Clinical Trials News

A New Option For The Treatment Of Malignant Pleural Mesothelioma (MPM)

2010-10-14T08:27:00.000-07:00

Raltitrexed (Tomudex®) in combination with cisplatin in the treatment of MPM improves median overall survival compared to treatment with cisplatin alone.1 With incidence rates expected to double over the next 20 years in many countries2, new and effective treatments are a welcome addition, concluded an eminent panel of international speakers at a symposium sponsored by Hospira at the 35th congress of the European Society for Medical Oncology (ESMO), Milan

Mesothelioma Medical Information

2008-11-23T10:39:00.000-08:00

Malignant mesothelioma is an aggressive but rare malignancy that principally affects the pleura and peritoneum. The pleura and peritoneum are lining that cover the lung (pleura) and the abdominal cavity (peritoneum). In recent years, a steady proportional increase in pleural tumors has been matched by a proportional decrease in peritoneal tumors. Roughly 80% of cases are believed to derive from occupational or paraoccupational exposure to primary asbestos fiber types (thus the high mesothelioma asbestos claim numbers); namely, crocidolite, amosite, and chrysotile in a ratio of 500:100:1, respectively, and, less commonly, by exposure to tremolite (which has little commercial value and is therefore mined in limited quantities). These are the cases most associated with mesothelioma lawsuits and claims across the country requiring the assistance of a mesothelioma lawyer. According to recent mesothelioma statistics from Great Britain's Health and Safety Executive's Epidemiology and Medical Statistics Unit, risk appears to be highest among workers associated with the following broad areas of asbestos use: shipbuilding, railway carriage and locomotive building, and installation/maintenance of insulation materials in buildings or industrial plants.

Epidemiologic Trends
Malignant mesothelioma develops after a long latency period that averages a mean of 32 years. Proportionally greater numbers of males vs females are affected (ratio approximately 3:1), and incidence follows a pattern that is defined by age and date of birth; this pattern parallels trends in asbestos exposure and associated changes in industrial consumption/use of asbestos fibers throughout the 20th century. Between 1973 and 1999, a total of 5266 mesothelioma cases were reported in the United States, at an average incidence rate of 0.97 per 100,000 people, and a higher overall incidence for men vs women (1.8/100,000 vs 0.4/100,000, respectively). Analogous to age-adjusted patterns, rates were nearly 50% higher in the 1980-1984 period compared with the 1975-1979 period, with the cohort effect peaking for males born between 1905 and 1909. Given exposure associations, the overall rate in females is unsurprisingly flat, and the estimated lifetime risk for women is 2.5 per 10,000 people. Because the use of asbestos has been banned in the United States since the 1970s, the number of male cases is expected to drop significantly during the next 50 years.
By contrast, during the same time period when asbestos was banned in the United States, asbestos imports were peaking in the United Kingdom. This accounts for the currently increasing incidence rate, from a current total of 1300 cases annually to a projected total of more than 3000 cases annually by the year 2021. In Western Europe -- specifically, Britain, France, Germany, Italy, The Netherlands, and Switzerland, which account for 75% of the entire Western European population -- asbestos use remained high until 1980, and substantial quantities are still used in several countries.

Summary and Conclusions
Although malignant mesothelioma has long been considered one of the more uncommon cancers in the Western hemisphere, a steady increase in case numbers, particularly in the United Kingdom, has created an urgency to find new treatments that offer fewer toxicities, better symptom control, increased antitumor activity, improved survival, and better overall QOL. Until recently, these goals remained elusive, and the strength of the evidence supporting any single treatment modality was weak.
Fortunately, the tide appears to be turning and the sense of nihilism surrounding mesothelioma treatment is dissipating. Greatly encouraging results from clinical trials suggest that combination chemotherapy utilizing at least one novel agent has an important, definitive role in disease management. At present, phase 3 data demonstrating significant improvements in survival, favorable tolerability, good antitumor activity, and increased QOL support the use of pemetrexed plus cisplatin as first-line therapy for malignant pleural mesothelioma. Other combinations, including gemcitabine plus cisplatin or carboplatin, and raltitrexed plus oxaliplatin, may, likewise, become standard therapy in the near future.
As mesothelioma information continues to mount that more firmly establishes the role of combination chemotherapy, researchers are beginning to make inroads into greater understanding of the biology of mesothelioma. Ultimately, new insights may provide novel therapeutic targets and a means to further improve outcomes.

Non Smoking Area

2008-09-13T05:30:00.000-07:00

Taking Opposite Approach To Treat Asthma

2008-04-11T03:50:00.000-07:00

One month of tough breathing may help asthma sufferers breathe easier in the long run, according to research from one University of Houston professor.

In a move that challenges one of the most basic tenets of the Hippocratic Oath - first do no harm - Richard Bond, associate professor of pharmacology at UH, is relying on a long-standing medical taboo to treat asthma. Although counterintuitive, Bond's studies are reminiscent of hair-of-the-dog folk wisdom to treat like with like, in this case using beta blockers (or antagonists) instead of stimulants (or agonists) in asthmatics.

Coining the term "paradoxical pharmacology" - treating patients with medicine that initially worsens their symptoms before eventually improving their overall health - Bond first applied this hypothesis in studies with mice and then moved on to two clinical trials with humans. Currently in the second clinical trial, the part of this research analyzing mice was recently published in the American Journal of Respiratory Cell and Molecular Biology, which cited the relevance of Bond's work as possibly leading to a paradigm shift in the treatment of asthma. The results of the first human trial were also recently published in Pulmonary Pharmacology and Therapeutics.

Acute asthma attacks have traditionally been treated with inhaler-type stimulant drugs that open constricted airways. Giving beta blockers to asthmatics has long been thought to be contraindicated, because their acute use may cause increased airway resistance. While the use of beta-stimulants is known to provide temporary relief, their effectiveness declines over time.

Bond's tests initially done on asthmatic mice and later replicated in his first clinical trial with humans showed that while beta blockers initially made breathing problems worse, their continued use resulted in improved respiratory function after a 28-day period. These longer-term effects demonstrate that chronic use of beta blockers alleviates asthma by helping the smooth muscle lining the airways to relax and dilate, thereby allowing air to flow more freely.

"In order to move certain ideas forward, science often needs to be a collaborative effort," Bond said. "You must find the right people willing to act as a team. I have been very lucky in that people have given my ideas a chance."

Enlisting the help of some pulmonologists in the Texas Medical Center, Bond collaborated with Dr. Nick Hanania at The Baylor College of Medicine on both human trials. Also, Dr. Burton Dickey, chair of the department of pulmonary medicine at M.D. Anderson Cancer Center, and his colleagues decided to assist Bond's research efforts when the mouse studies showed that chronic beta-blocker treatment has significant anti-inflammatory effects.

Using beta blockers when it seems a stimulant is called for defies medical dogma, but this is not a new concept. Bond's work builds on an earlier breakthrough in treating congestive heart failure (CHF), in which case patients had been treated for decades with stimulant drugs to increase cardiac output. Beta blockers were prohibited because they initially further reduced the heart's pumping power, but the stimulants ultimately caused the heart to wear out over time from the increased activity.

About a decade ago, the thinking on beta-blocker therapy was reversed when researchers discovered that although treatment with beta blockers reduced cardiac activity at first, the prognosis reversed itself after two to three months. This treatment shift reduced the mortality rate among CHF patients by up to 65 percent.

"Decades of conventional wisdom were overturned, and beta blockers replaced stimulants as the top drug for CHF patients," Bond said. "For 30 years, intellect told us that beta blockers wouldn't work to treat these patients, and unfortunately millions of heart patients died prematurely. It would be a tragedy to not have learned from that lesson."

With his work based on this precedent, Bond points out that beta blockers are not the only example of paradoxical pharmacology. Hyperactive children are treated with the amphetamine-like Ritalin®, and the skin irritant retinoic acid is used to treat acne. Additionally, there has been research into using antipsychotic drugs traditionally used for schizophrenic patients to decrease the incidence of Alzheimer's disease by suppressing the dopamine system, which is hypoactive in such neurodegenerative diseases. These examples further the case for investigating paradoxical approaches like Bond's.

In Bond's first clinical trial, he and his colleagues saw similar results in humans to what was seen in the mouse models. Mild asthmatics were treated for nine weeks with the beta blocker nadolol, with all subjects tolerating the drug and 80 percent experiencing a reduction in airway hyperresponsiveness. Laying the groundwork for continuing studies with beta blockers in the treatment of asthma, the results suggest there may be a way to counteract some of the negative aspects of traditional treatments.

"The principle that certain pharmacological compounds have different effects depending upon whether they are given for long or short periods has been demonstrated," Bond said. "And even if I am correct about beta blockers ultimately being used in the treatment of asthma, there probably always will be a need for the inhaler-type agonist drugs to handle acute asthma attacks. I do believe, though, that beta blockers hold promise in a maintenance or preventative regimen that could reduce the number or severity of attacks and improve a patient's quality of life."

This research has received funding from the National Institutes of Health, as well as from two San Francisco-based organizations - a private biotechnology company called Inverseon and the philanthropic Sandler Program for Asthma Research. As the scientific founder of Inverseon, Bond leads a distinguished panel of scientists on the company's advisory board, including Nobel Laureate in Medicine Sir James Black, who is considered the "father of beta blockers."

"If we continue down this path, replicating these results, this paradoxical approach to asthma treatment may well become an important new approach to asthma therapy," said Dr. William J. Garner, CEO of Inverseon. "We've already engaged in discussions with major pharmaceutical companies about taking this to the next level and are actively seeking additional funding for eventual product development."

MedImmune Advances Clinical Development Of Antibody Targeting Interleukin-9 In Patients With Asthma

2008-03-21T05:37:00.000-07:00

MedImmune announced that its clinical program studying an investigational treatment targeting interleukin-9 (IL-9) has advanced with the start of a new trial in patients with asthma. The company initiated a Phase 2a clinical trial designed to assess the potential of its anti-IL-9 monoclonal antibody (MAb), MEDI-528, in patients with stable asthma and exercise-induced bronchoconstriction. This trial is the fourth study of this antibody in patients with asthma.

"Commencing this trial is a promising step in the clinical development of MEDI-528, as preclinical data has suggested that blocking IL-9 may provide clinical benefit for patients with asthma," said Barbara White, vice president, clinical development, inflammatory disease. "We look forward to continuing to work with our network of collaborative researchers to discover and assess novel pathologies and approaches to inflammatory diseases."

The goal of this clinical trial is to assess the safety and tolerability of multiple fixed escalating doses of MEDI-528 in adult patients with stable asthma and exercise-induced bronchoconstriction. The study will also assess the effect of the antibody on exercise challenge testing, as well as the pharmacokinetics and immunogenicity of the investigational treatment. Enrollment of this randomized, double-blind, placebo-controlled trial has commenced at Northeast Medical Research Associates, Inc. and the study is expected to expand to additional sites throughout the United States and Canada. Preliminary safety results from an ongoing Phase 2 trial support the continued development of the antibody in patients with mild-to-moderate asthma.

About Interleukin-9

IL-9 has been associated with symptoms of asthma. It is one of at least 29 naturally occurring interleukins in the human body. Overexpression of IL-9 in animal models has been shown to result in many features of asthma, including increased airway inflammation and hyperreactivity. Blocking the actions of IL-9 has been shown to reduce the increased airway inflammation and airway hyperresponsiveness seen in animal models of asthma. MedImmune is conducting research to evaluate the potential to use MAbs targeting IL-9 to treat or prevent symptomatic, moderate-to-severe, persistent asthma.

About Asthma

Asthma is a chronic disease of the airways that may cause wheezing, breathlessness, chest tightness and coughing. According to the U.S. Centers for Disease Control and Prevention (CDC), more than 30 million Americans reported having a history of asthma in 2003, including nine million children. About 20 million said they currently had asthma. In 2000, the CDC reported that there were more than 10 million asthma-related outpatient visits to private physician offices and hospital clinics. The National Institutes of Health (NIH) have estimated asthma-related healthcare costs in the U.S. at $14 billion annually.

Results From Phase III Clinical Trial Of Tavocept(TM) For Lung Cancer

2008-03-21T04:53:00.000-07:00

BioNumerik Pharmaceuticals, Inc. ("BioNumerik") and ASKA Pharmaceutical Co., Ltd. ("ASKA") announced the results of a Phase III clinical trial of Tavocept(TM) in patients with advanced non-small cell lung cancer. Tavocept is an investigational new drug with potential for oncology and non-oncology indications that was originated and developed by BioNumerik.

The multicenter, double-blind, randomized, placebo controlled Phase III clinical trial was conducted by ASKA in Japan through the joint venture, KI Pharmaceuticals, Inc., with BioNumerik. The trial included 182 patients with advanced non-small cell lung cancer who received the chemotherapy drugs paclitaxel and cisplatin as first-line therapy every three weeks. Half of all patients in the trial received Tavocept along with their chemotherapy, while the other half received a placebo and chemotherapy. The primary trial endpoint was to evaluate Tavocept's potential for preventing and reducing the severity of sporadic and cumulative nerve damage, or neuropathy, experienced by patients receiving paclitaxel and cisplatin chemotherapy.

The trial results indicate that the number of patients reporting either severe sporadic or cumulative neuropathy was approximately 50% lower in the Tavocept arm of the trial compared to the placebo arm. While this outcome represents a strong trend in favor of Tavocept (p = 0.1565), the results are not statistically significant (p < 0.05). BioNumerik and ASKA believe the lack of statistical significance is likely due to the relatively small size of the trial.

A surprising and medically important observation from the trial was an observed increase in the median survival time for patients receiving Tavocept as compared to those receiving placebo. The median survival time observed for patients receiving Tavocept was approximately 40 days longer than for patients receiving placebo. For patients with adenocarcinoma, the most frequently occurring type of lung cancer, the median survival time was increased by approximately 138 days for patients receiving Tavocept as compared to those receiving placebo.

Frederick H. Hausheer, M.D., Chairman & Chief Executive Officer of BioNumerik, and Chairman of KI Pharmaceuticals, Inc. stated: "We are encouraged by the observed evidence of Tavocept's potential to protect against sporadic (i.e. intermittent) and cumulative chemotherapy-induced neuropathy. The observed survival benefit in this patient population along with significant reductions in renal toxicity, vomiting and anemia further support our belief in this drug's therapeutic potential. We observed that a substantial proportion of the patients from the trial are still alive and we will continue to monitor the survival of these patients. We believe that this Phase III trial outcome is an important step towards the validation of our approach to cancer drug discovery and development."

Hashime Kanazawa, Ph.D., Executive Director of ASKA, and President of KI Pharmaceuticals, Inc. stated: "We are pleased with this result, particularly the multiple statistically significant findings that were observed. This data will be the basis for further studies, which we intend to pursue expeditiously. We are currently in the process of reviewing a number of additional Tavocept clinical trial designs."

Additional observations from the trial included a statistically significant reduction in cisplatin-induced kidney damage (nephropathy) and a statistically significant reduction in chemotherapy-induced vomiting for patients receiving Tavocept in comparison to those receiving placebo. There were also substantially fewer instances of physician chemotherapy dose reductions, treatment delays or discontinuance of chemotherapy treatment due to neuropathy in the Tavocept arm of the study, compared to the placebo arm. Patient quality of life questionnaire scores were more favorable in the Tavocept arm of the study.

The trial results also included substantial evidence of the potential ability of Tavocept to maintain or stimulate hematological function in the body, as well as the potential to mitigate or prevent chemotherapy-induced anemia and to maintain or stimulate erythropoietin function or synthesis. Erythropoiesis is the process by which red blood cells are produced, and involves the release of a hormone called erythropoietin that stimulates the red bone marrow to begin red blood cell production.

In commenting on the observations from the trial, Ross C. Donehower, M.D., Director of Medical Oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Professor of Oncology and Medicine at the Johns Hopkins University School of Medicine; and a member of BioNumerik's Scientific Advisory Board stated: "This is the culmination of years of hard work and commitment on the part of BioNumerik leadership and employees, as well as the investigators and AKSA Pharmaceutical Co. It has the potential to improve cancer therapy and decrease toxicity in a meaningful way. It is a very exciting result."

Michael C. Perry, M.D., M.A.C.P., Professor of Hematology and Medical Oncology, Nellie B. Smith Chair Emeritus, Ellis Fischel Cancer Center, University of Missouri-Columbia; and a member of BioNumerik's Scientific Advisory Board, stated: "Multi-center randomized, double-blind, placebo- controlled phase III trials such as this one are usually regarded as the 'gold standard' for proving the efficacy of drugs in oncology. In this study of patients with advanced non-small cell lung cancer, the standard chemotherapy regime of paclitaxel and cisplatin was combined with Tavocept or placebo to evaluate Tavocept's potential for reducing troublesome peripheral neuropathy. There was an approximately 50% decrease in severe sporadic or cumulative neuropathy, not statistically significant, probably due to the study's size. Other side effects such as kidney damage and chemotherapy-induced vomiting were also less in Tavocept treated patients. Unexpectedly, there also was a longer median survival for patients receiving Tavocept, especially for patients with the adenocarcinoma subtype, the most common type of lung cancer in the United States. The findings of increased efficacy combined with decreased toxicity are very encouraging, but these results will require verification in other studies."

Previous Phase III clinical trials for Tavocept measured neuropathy only in terms of cumulative neuropathy and they were inconclusive. BioNumerik and ASKA believe the results from this trial demonstrate that chemotherapy-induced neuropathy is both sporadic and cumulative; a hypothesis that this trial tested prospectively in a multicenter, double-blind, placebo controlled setting.

BioNumerik has granted KI Pharmaceuticals, Inc. the exclusive right to develop, market, distribute and sell Tavocept in Japan. BioNumerik holds exclusive rights to Tavocept for territories outside of Japan.

Sorafenib (Nexavar) Dropped From Lung Cancer Trial

2008-02-19T04:31:00.000-08:00

Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals have stopped a late stage trial of their cancer drug Nexavar (sorafenib) in patients with nonsmall-cell lung cancer (NSCLC), because it was not showing the hoped for increase in survival.

Following a planned interim analysis, the trial's independent data monitoring committee (DMC) concluded that the drug was not going to meet the trial's main goal of improving overall survival.

In the phase 3 trial, a group of patients with squamous cell carcinoma of the lung who took the drug in combination with chemotherapy drugs carboplatin and paclitaxel showed a higher rate of death than a group that received chemotherapy alone.

The trial, which is called ESCAPE (Evaluation of Sorafenib, Carboplatin And Paclitaxel Efficacy in NSCLC), was otherwise showing safety events generally in line with those previously reported, said Bayer in a press statement.

The two drug companies are giving the DMC information to health authorities and other investigators studying the effects of Nexavar and will also be presenting the findings of the trial at a forthcoming scientific meeting.

The companies will also be reviewing the findings of this trial, including the DMC review, to see if they impact any other ongoing lung cancer trials using Nexavar.

Vice president of Therapeutic Area Oncology at Bayer HealthCare Pharmaceuticals, Dr Susan Kelley said that they were disappointed with this result, but the two companies were still very much committed to widening the scope of Nexavar in treating as many cancers as possible and will continue to extend trials to other cancers.

"Nexavar has proven significant clinical benefit for patients with liver cancer and advanced kidney cancer and we will continue to investigate its potential across a wide variety of tumors," said Kelley.

The ESCAPE study was a multicentre, randomized, double-blind, placebo controlled phase 3 trial involving more than 900 NSCLC patients at over 140 clinics in North and South America, Europe and Asia.

The main outcome sought was overall survival, but secondary endpoints included progression-free survival, tumour response, quality of life, and drug safety.

The participants had not received any systematic anti-cancer treatment for lung cancer before the trial, which was open to patients with all types of NSCLC, including squamous cell carcinoma or adenocarcinomas.

The patients were randomized to a drug group and a control (placebo) group. The drug group was given 400 mg of Nexavar, orally, twice a day, while the control group had a placebo. Both groups also had two chemotherapy drugs, carboplatin and paclitaxel. Both groups continued with the drug or placebo alone, after chemotherapy had finished (maintenance phase), until symptoms of tumour progression or side effects showed.

Nexavar (sorafenib) attacks both the tumour cell and the blood vessels that feed it. In studies before clinical trials, the drug showed ability to target kinase proteins thought to be involved in cell growth and development of blood supply, two essential cancer enablers. The kinases involved include: Raf kinase, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-B, KIT, FLT-3 and RET.

Nexavar is approved for the treatment of liver cancer in over 30 countries and for the treatment of advanced kidney cancer in over 60 countries. It is being evaluated for use with many other cancers such as breast cancer, metastatic melanoma, and as an adjuvant therapy for kidney cancer and liver cancer.