Biomedical subjects

Myron N Chang

Publications and source records attributed to Myron N Chang.

8 recordsLinked to original sources

PubMed2007

One- and two-stage designs for phase II window studies.

The primary goal of phase II window studies in cancer is testing new single agents or combination therapies for newly diagnosed patients who are less likely to have multiple-drug-resistant tumours than the typical phase II patients who have failed one or more chemotherapeutic regimens. In addition, by utilizing newly diagnosed patients, one can assess the responsiveness in a population more representative of where the phase II agent might be applied in a true phase III setting. In general, the outcome of a patient on a phase II window study can be categorized as response, stable disease, or early disease progression. Phase II window studies sometimes require early stopping rules for both insufficient response rate and excessive early progression rates. In this paper, one-stage and two-stage designs for phase II window studies are developed, requiring the monitoring of two rates. It is shown that the power function is monotone in response rate and early disease progression rate. Consequently, the significance level and power are easy to compute. Computational procedures are described and examples are provided. The proposed method can be applied to other studies with categorical outcomes.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2006

A prospective study of the natural history of transient leukemia (TL) in neonates with Down syndrome (DS): Children's Oncology Group (COG) study POG-9481.

A unique transient leukemia (TL) has been described in newborns with Down syndrome (DS; or trisomy 21 mosaics). This leukemia has a high incidence of spontaneous remission; however, early death and subsequent development of acute megakaryoblastic leukemia (AMKL) have been reported. We prospectively evaluated 48 infants with DS and TL to determine the natural history and biologic characteristics of this disease, identify the clinical characteristics associated with early death or subsequent leukemia, and assess the incidence of subsequent leukemia. Blast cells associated with TL in DS infants exhibited FAB M(7) morphology and phenotype. Most infants (74%) had trisomy 21 (or mosaicism) as the only cytogenetic abnormality in the blast cells. Most children were able to spontaneously clear peripheral blasts (89%), normalize blood counts (74%), and maintain a complete remission (64%). Early death occurred in 17% of infants and was significantly correlated with higher white blood cell count at diagnosis (P < .001), increased bilirubin and liver enzymes (P < .005), and a failure to normalize the blood count (P = .001). Recurrence of leukemia occurred in 19% of infants at a mean of 20 months. Development of leukemia was significantly correlated with karyotypic abnormalities in addition to trisomy 21 (P = .037). Ongoing collaborative clinical studies are needed to determine the optimal role of chemotherapy for infants at risk for increased mortality or disease recurrence and to further the knowledge of the unique biologic features of this TL.

Bilirubin↗

PubMed2005

Randomized use of cyclosporin A (CsA) to modulate P-glycoprotein in children with AML in remission: Pediatric Oncology Group Study 9421.

Relapse is a major obstacle in the cure of acute myeloid leukemia (AML). The Pediatric Oncology Group AML Study 9421 tested 2 different strategies to improve event-free survival (EFS) and overall survival (OS). Patients were randomized to receive standard-dose DAT (daunorubicin, cytarabine, and thioguanine) or high-dose DAT during induction. To interfere with P-glycoprotein (P-gp)-dependent drug efflux, the second randomization tested the benefit of cyclosporine (CsA) added to consolidation chemotherapy. Of the 282 children randomly assigned to receive standard DAT induction, 248 (87.9%) achieved remission compared to 253 (91%) of the 278 receiving high-dose DAT (P = ns). Children with HLA-identical sibling donors who achieved a complete remission received an allogeneic bone marrow transplant as consolidation. For the 83 patients receiving a matched related donor bone marrow transplantation (BMT), the 3-year disease-free survival (DFS) is 67%. Of the 418 children who achieved remission and went on to consolidation with and without CsA, the DFS was 40.6% and 33.9%, respectively (P = .24). Overexpression of P-gp was infrequent (14%) in this pediatric population. In this study, intensifying induction with high-dose DAT and the addition of CsA to consolidation chemotherapy did not prolong the durations of remission or improve overall survival for children with AML.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

One- and two-stage designs for stratified phase II clinical trials.

A global one-sample test for response rates for stratified phase II clinical trials is proposed. Such a test is analogous to that of a stratified log-rank test for time-to-event data. Both one- and two-stage tests are developed, and conditional and unconditional approaches are introduced in each case, where the conditional approach involves conditioning on the observed samples sizes within the strata. The methodology generates samples sizes and stopping boundaries that provide designs with the desired power and type I error probability. These methods are useful for designing stratified phase II clinical trials. An application to a Children's Oncology Group phase II clinical trial in relapsed neuroblastoma patients is presented.

Antineoplastic Agents↗

PubMed2004

Improved confidence intervals for a binomial parameter following a group sequential phase II clinical trial.

Group sequential procedures are widely employed in phase II clinical trials. It is often desirable to provide an interval estimate of the true response rate upon termination of a group sequential phase II clinical trial. The confidence intervals proposed by Jennison and Turnbull (Technometrics 1983; 25: 49-58) are conservative. Utilization of auxiliary statistics based on the overall disease status is proposed to reduce the discreteness of the underlying distribution. Confidence intervals generated by the proposed methods have confidence coefficients closer to the nominal level and have shorter average lengths than JT.

Antineoplastic Agents↗

PubMed2004

Gene expression profiles at diagnosis in de novo childhood AML patients identify FLT3 mutations with good clinical outcomes.

Fms-like tyrosine kinase 3 (FLT3) mutations are associated with unfavorable outcomes in children with acute myeloid leukemia (AML). We used DNA microarrays to identify gene expression profiles related to FLT3 status and outcome in childhood AML. Among 81 diagnostic specimens, 36 had FLT3 mutations (FLT3-MUs), 24 with internal tandem duplications (ITDs) and 12 with activating loop mutations (ALMs). In addition, 8 of 19 specimens from patients with relapses had FLT3-MUs. Predictive analysis of microarrays (PAM) identified genes that differentiated FLT3-ITD from FLT3-ALM and FLT3 wild-type (FLT3-WT) cases. Among the 42 specimens with FLT3-MUs, PAM identified 128 genes that correlated with clinical outcome. Event-free survival (EFS) in FLT3-MU patients with a favorable signature was 45% versus 5% for those with an unfavorable signature (P = .018). Among FLT3-MU specimens, high expression of the RUNX3 gene and low expression of the ATRX gene were associated with inferior outcome. The ratio of RUNX3 to ATRX expression was used to classify FLT3-MU cases into 3 EFS groups: 70%, 37%, and 0% for low, intermediate, and high ratios, respectively (P < .0001). Thus, gene expression profiling identified AML patients with divergent prognoses within the FLT3-MU group, and the RUNX3 to ATRX expression ratio should be a useful prognostic indicator in these patients.

Acute Disease↗

PubMed2004

Samples of exact k-stage group sequential designs for Phase II and Pilot studies.

That the test of H(0): p=p(0) versus H(1): p>p(0) can be based on a binomially distributed random variable is widely known among users of statistical methods. What is not generally known is that under certain very general conditions, it is possible to find an exact k-stage group sequential test whose total sample size is bounded above by the sample size for the single stage binomial test. That is, it is possible to find k-stage tests for detecting H(1) for which the sum of the sample sizes at each of the stages is bounded above by the sample size for the standard binomial test. This result is somewhat remarkable since the total sample size under the group sequential test setting can be strictly less than the sample size for the uniformly most powerful (UMP) one-stage binomial test. In other words, exact group sequential tests cannot only save the average sample size but can also save the maximum sample size when they are compared to the standard binomial test. In this paper, implications of existing theory are explored and a web application written by the authors is presented. No new theory is established. Applications are described and methods are demonstrated that use the web application to rapidly create efficient designs for Phase II and Pilot studies that put a minimum number of patients at risk and that facilitate the rapid progression through a scientific research agenda. While couched here in the context of clinical trials, the results may be used in any field of inquiry where inferences are made based on the size of a binomial random variable.

Binomial Distribution↗

PubMed2004

Sample sizes based on exact unconditional tests for phase II clinical trials with historical controls.

Investigated in the setting of phase II clinical trials is the two-sample binomial problem of testing H0: pe = pc H1: pe > pc, where pe and pc are the unknown target population response rates for the experimental and control groups, respectively, using the usual Z-statistic with pooled variance estimator. The cornerstones that make this paper unique are as follows. First, the emphasis is on determining the sample size given that the control group information has already been collected (historical control). Second, exact unconditional inference, rather than an asymptotic method, is utilized. Sample size tables, contrasting the exact and asymptotic methods, are provided. Although asymptotic results were usually fairly close to the exact results, some important differences were observed.

Clinical Trials, Phase II as Topic↗