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At least 19 recordsLinked to original sources
PubMed1998

Phase III, large-scale chemoprevention trials. Approach to chemoprevention clinical trials and phase III clinical trial of tamoxifen as a chemopreventive for breast cancer--the US National Cancer Institute experience.

Clinical trials to evaluate interventions for cancer prevention are designed as early (phase I, IIa, and IIb) or late-phase studies. Whereas the former are small and generally rely on intermediate endpoint biomarkers of carcinogenesis, the latter are large-scale, long-term, randomized, phase III studies that address endpoints such as cancer incidence. The Breast Cancer Prevention Trial, P-1, conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP), is discussed as an example of a large, extended, phase III trial designed to answer the question of whether tamoxifen reduces the incidence of breast cancer in women who are at increased risk for the disease.

Breast Neoplasms↗
PubMed1998

[Evaluation of clinical utility of 99mTc-MIBI scintigraphy in the localization of hyperfunctioning parathyroid lesions in patients with hyperparathyroidism--a report of multicenter phase III clinical trials].

Phase III clinical study in 78 patients with hyperparathyroidism was performed to determine clinical utility of 99mTc-MIBI in the localization of hyperfunctioning parathyroid lesions. Except slight tremor in one patient, no adverse events were reported. No abnormal changes in clinical laboratories or vital signs were noted. The clinical utility of the agent was evaluated in 70 patients. Out of 108 hyperfunctioning glands, 93 (86%) were detected with 99mTc-MIBI regardless of their histology, numbers, or location. Specifically, single or ectopic lesions were detected with high sensitivity (97% and 100%, respectively). Sensitivity in 53 glands with weight data was 79%, while 94% in 36 glands above 200 mg, which is extremely high compared to the 201T1-99mTc subtraction method. Specificity in a group of PHP patients with single adenoma who underwent surgery was 100% (63/63), though in case of coexistent thyroid disease obviously interfered parathyroid images. Our study indicates that 99mTc-MIBI is a safe and excellent agent for the localization of hyperfunctioning parathyroid tissues. Especially, the fact that 99mTc-MIBI detected ectopic glands with high specificity is a great advantage over the ultrasound or 201Tl-99mTc subtraction method.

Female↗
PubMed1998

[Evaluation of clinical utility of 99mTc-MIBI scintigraphy in the localization of thyroid, breast and lung/mediastinum tumors--a report of multicenter phase III clinical trials].

Phase III clinical study in 136 patients diagnosed or strongly suspected of thyroid, lung/mediastinum or breast cancer was performed to determine clinical utility of 99mTc-MIBI in the localization of tumors, and the results in 135 were evaluated. Except taste peculiar in 43 patients and nausea in one, no adverse events were reported. Seven abnormal changes in vital signs and 27 in clinical laboratories were noted, which were all judged as having no or unlikely relationship to the agent. Out of 177 malignant lesions, 156 (88%) were detected with 99mTc-MIBI regardless of their histology or location. Of 6 benign tumors, 3 were detected. Fifteen sites of false positive in 11 malignant tumor patients and 5 sites in 6 patients with non-tumor disease were observed. Our study indicates that 99mTc-MIBI is a safe and excellent agent for the localization of tumors. Especially, the fact that 99mTc-MIBI detected remote metastatic lesions with high sensitivity is a great advantage over the other conventional imaging modalities.

Adult↗
PubMed2000

[Evaluation of clinical utility of 123I-MIBG scintigraphy in localization of tumors of sympathetic and adrenomedullary origin--a report of multicenter phase III clinical trials].

Phase III clinical study was performed to evaluate clinical utility of 123I-MIBG in the localization of tumors in 48 patients with tumors of sympathetic and adrenomedullary origin, diagnosed or strongly suspected. Sixteen patients had pheochromocytoma, 23 had neuroblastoma, 7 had medullary carcinoma of the thyroid, and 2 had Sipple syndrome. In 3 out of 48 patients, 123I-MIBG scintigraphy was performed twice. The clinical utility of 123I-MIBG was evaluated in 50 cases. Out of 140 lesions, 123I-MIBG scintigraphy demonstrated 51 true positive, 79 true negative, 1 false positive, and 2 false negative. Seven lesions were not evaluable. Sensitivity was 96.2%, Specificity was 98.8%, and Accuracy was 97.7%. An acquisition between 4 hrs and a day after injection was adequate for tumor detection. Neither adverse reactions nor abnormal laboratory findings were noted in relation to 123I-MIBG injections. Our study indicates that 123I-MIBG is a safe and useful radiotracer for visualization and localization of tumors of sympathetic and adrenomedullary origin.

3-Iodobenzylguanidine↗
PubMed1992

Bayesian methods for phase I clinical trials.

Phase I clinical trials are conducted to determine the dose-response curve of a new drug with respect to toxic side effects and, in particular, to estimate the maximum tolerated dose (MTD). In this paper we take a Bayesian approach to the problem of making inferences about the MTD. Working with broad classes of priors, we obtain the posterior distribution of the MTD and study its properties. We also address the question of providing updated assessments of the risk of toxicity for new patients entering the study at a specific dose level. These assessments would be useful in deciding issues of study management and ethics. Our analysis pays particular attention to the sensitivity of the inferences and risk assessments to the choice of prior and the choice of model for the dose-response relationship.

Algorithms↗
PubMed2026

Network-Integrated Platform for Clinical Trial Navigation from the New South Wales Early Phase Clinical Trials Alliance.

PURPOSE: Access to early-phase clinical trials (EPCT) is increasingly constrained by delays in genomic testing and lack of coordinated system-level navigation. The New South Wales Early Phase Clinical Trials Alliance (NECTA) was established to improve EPCT access. Practical Assessment of NECTA Network Assistance in Cancer Outpatient Trials Access (PANNA-COTA) prospectively evaluated whether integrating circulating tumor DNA (ctDNA) profiling with a real-time, cross-site molecular tumor board (MTB) facilitates EPCT enrollment. PATIENTS AND METHODS: In this multicenter prospective study across nine NECTA sites, patients referred for EPCT consideration underwent ctDNA testing using the Guardant360 74-gene assay. The results were reviewed at a fortnightly MTB incorporating cross-site trial mapping and dynamic eligibility review. The primary endpoint was proportion enrolled into EPCTs. Secondary endpoints included ctDNA findings and trial outcomes. RESULTS: Of 104 consented participants, 101 were eligible. Participants had advanced, heavily pretreated solid tumors; 48% lacked prior tumor next-generation sequencing. ctDNA alterations were detected in 85%, with actionable alterations in 44%. Therapeutic options were identified in 88%, and EPCTs were recommended in 76%. Despite this, only 7% of participants received genomically matched therapy. In contrast, 37% enrolled in EPCTs within 3 months and 47% overall [95% confidence interval (CI), 0.37-0.56]. Among evaluable participants on trial, the disease control rate was 81% and objective response rate was 33%. CONCLUSIONS: PANNA-COTA demonstrates that integrating liquid biopsy with real-time, network-level trial navigation enables high rates of EPCT enrollment despite low rates of genomically matched therapy. These findings indicate that clinical trial access is influenced by navigation, eligibility, and system-level coordination rather than genomic actionability alone.

Humans↗
PubMed2005

Monitoring event times in early phase clinical trials: some practical issues.

BACKGROUND: In many early phase clinical trials it is scientifically inappropriate or logistically infeasible to characterize patient outcome as a binary variable. In such settings, it often is more natural to construct early stopping rules based on time-to-event variables. This type of design may involve a variety of complications, however. PURPOSE: The purpose of this paper is to illustrate by example how one may deal with various complications that may arise when monitoring time-to-event outcomes in an early phase clinical trial. METHODS: We present a series of Bayesian designs for a phase II clinical trial in kidney cancer. Each design includes a procedure for monitoring the times to a severe adverse event, disease progression and death. The first design, which is the simplest, is based on the time to failure, defined as any of the three events, assuming exponentially distributed failure times with an inverse gamma prior on the mean. This design is compared by simulation to the CMAP design (Cheung and Thall, Biometrics, 2002; 58: 89-97). The model and monitoring procedure are then extended successively to accommodate several common practical complications, and we also study the method's robustness. RESULTS: Our simulations show that 1) one may apply the monitoring rule periodically, rather than continuously, without a substantive degradation of the design's reliability; 2) it is very important to account for interval censoring due to periodic evaluation of disease status; 3) it is important to account for the effect of disease progression on the subsequent death rate; 4) conducting a randomized trial presents little additional difficulty and provides unbiased comparisons; and 5) the exponential-inverse gamma model is surprisingly robust in most cases. LIMITATIONS: The methods discussed here do not account for patient heterogeneity. This is an important but complex issue that may be dealt with by extending the models and methods given here to accommodate patient covariates and treatment-covariate interaction. CONCLUSIONS: Bayesian procedures for monitoring time-to-event outcomes offer a practical way to conduct a variety of early phase trials. Considerable care must be given, however, to modeling the important aspects of the trial at hand, and to calibrating the prior and the design parameters to ensure that the design will have good operating characteristics.

Bayes Theorem↗
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↗
PubMed2005

[Clinical phase trial of concurrent chemoradiotherapy combined TS-1 and nedaplatin].

We have treated head and neck carcinoma by concurrent chemoradiotherapy combined with 5-fluorouracil (5-FU) and cisplatin (CDDP). However,this chemoradiotherapy could not show an enormous effect in the advanced carcinoma of Stage III and IV. Therefore,we changed the contents of the chemotherapy, i.e., we replaced 5-FU, one of the agents with time dependency, to continuous administration of TS-1 for 2 weeks,also replacing CDDP, one of the agents with dose dependency, to nedaplatin (CDGP) in order to reduce kidney dysfunction. In this concurrent chemoradiotherapy, oral TS-1 was continued for 2 weeks and CDGP was administered on the 4 th day from the start of TS-1. In addition, radiotherapy was performed concurrently. In this way,we performed a phase I clinical trial of concurrent chemoradiotherapy combining TS-1 and nedaplatin (CDGP). As for the incidence of adverse events,grade 3 mucositis due to radiation was observed in two patients. As a result of the phase I clinical trial,we decided the maximum-tolerated dose (MTD) of TS-1 to be 80 mg/m2 (maximum 120 mg/body) and 100 mg/m2 for CDGP, and then determined the recommended dose(RD) of TS-1 as 80 mg/m2 (maximum 120 mg/ body) TS-1 and of CDGP as 9 0 mg/m2 CDGP.

Adult↗
PubMed2007

Diagnostic efficacy and safety of 99mtc-labeled monoclonal antibody ior c5 in patients with colorectal and anal carcinomas: final report clinical trial phase I/II.

UNLABELLED: Monoclonal antibody (mAb) ior c5 is an IgG1, which recognizes a glycoprotein tumor specific antigen IOR C2 over expressed in the surface of colon and ovarian cancer cells. The aim of the present work was to evaluate the diagnostic efficacy of the 99mTc-labeled mAb ior c5 for the detection of colorectal tumors, its metastases and recurrences. METHODS: Eighty six patients with colorectal or anal cancer, mean age 57 +/- 13 yrs, were involved in a phase 1/11 multicentric, open clinical trial to assess the ability of Radioimmunoscintigraphy (RIS) with 99mTc- mAb ior c5 to detect those tumors. Seventy-four patients received 1 mg of c5 labeled with 1480-1850 MBq to determinate diagnosis efficacy and safety of murine mAb by intravenously (i.v.) bolus injection (group 1). In order to evaluate pharmacokinetic, bio distribution and dosimetry of this radiolabel molecule, 12 patients received 3 mg of labeled ior c5. Planar anterior and posterior images of the lesion sites and suspected metastases were acquired at 2, 4 and 18-24 hours after injection using a matrix size 128 x128 and 500 Kcounts per view. SPECT were scanned at 5 hr post-injection, using a 360' circular orbit with 64 images. HAMA response was measured in serum at 2, 4, 8 and 12 week post-administration. RESULTS: Labeling efficiency was (97.8 - 0.6) %. No adverse reactions or side effects were observed. Overall sensitivity, specificity, accuracy, positive and negative predictive values of the immunoscintigraphy were 95.80%, 100%, 96.51%, 100.0% and 82.35%, respectively. Unknown metastases were detected in 37 of 86 cases (43.02%). No HAMA response was found. CONCLUSIONS: Immunoscintigraphy with 99mTc-labeled mAb ior c5 could be a useful procedure for the diagnosis and follow-up of the patients with colorectal tumors, its metastasis and recurrences.

Adolescent↗
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↗
PubMed1997

[Introduction of anticancer agents to phase I clinical trials].

Because about half of patients with cancer could not be cured by the present standard therapy, new effective anticancer agents should be developed and introduced at the clinical level. However, there are several important and specific issues from scientific, medical, statistical, and ethical viewpoints in the design and conducting of phase I clinical trials of new anticancer agents. Clinical safety data management is critically important in phase I clinical trials. Phase I clinical trials are vastly different from phase II or III clinical trials in terms of these issues. This paper discusses issues of early anticancer drug development to be solved or improved.

Antineoplastic Agents↗
PubMed2006

Identification of synovial biomarkers of response to experimental treatment in early-phase clinical trials in spondylarthritis.

OBJECTIVE: To identify biomarkers for effective treatment in early-phase clinical trials of spondylarthritis (SpA), by analyzing which synovial features can be reliably identified in patients with SpA. METHODS: Synovial biopsies were performed at weeks 0 and 12 in 20 SpA patients treated with infliximab, 20 treated with etanercept, and 12 who were not treated. Primary clinical outcome measures were patient and physician global assessment of disease activity. Extensive histologic evaluation included assessment of lining layer hyperplasia, vascularity, markers of cellular infiltration, and metalloproteinases (MMPs) in the lining and sublining layers. RESULTS: Changes in levels of CD163 (resident tissue macrophages) in the lining, and CD163, MMP-3, and myeloid-related protein 14 (MRP-14; infiltrating myeloid cells) in the sublining correlated significantly with changes in the primary clinical outcomes. Comparison between responders (n = 35) and nonresponders (n = 17) showed differences in the degree of change in the levels of CD163 in the lining and CD163, MMP-3, and CD3 in the sublining, whereas trends in change in the levels of MRP-8 and MRP-14 in the lining and sublining were similar in the 2 groups. Accordingly, the highest differences in standardized response means (SRMs) between the 2 groups were found for CD163 in the lining, MMP-3, CD163, CD3, and MRP-8 in the sublining, and the level of polymorphonuclear cells (PMNs). When comparing treated and untreated patients, high differences in SRMs were again found for CD163 in the lining, MMP-3, CD163, and MRP-8 in the sublining, and PMNs. These parameters performed prognostically as well as the erythrocyte sedimentation rate and better than the C-reactive protein level. Class prediction analysis yielded a 90% correct prediction using 8 synovial parameters, as follows: lining and sublining CD163, MRP-8, and MRP-14, sublining MMP-3, and PMNs. In validation analyses with independent samples, effective treatment was correctly predicted in 24 of 30 SpA patients and in 2 of 2 placebo-treated patients. CONCLUSION: Changes in synovial macrophage subsets, PMN levels, and MMP-3 expression reflect response to treatment in SpA. The ability of these parameters to correctly identify effective therapy makes them interesting biomarkers for use in early-phase clinical trials in SpA.

Adult↗
PubMed1995

Early-phase clinical trials in migraine: efficacy, safety and dose-finding.

Early-phase clinical trials with any new chemical entity have three main objectives: to establish that the drug is effective in the target disease and patient population; to assess tolerability and safety; and to select the optimum dose or doses for further evaluation. Clinical trials in migraine and other headache disorders pose additional problems because of the lack of specific objective diagnostic tests and the reliance on patient assessments of symptom relief. For these reasons particular care must be taken in selection of patients, design of the trials, choice of end-points and statistical analytical methodology. A wide range of doses must be evaluated to ensure that the dose-response curves for both efficacy and safety/tolerability are fully defined. Successful early-phase trials should then allow the optimum dose or doses of the drug to be identified for further evaluation in large-scale outpatient studies.

Analgesics↗
PubMed1999

A new statistical method for dose-finding based on efficacy and toxicity in early phase clinical trials.

Most statistical methods for dose-finding in phase I clinical trials determine a maximum tolerable dose based on toxicity while ignoring efficacy. Most phase II designs assume that an acceptable dose has been determined and aim to estimate treatment efficacy, possibly with early stopping rules for safety monitoring. The purpose of this paper is to describe a new statistical strategy for dose-finding in single-arm clinical trials where patient outcome is characterized in terms of both response and toxicity. The strategy, which may be considered a phase I/II hybrid, was first proposed by Thall and Russell [1] and subsequently modified by Thall [2]. The underlying mathematical model expresses the probabilities of response and toxicity as interdependent functions of dose. The method is based on fixed standards for the minimum probability of response and the maximum probability of toxicity appropriate for the particular trial. The best acceptable dose is chosen for each successive patient cohort adaptively, based on the fixed standards and the dose-outcome data from patients treated previously in the trial. The scientific goals are to select one best acceptable dose for future patients and to estimate the response and toxicity probabilities at that dose, or to stop the trial early if it becomes sufficiently unlikely that any dose is both safe and efficacious. An application of the method to a trial of donor lymphocyte infusion as salvage therapy for chemo-refractory AML/MDS patients is described. To illustrate the method's flexibility and potential breadth of application, two additional examples are provided, including a hypothetical trial in which a 5% response rate is of interest.

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↗
PubMed2006

Cognitive testing in early phase clinical trials: outcome according to adverse event profile in a Phase I study.

BACKGROUND: It has been proposed that objective cognitive testing provides additional information to that collected via adverse event (AE) recordings. However, in clinical trials of compounds with potentially negative effects on cognition, the results of cognitive testing may overlap with AE recordings. AIMS: To examine cognitive function in subjects who do and do not report sedation-related AEs in a Phase I clinical trial. METHODS: Five computerized cognitive tasks were administered to 28 healthy male volunteers enrolled in a simulated Phase I study using midazolam to induce sedation-related AEs and cognitive dysfunction. For each subject, the magnitude of cognitive change between pre-dose and 1 hr post-dose assessments was calculated. Group and individual level cognitive outcome was compared between subjects who did and did not report sedation-related AEs following administration of 1.75 and 5.25 mg midazolam. RESULTS: At both doses of midazolam, cognitive dysfunction was observed in both subject groups (i.e., those who did and did not report AEs). Analysis of individual outcomes identified consistent cognitive dysfunction among subjects who reported sedation-related AEs. Further, in the 5.25 mg condition a subset of individuals (66.7%) who did not report sedation-related AEs nevertheless displayed substantial cognitive dysfunction. CONCLUSIONS: Following administration of oral midazolam, there is a dissociation between sedation-related AE recordings and performance on computerized cognitive tests of motor function, attention, strategy use and problem solving, learning and delayed recall. Inclusion of computerized cognitive tests in early phase trials may allow identification of subtle cognitive change, beyond that which is possible by self-report and clinical observation.

Adolescent↗