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PubMed1999

Safety profile of ultrasmall superparamagnetic iron oxide ferumoxtran-10: phase II clinical trial data.

The safety data from the phase II clinical trial of ferumoxtran-10, an ultrasmall superparamagnetic iron oxide contrast agent, are presented. One hundred and four patients with focal liver or spleen pathologies underwent ferumoxtran-10-enhanced magnetic resonance (MR) imaging at doses of 0.8, 1.1, and 1.7 mg Fe/kg. Overall, 15% patients reported a total of 33 adverse events, regardless of causality. The adverse events most frequently seen were dyspnea (3.8%), chest pain (2.9%), and rash (2.9%). No serious adverse events were reported during the 48 hour observation period. There were no clinically significant effects on vital signs, physical examination, and laboratory results. Ferumoxtran-10 is a safe and well tolerated MR contrast agent.

Contrast Media↗
PubMed1994

[Clinical evaluation of CGS16949A in advanced or recurrent breast cancer--a multi-institutional late phase II clinical trial].

A multi-institutional late-phase II clinical trial of CGS 16949A was conducted at the dose of 1 mg twice daily in postmenopausal patients with advanced or recurrent breast cancer. Seventy patients entered into the study; 65 were eligible and 53 were complete cases. There were 3 CR, 11 PR, 10 long-NC, 14 NC and 25 PD with an overall response rate of 22.2% in 63 evaluable cases. The median period of overall duration of responses was 327.5 days. There were 22 cases that drug was found useful or better, and global usefulness rate was 33.8%. Forty six (76.7%) of patients experienced no side effects in this therapy. Grade 2 toxicities included anorexia (1 pt.), feeling of distension of abdomen (1 pt.), vomiting (1 pt.), fatigue (1 pt.), and only one patient experienced Grade 3 toxicity (anorexia). Grade 2 laboratory abnormalities were confirmed in two patients; one with elevated gamma-GTP and another with elevated LDH, and both were in the absence of liver metastasis. From these results, it is concluded that CGS16949A seemed to be a useful hormonal agent in the treatment of postmenopausal breast cancer.

Administration, Oral↗
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↗
PubMed2003

Decision-theoretic designs for phase II clinical trials allowing for competing studies.

This article describes an approach to optimal design of phase II clinical trials using Bayesian decision theory. The method proposed extends that suggested by Stallard (1998, Biometrics 54, 279-294) in which designs were obtained to maximize a gain function including the cost of drug development and the benefit from a successful therapy. Here, the approach is extended by the consideration of other potential therapies, the development of which is competing for the same limited resources. The resulting optimal designs are shown to have frequentist properties much more similar to those traditionally used in phase II trials.

Bayes Theorem↗
PubMedDate not supplied

An innovative approach to the care of patients on phase I and phase II clinical trials: the role of the experimental therapeutics nurse.

The tremendous strides in survival rates for childhood malignancies in large part can be attributed to the clinical trial mechanism. New and innovative therapies are being developed in the laboratory in an attempt to find a cure for those children who have relapsed or have refractory disease. Phase I and phase II clinical trials move this science from the laboratory to the patient's bedside. With increasing frequency, the oncology staff nurse may be managing the care of a patient receiving a phase I or phase II study drug. Administration of these agents goes beyond what is familiar, requires specialized knowledge, and demands a skill set beyond what is required for standard oncology care. At The Children's Hospital of Philadelphia, the role of the experimental therapeutics nurse was created in an effort to improve the process for identification, treatment, and follow-up of patients receiving these therapies. The broader role of nursing in clinical trials, the multidisciplinary challenges of experimental therapies, and the development of an innovative approach to caring for patients on phase I/II studies are discussed.

Child↗
PubMed2003

A phase II clinical trial to evaluate the effect of paclitaxel in patients with ascites caused by advanced or recurrent gastric carcinoma: a new concept of clinical benefit response for non-measurable type of gastric cancer.

A phase II clinical trial has started in the South West region of Japan to investigate the efficacy and safety of weekly paclitaxel chemotherapy for the treatment of patients with ascites-forming advanced gastric cancer. A novel trial design was created to assess more effectively prospective changes in symptomatology. The study design focuses on the typical features seen in patients with ascites-forming advanced gastric cancer, including girth of the abdomen and impaired performance status, which is evaluated in the endpoint of 'Clinical Benefit Response - Gastric Cancer'. The more traditional endpoints, objective tumor response and survival, are also included. As nearly 40% of patients with this disease are excluded from traditional phase II trials owing to the absence of 'measurable' disease, this study should more precisely illustrate the disease entity affecting patients with advanced gastric cancer.

Antineoplastic Agents, Phytogenic↗
PubMed2001

[Results of phase II clinical trial of cycloplatam in refractory solid tumors].

Cycloplatam, a new platinum derivative, evolved at N.S. Kurnakov Institute of General and Inorganic Chemistry in 1982, has been added to the arsenal of Russian cytostatic drugs. Having passed phase I trials, it was approved for treatment of pleural mesothelioma, ovarian carcinoma and multiple myeloma. Leukothrombocytopenia formation indicates toxicity-related limit of dosage. Phase II clinical trials are under way at the Center. They include treatment of solid tumors with cycloplatam alone in urinary bladder tumors, cervical carcinoma and malignant pleurites of various etiology as well as in combination with other cytostatics (carcinoma of the prostate, pleural mesothelioma and urinary bladder tumors). The drug may be recommended both for oral and intracavitary administration; side-effects may include moderate toxicity, chiefly, hematological one.

Adult↗
PubMed2006

Raloxifene, an oestrogen-receptor-beta-targeted therapy, inhibits androgen-independent prostate cancer growth: results from preclinical studies and a pilot phase II clinical trial.

OBJECTIVES: To determine, in preclinical in vivo animal and in clinical studies, whether raloxifene (a selective oestrogen-receptor (ER) modulator that targets ER-beta and induces apoptosis in vitro in androgen-independent prostate cancer, AIPC cells) affects prostate cell differentiation, proliferation and carcinogenesis, and in the pilot phase II clinical trial, the response rate and duration of patients with AIPC treated with a daily oral dose of raloxifene. PATIENTS, MATERIALS AND METHODS: Tumour proliferation rate in response to raloxifene treatment, and molecular markers of cell cycle and apoptosis, were evaluated in established ER-beta-positive androgen-dependent (AD) CWR22 and AI CWRSA9 human xenograft prostate cancer models. Twenty-one patients with AIPC and evidence of disease progression were enrolled into the clinical trial and given daily oral raloxifene. RESULTS: There was significant growth inhibition by raloxifene in the ADPC and AIPC xenograft models (CWR22 68%, P < 0.010; CWRSA9 64%, P < 0.001), with no tumour regression. There was evidence of G1 arrest by increased p27kip1 expression in the raloxifene-treated group. Eighteen patients comprised the efficacy analysis, as three withdrew before the first evaluation. At the first evaluation, five men had stable disease and continued on the study for a median of five cycles. The longest response was 17 cycles. Drug related toxicity was minimal. CONCLUSION: Raloxifene has activity in xenograft models, slowing disease progression. This translated to possible disease stabilization in patients with AIPC. Further studies are warranted.

Aged↗
PubMed2006

Phase II clinical trial design: methods in translational research from the Genitourinary Committee at the Eastern Cooperative Oncology Group.

Given the increase in novel agents and difficulty with planning and completing many phase III studies, various phase II trial design options should be considered to more effectively guide phase III trial plans. The need for novel phase II trial designs has increased, given the number of novel molecular targeted therapies now available for testing, an abundance of cytostatic agents, and limited resources to conduct phase III studies for all interesting agents or combinations. This review will focus on options for phase II trial designs. We review randomized phase II designs with placebo control, randomized selection designs, and randomized discontinuation designs. As agents become available for testing in the clinic, the strengths and weaknesses of different phase II trial designs should be considered to optimize a trial development plan that guides phase III trial decisions more effectively.

Advisory Committees↗
PubMed1988

Iproplatin and carboplatin induced toxicities: overview of phase II clinical trial conducted by the EORTC Early Clinical Trials Cooperative Group (ECTG).

Data of five phase II clinical trials on iproplatin and carboplatin, conducted by the ECTG, have been pooled in order to evaluate the extent of toxicities of these compounds. One hundred and seventy patients treated with iproplatin and 65 patients treated with carboplatin were evaluable. Most of them (81%) had been previously treated with chemotherapy. Doses ranged from 180 to 300 mg/m2 every 4 weeks for iproplatin, and from 350 to 450 mg/m2 every 5 weeks for carboplatin, according to the initial status of the patient. WHO criteria were used to grade toxic effects. Weekly blood counts were performed, and lowest observed counts were analysed by non-parametric methods. Censored data were analysed by actuarial methods. Thrombocytopenia was the dose-limiting toxicity and was dose related. Leucopenia was less severe. The risk of thrombocytopenia varied largely amongst patients, and could be predicted from the initial platelet count, the initial creatinine level and prior therapy with alkylating agents. The cumulative risk increased with the total dose, but with a decreasing hazard rate, and without additional delay to platelet recovery. Nausea, vomiting and diarrhoea were the most frequently observed non-haematological side-effects, and were more severe with iproplatin than with carboplatin. Peripheral neuropathy was observed in some cases, but could be due to prior treatments. Renal toxicity did not cause major problems. Our results confirm the findings of the phase I trials: thrombocytopenia is dose-limiting for both drugs, and renal side-effects are negligible. The risk model of thrombocytopenia, consistent with Egorin's model for carboplatin, could serve as a basis for dose adjustment. The feasibility of the scheme could be insufficient for prolonged treatment.

Adult↗
PubMed2005

Development of an allogeneic whole-cell tumor vaccine expressing xenogeneic gp100 and its implementation in a phase II clinical trial in canine patients with malignant melanoma.

A xenogeneic melanoma-antigen-enhanced allogeneic tumor cell vaccine (ATCV) is an appealing strategy for anti-cancer immunotherapy due to its relative ease of production, and the theoretical possibility that presentation of a multiplex of antigens along with a xenogeneic antigen would result in cross-reaction between the xenogeneic homologs and self-molecules, breaking tolerance and ultimately resulting in a clinically relevant immune response. In this study, we evaluated the efficacy of such a strategy using a xenogeneic melanoma differentiation antigen, human glycoprotein 100 (hgp100) in the context of a phase II clinical trial utilizing spontaneously arising melanoma in pet dogs. Our results demonstrate that the approach was well tolerated and resulted in an overall response rate (complete and partial response) of 17% and a tumor control rate (complete and partial response and stable disease of >6 weeks duration) of 35%. Dogs that had evidence of tumor control had significantly longer survival times than dogs that did not experience control. Delayed type hypersensitivity (DTH) to 17CM98 canine melanoma cells used in the whole cell vaccine was enhanced by ATCV and correlated with clinical response. In vitro cytotoxicity was enhanced by ATCV, but did not correlate with clinical response. Additionally, anti-hgp100 antibodies were elicited in response to ATCV in the majority of patients tested; however, this also did not correlate with clinical response. This approach, along with further elucidation of the mechanisms of tumor protection after xenogeneic immunization, may allow the development of more rational vaccines. This trial also further demonstrates the utility of spontaneous tumors in companion animals as a valid translational model for the evaluation of novel vaccine therapies.

Animals↗
PubMed2001

Irritable bowel syndrome: attrition rates of patients identified at primary care centers during a 50-week period versus those identified in hospitals in a phase II clinical trial.

Although most irritable bowel syndrome (IBS) patients are managed in primary care centers, most trials are performed in the hospital setting. A successful recruitment strategy is important for trial completeness and its external validity. To this end, it was important to assess the attrition rates of patients identified at primary care centers and hospitals in this phase II trial conducted in the outpatient clinics of 16 hospitals. IBS patients were identified through review of the centers' files (prescreening). After a 2-week single-blind placebo screening phase, the patients were randomized to receive an investigational drug or a matched placebo for 24 weeks (dose-ranging study). Thereafter, the patients were invited to participate in a 24-week, double-blind extension study. The attrition rates among patients identified at hospitals (group A) and at primary care centers (group B) were compared in each study phase and during the 50-week period by bivariate and multivariate regression analyses. Group A and B patients were identified in 13 hospitals and 51 primary care centers, respectively. Of 1,001 prescreened patients, 302 started the screening phase with attrition rates of 35% (of 132 patients) and 25% (of 170) for groups A and B, respectively (p = 0.054). The attrition rate during the double-blind phase was 14%. Of the 184 patients who completed the dose-ranging study, 39 (group A: 32%; group B: 14%; p = 0.005) did not wish to participate in the extension study. The attrition rate in the extension study was 15%. The overall attrition rates during the 50-week period were 67% and 53% (p = 0.016) for groups A and B, respectively. The multivariate regression analysis showed that the screening phases (p = 0.000) and unwillingness to participate in the extension study (p = 0.007) had the highest impact on attrition rates. We conclude that referring patients identified in primary care centers to hospitals seems appropriate to ensure potentially eligible patients for IBS trials. Patients identified in primary care centers are more likely than those identified in hospitals to participate in a 24-week extension study, which may be due to their positive feelings about being treated in a hospital rather than being referred back to their original primary care center. This strategy may be considered in future trials since, with a reasonably low attrition rate, it would enhance the external validity of the results obtained.

Adult↗
PubMed2005

Patient motivations surrounding participation in phase I and phase II clinical trials of cancer chemotherapy.

Successful advances in the treatment of advanced malignant diseases rely on recruitment of patients into clinical trials of novel agents. However, there is a genuine concern for the welfare of individual patients. The aim of this study was to examine motives of patients entering early clinical trials of novel cancer therapies. Questionnaire survey with both open- and close-ended questions. The patients were surveyed after they had given informed consent and before or during the first cycle of treatment. In all, 38 phase I/II trial patients participated and completed the survey. Obtaining possible health benefit was listed by 89% as being a 'very important' factor in their decision to participate, with only 17% giving reasons of helping future cancer patients and treatment. Other items cited as a 'very important' motivating factor were 'trust in the doctor' (66%), 'being treated by the latest treatment available' (66%), 'better standard of care and closer follow-up' (61%), and 'closer monitoring of patients in trials' (58%). Only 47% patients indicated that someone had explained to them about any 'reasonable' alternatives to the trial. In total, 71% strongly agreed that 'surviving for as long time as possible was the most important thing (for them)'. Nearly all (97%) indicated that they knew the purpose of the trial and had enough time to consider participation in the trial (100%). In this survey, most patients entering phase I and II clinical trials felt they understood the purpose of the research and had given truly informed consent. Despite this, most patients participated in the hope of therapeutic benefit, although this is known to be a rare outcome in this patient subset. Trialists should be aware, and take account of the expectations that participants place in trial drugs.

Adult↗
PubMed1998

Propentofylline in the treatment of vascular dementia and Alzheimer-type dementia: overview of phase I and phase II clinical trials.

Pathophysiologic processes common to both vascular (multi-infarct) dementia and dementia of the Alzheimer type may include microglial activation with resultant generation of inflammatory cytokines and neurotoxic free radicals, decreased secretion of nerve growth factor by astrocytes, excess release of glutamate with associated neurotoxicity, and loss of cholinergic neurons. The functional benefits and neuroprotective effects of propentofylline (PPF) stem from its interference with these overlapping pathways of neurodegeneration. The clinical pharmacology and safety of PPF were studied in a number of phase I studies in healthy young and elderly adults and in patients with renal or hepatic impairment. These studies have shown that PPF 300 mg t.i.d. is safe and well tolerated when taken on an empty stomach 1 h before meals. In a randomized, double-blind phase II study involving 190 elderly subjects with clinically and psychometrically documented mild to moderate dementia, 12 weeks of PPF therapy produced significantly greater improvements than placebo in Gottfries-Bråne-Steen (GBS) scores, Mini-Mental State Examination (MMSE) scores, and Clinical Global Impression (CGI) ratings. A subsequent phase II study using positron emission tomography (PET) revealed that cortical glucose metabolism improved significantly in patients with vascular dementia after 12 weeks of PPF treatment but deteriorated significantly with placebo. A third phase II study, which enrolled patients with Alzheimer-type dementia, demonstrated that PPF significantly enhanced functional reserve, as reflected by increases in regional cerebral glucose metabolism after stimulation with a verbal memory task. In contrast, patients randomized to placebo exhibited a significant decline in functional activation and significant worsening in their MMSE scores over the course of this 12-week study. Propentofylline proved to be safe, well tolerated, and free of severe side effects in all three of these phase II trials. Phase I trial results suggest that significant food interactions occur with PPF, indicating that the drug should be taken on an empty stomach 1 h before meals. Phase II trial results indicate that PPF yields clinically measurable improvements in the symptoms of dementia and prevents loss of stimulation-related increases in glucose metabolism over a treatment period of 3 months. Whether these results indicate that PPF can slow the progression of dementia can be determined only by long-term trials specifically designed to determine the drug's effect on disease progression.

Aged↗