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Results for “Clinical Trials, Phase III as Topic”

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PubMed1993

Data monitoring committees for Southwest Oncology Group clinical trials.

A monitoring committee policy was established by the Southwest Oncology Group in 1985 to address documented problems in study conduct. Committees consisting of the study coordinators, disease committee chair, study statistician, Group chair, Group statistician, an uninvolved Southwest Oncology Group clinician, an NCI representative, and a representative from each involved group for intergroup studies have been appointed for each phase III study. Business is conducted largely through the mail and through conference calls. Since then, problems identified in older studies have been largely resolved. Appropriate and timely decisions are being made at modest additional expense to the Group.

Clinical Trials as Topic↗

PubMed2004

[Radiation and concomitant chemotherapy after surgery for breast cancer].

In breast cancer, radiation therapy improves local control rate and survival. When chemotherapy and radiation are indicated the sequencing of the two treatments is still controversial. Several studies have suggested that adjuvant radiotherapy could be safely delayed until adjuvant chemotherapy was completed. Other studies, most of them retrospective, pointed out that a delay in the initiation of radiotherapy to give chemotherapy first, will result in a increased rate of local recurrence. Concomitant administration of the two treatments is an alternative. Pilot studies have suggested the feasibility of simultaneous administration using selected regimen as CMF or FNC. A randomized phase III trials has been conducted to compare sequential treatment with chemotherapy first and radiation versus concomitant treatments. Preliminary results of this study are presented.

Adult↗

PubMed1996

The human pharmacology of thrombin inhibition.

Heparin has an established place in the treatment of venous thrombosis. It is also effective in syndromes of arterial occlusion, such as unstable angina, although its benefit: risk ratio when combined with thrombolytic drugs in the treatment of myocardial infarction remains open to debate. Specific thrombin inhibitors have several theoretical advantages over heparin. However, they have failed to realize their promise in phase III trials, perhaps because of inadequacies in trial design. Our understanding of protease-activated receptors, such as that for thrombin, is modest and the comparative advantages of receptor antagonism versus specific thrombin inhibition are unknown. Increasing usage of low molecular weight heparins and glycoprotein IIb/IIIa antagonists provide a changing context for evaluation of these drugs. Problems in phase III clinical trials might be minimized by placing greater emphasis on dose finding in phase II.

Animals↗

PubMed2006

Confirmatory clinical trials with an adaptive design.

Adaptive designs are one of the most promising developments in statistics with applications to clinical trials. Obviously, knowledge at the beginning of a clinical trial will always be limited. Thus it may seem logical that the knowledge from accumulating information should be used to optimize the design of the trial. This paper discusses conditions under which this may be possible in phase III clinical trials where the principal aim is confirmation of hypotheses that have been developed in earlier stages of drug development.

Biometry↗

PubMed2006

Drug Insight: abatacept for the treatment of rheumatoid arthritis.

Although the development of tumor necrosis factor antagonists has improved the clinical outcome of many patients with rheumatoid arthritis (RA), some patients fail to respond to these drugs or have contraindications preventing their use. Other approaches for treating this disease are, therefore, keenly sought. As T cells promote numerous disease pathways in RA, these cells are a logical target for anti-inflammatory therapy. One of the approaches being investigated involves targeting the co-stimulatory signals that accompany antigen-derived signals involved in the activation of T cells. Abatacept is a recombinant fusion protein that interrupts the T-cell co-stimulatory signal mediated through the CD28-CD80/CD86 pathway. Several clinical trials have now confirmed the efficacy of this compound in the treatment of RA. This article discusses the proposed mechanism of action of abatacept and reviews the data from phase II and phase III clinical trials on the safety and efficacy of this drug in RA.

Abatacept↗

PubMed1995

The role of adjuvant therapy in melanoma management.

Adequate wide excision of a primary cutaneous melanoma is associated with a 10-year cure rate of 85% when the tumor's depth is less than 1.5 mm (American Joint Committee on Cancer [AJCC] Stage I). However, 50% of patients with deep (> 4 mm) primary melanomas, 60-85% of those with regional lymph node metastases (AJCC Stage III), and 95% of those with metastases to distant sites (AJCC Stage IV) will experience recurrence, which is associated with a dismal prognosis. Adjuvant therapy of melanoma assumes that treatment will be more effective when the tumor burden is small. In the 1970s and 1980s, randomized trials tested the efficacy of chemotherapy, nonspecific immunotherapy, levamisole, and regional perfusion therapy in patients with AJCC Stage II and III melanoma. Dacarbazine (DTIC) alone or in combination with other chemotherapeutic drugs or with nonspecific immunotherapy did not significantly improve disease free or overall survival. Of the four levamisole trials, only the study conducted by the National Cancer Institute of Canada revealed a reduction in recurrence and mortality; however, this reduction was not significant by multivariate analysis. The value of regional perfusion therapy following resection of high risk extremity melanomas is currently being determined by multiinstitutional studies conducted by the World Health Organization and the North American Perfusion Group. Multi-institutional trials also are examining the adjuvant role of interferon-alpha in patients with deep (> 3 mm) primary melanomas or positive regional lymph nodes; results should reveal its optimum dose and duration of treatment (3 x 10(6) U for > or = 2 years versus 10 x 10(6) U/m2 for 1 year, subcutaneously 3 times a week) and its impact on survival. A randomized trial of interferon-gamma undertaken by the Southwest Oncology Group was discontinued after interim analysis indicated an adverse effect. Phase II trials indicate that active specific immunotherapy can alter the natural course of AJCC Stage III and IV melanoma following surgical resection of nodal or distant metastases. Upcoming results of Phase III trials will establish the role of active specific immunotherapy for adjuvant treatment of patients with resected AJCC Stage III and IV melanoma.

BCG Vaccine↗

PubMed2006

[Palliative chemotherapy of head and neck cancer: present status and future development].

BACKGROUND: Patients with head and neck tumors are treated with palliative chemotherapy in case of the detection of distant metastases or local recurrence without the option of surgical therapy or radiation. Alongside 5-fluorouracil (5-FU) in combination with cisplatin or carboplatin, taxanes, gemcitabine and vinorelbine as well as monoclonal antibodies or small molecule tyrosine kinase inhibitors have been used. METHODS: This review analyses the published literature of the past 15 years, including selected abstracts with view to response rate, overall survival and adverse effects. RESULTS: 5-FU plus cisplatin or carboplatin can still be considered as standard treatment, achieving response rates of 20-30 %. The addition of taxanes increases the objective response rate but adds remarkable toxicity to the treatment protocol. Phase III studies demonstrate higher response rates but fail to demonstrate a significant increase of the overall survival after polychemotherapy as compared to monotherapy protocols. Thus, patients with a reduced performance can be treated with monotherapy. In case of disease progression after cisplatin-containing chemotherapy further treatment should only be offered to selected patients. For this situation, platin-free chemotherapy protocols containing taxanes, gemcitabine or vinorelbine seem promising. Recent studies with monoclonal antibodies or small molecule tyrosine kinase inhibitors report on a response rate of 10-20 %. CONCLUSION: The use of new drugs increases the response rate and amends the side effects of the chemotherapy. However, phase III studies documenting an improved overall survival are lacking. Targeted therapies broaden the therapeutic armament, and possibly, EGFR inhibition will help to overcome chemotherapy resistance in the future.

Animals↗

PubMed2006

Udenafil, a long-acting PDE5 inhibitor for erectile dysfunction.

Udenafil is an oral PDE5 inhibitor that is currently available in South Korea for the treatment of erectile dysfunction (ED). Phase II clinical data presented at the 11th World Congress of the International Society for the Sexual and Impotence Research showed that in men with mild-to-severe ED, the drug produced a significant improvement in erectile function after 12 weeks of treatment. Udenafil has been reported as being well tolerated, although in August 2005, the Korean Food & Drug Administration had demanded further details regarding the presence of carcinogenic substances in the drug. A phase IIa clinical trial for ED is currently underway in the US, and phase III trials are planned for 2006.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2000

[Clinical development of new molecular targeted therapeutics for cancer therapy].

Recently much attention has been paid to clinical development of new drugs targeting the important molecules involved in cell growth, motility, invasion, metastatic formation of cancer cells and tumor angiogenesis. Among them, several drugs are designed to inhibit those activities, by which cancer growth and/or metastasis may be controlled. A major problem in developing new molecular targeted therapeutics is determining the optimal biological dose in Phase I studies. Appropriate surrogate markers should be employed to evaluate their therapeutic efficacy before entering the Phase III study. A future strategy to evaluate the efficacy of new drugs in combination with conventional anticancer therapy (surgery, radiotherapy and chemotherapy) is required. For this, careful consideration must be given to the design of clinical Phase III trials. This paper discusses the present status and future strategy for development of new molecular targeted therapeutics in clinics.

Angiogenesis Inhibitors↗

PubMedDate not supplied

[The elderly healthy volunteer: a necessity].

Phase I and II clinical studies performed in healthy elderly volunteers appear as a necessity in the design of any drug development. This is particularly true for drugs which will be indicated in age-related disorders. The essential aim is to obtain a maximum of results on kinetics, dosage and tolerance in this target population. Difficulties and specificities of these studies will be developed. This issue will contribute to improve the quality of Phase III studies and appears as a money-saving strategy.

Age Factors↗

PubMed2001

Carboplatin and vinorelbine in untreated locally advanced and metastatic non-small cell lung cancer.

The aim of this study was to assess the activity and toxicity of carboplatin/vinorelbine combination chemotherapy in unresectable locally advanced and metastatic non-small cell lung cancer. Between April 1997 and June 1999 30 patients (22 M, eight F, median age 62) received treatment with carboplatin AUC 6 on day 1, and vinorelbine 25mg/m(2) on days 1, 8 and 15. Treatment was given every 28 days for six cycles unless progressive disease occurred. Twenty-three patients (77%) had stage IV disease, and seven (23%) stage IIIB. Ninety-three percent were WHO performance status 0-1. Twenty-three patients were fully assessable. Nine patients achieved partial responses (9/23, 39%) for an overall objective response rate of 9/30 (30%; 95% CI 15-49%). The median duration of response was 2.75 months (range 1-13 months). The median progression-free survival was 2 months and the median survival 5.25 months. The actuarial 1-year survival was 20%. The median number of cycles completed was two (range 1-6). Day 15 vinorelbine was administered in only 18% of cycles. The main toxicity was myelosuppression. WHO grade III/IV neutropenia was experienced in 50% of patients, however, there were only three episodes of febrile neutropenia. Eight patients required blood transfusion and one developed grade III thrombocytopenia. Treatment was ceased in one patient because of grade IV autonomic neuropathy. No patient had significant nausea and vomiting. There were no treatment-related deaths. These results indicate that carboplatin/vinorelbine is well tolerated and has similar activity to cisplatin/vinorelbine in patients with unresectable non-small cell lung cancer, however, the median survival was considerably shorter.

Actuarial Analysis↗

PubMed2002

Recombinant human activated protein C in severe sepsis.

The role of activated protein C (APC) in coagulation, inflammation, and fibrinolysis and the pharmacology, pharmacokinetics, and trials of recombinant human activated protein C (rhAPC), or drotrecogin alfa (activated), in sepsis are described. Protein C, a naturally occurring vitamin K-dependent serine protease in the blood, remains inactive until exposed to the thrombin-thrombomodulin complex. This change between the inactive and active forms occurs constantly in humans and serves to balance the coagulation cascade. APC functions in concert with protein S as an anticoagulant, a fibrinolytic agent, and an antiinflammatory agent. In response to serious infection, a procoagulant process is activated leading to thrombin and fibrin deposition in small vessels that results in decreased blood flow, decreased oxygen delivery, and organ failure. The body's natural defense during severe sepsis is to activate protein C through the thrombin-thrombomodulin complex in an attempt to restore the imbalance of the hemostatic systems. However, APC has a short half-life, and the pool of circulating protein C is rapidly depleted in severe sepsis. Low protein C levels have been correlated with poor outcome in patients with severe sepsis and in animal models. These observations led to a Phase III safety and efficacy trial of drotrecogin alfa (activated) that demonstrated a significant improvement in mortality compared with placebo (24.7% versus 30.8%). This 6.1% absolute difference in mortality translates to a 19.4% reduction in relative risk of death in the treated patients. The proper use of drotrecogin alfa (activated) will require careful consideration of appropriate patients to treat and further studies in patient populations that were excluded from the Phase III trial, as well as possible modification of dosing schemes on the basis of patient response.

Anti-Infective Agents↗

PubMed2006

Proof-of-principle phase II MRI studies in stroke: sample size estimates from dichotomous and continuous data.

BACKGROUND AND PURPOSE: Since the failure of a number of phase III trials of neuroprotection in ischemic stroke, the need for smaller phase II studies with MRI surrogates has emerged. There is, however, little information available about sample size requirements for such phase II trials and rarely enough patients in single studies to make robust estimates. We have formed an international collaborative group to assemble larger datasets and from these have generated sample size tables for MRI-based infarct expansion as the outcome measure. METHODS: Twelve centers from Australia, Europe, and North America contributed data from patients with hemispheric ischemic stroke. Infarct expansion was defined from initial diffusion-weighted images and later fluid-attenuated inversion recover or T2 images. Sample size estimates were calculated from data on infarct expansion ratios treated as dichotomous or continuous variables. A nonparametric approach was used because the distribution of infarct expansion was resistant to all forms of transformation. RESULTS: As an example, a 20% absolute reduction in infarct expansion ratio (< or = 1), 80% power, and alpha = 0.05 requires 99 patients in each arm. To achieve an equivalent effect size with a continuous approach requires 61 patients. CONCLUSIONS: These tables will be useful in planning phase II trials of therapy with the use of MRI outcome measures. For positive studies, biologically plausible surrogates such as these may provide a rationale for proceeding to phase III trials.

Australia↗

PubMed2005

Tetomilast.

Otsuka is developing a once-daily oral formulation of the phosphodiesterase-4 inhibitor tetomilast for the potential treatment of ulcerative colitis (phase III) and chronic obstructive pulmonary disease (phase II).

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2005

Properties of thalidomide and its analogues: implications for anticancer therapy.

Thalidomide and its immunomodulatory (IMiDs) analogs (lenalidomide, Revlimid, CC-5013; CC-4047, ACTIMID) are a novel class of compounds with numerous effects on the body's immune system, some of which are thought to mediate the anticancer and anti-inflammatory results observed in humans. Thalidomide is currently being used experimentally to treat various cancers and inflammatory diseases. It is approved for the treatment of dermal reaction from leprosy and is currently in phase III trials for multiple myeloma. Thalidomide and IMiDs inhibit the cytokines tumor necrosis factor-alpha (TNF-alpha), interleukins (IL) 1beta, 6, 12, and granulocyte macrophage-colony stimulating factor (GM-CSF). They also costimulate primary human T lymphocytes inducing their proliferation, cytokine production, and cytotoxic activity thereby increasing the T cells' anticancer activity. They induce an IL-2-mediated primary T cell proliferation with a concomitant increase in IFN-gamma production and decrease the density of TNF-alpha-induced cell surface adhesion molecules ICAM-1, VCAM-1, and E-selectin on human umbilical vein endothelial cells. Thalidomide stimulates the Th-1 response increasing IFN-gamma levels while CC-4047 increased IL-2 as well. Some of the above immunomodulatory activities along with anti-angiogenic, anti-proliferative, and pro-apoptotic properties are thought to mediate the IMiDs' antitumor responses observed in relapsed and refractory multiple myeloma and some solid tumor cancers. This has led to their use in various oncology clinical trials. The second generation IMiD, lenalidomide, has shown potential in treating the bone marrow disorders myelodysplastic syndrome and multiple myeloma. It is currently in phase II and III trials for these diseases respectively with numerous phase II trials in other hematologic and solid tumors.

Angiogenesis Inhibitors↗

PubMed2002

Phase I studies with bendamustine: an update.

Bendamustine is a novel agent with both alkylating and purine-like moieties that is currently in phase II/III trials for the treatment of hematologic malignancies and breast, lung, and gastrointestinal tumors. Bendamustine was developed in the early 1960s and first used clinically in 1969 in patients with multiple myeloma. Since then, various dose and treatment schedules have been used empirically. Although bendamustine has been in clinical use for over three decades, the early clinical trials do not conform to present-day standards of good clinical practice. Therefore, it was necessary to conduct a full range of clinical trials before application for a European marketing license could be made. To date, bendamustine has been investigated both as a single agent and in combination with other anticancer drugs, in phase I, II, and III clinical trials. This article presents an overview of the recent phase I trials and a summary of ongoing clinical trials.

Antineoplastic Agents↗

PubMed1995

Multimodality therapy in unresected stage III non-small cell lung cancer: the American Cooperative Groups' Experience.

Since the mid-1980s, the American Cooperative Cancer Treatment Groups (Cancer and Leukemia Group B, Eastern Cooperative Oncology Group, North Central Cancer Treatment Group. Radiation Therapy Oncology Group, Southwest Oncology Group) have performed several multimodality trials exploring combinations of chemotherapy and radiation in patients with Stage III non-small cell lung cancer. The initial trials had a sequential design with induction chemotherapy followed by radiation. Later trials have emphasized concurrent chemoradiation with or without induction chemotherapy. These trials have begun to have an impact on what is considered 'standard' therapy for patients with Stage III non-small cell lung cancer (NSCLC).

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2002

Seamlessly expanding a randomized phase II trial to phase III.

A sequential Bayesian phase II/III design is proposed for comparative clinical trials. The design is based on both survival time and discrete early events that may be related to survival and assumes a parametric mixture model. Phase II involves a small number of centers. Patients are randomized between treatments throughout, and sequential decisions are based on predictive probabilities of concluding superiority of the experimental treatment. Whether to stop early, continue, or shift into phase III is assessed repeatedly in phase II. Phase III begins when additional institutions are incorporated into the ongoing phase II trial. Simulation studies in the context of a non-small-cell lung cancer trial indicate that the proposed method maintains overall size and power while usually requiring substantially smaller sample size and shorter trial duration when compared with conventional group-sequential phase III designs.

Adenoviridae↗