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At least 19 recordsLinked to original sources
PubMed2007

Stochastically curtailed phase II clinical trials.

Phase II trials often test the null hypothesis H(0): p or=p(1), where p is the true unknown proportion responding to the new treatment, p(0) is the greatest response proportion which is deemed clinically ineffective, and p(1) is the smallest response proportion which is deemed clinically effective. In order to expose the fewest number of patients to an ineffective therapy, phase II clinical trials should terminate early when the trial fails to produce sufficient evidence of therapeutic activity (i.e. if p or=p(1)), the trial should declare the drug effective in the fewest patients possible to allow for advancement to a phase III comparative trial. Several statistical designs, including Simon's minimax and optimal designs, have been developed that meet these requirements. In this paper, we propose three alternative designs that rely upon stochastic curtailment based on conditional power. We compare and contrast the properties of the three approaches: (1) stochastically curtailed (SC) binomial tests, (2) stochastically curtailed (SC) Simon's optimal design, and (3) SC Simon's minimax design to those of Simon's minimax and Simon's optimal designs. For each of these designs we compare and contrast the number of opportunities for study termination, the expected sample size of the trial under the null hypothesis (p <or=p(0)), and the effective type I and type II errors. We also present graphical tools for monitoring phase II clinical trials with stochastic curtailment using conditional power.

Clinical Trials, Phase II as Topic↗
PubMed1995

Incorporating toxicity considerations into the design of two-stage phase II clinical trials.

Phase II study designs are proposed that evaluate both clinical response and toxicity, and that are similar in structure to Simon's two-stage designs. Sample sizes and decision criteria are chosen to minimize the maximum expected accrual, given that the treatment is unacceptable either in terms of clinical response or toxicity. This is achieved subject to control of error rates, either uniformly over all possible correlation structures linking response and toxicity, or alternatively, under an assumption of independence between response and toxicity. In the latter case, bounds on the error rates show that effective control is still uniformly achieved even if the independence assumption is relaxed.

Biometry↗
PubMed1990

Incorporating historical control data in planning phase II clinical trials.

Phase II studies of new medical treatments often use historical data on the standard treatment for comparative evaluation. Incorrectly disregarding inherent variability in the historical data may lead to erroneous conclusions regarding the efficacy of the experimental treatment. We propose an approach to phase II trial design which accounts for both inter-study and intra-study variation. Our results indicate that it is sometimes best to randomize a proportion of the patients to a control arm. We choose this proportion to maximize the precision of the estimated experimental treatment effect. We evaluate operating characteristics of the design numerically, and provide illustrations based on historical data from cancer chemotherapy trials.

Data Interpretation, Statistical↗
PubMed2005

Optimal two-stage randomized phase II clinical trials.

Randomized phase II clinical trials can be an efficient means of evaluating several potential new treatments prior to a comparative phase III clinical trial. However, selection designs do not allow for an assessment of minimal efficacy, nor do they allow early closing of a study arm for lack of efficacy, and so are only appropriate when all arms have met minimal efficacy requirements. Classic two-stage hypothesis testing based designs such as a Simon two-stage optimal design can satisfy these requirements, when used in parallel for the multiple treatment arms. However, these can be inefficient and impractical in terms of the maximum planned sample size required for such a study. This article proposes a two-stage randomized phase II clinical trial, where the sample size is adaptive at the second stage to the number of treatment arms passing through the first stage. The study design relies on optimality criteria, which are analogous to those used by Simon for single-arm studies. The proposed design maintains similar operating characteristics to a strategy of using multiple single-arm studies, in most situations of primary interest. Furthermore, it generally has smaller actual sample size when most of the treatments are effective than using multiple single-arm studies, leading to substantial efficiencies in terms of maximum planned sample size.

Clinical Trials, Phase II as Topic↗
PubMed1994

An optimal three-stage design for phase II clinical trials.

A phase II clinical trial in cancer therapeutics is usually a single-arm study to determine whether an experimental treatment (E) holds sufficient promise to warrant further testing. When the criterion of treatment efficacy is a binary endpoint (response/no response) with probability of response p, we propose a three-stage optimal design for testing H0: p < or = p0 versus H1: p > or = p1, where p1 and p0 are response rates such that E does or does not merit further testing at given levels of statistical significance (alpha) and power (1--beta). The proposed design is essentially a combination of earlier proposals by Gehan and Simon. The design stops with rejection of H1 at stage 1 when there is an initial moderately long run of consecutive treatment failures; otherwise there is continuation to stage 2 and (possibly) stage 3 which have decision rules analogous to those in stages 1 and 2 of Simon's design. Thus, rejection of H1 is possible at any stage, but acceptance only at the final stage. The design is optimal in the sense that expected sample size is minimized when p = p0, subject to the practical constraint that the minimum stage 1 sample size is at least 5. The proposed design has greatest utility when the true response rate of E is small, it is desirable to stop early if there is a moderately long run of early treatment failures, and it is practical to implement a three-stage design. Compared to Simon's optimal two-stage design, the optimal three-stage design has the following features: stage 1 is the same size or smaller and has the possibility of stopping earlier when 0 successes are observed; the expected sample size under the null hypothesis is smaller; stages 1 and 2 generally have more patients than stage 1 of the two-stage design, but a higher probability of early termination under H0; and the total sample size and criteria for rejection of H1 at stage 3 are similar to the corresponding values at the end of stage 2 in the two-stage optimal design.

Clinical Trials, Phase II as Topic↗
PubMed1979

Predictive probability early termination plans for phase II clinical trials.

A phase II clinical trial is designed to gather data to help decide whether an experimental treatment has sufficient effectiveness to justify further study. In a one-arm trial with dichotomous outcome, we wish to test a simple null hypothesis on the Bernoulli parameter against a one-sided alternative in a sample of N patients. It is advisable to have a rule to terminate the trial early when evidence accumulates that the treatment is ineffective. Predictive probabilities based on the binomial distribution and beta and uniform prior distributions for the binomial parameter are found to be useful as the basis of group sequential designs. Size, power and average sample size for these designs are discussed. A process for the specification of an early termination plan, advice on the quantification of prior beliefs, and illustrative examples are included.

Antineoplastic Agents↗
PubMed1996

[Assessment of clinical utility of 111In-DTPA-IgG scintigraphy in the detection of inflammation/infection--a report of multicenter phase II clinical trials].

A Phase II clinical study was performed in patients with strongly suspected focal sites of inflammation/infection to investigate clinical utility of 111In-DTPA-IgG. Neither adverse effects nor abnormal laboratory changes were noted in the all cases. Out of 59 patients, the clinical utility was evaluated in 56 patients with a total of 67 suspicious sites (19 in thorax, 13 in abdomen and pelvis, 30 in musculoskeletal system, and 5 in other regions). True positive results were obtained in 100% of lesions in the thorax (13/13) and the musculoskeletal system (26/26). There were three false negative and five false positive results. Overall sensitivity and specificity was 94.0% and 70.6%, respectively. Most of the true positive scintigram with the best image quality was acquired at Day 1 or Day 2 post-injection. A dose of 80 MBq was considered to be a practical dose for imaging. Our study indicates that 111In-DTPA-IgG is a safe and promising imaging agent for the detection of inflammation/infection, and that it is reasonable to proceed with Phase III studies to further evaluate clinical utility of the agent.

Adult↗
PubMed2002

Early selection in a randomized phase II clinical trial.

A randomized phase II clinical trial design can be employed when one wishes to be able to select one of several similar therapies or variants of a therapy for inclusion in a subsequent, definitive, phase III trial. It is not necessary in this type of trial to formally identify a superior arm using the usual parameters and stringent criteria employed for hypothesis testing. Simon, Wittes and Ellenberg have described methods and sample sizes for selecting the superior arm from among k possible arms. In this paper, we describe an approach based on statistical selection theory which allows one to potentially make a decision to end accrual to a randomized phase II trial at an interim point of the trial, and to select one of two arms as being worthy of further evaluation in a subsequent study. This method requires that an adequate gap in the number of responses between the two arms be observed at the interim point in order to limit the probability that the selected arm is actually inferior by more than an indifference amount. Published in 2002 by John Wiley & Sons, Ltd.

Clinical Trials, Phase II as Topic↗
PubMed2002

Monitoring the rates of composite events with censored data in phase II clinical trials.

In many phase II clinical trials, interim monitoring is based on the probability of a binary event, response, defined in terms of one or more time-to-event variables within a time period of fixed length. Such outcome-adaptive methods may require repeated interim suspension of accrual in order to follow each patient for the time period required to evaluate response. This may increase trial duration, and eligible patients arriving during such delays either must wait for accrual to reopen or be treated outside the trial. Alternatively, monitoring may be done continuously by ignoring censored data each time the stopping rule is applied, which wastes information. We propose an adaptive Bayesian method that eliminates these problems. At each patient's accrual time, an approximate posterior for the response probability based on all of the event-time data is used to compute an early stopping criterion. Application to a leukemia trial with a composite event shows that the method can reduce trial duration substantially while maintaining the reliability of interim decisions.

Bayes Theorem↗
PubMed2000

[New trends in assessment in anticancer treatments by phase II clinical trials].

The aim of phase II clinical trials in oncology is to judge if a new treatment have a sufficient antitumor activity to justify further studies. They represent a crucial step in a new anticancer therapy development. The aim is to present phase II clinical trials planification and interpretation methods, end points, recent methods and news in tumor response assessment. Changes of the place of phase II clinical trials in a new treatment development strategies are finally shown. Non randomized trials planification methods (unique analysis, Gehan's method, Simon's procedure, Fleming's multi-stages procedure, triangular test) are described. Usual primary end point is tumor size diminution. Some studies are interested in secondary end points like survival data or treatment toxicity. New planification methods are exposed : randomized phase II clinical trials, phase II within a phase III trial, cross-over studies and bayesian theories are presented. Recent tumor response evaluation theories ("Recist") are described. Phase II trials function in new treatment development is progressing : they could be sufficient, in some cases, to allow a temporary marketing authorization if a treatment show great efficacy. Global reflection upon new treatment and methods allowing marketing authorization is required.

Clinical Trials, Phase II as Topic↗
PubMed1990

Application of the triangular test to phase II cancer clinical trials.

Phase II cancer clinical trials are primarily designed to determine whether the response rate p to the treatment under study is greater than a specified value p0, that is to test the null hypothesis H0: p less than or equal to p0 against an alternative hypothesis H1 : p greater than p0 specified by p = p1. As an alternative to the single and multistage procedures and to Wald's continuous sequential probability ratio test (SPRT), we applied the group sequential methods proposed by Jones and Whitehead, namely the triangular test (TT) and the discrete SPRT, to the comparison of p with p0, and we expressed H0 and H1 in terms of the log odds-ratio statistic log [p(1 - p0)/p0(1 - p)]. A stimulation study showed that both the TT and the discrete SPRT had type I error and power close to the nominal values, and they compared favourably with multistage methods in terms of the average sample size.

Clinical Trials as Topic↗
PubMed1980

[L-asparaginase study results (phase II of the clinical trials)].

Phase II clinical trials of L-asparaginase of leunase manufactured by "Kyowa" (Japan) was performed in cooperation by 5 institutions of the USSR on 49 patients with various forms of hemoblastosis, including 15 patients aged 1 to 15 and 34 patients aged 16 to 75. The drug was used in a daily dose of 200 IU per 1 kg body weight administered as intravenous drips daily for 2--3 weeks. The daily dose was divided into 2 doses administered at an interval of 12 hours. The efficiency of the treatment did not depend on the patients' sex. Significant efficiency of leunase was observed in children with acute lymphoblastic leukemia (85.7 per cent). The use of the drug in treatment of adults with systemic malignant blood affections was less effective. Some effects recorded in patients with generalized forms of hematosarcoma were transient. The following side effects were noted: nausea, vomiting in 8 children and 13 adults, allergic reactions in the form of pruritus and rashes in 8 adults, impairment of liver and pancreatic functions in 2 children and 1 adult. Acute pancreatonecrosis was recorded in one child. The effect on the peripheral blood was insignificant. Leunase has probably no advantages as compared to other L-asparaginase preparations.

Adolescent↗
PubMed2001

Gemcitabine plus vinorelbine in stage IIIB or IV non-small cell lung cancer (NSCLC): a multicentre phase II clinical trial.

A phase II study in patients with stage IIIB/IV non-small cell lung cancer (NSCLC) was carried out to evaluate the clinical activity and toxicity of the chemotherapeutic combination of gemcitabine+vinorelbine (GEM/VNR). Forty-five patients (40 male, 5 female) with a median age of 67 years (range 37-73) and a median ECOG performance status of 1 (range 0-2) were enrolled into the trial. Twenty patients had stage IIIB (two positive supraclavicular nodes and 20 cytologically positive pleural effusion), and 25 had stage IV NSCLC. GEM 1000 mg/m(2) diluted in 250 cc(3) of normal saline was administered iv on days 1, 8, and 15, while VNR was given 30 mg/m(2) on days 1 and 8 every 4 weeks. The median number of courses/patient was 4 (range 3-7). According to an intent-to-treat analysis 2 (4%) patients had a complete response and 16 (36%; 95% CL 22-52%) had a partial response for an overall response rate of 40% (95% CL 26-56%). Twelve (27%) patients had stable disease and 15 (33%) were considered as treatment failures. Median overall survival of the whole series was 8+ months with 33% of patients alive at 1 year. Toxicity was generally mild. WHO grade 3-4 neutropenia was recorded in 22% of cases, grade 1-3 liver toxicity in 6% of patients and neutropenia-unrelated fever in 9%. This multicentre phase II study suggests that the GEM/VNR combination regimen is an active and well tolerated regimen in patients with stage IIIB/IV NSCLC. Larger studies comparing cisplatin-based regimens to new schedules without cisplatin are warranted.

Adult↗
PubMed1993

[Phase II clinical trials in patients with lung cancer].

The goal of phase II clinical trials is to determine whether a new drug has activity against particular cancers. This trial, therefore, is the most important study in the process of development of investigational new agents and frequently may give misleading results. The design of phase II clinical trials of new anticancer agents in lung cancer has been reviewed based on the Guidelines for the Clinical Evaluation of Antineoplastic Agents notified by the Ministry of Health and Welfare in Japan. These guidelines present general approaches to clinical trials and should be adhered to in the development of investigational drugs in humans, although they are not directly mandated by law or regulations. We considered the policies of these guidelines and instituted them based on the actual circumstances in Japan, in order to develop a scientific and rational approach for clinical phase II trials. In addition, we introduced new active agents having a novel mechanism of action that show clinical activity in the treatment of lung cancer, such as irinotecan (CPT-11), a topoisomerase I inhibitor, and paclitaxel (taxol) and taxotere, targeting the microtubules.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Oral magnetic particles. Results from clinical phase II trials in 216 patients.

Oral magnetic particles (OMP) have been evaluated in a clinical phase II trial program comprising 216 patients in 7 European centers. Adult patients referred for MR imaging for various abdominal pathologies were examined. The patients received OMP at a concentration of 0.1 g/l (ultralow field) or 0.5 g/l (mid/high field) and OMP was diluted in water or in a more viscous liquid formulation. Depending on the area of interest, OMP was ingested in a volume of 300 to 800 ml. OMP was well tolerated with no serious adverse events and the patient acceptability was good. OMP had a good contrast effect on all applied pulse sequences. The viscous formulation of OMP was homogeneously distributed through the entire gastrointestinal tract without inducing disturbing susceptibility artifacts. The postcontrast diagnostic information was improved in 70% of the cases. Based on the encouraging results in phase II, OMP has been advanced to phase III clinical trials.

Abdomen↗
PubMed2006

Safety and efficacy of a novel hepatobiliary MR contrast agent, Gd-DTPA-DeA: results of phase I and phase II clinical trials.

PURPOSE: To assess the safety, effective dose, and efficacy of a novel hepatobiliary MR contrast agent Gd-DTPA-DeA for imaging liver tumors, from the clinical phase I and phase II trials in Japan. MATERIALS AND METHODS: In a phase I trial, 33 healthy volunteers were intravenously administered a single dose of 0.03-10 micromol/kg of Gd-DTPA-DeA. In a nationwide phase II trial, 80 patients suspected to have hepatic mass were divided into three dosing groups: 2.5, 5.0, or 7.5 micromol/kg. T1-weighted gradient echo images were obtained before and after Gd-DTPA-DeA administration at three time points. Liver signal-to-noise ratio (SNR) and lesion-liver contrast-to-noise ratio (CNR) were calculated at each time point. A reading committee evaluated the contrast, diagnostic, and overall efficacy using a five-point scale. RESULTS: In a phase I trial, dosages up to 10 micromol/kg were well tolerated by healthy volunteers. In a phase II trial, the contrast, diagnostic, and overall efficacy increased dose-dependently. The overall efficacy was 63.0%, 85.2%, and 88.0%, for 2.5, 5, and 7.5 micromol/kg, respectively. Liver SNR and CNR increase was greater at late phase than at early phase. No serious adverse events occurred. CONCLUSION: Gd-DTPA-DeA is a well-tolerated and promising contrast agent for liver MR imaging.

Contrast Media↗
PubMed2007

A method for therapeutic dose selection in a phase II clinical trial using contrast statistics.

This paper proposes a statistical method for determining the therapeutic dose of a test drug in a confirmatory clinical trial based on a phase II clinical trial using 3 or 4 doses of the drug. This method assumes the primary variable has a normal distribution with a common variance, that a test-drug effect is seen when the population means show a response pattern indicating a monotonic increase with dose, and that there is a prior distribution for the population means. Under the proposed method, multiple contrast statistics are determined, such as contrast statistics for linear increase and plateau, and a response pattern is selected based on the maximum contrast statistic. The posterior probability that the selected response pattern is the true one is evaluated, and if this exceeds the cut-off value a therapeutic dose is selected based on the estimated response pattern. To select the appropriate cut-off value, a simulation study was conducted using a loss function for which the loss due to overestimation is greater than the loss due to underestimation. It was found that, as a rule, the appropriate cut-off value to reduce the expected loss for various response patterns is 0.75 for a 3-group trial and 0.70 for a 4-group trial. Using these cut-off values, the proposed method was applied to a previous clinical trial of a leukotriene receptor antagonist in patients with bronchial asthma. The method enabled the selection of what are considered appropriate response patterns and a therapeutic dose. Thus, the proposed method appears reasonable.

Asthma↗
PubMed1990

Changing response of clonogenic myeloid leukemia blasts to granulocyte-macrophage colony-stimulating factor (GM-CSF) during anti-leukemic therapy--a case report on the basis of a clinical phase II trial.

In a clinical phase II trial GM-CSF was applied to 23 patients with acute leukemias carrying a high risk of early death because of old age or advanced disease. Concomitant laboratory investigations included the analysis of colony assays for normal granulopoietic progenitors (CFU-GM) and leukemic CFU-L with and without the addition of GM-CSF, as well as DNA measurements by flow cytometry (FCM) for the detection of DNA-aneuploidies. The present analysis is focused on one particular patient with acute myeloid leukemia (AML) in whom the detection of a DNA aneuploidy provided the readily accessible means to monitor the response of leukemic blasts to induction chemotherapy and subsequent GM-CSF treatment in vivo complementing the colony assay analyses performed in vitro. Prior to therapy 60% of cells revealed a DNA aneuploidy with a DNA index of 1.26 and in-vitro exposure of leukemic bone marrow blasts to GM-CSF (100 U/ml) enhanced the growth of CFU-L and CFU-GM with a significantly higher stimulatory index for CFU-L (1:19 versus 1:5.5). Three days after the completion of two cycles of induction therapy with thioguanine, cytosine arabinoside and daunorubicin (TAD 9) a morphologic bone marrow evaluation revealed aplasia without leukemic blasts. By FCM DNA analysis, however, 8% residual aneuploid cells were found. No growth of CFU-L was observed at this time point neither spontaneously nor after the addition of GM-CSF which induced the growth of CFU-GM, only. In-vivo application of GM-CSF (250 micrograms/mg2/day by continuous 24-h infusion) led to the recovery of normal granulopoiesis without evidence of a concomitant stimulation of aneuploid leukemic cells. These data indicate a change in the susceptibility of leukemic blasts to GM-CSF before and after chemotherapy. A reduction of the leukemic cell burden below a critical level or a selection of GM-CSF non-responsive early leukemic precursor cells may account for these observations.

Aged↗