last 4 years and were being monitored without further intervention for change in PSA levels. Psychological and physical health surveys were administered and peripheral blood for PSA levels and immune assays was obtained upon study enrollment and again at 3 and 6 months post enrollment. Multivariate analyses were used to examine how the expressive disclosure impacted the hypothesized domains of functioning: physical and psychological symptoms; health care utilization; and immunocompetence. RESULTS: Compared to controls, patients in the expressive disclosure condition showed improvements in the domains of physical symptoms and health care utilization, but not in psychological variables nor in disease relevant aspects of immunocompetence. CONCLUSIONS: Study results support the feasibility of an expressive disclosure intervention for men with prostate cancer. The intervention was well accepted by this population, and participation/adherence was quite high. Results provide only limited support for the hypothesis that a written emotional disclosure task can positively impact health outcomes in a cancer population. However, this pilot study may have lacked adequate power to detect possible intervention benefits. Further studies with larger samples are needed to better assess the intervention's impact on psychological well-being and immunocompetence.
Affect↗
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↗