Biomedical subjects

Gary L Rosner

Publications and source records attributed to Gary L Rosner.

7 recordsLinked to original sources

PubMed2003

Effects of prednisone and genetic polymorphisms on etoposide disposition in children with acute lymphoblastic leukemia.

Etoposide is a substrate for P-glycoprotein, CYP3A4, CYP3A5, and UGT1A1. Glucocorticoids modulate CYP3A and P-glycoprotein in preclinical models, but their effect on clinical etoposide disposition is unknown. We studied the pharmacokinetics of etoposide and its catechol metabolite in children with acute lymphoblastic leukemia, along with polymorphisms in CYP3A4, CYP3A5, MDR1, GSTP1, UGT1A1, and VDR. Plasma pharmacokinetics were assessed at day 29, after 1 month of prednisone (n = 102), and at week 54, without prednisone (n = 44). On day 29, etoposide clearance was higher (47.4 versus 29.2 mL/min/m2, P <.0001) than at week 54. The day 29 etoposide or catechol area under the curve (AUC) was correlated with neutropenia (P =.027 and P =.0008, respectively). The relationship between genotype and etoposide disposition differed by race and by prednisone use. The MDR1 exon 26 CC genotype predicted higher day 29 etoposide clearance (P =.002) for all patients, and the CYP3A5 AA and GSTP1 AA genotypes predicted lower clearance in blacks (P =.02 and.03, respectively). The UGT1A1 6/6, VDR intron 8 GG, and VDR Fok 1 CC genotypes predicted higher week 54 clearance in blacks (P =.039,.036, and.052, respectively). The UGT1A1 6/6 genotype predicted lower catechol AUC. Prednisone strongly induces etoposide clearance, genetic polymorphisms may predict the constitutive and induced clearance of etoposide, and the relationship between genotype and phenotype differs by race.

Base Sequence↗

PubMed2003

Bayesian meta-analysis for longitudinal data models using multivariate mixture priors.

We propose a class of longitudinal data models with random effects that generalizes currently used models in two important ways. First, the random-effects model is a flexible mixture of multivariate normals, accommodating population heterogeneity, outliers, and nonlinearity in the regression on subject-specific covariates. Second, the model includes a hierarchical extension to allow for meta-analysis over related studies. The random-effects distributions are decomposed into one part that is common across all related studies (common measure), and one part that is specific to each study and that captures the variability intrinsic between patients within the same study. Both the common measure and the study-specific measures are parameterized as mixture-of-normals models. We carry out inference using reversible jump posterior simulation to allow a random number of terms in the mixtures. The sampler takes advantage of the small number of entertained models. The motivating application is the analysis of two studies carried out by the Cancer and Leukemia Group B (CALGB). In both studies, we record for each patient white blood cell counts (WBC) over time to characterize the toxic effects of treatment. The WBCs are modeled through a nonlinear hierarchical model that gathers the information from both studies.

Bayes Theorem↗

PubMed2003

Phase I evaluation of prolonged-infusion gemcitabine with fludarabine for relapsed or refractory acute myelogenous leukemia.

PURPOSE: The purpose of this study was to determine the maximum tolerated duration of infusion of gemcitabine at 10 mg/m(2)/min in combination with fludarabine at 25 mg/m(2) daily for 5 days in the treatment of relapsed or refractory acute myelogenous leukemia. EXPERIMENTAL DESIGN: Eighteen patients with relapsed or refractory acute myelogenous leukemia were enrolled. The median age was 54.5 years (range, 21-80 years). Patients received a 30-min infusion of fludarabine at 25 mg/m(2) daily for 5 days. i.v. gemcitabine was given as a single infusion at 10 mg/m(2)/min with the duration adjusted following a modified continuous reassessment method. RESULTS: After 18 patients, the maximum recommended duration of infusion of gemcitabine in combination with fludarabine was selected as a 15-h infusion given at 10 mg/m(2)/min (9,000 mg/m(2)). Severe stomatitis or esophagitis was the most common nonhematological dose-limiting toxicity. Myelosuppression was universal. Febrile neutropenia was common, and 3 of 18 (17%) patients developed bacteremia. Occasional nausea, vomiting, or diarrhea was also reported. There were three complete responses and two partial responses for an overall response rate of 28%. CONCLUSIONS: Prolonged-infusion gemcitabine at a fixed dose rate of 10 mg/m(2)/min for 15 h with 25 mg/m(2)/day fludarabine for 5 days is a tolerable induction regimen for relapsed or refractory leukemia. Stomatitis, esophagitis, febrile neutropenia, and myelosuppression should be anticipated; however, this regimen may be beneficial in patients with relapsed or refractory leukemia.

Adult↗

PubMed2002

Randomized discontinuation design: application to cytostatic antineoplastic agents.

PURPOSE: Propose a phase II study design to evaluate the activity of a putative cytostatic agent, acknowledging heterogeneity of tumor growth rates in the population of patients. METHODS: In the setting of renal cell carcinoma, some patients' tumors will grow slowly naturally. An appropriate design has to distinguish antiproliferative activity attributable to the novel agent from indolent disease. We propose a randomized discontinuation design that initially treats all patients with the study agent (stage 1) and then randomizes in a double-blind fashion to continuing therapy or placebo only those patients whose disease is stable (stage 2). This design allows the investigators to determine if apparent slow tumor growth is attributable to the drug or to selection of patients with naturally slow-growing tumors. RESULTS: By selecting a more homogeneous population, the randomized portion of the study requires fewer patients than would a study randomizing all patients at entry. The design also avoids potential confounding because of heterogeneous tumor growth. Because the two randomly assigned treatment groups each comprise patients with apparently slow growing tumors, any difference between the groups in disease progression after randomization is more likely a result of the study drug and less likely a result of imbalance with respect to tumor growth rates. Stopping rules during the initial open-label stage and the subsequent randomized trial stage allow one to reduce the overall sample size. Expected average tumor growth rate is an important consideration when deciding the duration of follow-up for the two stages. CONCLUSION: The randomized discontinuation design is a feasible alternative phase II study design for determining activity of possibly cytostatic anticancer agents.

Antineoplastic Agents↗

PubMed2002

Phase I evaluation of prolonged-infusion gemcitabine with irinotecan for relapsed or refractory leukemia or lymphoma.

PURPOSE: To estimate the maximum-tolerated duration of infusion of gemcitabine at 10 mg/m(2)/min in combination with irinotecan at 40 mg/m(2) daily for 3 days in the treatment of relapsed or refractory acute leukemia or lymphoma. PATIENTS AND METHODS: Patients with leukemia or lymphoma were escalated in separate strata. Stratum I consisted of 11 patients, median age of 47 years (range, 18 to 68 years), with relapsed or refractory leukemia. Stratum II contained nine patients, median age of 48 years (range, 39 to 68 years), who had refractory non-Hodgkin's lymphoma. Patients received irinotecan at 40 mg/m(2) daily for 3 days, beginning just before the first dose of gemcitabine. Gemcitabine was given at 10 mg/m(2)/min, with the total duration adjusted following a modified continuous reassessment model. RESULTS: Severe myelosuppression and stomatitis/esophagitis were the most serious hematologic and nonhematologic toxicities. Several patients developed febrile neutropenia, nausea, or vomiting. In both strata, the maximum recommended duration of infusion of gemcitabine was 12 hours delivered at 10 mg/m(2)/min (7,200 mg/m(2)). The overall response rate for one cycle of this therapy in this phase I trial for patients with leukemia was 18% (95% confidence interval, 8% to 45%), and for those with lymphoma, 33% (95% confidence interval, 17% to 66%). CONCLUSION: A prolonged infusion of gemcitabine at 10 mg/m(2)/min for 12 hours with 3 days of irinotecan at 40 mg/m(2)/d is a tolerable induction regimen for patients with acute leukemia or lymphoma. Stomatitis/esophagitis should be anticipated; however, this regimen may induce responses in patients with difficult-to-treat hematologic malignancies.

Adult↗

PubMed2002

Phase I evaluation of prolonged-infusion gemcitabine with mitoxantrone for relapsed or refractory acute leukemia.

PURPOSE: To ascertain the maximum tolerated duration of infusion of gemcitabine at 10 mg/m(2)/min in combination with mitoxantrone at 12 mg/m(2) daily for 3 days in the treatment of acute leukemia. PATIENTS AND METHODS: Thirty-four patients were enrolled. Stratum I consisted of 26 patients, median age 50 years (range, 25 to 71 years), with relapsed or refractory leukemia. Stratum II contained eight patients, median age 62.5 years (range, 38 to 83 years), who had received fewer than three cycles of myelotoxic therapy for chronic myeloid leukemia or myelodysplasia that had evolved into leukemia. Patients received mitoxantrone at 12 mg/m(2) daily for 3 days. After the first mitoxantrone dose, gemcitabine was provided intravenously at 10 mg/m(2)/min with the duration adjusted by following a continuous reassessment model. RESULTS: Severe myelosuppression, and stomatitis or esophagitis were the most common hematologic and nonhematologic dose-limiting toxicities. Several patients developed febrile neutropenia, nausea, or vomiting. In both strata, the maximum recommended duration of infusion of gemcitabine was 12 hours (7,200 mg/m(2)). The mean steady-state concentration of gemcitabine was 24.72 micromol/L and varied over a fivefold range among patients. Overall response rates in this phase I trial for strata I and II were 42% and 63%, respectively. CONCLUSION: Prolonged-infusion gemcitabine at a fixed dose rate of 10 mg/m(2)/min for 12 hours with 12 mg/m(2)/d mitoxantrone for 3 days is a tolerable induction regimen and achieves plasma concentrations sufficient for maximal intracellular activation. Stomatitis or esophagitis should be anticipated; however, this regimen may induce significant responses in patients with difficult-to-treat leukemias.

Acute Disease↗

PubMed2002

A phase I trial of escalating doses of trastuzumab combined with daily subcutaneous interleukin 2: report of cancer and leukemia group B 9661.

PURPOSE: The purpose of this study was to determine the toxicity of escalating doses of trastuzumab when combined with a fixed dose regimen of interleukin (IL)-2. EXPERIMENTAL DESIGN: Eligible patients had nonhematological malignancies for which standard therapy did not exist or was no longer effective and had tumors that overexpressed HER2. IL-2 was initially administered at a dose of 1.25 million IU/m(2) (low dose) s.c. daily except for 3 days every 2 weeks, when it was given at a dose of 15 million IU/m(2) (intermediate dose). These doses were reduced to 1.0 million and 12 million IU/m(2) after the first 18 patients. Trastuzumab was administered i.v. just before the first intermediate IL-2 dose and was escalated in cohorts of six or more patients from 1 mg/kg every 2 weeks to 8 mg/kg weekly. In vitro cytotoxicity testing was performed with patient peripheral blood mononuclear cells and HER2-overexpressing cell lines. RESULTS: Forty-five patients were treated. Dose-related toxicity from trastuzumab was not observed. IL-2-related toxicities such as fever, chills, and fatigue were less common with the reduced doses of IL-2. There were two grade 3 and three grade 4 pulmonary reactions. Four major responses were observed, all in breast cancer patients treated with trastuzumab doses of at least 4.0 mg/kg. Although IL-2 produced expansion of natural killer cell subsets, there was no correlation between in vitro cytotoxicity and clinical response. CONCLUSIONS: A regimen of IL-2 combined with trastuzumab is feasible, and response numbers are encouraging. Further testing of this regimen is warranted if the pulmonary toxicity can be ameliorated.

Adult↗