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PubMed2006

Drug evaluation: tesamorelin, a synthetic human growth hormone releasing factor.

Theratechnologies, under license from Valeant, is developing tesamorelin as a potential vaccine adjuvant and for the potential treatment of wasting, hip fracture recovery, immune disorders, HIV-related lipodystrophy, sleep maintenance insomnia and mild cognitive impairment. Phase III clinical trials for the treatment of HIV-associated lipodystrophy and phase II clinical trials for sleep disorder, chronic obstructive pulmonary disorder, hip fracture and immune system dysfunction are underway. Phase II trials are also assessing the influenza vaccination immune response and cognitive effects of tesamorelin.

Adjuvants, Immunologic↗

PubMed2003

Technology evaluation: bevacizumab, Genentech/Roche.

Bevacizumab, an antivascular endothelial growth factor monoclonal antibody, is being developed by Genentech and Roche as an anti-angiogenesis therapy for the potential treatment of solid tumors. In June 2003, bevacizumab was granted Fast Track status by the FDA for the potential treatment of first-line colorectal cancer. The antibody is currently in phase III trials for non-small-cell lung, colorectal and breast cancers, and in phase II trials for various other solid tumor types.

Angiogenesis Inhibitors↗

PubMed2004

Epothilone D (Kosan/Roche).

Kosan and Roche are developing the microtubule inhibitor epothilone D (KOS-862 and NSC-703147), an analog of epothilone B for the potential treatment of cancer. Phase II trials in colorectal, metastatic breast and non-small-cell lung cancers were initiated in December 2003.

Animals↗

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↗

PubMed2002

[Chemotherapy of gastric cancer--a review of clinical trials in Japan].

This review focused on the clinical trials in patients with gastric cancer in Japan. Oral fluoropyrimidines have been extensively used in Japan. Through the decades, these oral fluoropyrimidines have been examined in a variety of combinations. Most of the reports are about randomized phase II trials using overall response rate as a primary endpoint, and are a few phase III trials were conducted. S-1 (TS-1), a novel oral fluoropyrimidine, has demonstrated promising activity in phase II trials. Ongoing phase III trials on S-1 would be defining this as standard chemotherapy for metastatic gastric cancer.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2003

Clinical experience with the HER1/EGFR tyrosine kinase inhibitor erlotinib.

In phase I trials in healthy volunteers and patients with refractory cancers, erlotinib (Tarceva) was well tolerated and showed activity against non-small-cell lung cancer and other tumors. The dose identified for further clinical development was 150 mg/d; at this dose, erlotinib achieves high exposure, with maximum concentrations greater than 2,000 ng/mL and 24-hour area under the concentration-time cure greater than 35,000 ng.h/L. In a phase II trial in 57 patients with previously treated advanced non-small-cell lung cancer, erlotinib treatment produced an objective response rate of 12.3% and a stable disease rate of 38.6%, with median duration of response of 19.6 weeks; median overall survival was 8.4 months and 1-year survival was 40%, with 9 patients remaining alive over follow-up of greater than 18 months. No grade 4 toxicity was observed, and grade 3 toxicity was minimal. In an ongoing phase II trial in bronchioloalveolar carcinoma, erlotinib treatment has produced objective response in 26% of 50 evaluable patients, with median duration of response not yet having been reached. An ongoing phase II trial is examining the combination of erlotinib with the angiogenesis inhibitor bevacizumab (Avastin) in previously treated non-small-cell lung cancer; phase I evaluation revealed no dose-limiting toxicities at tested doses and provided evidence of antitumor activity. Two phase III trials are examining erlotinib in combination with carboplatin (Paraplatin)/paclitaxel (the TRIBUTE trial) or cisplatin/gemcitabine (Gemzar) (the TALENT trial) as first-line treatment in advanced non-small-cell lung cancer. The phase III BR.21 trial is assessing erlotinib monotherapy in advanced refractory non-small-cell lung cancer. Results of these phase II trials will soon be available.

Angiogenesis Inhibitors↗

PubMed1997

Review of docetaxel/doxorubicin combination in metastatic breast cancer.

Docetaxel (Taxotere) and doxorubicin (Adriamycin) have each demonstrated significant activity in metastatic breast cancer. Thus, the combination of docetaxel and doxorubicin has been evaluated in phase I trials to establish the dose-limiting toxicity, maximum tolerated dose, recommended dose for future phase II and III studies, and toxicity profile of the two agents used in combination. Results from phase I trials in patients with metastatic breast cancer indicate that the docetaxel/doxorubicin combination is well tolerated. The recommended dose for the combination regimen is either 50 mg/m2 of doxorubicin followed by 75 mg/m2 of docetaxel or 60 mg/m2 of both drugs, without granulocyte colony-stimulating factor (G-CSF) support. Febrile neutropenia complicated by grade 3 infection was the dose-limiting effect at the maximum tolerated dose. The response rate at this dose level was 90%. Based on the preliminary results of phase I studies, further phase II and III studies of a docetaxel/doxorubicin combination regimen are warranted.

Adult↗

PubMed2005

Applying a phase II futility study design to therapeutic stroke trials.

BACKGROUND AND PURPOSE: Most large, randomized phase III efficacy trials of therapeutic agents in ischemic stroke have failed to find treatment benefit. We determined whether some phase III studies could have been avoided if preceded by smaller single-arm phase II studies to evaluate the futility of proceeding to phase III. METHODS: To provide examples of the application of phase II methodology, we obtained primary outcome data for the active treatment group of 6 phase III ischemic stroke therapy trials. For each study, we estimated the sample size number required for a multistage single-arm study using parameters specified in the original study. We evaluated outcome data for the first number of subjects in the phase III study treatment arm ordered by enrollment dates. We compared the proportion of favorable outcomes to prespecified stopping criteria derived from a single-arm phase II futility design. If the observed proportion of favorable outcomes was less than the stopping criterion, we declared the treatment not sufficiently effective to warrant further evaluation in phase III. RESULTS: We identified 3 trials as futile in phase II; none of 3 showed treatment efficacy in phase III. In the 3 remaining phase II trials in which we did not show futility, one showed efficacy in phase III. CONCLUSIONS: Single-arm phase II futility studies have been underused in stroke research, but provide a strategy for discarding treatments likely to be ineffective in phase III trials.

Clinical Trials as Topic↗

PubMed2003

DU-127090 Solvay/H Lundbeck.

DU-127090 is a mixed dopamine antagonist/serotonin agonist in development by Solvay and H Lundbeck as a potential treatment for psychosis and schizophrenia, for which it is in phase II clinical trials. In August 2002, phase II trials were ongoing and Lundbeck expected to commence phase III trials in 2003 and file an NDA after 2004. DU-127090 is also under development for Parkinson's disease, for which it is in phase I clinical trials.

Antipsychotic Agents↗

PubMed2000

Anticytokine therapies for acute inflammation and the systemic inflammatory response syndrome: IL-10 and ischemia/reperfusion injury as a new paradigm.

The results of recent anticytokine trials for sepsis syndrome have been disappointing. Several Phase II and Phase III clinical trials have shown a modest benefit in various subsets of patients; however, there has been no reported benefit in the primary endpoint of 28-day all-cause mortality. The failure of these trials is clearly multifactorial, and causes include the overall complexity of the inflammatory response, heterogeneity of the patient populations, absence of a hypercytokine response at the time of drug treatment, and the relatively short half-life of the administered drugs. The failure of anticytokine therapies may represent inadequate application of the treatment modality rather than any inherent weakness of the treatment itself. We have recently initiated a Phase I clinical trial examining the role of the anti-inflammatory cytokine IL-10 during surgical repair of a thoracoabdominal aortic aneurysm. This study may overcome some of the-design limitations of previous anticytokine trials in sepsis, and serve as a paradigm for future anticytokine therapy trials. Although the incidence of thoracoabdominal aortic aneurysms is relatively low, the patient population is homogeneous and the surgical injury associated with its repair reproducible. Additionally, postoperative mortality and morbidity rates are significant. Most importantly, the operative repair is associated with an obligatory visceral ischemia and reperfusion injury that appears to be associated with a proinflammatory cytokine response and postoperative organ dysfunction. IL-10 is a pleuripotent anti-inflammatory cytokine that both inhibits TNFalpha and IL-1 synthesis, and antagonizes their actions through upregulation of cytokine antagonists. Furthermore, IL-10 administration has been associated with only minimal adverse side effects during Phase I and Phase II trials.

Animals↗

PubMed2000

Clinical strategy for the development of angiogenesis inhibitors.

Angiogenesis inhibitors differ from conventional cytotoxic chemotherapy agents by targeting normal cells rather than tumor cells, which may contain multiple mutations. Because of this, the traditional strategy used in clinical development of cytotoxic agents may not be appropriate for these novel agents. Many clinical studies are now evaluating these agents with a new approach, referred to as the cytostatic paradigm. The cornerstone of the cytostatic paradigm is the use of time to progression (TTP) of disease as the decision-making criterion for "go/no go" in the early phases of clinical development. However, the use of TTP as the main criterion for clinical trials is complicated for a variety of reasons, including: A) the lack of standardized criteria accepted by regulatory authorities; B) the heterogeneity of the historical database, and C) the larger number of patients needed for the "go/no go" decision-making process. In addition, clinical trials of cytotoxic agents have traditionally used objective response (despite the controversy regarding objective response as a surrogate for clinical activity) as the main criterion for determining whether the results of phase II studies justify the pivotal phase III studies. Another aspect of the clinical development strategy is combining angiogenesis inhibitors with cytotoxic chemotherapy. The rationale for combination of angiogenesis inhibitors with cytotoxic agents is based on: A) different targets for these agents; B) lack of cross-resistance patterns; C) lack of myelosuppression with angiogenesis inhibitors allows administration of full doses of all agents, and D) the assumption that combining these agents will result in additive antitumor activity. Combination therapy with angiogenesis inhibitors may be attractive to both clinicians and their patients because it allows cytostatic agents to be used upfront in treatment while contributing to drug registration strategy (cytostatic/cytotoxic combination therapy versus cytotoxic therapy). The clinical development of the angiogenesis inhibitor SU5416, a small molecule inhibitor of vascular endothelial growth factor, is currently ongoing. In phase I trials, SU5416 demonstrated activity in both colorectal and non-small-cell lung cancer patients. Based on these encouraging results, phase III studies to evaluate combination of SU5416 with established cytotoxic therapy are planned. These studies will include an interim analysis, the equivalent of a phase II evaluation of clinical activity. If successful, this strategic approach will save significant time in the clinical development process.

Angiogenesis Inhibitors↗

PubMed1997

Docetaxel in combination with platinums in patients with advanced non-small-cell lung cancer.

Docetaxel (Taxotere) is a semisynthetic taxoid that possesses significant activity as a single agent in the treatment of patients with non-small-cell lung cancer. In previously untreated patients with non-small-cell lung cancer, 100 mg/m2 of docetaxel administered as an intravenous infusion over 1 hour once every 3 weeks produced response rates that ranged from 21% to 38% and median survivals of 25.2 to 47.0 weeks. In patients with advanced non-small-cell lung cancer who had previously failed cisplatin (Platinol)-based chemotherapy, docetaxel produced median response rates of 20% to 21% and median survival of 28 to 42 weeks. This review summarizes results from key phase I and II studies demonstrating the antitumor activity and tolerability of docetaxel combined with platinum compounds for patients with advanced non-small-cell lung cancer. Phase I trials determined that 75 mg/m2 of docetaxel and 75 mg/m2 of cisplatin is the recommended dose for phase II and III trials. Overall, response rates with docetaxel and cisplatin have ranged from 21% to 48% and median survival of 8 to 13 months has been achieved in phase II trials. Regarding docetaxel and carboplatin, results from phase I trials in patients with nonhematologic solid tumors indicate that this combination is well tolerated. The maximum tolerated dose of docetaxel in combination with carboplatin (target area under the time-concentration curve of 6 mg/mL.min) is 90 mg/m2 without granulocyte-colony stimulating factor (G-CSF) (filgrastim [Neupogen]) support and 100 mg/m2 with G-CSF support. The combination of docetaxel and carboplatin is presently being evaluated in a multicenter phase II study for patients with advanced non-small-cell lung cancer.

Antineoplastic Agents↗

PubMed2005

Prospective clinical trials of biotherapies in solid tumors: a 5-year survey.

PURPOSE: To review the content and quality of prospective clinical trials of biotherapies in solid tumors. METHODS: Data were collected from the literature between 1990 and 2002 on general study characteristics, patient and disease factors, study methodology, and factors related to completeness of reporting. Quality of phase II studies was evaluated by an ad hoc questionnaire. Descriptive statistics, contingency tables, and the chi-square test were applied. RESULTS: A total of 334 studies were selected, of which about three quarters were multicenter, with 42.5% reporting phase I, 42.2% phase II or I/II, and 11.9% phase III or II/III studies. Only 13.7% were randomized, and a study design emphasizing statistical analysis was lacking in as many as one third. The assessment of biological endpoints was stated as the primary or secondary goal in half of these studies. Melanoma (17.1%), renal carcinoma (11.1%), gastrointestinal neoplasms (11.1%), and lymphomas (6.3%) were the most studied diseases. Immunotherapies accounted for 182 studies; the remaining 152 reported other biotherapies. Patients with (1) advanced disease (P = 0.003), (2) heavily pretreated neoplasms (P < 0.0001), (3) poor performance status (PS < 2) (P < 0.0001), were more frequently enrolled in studies of biotherapy. Biotherapies were less frequently evaluated in phase III studies (7/152) compared with immunotherapies (33/182) (P < 0.0001). A statistical study design was more frequently identified in biotherapy trials (127/152) compared with immunotherapy trials (98/182) (P < 0.0001). Biological endpoints were less frequently evaluated in phase III studies in both biotherapies (100% no vs 0% yes) and immunotherapies (81.8% no vs 18.2% yes) (P = 0.01, for biotherapies; P < 0.0001, for immunotherapies). Phase I immunotherapy studies more frequently applied biological or molecular criteria for patient selection (41.1%) than phase II (29.3%) and III (3.1%) studies (P < 0.0001). CONCLUSIONS: The very wide diversity in modalities of conducting and reporting clinical trials of biotherapies of solid tumors and the presence of some methodological pitfalls suggest that the methodological standards for conducting and publishing clinical trials in biotherapies should be improved to enhance the reliability of the body of published data.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1998

Perspectives in the management of Alzheimer's disease: clinical profile of donepezil.

Donepezil HCI is a piperidine-based reversible acetylcholinesterase (AChE) inhibitor, chemically distinct from other cholinesterase (ChE) inhibitors and rationally designed to treat the symptoms of Alzheimer's disease (AD). It is highly selective for AChE in the central nervous system (CNS), with little or no affinity for butyrylcholinesterase (BuChE). In preclinical studies in animals, donepezil produced increased CNS acetylcholine. The resultant enhancement of cholinergic activity gave rise to improved performance by rats on tests of learning and memory, with no evidence of hepatic or renal toxicity. In subsequent phase I clinical evaluations in healthy volunteers, donepezil demonstrated favorable pharmacokinetic, pharmacodynamic and safety profiles. Its long terminal disposition half-life supported once-daily administration, with no requirement for dose modification in the elderly or in patients with renal or hepatic impairment. A 14-week, phase II dose-finding study in patients with mild to moderate AD (Clinical Dementia Rating [CDR], 1-2; Mini-Mental State Examination [MMSE], 10-26) showed that donepezil at a dose of 5 mg/day produced highly significant improvements in cognition (as measured by the Alzheimer's Disease Assessment Scale, cognitive subscale [ADAS-cog]). Subsequently, two pivotal parallel-group, placebo-controlled phase III trials (of 15 and 30 weeks' duration) showed highly statistically significant improvements in ADAS-cog, MMSE, Clinician's Interview-Based Impression of Change with caregiver input (CIBIC plus) and CDR-SB (Sum of the Boxes) scores, compared with placebo, in mild to moderate AD patients treated with either 5 or 10 mg/day donepezil. Adverse events in the phase II and III trials were mild and transient and resolved with continued donepezil administration. The donepezil clinical trials program has shown that this drug is a clinically effective and well-tolerated once-daily treatment for the symptoms of mild to moderate AD.

Alzheimer Disease↗

PubMed1995

Clinical studies with modulators of multidrug resistance.

Improved understanding of the mechanisms underlying chemotherapeutic failure has led to new strategies to circumvent drug resistance. Expression of the multidrug transporter, P-glycoprotein (P-gp), is likely to be a significant mechanism contributing to the clinical resistance of some cancers to chemotherapy. Phase I trials of currently available MDR modulators have yielded important pharmacologic principles pertaining to normal tissue P-gp function and its influence on the disposition of MDR-related anticancer drugs. Currently available P-glycoprotein inhibitors lack the potency to completely reverse the MDR phenotype at clinically achievable concentrations. Despite this, encouraging clinical results have been obtained in the hematolymphoid malignancies. As these more potent modulators become available, careful characterization of pharmacologic interactions with MDR-related cytotoxins will be critical to the rational design of Phase II and III studies that will ultimately test the efficacy of MDR modulation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2002

Therapeutic potential of the bactericidal/permeability-increasing protein.

Innate immune mechanisms respond rapidly to bacterial infection. A key cellular component of the innate immune response is the neutrophil, whose cytoplasmic granules contain a variety of antimicrobial proteins and peptides. Among these is the bactericidal/permeability-increasing protein (BPI), a cationic 55 kDa protein whose selective anti-infective action against Gram-negative bacteria is based on its high (nM) affinity for lipopolysaccharide (LPS, or "endotoxin"). Binding of BPI to Gram-negative bacteria results in growth inhibition, serves as an opsonin that enhances phagocytosis of bacteria and inhibits bacteria-induced inflammatory responses by blocking the interaction of LPS with host pro-inflammatory pathways. Expression of BPI appears to be developmentally regulated as human newborns apparently have lower neutrophil BPI levels than adults. BPI expression has also recently been demonstrated in human epithelial cells where it appears to be inducible by endogenous anti-inflammatory lipids (lipoxins). BPI's potent anti-endotoxic activity against a broad range of Gram-negative bacterial pathogens is manifest in biological fluids and renders it an attractive template for pharmaceutical development. Indeed, rBPI(21), an active recombinant protein derived from human BPI, has proven safe in Phase I human trials, shown promise in Phase II trials and has recently completed a Phase III trial for severe meningococcaemia with apparent benefit. Identification and evaluation of additional disease entities characterised by Gram-negative bacteraemia and/or endotoxaemia as possible targets for BPI therapy continues.

Anti-Bacterial Agents↗

PubMedDate not supplied

[Evaluation of patient information sheets in clinical trials].

When an investigator invites a patient to take part in a clinical trial, he explains the purposes and details of the trial and gives him an information sheet. We decided to assess this information comparing it with the Huriet-Serusclat law and ICH norms. Seventy four information sheets from phase II and III trials were analysed. The research setting is always specified whereas the aim of the trial is presented in 96% of cases. The sequence of events is detailed in 76% of cases, and the benefits two times out of three. The text is often presented in only one paragraph and the average number of pages is about 2.6. For 25 percent of cases, information is lacking with regard to the progression of the trial; in other cases, the sheets are too long and patients are lost in an excess of information. Information sheets in clinical trials must be practical and short and rely on ICH recommendations.

Clinical Trials as Topic↗

PubMed1997

The clinical evaluation of cancer prevention agents.

The clinical development of cancer chemoprevention agents is similar to that of cytotoxic agents. On the basis of promising preclinical studies, agents with potential efficacy are introduced to the clinic as a phase I trial to study the dose-toxicity relationship of the agent and its human pharmacology. If doses projected to have biological activity have acceptable side effects, the agent proceeds to a phase II trial, which enrolls a larger number of participants and administers the agent for a longer time period (up to 5 years). Phase IIb trials test the effect of these agents on potential biomarkers of carcinogenesis to get some indication if the agent has activity. The phase II trial also pilots study design, mechanisms of recruitment, and adherence for future phase III trials. The phase III trial of a chemopreventive agent determines its effect on cancer incidence. Close attention is also paid to long-term side effects. The unique features of cancer prevention agents and their evaluation must be considered in this stepwise clinical evaluation. These features include (i) populations recruited to prevention trials are healthy; (ii) in this population there is a low tolerance for side effects; and (iii) the clinical end point of the trial, cancer, is statistically an uncommon event. The evaluation of beta-carotene and retinol as studied in the Carotene and Retinol Efficacy Trial (CARET) is used to illustrate this stepwise clinical development.

Anticarcinogenic Agents↗