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PubMed1995

Potential impact of low efficacy HIV-1 vaccines in populations with high rates of infection.

A safe and effective HIV vaccine to prevent infection and/or to moderate disease is urgently needed. Research progress has been slower than anticipated for a variety of reasons including uncertainty over which immunogen to use (i.e. recombinant subunit envelope proteins or whole HIV-1 products), confusion on which immunological markers best correlate with protection, the relevance of the HIV-1 chimpanzee model to infection in humans and the significance of the rapid evolution of HIV-1, with different clades of the virus emerging in different parts of the world. However, what some would interpret as encouraging results, from Phase I and II trials of recombinant envelope glycoprotein vaccines, have raised the question of whether the time is right to start Phase III trials in humans with immunogens that may have low to moderate efficacy. By using mathematical models and data from epidemiological studies, we examine the potential impact of such vaccines within heterosexual communities with high rates of infection. Analyses suggest that it will be difficult to block HIV-1 transmission even with very high levels of mass vaccination. The cost of sustaining high levels of herd immunity with a vaccine of short protection duration is likely to be high. However, assessments of impact over the long duration of an HIV-1 epidemic indicate that many cases of HIV infection and associated mortality can be prevented by immunogens with efficacy of 50% or less and a five year protection duration.(ABSTRACT TRUNCATED AT 250 WORDS)

AIDS Vaccines↗

PubMed2001

The translational research chain: is it delivering the goods?

PURPOSE: To address whether the translational research chain has influenced clinical practice in radiation oncology. METHODS AND MATERIALS: Merits and limitations of the various steps of the translational chain, i.e., in vitro studies, animal experiments, biomathematical modeling, Phase I and II trials, and randomized Phase III trials are briefly reviewed. The process and value of translational research in radiation oncology are addressed using dose fractionation and the time factor in tumors as examples. RESULTS: The examples show that translational research may indeed change clinical practice in radiation oncology. However, it takes several decades and considerable efforts to define and test new strategies. The "translational process" is by no means unidirectional but a continuing multiway dialog among basic scientists, applied scientists, clinical scientists, and clinical oncologists. CONCLUSION: Translational research works in radiation oncology, and it is difficult to conceive a better alternative for future improvement of therapy. The slow speed of the translational process indicates that there is a need for improving the various steps of the translational network and the interaction as a whole. Massive investments in one part of the network are likely to be at least partly wasted unless the other links are strengthened as well.

Animals↗

PubMed2001

The Ancure endografting system: an update.

The Ancure endografting system (Guidant Cardiac and Vascular Division, Menlo Park, Calif) features a unibody, nonsupported woven polyester graft designed to treat abdominal aortic aneurysms. It is constructed in tube, bifurcated, and aortoiliac configurations. The attachment system consists of a frame with four independent V-shaped double hooks that penetrate the arterial wall for fixation. There are separate attachment systems at the proximal and distal ends of the endoprosthesis. In September 1999, the Food and Drug Administration (FDA) approved the tube and bifurcated devices for general use. The aortoiliac device is under present consideration of the FDA. Phase II and III clinical trials of the system enrolled over 870 patients from the end of 1995 to the summer of 1999. The device was deployed successfully in 90% to 96% of cases, depending on the configuration and the phase of the trial. Mortality rates were similar to those of concurrent open surgical control rates, but serious morbidity was reduced. Long-term follow-up of the bifurcated group from phase II showed only one migration and no ruptures. Aneurysm size reduction in this group was noted in 51.3% of patients at 1 year and 68.5% at 2 years. In the same subset, type I endoleaks were noted in 2.7% at 1 year and 1.3% at 2 years. All postoperative imaging studies were reviewed by a core laboratory facility. The advantages of the ancure system include solid fixation, flexibility in accommodating morphologic changes, and excellent long-term clinical performance. The disadvantages include a large introducer system and the potential for limb obstruction by compression or angulation. However, limb compromise responds well to intraluminal stenting. The expected FDA approval of the aortoiliac device and a larger variety of graft sizes should expand the number of patients who can be treated with this system.

Angioplasty↗

PubMed2003

[Docetaxel (Taxotere) as first-line therapy of advanced non-small cell lung cancer (NSCLC)].

Taxotere as a 'stabilizing antitubuline' and a second-generation Taxan has anti-tumor activity in a variety of solid neoplasms. In NSCLC Taxotere has shown encouraging response rates across a range of phase-II studies, and phase-III trials have confirmed its effectiveness in pretreated and chemotherapy-naive patients. Single agent Taxotere has shown that it can significantly improve both survival and quality of life when compared to either best supportive care or standard chemotherapy in previously treated patients. Therefore, it is considered standard for NSCLC second-line chemotherapy. Taxotere has also been evaluated in combination with platinum-compounds and non-platinum-based drugs for first-line treatment of NSCLC. The results recently published from a phase-III registration trial (TAX 326) have shown that the overall survival among patients randomized to receive Taxotere/Cisplatin was better than that among patients treated with Vinorelbin/Cisplatin and similar compared to Vinorelbin/Cisplatin for those patients who received Taxotere/Carboplatin. Given concomitantly or sequentially with non-platinum-based compounds (i.e. Gemcitabine, Vinorelbine) Taxotere has also shown promising activity in randomized studies and may offer advantages for patients not eligible to receive platinum-based compounds.

Antineoplastic Agents, Phytogenic↗

PubMed1999

Incremental costs of enrolling cancer patients in clinical trials: a population-based study.

BACKGROUND: Payment for care provided as part of clinical research has become less predictable as a result of managed care. Because little is known at present about how entry into cancer trials affects the cost of care for cancer patients, we conducted a matched case-control comparison of the incremental medical costs attributable to participation in cancer treatment trials. METHODS: Case patients were residents of Olmsted County, MN, who entered phase II or phase III cancer treatment trials at the Mayo Clinic from 1988 through 1994. Control patients were patients who did not enter trials but who were eligible on the basis of tumor registry matching and medical record review. Sixty-one matched pairs were followed for up to 5 years after the date of trial entry for case patients or from an equivalent date for control patients. Hospital, physician, and ancillary service costs were estimated from a population-based cost database developed at the Mayo Clinic. RESULTS: Trial enrollees incurred modestly (no more than 10%) higher costs over various follow-up periods. The mean cumulative 5-year cost in 1995 inflation-adjusted U.S. dollars among trial enrollees after adjustment for censoring was $46424 compared with $44 133 for control patients. After 1 year, trial enrollee costs were $24645 compared with $23 964 for control patients. CONCLUSIONS: This study suggests that cancer chemotherapy trials may not imply budget-breaking costs. Cancer itself is a high-cost illness. Clinical protocols may add relatively little to that cost.

Cancer Care Facilities↗

PubMed2002

Nuvion. Protein Design Labs.

Protein Design Labs Inc (PDL) is developing SMART anti-CD3 (Nuvion) as a potential therapeutic for autoimmune diseases such as inflammatory bowel disease (IBD), and as a prophylactic for transplant rejection. The therapy had been in phase II trials for the prevention of kidney rejection, but in December 2000 PDL decided not to continue the development of Nuvion in kidney transplantation to allow the company to focus on the rapid development of Nuvion for the treatment of acute GvHD, as well as on the larger autoimmune indications 13921621. In April 1999, Nuvion was in phase I/II trials for the treatment of psoriasis and phase I trials for GvHD, with phase II/III trials planned for 2001 for this indication. Following the release of disappointing trial results in June 2001, however, the development of Nuvion for the psoriasis indication was dropped. As of December 2000, PDL planned to initiate a phase I trial in IBD in the near future. In March 1999, Protein Design Labs was issued US-05834597. The patent relates generally to certain modifications of the constant (Fc) region of IgG2 antibodies and more specifically to anti-CD3 antibodies incorporating these modifications, including the company's SMART anti-CD3 antibody. In January 2002, analysts at Salomon Smith Barney predicted that the product would make sales of US $3.13 million in 2005, rising to US $7.20 million in 2006.

Antibodies, Monoclonal↗

PubMed1997

Willingness to participate in HIV-1 vaccine efficacy trials and the effect of media events among gay and bisexual men in New York City: Project ACHIEVE.

Efficacy trials of candidate HIV-1 vaccines require study populations at high risk of infection who adhere to study protocols and who are willing to participate. Data from HIV-1 antibody-negative men (n = 698) enrolled in Project ACHIEVE in New York City were analyzed to assess willingness to participate in efficacy trials, factors influencing willingness, and the effect on willingness of the June 1994 media events about the decision not to proceed with phase III trials and about breakthrough infections during phase I and II vaccine trials. Sixty-eight percent indicated they would definitely or probably be willing to participate. Men enrolled during the time of media events were significantly less willing compared with men enrolled during other periods. These men were also more likely to mention safety of the vaccine, fear or mistrust of research or government, and social risks as important factors in their decision compared with men enrolled during other periods. The most frequently cited motivator for participation was altruism (57%); the most frequently cited barriers were vaccine safety (36%) and vaccine-induced seropositivity (19%). A substantial proportion of this cohort was willing to participate in future vaccine efficacy trials. However, because willingness may be affected by issues of vaccine safety, vaccine-induced seropositivity, and media coverage of these issues, significant efforts are needed for participant and community education, and specific concerns must be addressed in the design and implementation of trials.

Adult↗

PubMed2005

Current status of therapeutic vaccines for non-Hodgkin's lymphoma.

PURPOSE OF REVIEW: Therapeutic vaccines targeting B cell lymphoma idiotype have reached an advanced stage of clinical development, with three multicenter randomized clinical trials ongoing. This review describes the rationale and development of this immunotherapeutic approach, the design of current phase III trials, and other active vaccination approaches likely to move forward into clinical testing for lymphomas. RECENT FINDINGS: Several groups have achieved promising results in phase II trials of patient-specific idiotype vaccines, with very few side effects noted. Anti-idiotype antibodies, in addition to cytotoxic T cells, are now believed to be important effectors of antitumor immunity after idiotype vaccination. The manufacturing of autologous tumor idiotype proteins is being rapidly refined by the use of molecular technologies. Two trials involving more than 1000 patients are now under way, which use idiotype vaccination after induction chemotherapy; one trial completed accrual in early 2004. A third trial opened in 2004, using rituximab followed by idiotype vaccine with maintenance booster vaccines continuing throughout the period of normal B cell recovery. In accordance with the United States Food and Drug Administration, progression-free survival serves as the accepted primary efficacy endpoint in these studies. SUMMARY: Lymphoma idiotype vaccination represents a promising immunotherapeutic approach targeting a patient-specific tumor antigen. The results of pivotal phase III trials for three first-generation idiotype vaccines will become available in the next several years. Advanced manufacturing techniques should permit application of this tailor-made treatment to large numbers of non-Hodgkin's lymphoma patients.

Cancer Vaccines↗

PubMed1998

A phased approach to clinical testing: criteria for progressing from Phase I to Phase II to Phase III studies.

The overall intent of clinical testing is to establish, in a series of phased studies, the clinical tolerance and acceptable "safety" of the candidate vaccine, as well as the type, level and persistence of the immune response after its inoculation, to a representative target population, according to a convenient administration schedule. The final stages involve the direct or indirect demonstration of protective efficacy, if possible in the population(s) for which the vaccine is intended. In addition, consistency of production must be demonstrated. At all these stages, the amount of prior information from preclinical and other studies affects and informs the objectives and design of subsequent studies. Progression from one testing phase to the next is dependent upon attaining the pre-set objectives of each series of studies. The precise objectives to be met will be decided on a case-by-case basis. The earliest assessments in humans (Phase I) involve evaluation of short-term clinical tolerance as measured by local and general reactogenicity, and gross assessments of immunogenicity, in a small number of highly selected individuals in an idealised situation. The selection of "optimal" dose and schedule are the result of further dose-ranging investigations (Phase II), involving more volunteers, with longer, more detailed follow-up assessments. It is at this stage that the accumulated evidence on its immunogenicity profile should be sufficient to assess whether or not the vaccine is worthy of further development. The next level of investigation (Phase III) aims to measure with greater precision the vaccine protective efficacy in the intended target population(s) by comparison of infection and/or disease attack rates in vaccine and placebo recipients. In consistency studies different production lots, manufactured at commercial scale, are tested to demonstrate consistency of manufacture. Additional bridging studies to establish similarity of lots at different production scales, or studies of the duration of the immunity conferred, are conducted in parallel with the progression of the studies in the different phases mentioned above. These latter types of studies are usually carried out concurrently with Phase III studies. This progression continues into the post-marketing period (Phase IV) with surveillance of long term efficacy and observational studies of possible rare adverse events to establish "safety" with more confidence. This paper examines, in general, the aims and designs of studies in each phase as an introduction to the more specific publications that follow.

Clinical Trials as Topic↗

PubMed2002

Ximelagatran (AstraZeneca).

AstraZeneca (formerly Astra) is developing ximelagatran, an orally active thrombin inhibitor and prodrug of melagatran, for the potential prevention and treatment of venous thromboembolism (VTE) in hip and knee replacement, for prevention of stroke in atrialfibrillation (AF) and for post acute coronary syndrome. As of December 1999, the compound was undergoing phase III trials for the prevention of VTE [349551]; these were ongoing in December 2001. By December 2000, ximelagatran had entered phase III trials for the prevention of stroke in atrial fibrillation [395212]. In September 2000, the company expected global NDA filing for this indication to take place in the middle of 2001 [383469]; however, in December 2000 this was revised to the second half of 2002 [395212], and in March 2001, to the second quarter of 2003 [402040], [416882], [431673]. By December 2000, a phase II trial was underway of ximelagatran as a potential treatment following myocardial infarction [395237]. In December 2001, early phase clinical trials were ongoing for post acute coronary syndrome [431673]. By December 2001, EU and US filings for VTE prevention were anticipated in the third quarter of 2002 and the second quarter of 2003, respectively [3144721, [350050], [431673]. Exanta is the trade name for both melagatran and ximelagatran. In 1998, marketing of ximelagatran in the US was to be assigned to the Astra/Merek joint marketing venture, prior to the merger [276577]. In April 1999, ABN predicted sales of 4 pounds million in 2003 [328676], [394606]. In December 2000, Lehman Brothers estimated peak sales to be $1.4 billion [394606]. At the same time, ABN-AMRO predicted peak sales of more than $1 billion [395237]. In June 2000, Deutsche Bank predicted sales of $70 million in 2002, rising to $245 million in 2003 [374500]. In September 2000, Merrill Lynch predicted sales of 125 pounds million in 2002, rising to 625 pounds million in 2004 [383742]. In February 2001, Merrill Lynch estimated that peak sales would reach $924 million in 2005 [429697].

Azetidines↗

PubMed1996

Clinical trials of irinotecan hydrochloride (CPT, campto injection, topotecin injection) in Japan.

CPT-11 was synthesized in 1984 at the laboratory of Yakult Honsha. Phase I study of CPT-11 was begun in 1986. The appropriate doses for phase II studies were decided to be 100 mg/m2 weekly or 150 mg/m2 every 2 weeks. Phase II study was conducted and this drug was approved for NSCLC, SCLC, uterine cancer and ovarian cancer by MHW in 1994. It obtained approval for stomach cancer, colorectal cancer, breast cancer, skin cancer and non-Hodgkin's lymphoma in 1995. The combination chemotherapies including CPT-11 have been conducted by using various regimens such as CPT-11 + CDDP, CPT-11 + VP-16, CPT-11 + 5-FU and CBDCA + CPT-11. In stage IV SCLC two prospective randomized controlled trials are on going comparing CPT-11 vs. CPT-11 + CDDP vs. VDS + CDDP and CPT-11 + CDDP vs. VDS + CDDP. In advanced SCLC Japanese Clinical Oncology Group (JCOG) started a randomized controlled trial comparing CPT-11 + CDDP vs. VP-16 + CDDP. In stage III NSCLC the dose escalation studies of CPT-11 (CPT-11) in the combination with TRT are ongoing by JCOG. The problem of CPT-11 in the combination chemotherapy and combined modality is that it is quite difficult to increase the dose of CPT-11 to full dose to obtain the maximum effect.

Antineoplastic Agents, Phytogenic↗

PubMed2003

[Development of novel molecular targeted drug, "Iressa", for the treatment of malignant diseases--its basic and clinical studies].

One year has passed since the launch of a new molecular targeted agent, Iressa (generic name: Gefitinib), in Japan ahead of other countries in the world. Gefitinib is the first selective Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor. Gefitinib was investigated clinically by a single dose ascending study and 3-day multiple dosing study in male volunteers in the UK initially. On confirmation of tolerability by those studies, 4 Phase I studies were conducted in patients with solid tumours generally known to over-express EGFR, with a result of 250 mg or 500 mg (oral administration) decided to be chosen as the recommended dose for Phase II studies. A Phase II study was then conducted in 9 countries including European countries, Australia, and Japan, using once daily oral dosing regimen. In this study gefitinib demonstrated response rate of 18.4% (19/103), and disease control rate of 54.4% (56/103) in advanced non-small cell lung cancer patients (with 1 or 2 previous chemotherapy regimens) at a dose level of 250 mg/day. Symptom improvement rate, which was determined using lung cancer sub-scale (LCS) for QOL assessment, was 40.3% (27/67), and median time to symptom improvement was 8 days (on the initial assessment). In 3 months after the launch, 39 lung injury deaths of patients were reported including deaths attributed to interstitial pneumonia, which was covered broadly by mass media. It is, however, considered that development of Iressa, the first EGFR tyrosine kinase inhibitor showing effects on solid tumours, for clinical use through assiduous researches on molecular targeted agents has truly great significance. This paper gives an overview covering development history to date, clinical study results, and post-launch safety reports.

Animals↗

PubMed1996

Paclitaxel and doxorubicin, a highly active combination in the treatment of metastatic breast cancer.

The activity of single-agent paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has been documented in untreated and previously treated metastatic breast cancer, including both patients with anthracycline-resistant disease and those with extensive pretreatment. Such activity has prompted investigations of the optimal doses and schedules of paclitaxel/doxorubicin combinations. With one exception, paclitaxel has been administered as either a 24- or a 3-hour infusion, while the administration times for doxorubicin vary from bolus injection to 72-hour infusion. Results of these completed phase I and II trials are reviewed. Also reported are two European trials that have achieved promising results. In Milan, a phase I/II trial has shown a preliminary response rate exceeding 90% in 32 chemotherapy-naive patients treated with an alternating schedule of paclitaxel given over 3 hours and intravenous bolus doxorubicin. At doses of paclitaxel 200 mg/m2 and doxorubicin 60 mg/m2, the dose-limiting toxicities were neutropenia, oral mucositis, myalgias, and peripheral neuropathy. Congestive heart failure occurred in six patients. A phase I/II study of a 30-minute doxorubicin infusion preceding a 3-hour paclitaxel infusion every 3 weeks in minimally pretreated patients also is reported. Of 29 patients evaluable for response, 17 have achieved partial responses and seven complete responses, for an overall response rate of 83% (95% confidence interval, 79% to 99%). Toxicities observed were grades 3 to 4 neutropenia and moderate paresthesias, nausea/vomiting, alopecia, myalgia, and mucositis. Cardiotoxicity also occurred, as 15 patients had a significant decrease in left ventricular ejection fraction measured by isotope cardiography. Six of these developed congestive heart failure. This effect has been observed only in studies using short infusions of both drugs, and it is now being investigated whether lowering the peak doxorubicin concentration will preclude it.

Antibiotics, Antineoplastic↗

PubMed2002

Pexelizumab Alexion.

Alexion and Procter & Gamble (P&G) are developing pexelizumab (h5G1.1-SC), a short-acting, recombinant complement C5 inhibitor for the potential treatment of complications of cardiovascular surgery, such as complement activation during cardiopulmonary bypass (CPB) procedures, for which it has completed phase II trials [275707]. By November 2001, the companies were also conducting two phase II trials for the treatment of acute myocardial infarction (MI) and by March 2002, patient accrual in the first of these MI trials (COMPLY) had been completed [429171], [443067]. In April 2002, accrual in the second MI trial (COMMA) was also completed [446377]. Results from the MI trials had been expected in the first half of 2002 [435888]. By January 2002, pivotal phase III trials had been initiated in patients undergoing coronary artery bypass graft (CABG) with CPB [435058]. The compound may also have potential in the treatment of stroke [188595]. In September 2000, the US FDA granted Alexion Fast Track status for pexelizumab for CPB patients [381531]. The company is collaborating with P&G to develop and commercialize this inhibitor drug for patients undergoing CPB during CABG [313015]. In December 2001, the terms of the collaboration were altered and as a result Alexion was to play an increased role in the development and marketing of pexelizumab in the US [433296]. Alexion licensed the complement protein C5 technology from Enzon Inc, developed during Enzon's short chain antigen binding (SCA) proteins program, in May 1996 [352743]. Analysts at US Bancorp Piper Jaffray predicted in January 2002 that pexelizumab has potential peak sales of US $350 million. At this time, approval for the CPB indication was expected in the US in the second half of 2004, and sales in 2005 were expected to reach US $50 million, rising to US $227 million in 2008. In the rest of the world, CPB approvals were expected to begin in the second half of 2005. Sales in 2006 were expected to reach US $35 million, rising to US $110 million in 2008 [438051].

Animals↗

PubMed1994

Photodynamic therapy of lung cancer.

Photodynamic therapy (PDT) has been used investigationally for the treatment of lung cancer since 1980. Following systemic administration of a photosensitizing agent such as porfimer sodium (Photofrin; manufactured by Lederle Parenterals, Carolina, Puerto Rico, under license from Quadra Logic Technologies, Inc, Vancouver, British Columbia, Canada), specialized optical delivery systems are engaged to deliver light of a specific wavelength (630 nm for porfimer sodium) to neoplastic tissue. A promising use of PDT appears to be treatment of early stage lung carcinoma. Phase I-II clinical trials by Hayata's group in Japan showed that for superficial early lung cancer less than 1 cm in surface diameter, complete eradication can be achieved in approximately 90% of cases. Additional phase II-III clinical trials have demonstrated an average of 90% complete response rates for superficial tumors less than 1 cm in diameter. Preoperative PDT may be useful for larger neoplasms to reduce tumor burden and potentially lessen the degree of surgery required. At the British Columbia Cancer Agency, 22 patients with 30 radiologically occult cancers were treated with PDT. In contrast to Hayata's studies, most of these patients had rather extensive tumor burden. Thirty percent of the tumors involved two or more bronchi, and more than half of them were greater than 1 cm in surface diameter. Twenty-three percent of the cases were bronchial stump recurrences. In the group of patients with bronchial stump recurrence, although a complete response was obtained with PDT initially, local recurrences occurred in 75% of cases. These results suggest that recurrent tumor in the bronchial stump should not be treated with PDT because of difficulty in delivering light endobronchially to distal tissues. Photodynamic therapy may have a role in the palliation of advanced, inoperable, obstructive bronchial tumors. Phytodynamic therapy in combination with external radiotherapy may produce better local control than external radiotherapy alone in patients with obstructive bronchial cancers. Photodynamic therapy and conventional Nd:YAG laser therapy appear to be equally effective in relieving intraluminal obstruction by tumor. An advantage of PDT for this purpose is longer time to treatment failure; a disadvantage is photosensitization that usually occurs for up to 4 weeks after treatment. In summary, PDT is a promising curative treatment for patients with small early bronchial cancers.

Airway Obstruction↗

PubMed2005

Management of the relapsed/refractory myeloma patient: strategies incorporating lenalidomide.

The immunomodulatory drug (IMiD) lenalidomide is a more potent immunomodulator than thalidomide with respect to its effects on cytokine modulation and increased T-cell proliferation. Of all the IMiDs, clinical trial data are most mature for lenalidomide. In phase I studies, dose-limiting toxicities of lenalidomide were limited to myelosuppression and a response rate of 72% was seen in relapsed/refractory patients. Three phase II studies subsequently evaluated the efficacy of single-agent lenalidomide or lenalidomide in combination with dexamethasone. As a single agent for post-transplant salvage therapy, lenalidomide 25 mg every 3 weeks has shown response rates as high as 44%. For patients with relapsed/refractory multiple myeloma, the MM-007 study has shown that lenalidomide alone or in combination with dexamethasone provides response rates between 37% and 41%. In MM-007, median progression-free survival was 5.5 months at early analysis and the median overall survival has yet to be reached. Preliminary data for the single-arm, multicenter, open-label MM-014 study showed that median time to progression was 5.6 months. Response rates indicate that 70% of patients had stable disease or better as the best response to treatment. Two randomized, phase III trials (MM-009 and MM-010) evaluated lenalidomide with high-dose dexamethasone versus high-dose dexamethasone alone for the treatment of relapsed/refractory multiple myeloma. Both MM-009 and MM-010 provided remarkably similar response rates for patients receiving lenalidomide and dexamethasone. In both trials response rates with the combination were greater than twice the response rates seen with high-dose dexamethasone alone. Indeed, an independent Data Monitoring Committee determined that both trials exceeded the prespecified efficacy value of P<.0015, recommending that the trials be discontinued and that lenalidomide be offered to patients on the dexamethasone arm of the trial if clinically indicated. Toxicities observed in studies of lenalidomide alone were low; the incidence of peripheral neuropathy was significantly lower than those noted in trials using thalidomide. Thrombocytopenia was a significant grade 3 or 4 toxicity observed; however, it was manageable with dose reduction. In contrast with high-dose dexamethasone, deep vein thrombosis has emerged as an important toxicity. Lenalidomide is currently being tested in combination with both standard and novel agents, including bortezomib, for patients with relapsed/refractory multiple myeloma.

Antineoplastic Combined Chemotherapy Protocols↗

PubMedDate not supplied

[Difficulties with conducting clinical trials in France].

France ranks third among European countries as regards the level of investment in clinical R&D and, overall, accounts for a contributive effort proportional to the size of its population and pharmaceutical market respectively. However, there is a trend for phase II and III studies to become proportionally fewer than in the past, while the number of phase IV studies is increasing. In a growing proportion of the mega-trials, which are instrumental for establishing evidence-based practice, French experts, investigators and, even more seriously, French patients, are insufficiently represented. Though studies in France are initiated relatively fast due to a clear regulatory framework and perform equally well as far as quantitative and qualitative factors are concerned, compared with most European countries involved in clinical research the costs incurred per completed patient are higher than those recorded in the other countries. Academic research shares most of these constraints and suffers from a lack of financial and human resources, while it faces additional delays in implementing studies because of longer administrative processes. Given the stakes in play, specific solutions should be implemented to maintain and further develop French competitiveness in clinical R&D. At the patient level, positive perception and awareness of the usefulness and safety of participating in clinical trials need to be emphasized. Education at the school level and using the lay media should be developed. Intervention of institutional and government officials is much needed. Direct patient recruitment should be developed through advertisement and the Internet, as well as within doctors' offices and through collaboration with patients' organizations. Patient information and consent forms should be made much simpler than those imposed within the framework of global studies because of FDA requirements. The French health system discourages the recruitment of patients by investigators who are not the family doctor or the usual care provider. Thus, motivation and education of general practitioners and hospital doctors may be increased by involving them during the trial design phase and in the publication process. Specific administrative solutions, within private or public institutions, need to be developed for investigators who do not personally wish to receive investigation fees. Because of lack of availability, investigators need to be assisted with study nurse services and site management organizations, particularly within hospitals and clinics, using the model of the Clinical Investigation Centres. Networks of clinical investigation centres and of individual investigators need to be created. Implementing these solutions should lead to better implications for and reputation of French clinical research.

Clinical Trials as Topic↗

PubMed2004

Pharmacology, pharmacokinetics, and practical applications of bortezomib.

Bortezomib (PS-341, Velcade) is a novel, first-in-class proteasome inhibitor with antitumor activity against a number of hematologic and nonhematologic malignancies. Based on the results of phase II clinical trials, bortezomib received accelerated US Food and Drug Administration approval on May 13, 2003, for the treatment of multiple myeloma patients whose disease has progressed after they have received at least two prior conventional therapies. The results of phase III studies evaluating bortezomib as first- or second-line therapy, or in combination with other commonly prescribed therapies in multiple myeloma patients, are eagerly awaited. Studies assessing the antitumor effects of bortezomib in other hematologic malignancies and solid tumors are also under way. A thorough understanding of the pharmacology, pharmacodynamics, and pharmacokinetics of this novel compound is essential for appropriate prescribing and monitoring of bortezomib therapy. Bortezomib is rapidly distributed into tissues after administration of a single dose, with an initial plasma distribution half-life of less than 10 minutes, followed by a terminal elimination half-life of more than 40 hours. Maximum proteasome inhibition occurs within 1 hour and recovers close to baseline within 72 to 96 hours after administration. Bortezomib is primarily metabolized by oxidative deboronation to one of two inactive enantiomers that are further processed and eliminated, both renally and in bile. Bortezomib has been shown to be a substrate of several cytochrome P450 isoenzymes using in vitro systems. Adverse effects of bortezomib are generally mild and effectively managed with supportive care. Bortezomib should be administered with caution to patients with preexisting fluid retention and patients with baseline platelet counts of less than 70,000/microL. Dose reductions are recommended for patients experiencing peripheral neuropathy, grade 3 or higher nonhematologic toxicities, or grade 4 hematologic toxicities. Formal drug interaction studies have not been performed, but bortezomib has been administered in combination with a variety of antitumor agents without significant alterations to its pharmacokinetic or pharmacodynamic profile.

Animals↗