SEARCH · PubMed Health

Results for “Clinical Trials, Phase II as Topic”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 73 records · Page 4Linked to original sources

PubMedDate not supplied

Radiotherapy and oral capecitabine in the preoperative treatment of patients with rectal cancer: rationale, preliminary results and perspectives.

Preoperative radiotherapy alone or combined with chemotherapy increases the chances of tumor down-staging and down-sizing and facilitates sphincter-sparing surgical procedures, thereby improving survival and quality of life. Though several innovative agents are being investigated in combination with radiotherapy, 5-fluorouracil in continuous infusion remains the common schedule used in the preoperative chemoradiation setting. However, the protracted venous infusion of 5-fluorouracil requires specialized pumps and long-term venous access, which makes patients susceptible to infections or thrombosis. To overcome the 5-fluorouracil infusion-related problems, oral 5-fluorouracil precursors and inhibitors of 5-fluorouracil degradation have been developed and explored. These include oral fluoropyrimidines such as tegafur (ftorafur), uracil plus tegafur (UFT), S-1, eniluracil and the oral carbamate capecitabine. Phase I trials have demonstrated the feasibility of the capecitabine-radiotherapy combination with respect to the bolus or infusion 5-fluorouracil-radiation approach and have defined the optimal dose of capecitabine during radiotherapy (825 mg/m2/day through a bid administration). Severe hand-foot syndrome occurred in 7-15% of patients, representing the most commonly observed toxicity. It is noteworthy that severe diarrhea with capecitabine during radiotherapy was not common. Leukopenia frequently occurred but was mild and reversible. Phase II trials, although limited in number, have evidenced a high probability of pathological complete response (up to 31%) with capecitabine and radiation, with an increased probability of sphincter-sparing surgical procedures. Although it is too early to assess whether oral capecitabine will be able to replace iv 5-fluorouracil in combination with preoperative radiotherapy, the NSABP will address this question in a large randomized trial. Finally, phase I-II trials evaluating escalating doses of capecitabine associated with oxaliplatin or irinotecan with radiotherapy are being carried out to assess the maximum-dose tolerance and efficacy in the preoperative setting. It is likely that these new chemoradiation associations might increase rectal cancer clearance, hopefully without increasing toxicity.

Administration, Oral↗

PubMed1998

Compilation of phase I and II trial data of docetaxel and doxorubicin in the treatment of advanced breast cancer and other malignancies.

Doxorubicin and docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) are the most active cytotoxic agents in the treatment of advanced breast cancer. In the pre-taxane era, randomized trials demonstrated that doxorubicin-containing chemotherapy regimens are associated with higher response rates and improved survival compared with non-doxorubicin-containing regimens. Doxorubicin-containing regimens were therefore considered the standard of care at that time. Because of the substantial activity of the taxanes in anthracyline-resistant breast cancer, there is a clear rationale for combining doxorubicin with the taxanes as initial therapy for patients with metastatic disease. The combination of doxorubicin plus paclitaxel has been extensively studied. Impressive response rates were noted in at least two studies, although the treatment also resulted in an unacceptably high risk of congestive heart failure. Paclitaxel is known to perturb the metabolism of doxorubicin, thereby increasing drug exposure and augmenting the cardiotoxicity of the anthracycline. The cardiotoxicity of the combination may be ameliorated by restricting the cumulative doxorubicin dose to less than 360 mg/m2, by increasing the interval between administration of the two drugs to at least 4 hours, or by adding the cardioprotective agent dexrazoxane. The Eastern Cooperative Oncology Group performed a randomized phase III trial comparing doxorubicin alone, paclitaxel alone, or the doxorubicin/paclitaxel combination in patients with metastatic breast cancer. Although the response rate and time to treatment failure improved with the combination, survival did not. There have been two phase II trials investigating the combination of doxorubicin plus docetaxel. The regimen was highly effective and did not seem to be associated with an increased risk of congestive heart failure. These findings justify further evaluation of the doxorubicin/docetaxel combination in patients with advanced and operable breast cancer. Such trials are currently in progress and will define the role for this combination in the management of patients with breast cancer.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2002

ZD1839: targeting the epidermal growth factor receptor in cancer therapy.

The erbB family of receptors, which includes the epidermal growth factor receptor, has been widely implicated in promoting proliferation of malignant cells. The critical role played by epidermal growth factor receptor in cancer has resulted in extensive research for selective inhibitors of the epidermal growth factor receptor signalling pathway. Selective small molecule epidermal growth factor receptor-tyrosine kinase inhibitors, such as ZD1839 (Iressa), block signal transduction pathways implicated in proliferation and survival of cancer cells and other host-dependent processes promoting cancer cell growth. In preclinical studies, ZD1839, alone and in combination with other agents, has demonstrated antitumour activity in a range of tumour types. Results from Phase I trials, in healthy volunteers and in patients with advanced disease, have shown that ZD1839 has excellent bioavailability and an acceptable tolerability profile. In these studies, ZD1839 has also shown promising clinical activity in patients with a variety of tumour types. Furthermore, Phase II studies confirmed clinically meaningful antitumour activity and have demonstrated symptom relief in the second- and third-line treatment of non-small cell lung cancer. Phase III trials are currently evaluating ZD1839 in combination with gemcitabine/cisplatin or paclitaxel/carboplatin as first-line treatment of non-small cell lung cancer and an ongoing clinical trial programme is investigating other tumours (i.e., head and neck, prostate, colon and breast) and other combinations. This article provides an overview of the current profile of ZD1839.

Adult↗

PubMed2006

[Characteristics of clinical trials in oncology: pharmacist's implication].

French hospital pharmacists have been officially involved in the organization of clinical trials since 1988. New responsibilities included reception of clinical treatment units and nominative dispensation of these drugs. For quality assurance, they organized all the procedures to secure drugs utilization according to good clinical practices and ICH guidelines. The pharmacists can be participate in ethical counselling and training in methodology. For oncology trials, only a few pharmacies are involved because clinical trials for evaluation of cytotoxic drugs have been regulated by very strict standardized procedures since 1960 in accordance with international rules. Using these rules, Phase I studies determine the useful dose for human administration with tolerable toxicities. Phase II studies determine the efficacy in specific cancer localizations. Good response in a particular indication is usually followed by drug approval for Phase III. New clinical and biological end points are arising especially for new non-cytotoxic therapeutic agents. This activity is at the present time limited to inpatient treatments, but with the growing development of outpatient care networks, dispensary pharmacists will come to be more involved in the necessary research and development of new anticancer agents.

Antineoplastic Agents↗

PubMed2004

[Production and diffusion of scientific results in oncology].

The production of data from oncological research must follow specific steps linked to the type of research carried out. Research can be subdivided into the following areas: translational research, clinical research (Phases I, II and III), pharmacoutilization research, meta-analysis, and guidelines. A topic for discussion is represented by levels of evidence (LOE) of research, considered necessary for the transferral of therapeutic approaches to clinical practice. These involve production times of scientific research, and, in particular, the end-points deemed necessary by the appropriate regulatory bodies to permit the commercialization of drugs (problem of surrogate end-points). The interrelation between researchers and pharmaceutical companies has also recently become an object of reflection and research to find solutions that will guarantee both the independence of research and the legitimate needs of companies. A particularly important issue is the correct transmission of scientifically relevant data to the public by mass media sources. The communication of therapeutic advances obtained through research and scientific innovations should not lead to unrealistic expectations in the general population, which rather serve to weaken the already fragile relationship between the official world of oncology and the diverse universe of patients and their families.

Biomedical Research↗

PubMedDate not supplied

Development and scale-up of a microsphere protein delivery system.

This paper reviews the development path for the ProLease injectable microsphere delivery system for proteins using human growth hormone as an example. The process consists of four stages, the selection of a lead formulation for clinical testing, the preclinical evaluation of the lead formulation including toxicology and stability studies, the manufacture of phase I clinical supplies, and the scale-up for phase II and phase III clinical trials. The approaches used to overcome obstacles during each stage are summarized including ways of stabilizing the protein, obtaining desirable release kinetics, and manufacturing sterile batches for clinical testing. Stability, release, toxicology, and scale-up results for ProLease recombinant human growth hormone (rhGH) are given. The phase I clinical data show that bioactive rhGH was released for about 1 month in humans. This work shows that processes and procedures have been developed that enable the production of microsphere sustained release formulations for proteins suitable for clinical trails and commercialization.

Animals↗

PubMedDate not supplied

Approaches to the development and marketing approval of drugs that prevent cancer.

The broad concept of chemoprevention applies to the prevention of clinical cancer by the administration of chemical agents. Current approaches to the development and marketing approval of drugs to prevent cancer are described by a Working Group from the National Cancer Institute and the Food and Drug Administration. A strategy is presented that identifies candidate drugs, with examples that illustrate how drugs are characterized for efficacy through in vitro transformation modulation and mechanistic assays, and in vivo tumor modulation models of carcinogenesis. Requirements and recommendations for safety evaluation in toxicology testing are given, and the evaluation of pharmacokinetic and pharmacodynamic drug effects and potential surrogate end point biomarkers in Phase I trials are discussed. Appropriate subject populations are identified. Phase II trials should emphasize the evaluation of surrogate end point biomarkers that are highly correlated with cancer incidence and may serve as an estimate of cancer incidence reduction. In Phase III trials the interim analysis of a validated surrogate end point of cancer incidence may facilitate timely and cost-effective marketing of efficacious drugs.

Animals↗

PubMed2004

Development of the novel biologically targeted anticancer agent gefitinib: determining the optimum dose for clinical efficacy.

The emergence of novel, biologically targeted anticancer agents such as gefitinib ('Iressa', ZD1839) has raised the question of how the dose for later-stage clinical development and clinical use is best determined. For cytotoxic drugs, because toxic effects and antitumor activity often fall within the same dose range and are dose dependent, the clinically used dose will depend on the therapeutic window. Therefore, the maximum tolerated dose identified in Phase I trials is typically used to determine the dose level for Phase II and III trials. However, because biologically targeted agents are expected to provide clinical benefits that are not predicted by surrogate end points of toxicity to normal replicating tissue, new Phase I trials have been designed to determine the optimum biological dose for use in further studies. A large, multifaceted Phase I program was designed to evaluate the pharmacokinetics, safety, efficacy, and targeted biological activity of a once-daily oral dose of gefitinib. The maximum tolerated dose was >or=700 mg/day, although doses as low as 150 mg/day provided (a). plasma concentrations sufficient for pharmacological activity, (b). evidence of targeted biological effect, and (c). antitumor activity. From these observations, two large Phase II trials ('Iressa' Dose Evaluation in Advanced Lung Cancer 1 and 2) evaluated 250- and 500-mg/day doses of gefitinib in patients with advanced non-small cell lung cancer (NSCLC). As predicted from the Phase I trials, doses >250 mg/day provided no additional efficacy benefit, whereas adverse effects increased in a dose-dependent manner. Consequently, the recommended dose of gefitinib in NSCLC is 250 mg/day. The early clinical trial development of gefitinib provides a model for the development of novel, noncytotoxic anticancer agents.

Antineoplastic Agents↗

PubMed2001

Alicaforsen. Isis Pharmaceuticals.

Alicaforsen (ISIS-2302) is an RNase H-dependent antisense inhibitor of the intercellular adhesion molecule ICAM-1 under development by Isis Pharmaceuticals, for the potential treatment of a variety of inflammatory disorders [175741]. As of April 1997 it was in phase III trials for Crohn's disease (CD); however, the trial failed and, in December 1999, the company suspended development for this indication [352801]. In October 2000, the company re-initiated development in CD [384820] and new phase III trials had begin by May 2001 [409704]. In August 2000, phase II studies of alicaforsen in an enema formulation for ulcerative colitis and a topical formulation for psoriasis were ongoing [378715]. Development of the compound for the potential treatment of rheumatoid arthritis (RA) was discontinued in 1999 [347579]. By the end of 1998, alicaforsen was in phase II trials for kidney transplant rejection. At this time, these trials were expected to finish in mid-1999 [343460]. However, they were ongoing in September 1999, although no further development has been reported for this indication since that time [338672]. In February 1995, Isis Pharmaceuticals and Boehringer Ingelheim (BI) signed a collaborative agreement on cell adhesion inhibitors, including alicaforsen [174111]. By early 1999, Isis and BI were to decide on the next developmental step for alicaforsen following further analyses of its performance against CD [292915], [315439]. Their joint development agreement was terminated in 1999; Isis regained rights to the product and by September 1999 was in talks to license alicaforsen to another partner for CD [338672]. In June 2000, Cytogenix entered into a sponsored research agreement with Baylor College of Medicine at the Texas Medical Center Houston for the use of its ssDNA expression system for the development of antisense strategies directed against intercellular adhesion molecules for the purpose of reducing lung inflammation and injury in disease states and conditions [369677]. US-05514788, and other patents, cover antisense cell adhesion molecule inhibitors [212289], [234792].

Animals↗

PubMed2006

Cytotoxic chemotherapy for pancreatic cancer: Advances to date and future directions.

Chemotherapy remains the mainstay of treatment for pancreatic cancer as most patients present with advanced disease, which precludes locoregional treatment. However, the efficacy of chemotherapy is limited. Gemcitabine is the only agent that improves symptoms and confers a modest survival advantage. Many combination therapy regimens have been studied in phase II settings. Eleven randomised phase III trials have been conducted to compare gemcitabine-containing regimens with gemcitabine monotherapy since gemcitabine became available clinically. The combination of gemcitabine plus capecitabine has demonstrated a survival advantage over gemcitabine, whereas gemcitabine plus oxaliplatin and gemcitabine plus cisplatin have shown improved progression-free survival or time to tumour progression but failed to demonstrate a survival advantage over gemcitabine. The search for effective therapy for advanced pancreatic cancer continues. Gemcitabine in combination with cytotoxic agents or molecular targeted agents hold promise.

Antimetabolites, Antineoplastic↗

PubMed2003

A model to select regimens for phase III trials for patients with advanced-stage non-small cell lung cancer.

PURPOSE: Historical data from pilot, Phase II, and Phase III studies for patients with advanced-stage non-small cell lung cancer (NSCLC) were used to evaluate a statistical model developed to provide assistance in selecting regimens from pilot studies for subsequent use in larger Phase III randomized studies. EXPERIMENTAL DESIGN: Information from 33 Phase III trials for patients with advanced-stage NSCLC performed from 1973 and 1994 in the United States and Canada was collected. The data from antecedent pilot or Phase II and subsequent Phase III trials were analyzed using a predictive statistical model. This model uses the number of patients in the pilot/Phase II study, the median survival of patients in the pilot, and the number of deaths observed, to estimate the statistical likelihood that the pilot regimen will be shown superior to standard therapy in a subsequent Phase III trial. RESULTS: Ten pilot/Phase II studies were identified that preceded eleven subsequent Phase III studies. The three pilot regimens associated with Phase III trials, revealing statistically significant longer survival, had an expected power of 0.69, 0.85, and 0.94 respectively. The regimens from the seven other pilot studies for which the median power expected was 0.38 (range, 0.07-0.80) showed no difference when compared with standard treatment in a Phase III trial. CONCLUSION: The use of the expected power model provides an important enhancement to the screening of new therapies. Regimens with an expected power of >0.55 may be good candidates for testing in Phase III trials.

Carcinoma, Non-Small-Cell Lung↗

PubMed2001

(S)-Zopiclone Sepracor.

(S)-Zopiclone, a cyclopyrrolone sharing activity with benzodiazepines in the CNS, is a short-acting sedative being developed by Sepracorfor the potential treatment of sleeping disorders. In August 2000, the company had completed phase II trials of (S)-zopiclone for insomnia [380377]; by September 2000, patient enrollmentfor phase III studies for insomnia was completed and the trial initiation was planned for October 2000 [381361]. Merrill Lynch expects US filing to take place in the second half of 2001 [383230]. Sepracor was granted US-05786357 in August 1998 covering methods and compositions of (S)-zopiclone in the treatment of sleeping disorders [342938]. In August 2000, Merrill Lynch predicted (S)-zopiclone sales of US $30 million in 2002, rising to US $150 million in 2004 [383230].

Animals↗

PubMed2002

Fulvestrant (AstraZeneca).

Fulvestrant (Faslodex) is an estrogen receptor (ER) downregulator under development by AstraZeneca for the potential treatment of breast cancer [172191], [237518], [314472], [349551]. In March 2001, an NDA was filed in the US for the second-line treatment of advanced breast cancer in postmenopausal women who have progressed on prior hormonal therapy [403574], [434825]; in December 2001, AstraZeneca was expecting to launch the compound in the US in thefirst half of 2002 [431887]. In August 2001, late-stage clinical trials were ongoing in Japan for breast cancer [422343]. Fulvestrant also has potential in the treatment of other estrogen-responsive tumors, such as uterine tumors [178081]. By 1997, fulvestrant was in phase II trials for uterine fibroids [272162], and by February 1999, it was reported that phase II trials for endometriosis were ongoing [314472], [336599]. However, no development has been reported for these indications since that time. In October 2001, Morgan Stanley expected launch in 2002, with estimated sales of $80 million in 2002 rising to $208 million in 2007 [429700]. Analysts at Lehman Brothers predicted in December 2001, that the product has a 90% chance of making it to market in 2002, with peak sales potential in this year of $800 million [434768].

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↗

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↗

PubMed1994

Vinorelbine (Navelbine) in non-small cell lung cancer: future directions.

Randomized clinical trials of vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Médicament, Paris, France) as a single agent and in combination with cisplatin have demonstrated antitumor activity in patients with advanced non-small cell lung cancer (NSCLC). Administered as a single agent on a weekly schedule, the vinorelbine therapeutic profile compares favorably with other regimens currently used in palliative treatment of patients with advanced NSCLC. Vinorelbine is also being considered in other treatment settings as well: adjuvant treatment in stage I and II disease, and regimens with curative intent in stage IIIa and IIIb disease. Future directions for vinorelbine in the treatment of NSCLC are likely to be directed toward combination trials with other agents active in NSCLC. Current phase I-II trials, for example, combine vinorelbine with cisplatin, 5-fluorouracil/leucovorin, mitomycin-C, ifosfamide, carboplatin, and paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ). Some phase III trials are planned and some are under way. Vinorelbine has been a focus of interest in multimodality trials. A Canadian trial, for example, combined vinorelbine and cisplatin, followed by accelerated radiation. Results from all these trials can be expected to guide the further development of vinorelbine in adjuvant and neoadjuvant settings in NSCLC. Moreover, trials that are documenting the efficacy of vinorelbine in small cell lung cancer are just beginning.

Antineoplastic Agents↗

PubMed2004

Bcl-2 antisense therapy in hematologic malignancies.

PURPOSE OF REVIEW: Overexpression of the Bcl-2 oncoprotein is noted in various malignant disorders. In patients with hematologic malignancies, increased production of the Bcl-2 oncoprotein is associated with chemotherapy resistance, aggressive clinical course, and poor survival. Bcl-2 is an important molecular target. Downregulating Bcl-2 can potentially reverse inherent tumor resistance to, and possibly improve response to therapy. This review focuses on the preclinical data, as well as the current clinical information available on oblimersen, a novel antisense approach targeting Bcl-2 in malignant hematologic disorders. RECENT FINDINGS: Early clinical trials have shown single-agent activity of oblimersen in patients with chronic lymphocytic leukemia and non-Hodgkin lymphoma, and thus, provide proof of principle for antisense therapy. Phase I and phase II studies using oblimersen in combination with conventional chemotherapy have shown encouraging results in patients with non-Hodgkin lymphoma, chronic lymphocytic leukemia, and acute myeloid leukemia. Phase III studies in patients with multiple myeloma and chronic lymphocytic leukemia have completed accrual and results are awaited. SUMMARY: Bcl-2 is a clinically meaningful target in patients with hematologic malignancies. Downregulation of the Bcl-2 oncoprotein can be achieved with oblimersen (antisense molecule specific for Bcl-2). Early clinical results suggest a possible role of this antisense approach in targeting Bcl-2. Ongoing clinical trials will establish the clinical utility of oblimersen in patients with hematologic malignancies.

Antineoplastic Agents↗

PubMed2004

Bevacizumab in the treatment of breast cancer: rationale and current data.

Vascular endothelial growth factor (VEGF) has emerged as a key target for the treatment of cancer. As the ligand to the VEGF receptor, it plays a central role in promoting tumor angiogenesis. Overexpression of VEGF leads to poor outcomes in patients with breast cancer and other tumors. Preclinical studies have shown that the humanized monoclonal antibody to VEGF, bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA), can reduce tumor angiogenesis and inhibit the growth of solid tumors, either alone or in combination with chemotherapy. As a single agent or added to vinorelbine, bevacizumab has produced encouraging results in phase II clinical trials in patients with refractory metastatic breast cancer. When added to capecitabine chemotherapy in a phase III trial, bevacizumab produced a greater response rate, but did not prolong progression-free survival. This may reflect the late disease stage and poor prognostic factors in the patient population. A large, ongoing, phase III, cooperative group trial is evaluating the effect of bevacizumab in combination with paclitaxel as first-line therapy for metastatic disease. The adverse effect profile of bevacizumab differs from that of cytotoxic chemotherapy and includes hypertension, proteinuria, thrombosis, and epistaxis.

Angiogenesis Inhibitors↗