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PubMedDate not supplied

Adapting the sample size planning of a phase III trial based on phase II data.

Traditionally, in clinical development plan, phase II trials are relatively small and can be expected to result in a large degree of uncertainty in the estimates based on which Phase III trials are planned. Phase II trials are also to explore appropriate primary efficacy endpoint(s) or patient populations. When the biology of the disease and pathogenesis of disease progression are well understood, the phase II and phase III studies may be performed in the same patient population with the same primary endpoint, e.g. efficacy measured by HbA1c in non-insulin dependent diabetes mellitus trials with treatment duration of at least three months. In the disease areas that molecular pathways are not well established or the clinical outcome endpoint may not be observed in a short-term study, e.g. mortality in cancer or AIDS trials, the treatment effect may be postulated through use of intermediate surrogate endpoint in phase II trials. However, in many cases, we generally explore the appropriate clinical endpoint in the phase II trials. An important question is how much of the effect observed in the surrogate endpoint in the phase II study can be translated into the clinical effect in the phase III trial. Another question is how much of the uncertainty remains in phase III trials. In this work, we study the utility of adaptation by design (not by statistical test) in the sense of adapting the phase II information for planning the phase III trials. That is, we investigate the impact of using various phase II effect size estimates on the sample size planning for phase III trials. In general, if the point estimate of the phase II trial is used for planning, it is advisable to size the phase III trial by choosing a smaller alpha level or a higher power level. The adaptation via using the lower limit of the one standard deviation confidence interval from the phase II trial appears to be a reasonable choice since it balances well between the empirical power of the launched trials and the proportion of trials not launched if a threshold lower than the true effect size of phase III trial can be chosen for determining whether the phase III trial is to be launched.

Clinical Trials, Phase II as Topic↗
PubMed2002

Past, present and future of HIV vaccine trials in developing countries.

A safe, effective and accessible preventive vaccine is our best long-term hope for the control of the HIV/AIDS pandemic. The first phase I trial of an HIV vaccine was conducted in the US in 1987. Since then, >30 candidate vaccines have been tested in over 60 phase I/II clinical trials, involving >8000 healthy human volunteers. The majority of these trials have been conducted in the US and Europe, however, trials have also been conducted in developing countries (Brazil, China, Cuba, Haiti, Kenya, Thailand, and Uganda), including an ongoing phase III efficacy trial of a rgp120 candidate vaccine in Thailand. The effort to develop and evaluate HIV vaccines must increase, especially in Africa.

AIDS Vaccines↗
PubMedDate not supplied

[Interferon-alpha2b recombinant improved the cognitive dysfunction in patients with relapsing remitting multiple sclerosis].

INTRODUCTION: Some experimental, Phase II clinical trials and the preliminary reports of the Cuban Phase III clinical trial indicate that alpha-IFN (IFN) may be useful in relapsing remitting (RR) multiple sclerosis (MS). The reports in Cuba showed that 70% of the MS patients have cognitive dysfunction. OBJECTIVE: To assess the efficacy of IFN-alpha2b recombinant in the cognitive dysfunction of RR MS. PATIENTS AND METHODS: 57 RR-MS clinical definite patients from the randomised, double blind, placebo controlled study of 225 patients with RR-MS and brain MRI confirmed. Patients were randomly assigned to receive intramuscular IFN-alpha2b (Heberon R) 10 million IU (high dose), 3 million IU (low dose) or placebo twice week for 2 years. Outcome results were blinding evaluated considering changes in the following tests: Luria, WAIS, Benton and PASAT-3. Adverse events and side effects were not evaluated to maintain physician blinding. RESULTS: The initial comparison of the groups did not show any differences among the placebo (n=20), low dose (n=18) and high dose (n=19) considering age (p=0.234), gender, ethnic group (p=0.012), years ill (p=0.787), EDSS (p=0.203) and rate of relapses (p=0.432). The Luria's Test showed an improved in the low dose group from 2.50 +/- 1.34 to 1.39 +/- 1.85 (p=0.029) and in the high dose group from 3.22 +/- 1.89 to 2.17 +/- 1.50 (p=0.006) vs placebo 2.85 +/- 1.66 to 2.90 +/- 1.97 (p=0.723). The results of the Benton's test demonstrated that the low dose group had an improved from 5.50 +/- 1.10 to 6.22 +/- 1.31 (p=0.047), in the high dose group from 4.87 +/- 1.85 to 5.78 +/- 1.35 (p=0.005) where as in the placebo group worse from 5.15 +/- 1.76 to 5.05 +/- 2.11 (p=0.893). The WAIS test showed the same results, the low dose group increased from 5.17 +/- 1.34 to 6.06 +/- 1.21 (p=0.022), the high dose group from 4.56 +/- 1.38 to 5.39 +/- 1.29 (p=0.007) and the placebo group worse from 5.25 +/- 1.25 to 5.05 +/- 1.57 (p=0.354). Finally, the PASAT-3 test increased in the IFNs groups: from 45.72 +/- 10.61 to 49.94 +/- 11.68 (p=0.015) in the low dose group, from 42.67 +/- 11.04 to 48.72 +/- 8.84 (p=0.03) in the high dose group, but in the placebo group worse from 44.55 +/- 10.86 to 41.95 +/- 13.74 (p=0.655). CONCLUSION: IFN-alpha improved the cognitive dysfunction in RR-MS patients. The higher dose is more beneficial.

Adult↗
PubMed2004

Modern diagnostics in chronic myeloproliferative diseases (CMPDs).

According to the new WHO classification a group of chronic myeloproliferative diseases (CMPDs) were defined: chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia and hypereosinophilic syndrome (CEL/HES), polycythemia vera (PV), chronic idiopathic myelofibrosis (with extramedullary hematopoiesis, CIMF), essential thrombocythemia (ET), and so called CMPD/unclassifiable. As clinical features and laboratory findings differ widely between these diseases several diagnostic approaches are mandatory at diagnosis for classification and are needed also for follow up studies, especially for the measurement of minimal residual disease (MRD). We here outline the laboratory set up at diagnosis and during follow up in CMPDs with specific focus on the respective therapeutical consequences. Only by using a comprehensive diagnostic panel including cytomorphology, cytogenetics, and molecular genetic methods establishing the correct diagnosis, optimizing treatment as well as evaluating treatment response is possible in CMPDs today.

Blood Cell Count↗
PubMed2005

Improving accrual of older persons to cancer treatment trials: a randomized trial comparing an educational intervention with standard information: CALGB 360001.

PURPOSE: To design and test a geriatric educational intervention to improve accrual of cancer patients age 65 years and older to cooperative group-sponsored treatment trials. METHODS: Main member institutions of the Cancer and Leukemia Group B (CALGB) and its affiliates were randomly assigned to receive standard information (n = 73) or educational intervention (n = 53). Standard information included CALGB Web site access and periodic notification about existing trials. The geriatric educational intervention included standard information plus: (1) an educational seminar; (2) educational materials; (3) a list of available protocols for use on charts; (4) a monthly e-mail and mail reminders for 1 year; and (5) a case discussion seminar. The main outcome was percentage of accrual of older persons to phase II and III treatment protocols after study initiation compared with baseline. RESULTS: There were 3,032 patients entered onto trials in the baseline year, and 2,160 and 1,239 during the 2 years postintervention, respectively. Overall percentage of accrual of older patients was 37% at baseline, and 33% and 31% during the first and second years after intervention. There was no improvement in accrual in the intervention versus control arm: 36% v 32% in the first year and 31% v 31% in the second year. CONCLUSION: Accrual of older patients was not increased by this intervention. Reasons for lack of effect include low intervention intensity, high baseline accrual rates, and closure of several high-accruing protocols during the study. More intense and multifaceted approaches will be needed to change physician (and patient) behavior and to increase accrual of older persons to clinical trials.

Age Factors↗
PubMed2004

Cancer trial enrollment after state-mandated reimbursement.

BACKGROUND: Recruitment of patients into cancer research studies is exceedingly difficult, particularly for early phase trials. Payer reimbursement policies are a frequently cited barrier. We examined whether state policies that ensure coverage of routine medical care costs for cancer trial participants are associated with an increase in clinical trial enrollment. METHODS: We used logistic Poisson regressions to analyze enrollment in National Cancer Institute phase II and phase III Clinical Trials Cooperative Group trials and compared changes in trial enrollment rates between 1996 and 2001 of privately insured cancer patients who resided in the four states that enacted coverage policies in 1999 with enrollment rates in states without such policies. All statistical tests were two-sided. RESULTS: Trial enrollment rates increased in the coverage and noncoverage states by 24.9% (95% confidence interval [CI] = 22.8% to 27.0%) and 28.8% (95% CI = 27.7% to 29.8%) per year, respectively, from 1996 through 2001. After implementation of the coverage policies in 1999 in four states, there was a 21.7% (95% CI = 3.8% to 42.6%) annual increase in phase II trial enrollment in coverage states, compared with a 15.6% (95% CI = 8.8% to 21.8%) annual decrease in noncoverage states (P<.001). After accounting for secular trend, cancer type, and race in multivariable analyses, the odds ratio (OR) for a phase II trial participant residing in a coverage versus a noncoverage state after 1999 was 1.59 per year (95% CI = 1.22 to 2.07; P =.001). In a multivariable analysis of phase III trial participation, there was a decrease in the odds of residing in a coverage state after 1999 (OR = 0.90, 95% CI = 0.84 to 0.98; P =.011). CONCLUSION: State coverage policies were associated with a statistically significant increase in phase II cancer trial participation and did not increase phase III cancer trial enrollment.

Breast Neoplasms↗
PubMedDate not supplied

[Topotecan, a recent discovery and prospects for treating tumors of the lung].

Topotecan is a new active drug in the treatment of lung cancer. In advanced non small cell lung cancer (NSCLC) it showed 0-15% of objective response (OR) with 15% in the largest phase II study performed on 40 patients at the M.D. Anderson Cancer Center. Interesting results have been reported in combination chemotherapy with new drugs, in particular with gemcitabine. However, the role of topotecan in NSCLC must be developed in further trials. Topotecan is one of the most active drug in small cell lung cancer (SCLC). Particularly, it showed active in sensitive pretreated patients with 14%-38% OR. In a phase III randomized trial performed in pretreated patients, single agent topotecan showed similar OR and survival but better palliative effect compared to the CAV regimen (cyclophosphamide + adryamicin + vincristine). In first line chemotherapy topotecan showed 39% OR as single agent. Interesting results have been showed in combination chemotherapy in particular with taxol. Several studies are ongoing. Topotecan as first line chemotherapy could be developed in old doublet combinations (such as cisplatin or carboplatin + topotecan), new doublet combinations (such as taxol or vinorelbine or gemcitabine + topotecan), triplet chemotherapy combinations (such as cisplatin or carboplatin + taxol + topotecan) and sequential or alternate chemotherapy regimens. Topotecan reaches high drug concentration in the brain. It showed activity in brain metastases of SCLC with 40%-63% OR and 13%-43% of complete response in pretreated patients. This particular activity could be considered in first line chemotherapy as prophylaxis of brain metastases or to treat patients with brain metastases at diagnosis. Oral topotecan is a very interesting drug. It showed 36% OR in outfit untreated SCLC patients and 23% in pretreated patients, respectively. Oral formulation seems to induce less toxicity when compared to the intravenous drug. In the future topotecan should be developed as first line combined radio-chemotherapy treatment to make the best of its radiosensitizer effect. The activity on brain metastases also must be developed. Oral formulation is interesting because it is less toxic and could be considered in less toxic regimens in particular in outfit or elderly patients. However in the next years the role of topotecan will be better defined performing phase III randomized trials.

Administration, Oral↗
PubMed2003

Trials and tribulations: current challenges in conducting clinical trials.

Randomized controlled trials are the gold standard for the evaluation of new therapies and surgical procedures and as such require strict attention to study design and statistical analysis. There are, however, multiple challenges in conducting a well-designed clinical trial. This article describes the difficulties encountered at a single institution participating in a multicenter drug study and reviews the challenges involved in developing a high-quality randomized controlled study.

Acetaminophen↗
PubMed1994

Representation of older patients in cancer treatment trials.

In 1990, the five leading causes of cancer death in men aged 65 and older were carcinomas of the lung, prostate, colon and rectum, and pancreas, and leukemia. For women in this age group, the five leading causes of cancer death were carcinomas of the lung, breast, colon and rectum, pancreas, and ovary. To determine the representation of the elderly in clinical trials, the 1992 accrual of the National Cancer Institute (NCI)-sponsored Clinical Cooperative Group treatment trials (which included more than 8000 elderly patients) for the aforementioned sites was compared with the 1990 incidence data from the NCI's Surveillance, Epidemiology, and End Results program. Of the male patients enrolled in the trials, an average of 39% were older than 65 (47.3% lung, 79.5% prostate, 47.5% colorectal, 45.6% pancreas, and 9.6% leukemia); whereas 25.9% of all women enrolled in trials were 65 or older (43.6% lung, 17.3% breast, 46.2% colorectal, 59.6% pancreas, and 35.4% ovary). With respect to incidence, older patients generally are underrepresented in cancer treatment trials. With the exception of the data on prostate cancer, each of the comparisons using the Z statistic gave probability values of less than 0.01. The most significant discrepancies between incidence and participation in cancer treatment protocols were noted for leukemia in males and breast cancer in females. Possible explanations for these findings include (1) a research focus on aggressive therapy, which may be unacceptably toxic to the elderly; (2) presence of comorbidity in the elderly; (3) fewer trials available specifically aimed at older patients; (4) limited expectations for long term benefits on the part of physicians, relatives, and the patients themselves; and (5) a lack of financial, logistic, and social support for the participation of elderly patients in clinical trials. Recognizing this situation, NCI recently sponsored a number of trials that specifically target the elderly. This paper describes the status of all major Phase II and III clinical trials that recently were closed, still are active, or now are in review that address the clinical care of this important segment of the U.S. population.

Aged↗
PubMed2002

Developmental chemotherapy in advanced ovarian cancer: incorporation of newer cytotoxic agents in a phase III randomized trial of the Gynecologic Oncology Group (GOG-0182).

Despite improvements in median and overall survival using a combination of platinum and paclitaxel, long-term survival rates for patients with advanced epithelial ovarian carcinoma (EOC) remain disappointing, and the development of more effective primary therapy remains a priority. In particular, several interesting chemotherapy agents have demonstrated activity individually in patients with recurrent EOC. Among these are gemcitabine, topotecan, liposomal doxorubicin, and prolonged oral etoposide. Preclinical models have suggested an advantage for combinations of these agents with platinum, which has been attributed to inhibition of DNA synthetic pathways involved in the repair of platinum-DNA adducts. However, efforts to develop multidrug combinations with platinum and paclitaxel have encountered substantial bone marrow toxicity, prompting exploration of alternative schedules and sequences of drug administration. In this regard, the Gynecologic Oncology Group (GOG) and other organizations have conducted a series of phase I pilot studies in previously untreated patients to define combinations that are suitable for group-wide phase III trials. With international collaboration, GOG has launched a five-arm trial (GOG-0182) that will compare these combinations against carboplatin-paclitaxel. The selection of candidate regimens for this trial illustrates the challenges of drug development in EOC.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

A model to select chemotherapy regimens for phase III trials for extensive-stage small-cell lung cancer.

BACKGROUND: Many more phase II studies have favorable outcomes than the subsequent phase III trials. We used historical data from phase II and phase III studies for patients with extensive-stage small-cell lung cancer (SCLC) to generate a statistical model to provide assistance in selecting chemotherapy regimens from phase II studies for subsequent use in phase III randomized studies. METHODS: Information from 21 phase III trials for patients with extensive-stage SCLC initiated during the period from 1972 through 1990 was reviewed to identify those that were preceded by phase II studies of the same regimen. We used data from all the trial pairs to develop a statistical model in which the number of patients, the median survival of patients, and the number of deaths observed in the phase II trial are used to estimate the statistical power of the subsequent phase III trial. All statistical tests were two-sided. RESULTS: Nine phase II studies were identified that preceded phase III trials of the same regimen. The regimens from two phase II studies with the greatest expected power in the phase III trial (0. 62 and 0.58) both demonstrated significantly prolonged survival when compared with standard treatment in subsequent phase III trials (P<. 001 and P =.002, respectively). The regimens from six of the other phase II studies, for which the median power expected in the phase III trial was 0.28 (range, 0.19-0.52), showed no difference when compared with standard treatment in a phase III trial. CONCLUSIONS: Phase II studies for particular regimens that have an expected power of greater than 0.55 provide a reasonable basis for proceeding with a phase III trial.

Antineoplastic Agents↗
PubMed2005

Telavancin (Theravance).

Theravance is developing telavancin, an injectable peptidoglycan inhibitor antibiotic for potential use in the treatment of Gram-positive bacterial infection. Phase III trials in complicated skin and skin structure infections commenced in September 2004.

Aminoglycosides↗
PubMed2004

Advanced preclinical and clinical trials of natural products and related compounds from marine sources.

The marine environment has proven to be a very rich source of extremely potent compounds that have demonstrated significant activities in anti-tumor, anti-inflammatory, analgesia, immuno-modulation, allergy and anti-viral assays. Although the case can and has been made that the nucleosides such as Ara-A and Ara-C are derived from knowledge gained from investigations of bioactive marine nucleosides, no drug directly from marine sources (whether isolated or by total synthesis) has yet made it to the commercial sector in any human disease. However, as shown in this review, there are now significant numbers of very interesting molecules that have come from marine sources, or have been synthesized as a result of knowledge gained from a prototypical compound, that are either in or approaching Phase III clinical trials in cancer, analgesia and allergy, with a very substantial number of other, quite different potential agents following in their wake, in these and in other diseases.

Alzheimer Disease↗
PubMedDate not supplied

Vampire bats yield potent clot buster for ischemic stroke.

While tissue-type plasminogen activator (tPA) is currently the standard "clot-busting" drug used to treat patients with acute ischemic stroke, another new option for treatment is now under clinical study. Desmodus rotundus plasminogen activator (DSPA), an enzyme found in the saliva of vampire bats, may offer another therapeutic option instead of tPA, a current therapy for stroke. Animal research indicates that tPA may mediate neuronal death as well as increase systemic plasminogen consumption and fibrinogenolysis. Conversely, DSPA's activity is dependent on the presence of fibrin and therefore has not been associated with the systemic plasminogen consumption and fibrinogenolysis that potentially may occur in those receiving tPA. In animal studies, tPA was found to exhibit "inherent neurotoxic properties" not seen with DSPA. In addition, DSPA may be administered up to 9 hours after the onset of symptoms, unlike tPA, which cannot be given after 3 hours without potential risk of additional brain injury. Phase II clinical trials have demonstrated a positive result in human subjects. Phase III trials are currently under way in stroke populations.

Animals↗
PubMed2006

Docetaxel in the treatment of gastric cancer.

Docetaxel is part of the standard chemotherapy in breast, non-small cell lung cancer and androgen-independent metastatic prostate cancer and has recently been approved for advanced gastric cancer. It demonstrated promising single-agent efficacy in gastric cancer and was therefore investigated in different combination regimens. The combination of docetaxel with 5-fluorouracil (5-FU), capecitabine, irinotecan or cisplatin demonstrated high efficacy. The triple combination of docetaxel/cisplatin and 5-FU (DCF) was investigated in randomized Phase II trials and a randomized Phase III study (TAX325). In TAX325, DCF demonstrated superiority in terms of time to tumor progression, response rate and survival against a cisplatin/5-FU combination. Docetaxel was therefore approved for advanced gastric cancer by the US FDA and the European Agency for the Evaluation of Medicinal Products and will evolve as an integral part of routine combination regimens against gastric cancer. This review will discuss and interpret the different Phase II and III trials of docetaxel in gastric cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Natalizumab. Elan/Biogen.

Natalizumab is a humanized monoclonal antibody to alpha 4 beta 1 integrin (VLA-4) currently under development by Elan and Biogen for the treatment of Crohn's disease and multiple sclerosis. Phase II trials in both indications have been completed, and by December 2002 phase III trials in Crohn's disease and multiple sclerosis had been initiated.

Animals↗