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The American Society of Clinical Oncology (ASCO) has released a position statement calling for the removal of all barriers to high quality end-of-life care. ASCO's recommendations include greatly expanded access to care, more intensive training, and increased research attention to the problem.
The statement, entitled "Cancer Care During the Last Phase of Life," developed over the last year by a 20-member panel of oncologists and other cancer professionals, identifies the leading barriers to providing high quality end-of-life care, and the specific steps needed to improve care for the nearly 50% of cancer patients who do not survive the disease.
The statement is published in the May issue of ASCO's Journal of Clinical Oncology. It does not take an official position on physician-assisted suicide, citing widely varying beliefs in the professional community and the public. ASCO maintains that physician-assisted suicide remains an extremely rare event, and often results from inadequate pain control or depression—symptoms that can and should be relieved through better palliative care and psychosocial support.
ASCO also released the results of a survey of its members at the Society's annual meeting May 16-18, 1998, in Los Angeles. The survey of physician practices in caring for the terminally ill will address topics ranging from pain management to physician-assisted suicide.
"Most people when nearing death want empathetic care that preserves their dignity," said Robert Mayer, ASCO president, who has emphasized the need for improved end-of-life care during his presidency. "It is oncologists' professional responsibility to care for patients from diagnosis throughout the course of illness, including the last phase of life. Better physician education, greatly expanded research on end-of-life care, and relief from the economic burden of caring for the terminally ill must be aggressively addressed."
The ASCO position statement identifies the most significant obstacles to improving end-of-life care of cancer patients, and proposes a series of remedies:
Remove Economic Barriers:
Physician-Assisted Suicide Infrequent, Points to Inadequate End-of-Life Care:
Better Educate Physicians:
Greatly Expand Investigative Efforts into Physical, Psychosocial, and Socioeconomic Issues:
Expand and Support Hospice Programs:
FDA Accelerated Approval Given Xeloda, Oral Breast Cancer Drug
Hoffmann-La Roche Inc. of Nutley, NJ, received an accelerated U.S. Food and Drug Administration approval for Xeloda (capecitabine), making it the first approved oral anticancer drug for metastatic breast cancer resistant to standard chemotherapy with paclitaxel and an anthracycline-containing regimen.
In a phase II trial, Xeloda was shown to reduce tumor size by more than 50% in one out of four (11/43) patients with hard-to-treat tumors, the company said. Xeloda's phase II multi-center trial involved 162 patients with metastatic breast cancer.
As a condition of accelerated approval, Roche has agreed to continue ongoing studies to confirm clinical outcomes.
The FDA decision was based on a subset of 43 patients resistant to paclitaxel and an anthracycline-containing regimen. In that subset, the response rate was 26.5%, the company said. The overall results showed that 18.5% of patients experienced a reduction in tumor size of more than 50%, and a single patient experienced a complete remission, the company said.
"Xeloda is a significant advance in the treatment of metastatic breast cancer," said Linda Vahdat, assistant professor of medicine and director of the autologous transplant program for breast cancer at Columbia-Presbyterian Medical Center. "At last, patients can take an effective pill, in their homes, to treat their cancer."
"Patients often associate chemotherapy with hair loss and bone marrow suppression, which can have a serious impact on a person's quality of life," said Thomas Griffin, medical director of oncology at Roche. "We anticipate that Xeloda will help redefine chemotherapy." Xeloda caused minimal hair loss and limited bone marrow depression, the company said.
The most frequently reported side effects included diarrhea, nausea, vomiting, stomatitis, fatigue, and hand-foot syndrome (palms of the hands or soles of the feet tingle, become numb, painful, swollen, or red). These side effects were generally manageable and reversible after dosage adjustment, the company said.
According to the company, the drug was associated with serious risks such as severe diarrhea (gastrointestinal side effects greater in patients older than 80), and some grade 3 or 4 neutropenia (4%), thrombocytopenia (2%), and decreases in hemoglobin (3%), and may cause fetal harm when given to a pregnant woman.
FDA Approves Neupogen for Post-Chemo Use in AML
Amgen Inc. of Thousand Oaks, CA, said Neupogen (filgrastim), a granulocyte colony-stimulating factor, was approved by the FDA for a fifth indication, reducing the time to neutrophil recovery and the duration of fever following chemotherapy treatment in patients being treated for acute myelogenous leukemia.
European Union member states have also agreed to authorize Neupogen for use in AML patients, although local approvals are still pending. The U.S. approval covers use in both the induction and consolidation phases of chemotherapy for all adult patients, as does the European approval. The license extension broadens the indications of Neupogen to cover the reduction of neutropenia in patients treated with myelosuppressive chemotherapy for all solid tumors and AML.
In the trial, Neupogen improved the ability of patients with AML to tolerate treatment while maintaining the overall survival benefits of chemotherapy, the company said.
Last July, the FDA Biological Response Modifiers Advisory Committee unanimously recommended approval for the new indication.
In data submitted to the FDA, Neupogen, compared to placebo, was shown to decrease the duration of neutropenia from 19 days to 14 days. The data were derived from a double-blind, randomized, placebo-controlled, phase III trial of 521 people treated at 31 centers. In the study, Neupogen also reduced the median number of days of fever from 8.5 days to 7 days.
Use of Neupogen following induction chemotherapy also produced a number of cost savings, the company said. The median number of days of hospitalization was 20 days (versus 25 days), and the median number of days of non-prophylactic antibiotics was 15 days (versus 18.5 days) in patients receiving Neupogen as compared to placebo.
In the phase III trial, adverse events in both the Neupogen and placebo groups were typical of those generally seen in this patient population undergoing intensive chemotherapy, the company said. The frequency of all reported adverse events was similar in both Neupogen and placebo groups (83% versus 82% in induction 1; 61% versus 64% in consolidation 1), respectively. Adverse events reported more frequently in the Neupogen-treated group included: petechiae (17% versus 14%), epistaxis (9% versus 5%), and transfusion reactions (10% versus 5%). There were no significant differences in the frequency of these events, the company said.
"This action by the FDA is significant for patients as well as health care providers," said Marshall Lichtman, executive vice president of research and medical programs for the Leukemia Society of America. "Growth factors represent an important advance in enabling AML patients to decrease the infection-related risks associated with their chemotherapy treatments."
Schering Licenses Sparta's Drug Delivery Technology
Schering-Plough Corp. has licensed a drug delivery technology developed by Sparta Pharmaceuticals Inc. of Horsham, PA. Spartaject, the delivery technology, will be applied to Schering-Plough's oral anticancer agent, Temodal (temozolomide), which is currently in development for the treatment of patients with recurrent malignant gliomas, such as gliobastoma multiforme and anaplastic astrocytoma.
The Spartaject technology encapsulates fine particles of a specified insoluble drug with a fatty (phospholipid) layer, permitting the creation of a suspension of the drug, and allowing its intravenous injection without the use of potentially toxic solubilizing agents, the company said.
Sparta originally licensed the technology from RTP Pharma of Montreal. Currently, phase I trials are under way in the U.S. and the U.K. using Spartaject busulfan, a product developed by Sparta.
Schering-Plough has exclusive worldwide rights to market temozolomide through a licensing agreement with Cancer Research Campaign Technology Ltd., of the U.K.
Sparta said application of Spartaject to Temodal may allow for intravenous administration in patients who require high concentration levels in the blood or for the administration of Temodal in localized areas in direct contact with certain tumors.
In a related development, Sparta announced pharmacokinetic results of an ongoing Spartaject busulfan phase I clinical trial.
The study was presented by Lori Hollis, Louise Grochow and colleagues at Johns Hopkins University School of Medicine and Duke University at a meeting of the American Association for Cancer Research. Patients in the study are being treated with a new intravenous form of busulfan for bone marrow ablation prior to bone marrow transplantation. Busulfan is currently available only in tablet form.
According to the company, busulfan (oral) and Spartaject busulfan (i.v.) were administered to patients in the study, and safety and bioavailability at low and high dose were assessed. No unexpected toxicities were noted, and busulfan blood levels were less variable after Spartaject busulfan than after oral busulfan, the company said.
Zeneca to Develop AnorMED Anticancer Agent AMD473
AnorMED Inc. of Langley, British Columbia, agreed to license to Zeneca Ltd. of Wilmington, DE, its anticancer agent AMD473, the companies said. The exclusive agreement will allow Zeneca to further develop and commercialize the drug.
AMD473 is a third-generation platinum compound which has shown activity against cisplatin- and carboplatin-resistant tumors in animal studies. The agent has potential to treat tumors in humans which have proved resistant to existing treatments, the companies said. Possible targets include non-small cell lung carcinoma, and ovarian, lung, colorectal, and bladder cancers. Phase I trials began in late 1997.
Under the agreement, Zeneca made an initial payment to AnorMED in consideration for patent rights, recognizing AnorMED's research and early development efforts, the companies said.
Additional milestone payments will be linked to the achievement of development and commercialization targets. The agreement includes provision for the payment of royalties, which will vary according to the level of product sales achieved. Zeneca will assume responsibility for the worldwide development and commercialization of this promising anticancer agent, the companies said.
"AMD473 provides a significant opportunity to add another novel cytotoxic agent to Zeneca's broadening development portfolio in the oncology area," said Richard Auty, research and development director for Zeneca Pharmaceuticals. "We believe that AMD473 has exciting potential for the treatment of a range of tumors and, to realize that potential, it was important that this compound be licensed for clinical development and commercialization to an appropriate major pharmaceutical company," said Michael Abrams, CEO of AnorMED.
Phase III Trial Finds 37% of Kaposi's Sarcoma Patients Respond to Panretin
Ligand Pharmaceuticals, Inc. of San Diego, CA, announced the unblinding and analysis of the final results of an international phase III trial for Panretin gel in 134 patients with AIDS-related Kaposi's sarcoma (KS). In the final analysis of the trial data, 37.1% of patients (23/62) treated with Panretin gel experienced complete or partial response, compared to 6.9% of patients (5/72) using a placebo (vehicle gel with no active ingredient), producing a p-value of 0.00003, the company said.
The company said that based on the results of both the North American and international phase III trials, the company intends to file an NDA by the end of May. The company said Panretin gel would be the first NDA submitted to the FDA for a topical product to be used in the treatment of KS. "We believe the additional positive information from the final results of this pivotal phase III trial provides significant added strength to an already strong first NDA submission," said David Robinson, Ligand chairman, president and CEO.
The trial was stopped early in August 1997 at 82 patients because a planned interim analysis specified in the protocol showed a 42% (15/36 patients) response to Panretin gel compared with a 7% (3/46 patients) response to placebo.
The p-value of the interim analysis was 0.00027, and the p-value of the final analysis is 0.00003, making the results statistically similar and strongly positive, the company said. These results were consistent with the final results of the North American phase III trial of Panretin gel in KS, which were reported in December 1997, and with the final and interim data from that trial, which will be presented in June at the 12th International AIDS Conference in Geneva.
"We have treated approximately 450 KS patients to date, and the results of all of our clinical trials with Panretin gel in KS have been consistent and demonstrate the activity of Panretin gel in AIDS-related Kaposi's sarcoma," said Steven Reich, Ligand senior vice president, clinical research.
The trial was a randomized, double-blind, placebo-controlled, 12-week study of topical Panretin gel in the treatment of cutaneous AIDS-related KS, the company said. The protocol for the international trial called for patients to be treated with either a 0.1% gel formulation of Panretin or placebo vehicle gel, applied twice daily to cutaneous KS lesions for 12 weeks. Patients were seen for assessment at 2, 4, 8 and 12 weeks after trial entry and responses were defined using AIDS Clinical Trial Group criteria applied to topical therapy of designated KS index lesions. After 12 weeks, qualifying patients could continue treatment with open-label Panretin gel on a separate protocol.
The international phase III trial included 134 patients in the final analysis, the company said. The trial, conducted at approximately 30 centers in the U.S., the U.K., France, Germany and Australia, began in September 1996.
"Panretin gel was very well tolerated and was associated with a fivefold improvement in response rate when compared to vehicle gel in the international phase III trial," said Neil Bodsworth, of Taylor Square Private Clinic of Sydney, Australia, a clinical investigator for the study.
Results of the phase III North American trial demonstrated that 35.1% (47/134) of patients treated topically with Panretin gel experienced complete or partial response compared to 17.9% (24/134) of patients using a placebo, a result that was statistically significant at a p-value of 0.002.
Rockefeller University Licenses Gene Rights To Myriad
Myriad Genetics Inc., of Salt Lake City, UT, and Rockefeller University have entered into an agreement under which Myriad will have the exclusive rights to certain genes involved in the control of cancer cell growth and will investigate their role in human cancer, the company announced. Myriad has received a worldwide, exclusive license to all therapeutic and diagnostic products developed through this investigation.
Myriad's track record in discovery and sequencing of important cancer genes includes both the BRCA1 and BRCA2 breast and ovarian cancer genes, the MTS1 melanoma gene, the MTS2 and MTS3 cell-cycle control genes and the MMAC1 and MMSC1 brain cancer and metastatic cancer genes.
Myriad discovers and commercializes genes involved in major common disorders, including cancer. The company licenses non-exclusive access to its ProNet database to pharmaceutical companies, and is involved in strategic alliances with Schering-Plough, Novartis, Bayer, and Eli Lilly and Co.
Bristol-Myers Squibb and Seattle Genetics Announce Agreement
Bristol-Myers Squibb Co. (BMS), of Princeton, NJ, and Seattle Genetics Inc., of Seattle, WA, announced an agreement in which a monoclonal antibody-based cancer targeting program started by Bristol-Myers Squibb will be licensed to Seattle Genetics.
According to the companies, BMS will receive a one-time licensing fee from Seattle Genetics for tumor targeting compounds and technology. Among the tumor targeting compounds is an immunotoxin which had advanced into clinical trials. BMS also will receive royalties on any resulting marketed products.
Seattle Genetics is a biotechnology company founded by two former BMS scientists, H. Perry Fell and Clay Siegall.
CellPro Expands Use of Ceprate
CellPro Inc., of Seattle, WA, said the FDA has issued an approvable letter to expand the uses of the Ceprate SC Stem Cell Concentration System to include selection of peripheral blood progenitor cells and tumor purging.
In the letter, the FDA stated that CellPro's application for an expanded label is approvable subject to a commitment to submit long-term, follow-up data on patients enrolled in CellPro's completed phase III trial and a European phase III trial, as well as submission of final labeling, the company said.
The FDA decision was based on data presented March 24, 1998, to the FDA Biological Response Modifiers Advisory Committee. The data from a multi-center, randomized phase III trial involving 131 multiple myeloma patients demonstrated a greater than 100-fold reduction of tumor cells, the company said. The trial also met its primary safety endpoint of demonstrating equivalent neutrophil engraftment.
Dendreon and Fresenius Critical Care International Form Partnership
Dendreon Corp., of Mountain View, CA, and Fresenius Critical Care International announced the signing of a corporate partnership to market and distribute worldwide the DACS 300 system developed and manufactured by Dendreon. Fresenius Critical Care is a unit of Fresenius Medical Care AG, based in Bad Hamburg, Germany.
The DACS 300 system facilitates the preparation of CD34+ cells from peripheral blood, Dendreon said. This cell population contains the hematopoietic stem cell which reconstitutes a patient's immune system following high-dose chemotherapy.
GenVec and Asahi Enter Into Gene Therapy Agreement
GenVec Inc., a privately held biotechnology company in Rockville, MD, said it has licensed U.S. rights for all gene therapy applications of the tumor necrosis factor alpha (TNF-
) gene from Asahi Chemical Industry Co., Ltd. of Tokyo.
The companies said preclinical studies have shown that TNF- delivered by gene therapy and used in combination with radiation treatment disrupts the tumor's blood vessels.
"GenVec will pursue the development of TNF- gene-based pharmaceuticals for use in combination with radiation therapy," said Paul Fischer, GenVec president and CEO. He said the initial clinical studies will be conducted in collaboration with Varian Associates Inc., through Varian Biosynergy subsidiary, a manufacturer of medical linear accelerators and related radiotherapy products for the treatment of cancer. In March, 1998, GenVec entered into a collaborative agreement with Varian for the conduct of preclinical and clinical research.
Matritech Expands Market of Bladder Cancer Test Kit
Matritech Inc., of Newton, MA, announced that it has reached an agreement on marketing and product purchase terms relating to the Matritech NMP22 Test Kit for bladder cancer with the Barcelona-based subsidiary of Organon Teknika for distribution of the product in Spain and Portugal.
The test kit detects a nuclear matrix protein found in human epithelial cells. The majority of patients with bladder cancer have been shown to release large quantities of NMP into their urine. In 1996, FDA approved the product for sale in the U.S.
Xerecept Qualifies for FDA Orphan Drug Designation
Neurobiological Technologies Inc., of Richmond, CA, announced that it has received notification from the FDA that Xerecept, the company's synthetic preparation of human Corticotropin-Releasing Factor, qualifies for orphan drug designation.
The company is enrolling patients in a randomized, double-blind, positive-controlled phase II trial to evaluate Xerecept's ability to control neurological symptoms caused by peritumoral brain edema.
Gliadel Wafer Approved for Marketing in Argentina
Rhône-Poulenc Rorer, a subsidiary of Rhône-Poulenc S.A., of Collegeville, PA, and Antony, France, said it has received approval to market Gliadel Wafer (polifeprosan 20 with carmustine implant) in Argentina for the treatment of recurrent malignant glioblastoma multiforme. The company said it filed for market clearance in France and Israel.
Gliadel is available in the U.S. and Brazil for use as an adjunct to surgery for patients with recurrent glioblastoma multiforme.
Novartis Institute for Functional Genomics
Novartis Research Foundation of Basel, Switzerland, announced the formation of the Novartis Institute for Functional Genomics, a research institute devoted entirely to functional genomics.
"Through close interaction with our external partners, such as The Scripps Research Institute and other academic groups, we will have the ability to work simultaneously on a large number of known genetic links, thereby accelerating the pace of our discovery efforts," said Daniel Vasella, president of Novartis.
The institute will house 20 laboratories dedicated to functional genomics research, including molecular epidemiology, molecular and structural biology, bioinformatics, combinatorial chemistry, high-throughput screening, proteomics, model organisms including transgenics, and differential expression. Work will focus on genetic pointers from both the public domain and external partners, as well as on unpublished genes discovered in-house at Novartis.
The institute will receive a total investment of $250 million, the company said. The institute will be built adjacent to The Scripps Research Institute in La Jolla, CA. Building is scheduled to begin in 1998, with completion anticipated in 1999.
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