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© 1998 AlphaMed Press
News and Special Reports |
The Oncologists News Bulletin
Intergroup Multiple Myeloma Study: U.S., European Research Groups to Exchange Tumor Specimens for Drug Resistance TestingA collaboration of North American and European researchers may answer the question as to why cancer patients become resistant to drugs. Researchers will share biopsy material from 420 multiple myeloma patients and conduct a phase III double-blind trial comparing standard therapy with and without a multiple drug resistance modulator.
The therapeutic outcome in three years "will lead to novel therapies that target various mechanisms of drug resistance," said William Dalton, of the University of South Florida.
"The most significant problem in curing multiple myeloma today is drug resistance," Dalton said to the American Society of Hematology meeting recently in San Diego. "Despite intensive efforts to improve therapies with combination drugs, we have not been able to improve survival."
Four research groups in the U.S. (CALGB, ECOG, SWOG and the National Cancer Institute) will exchange tumor specimens with two groups in The Netherlands to make sure that they all agree on which patients are drug resistant. This "very unique collaboration is unprecedented, and speaks to the problem we face," Dalton said.
A major attempt has been made to understand drug resistance at the cellular level. The mechanism most understood is p-glycoprotein (P-gp), which was discovered 15 years ago. Most chemotherapy drugs enter the cell by passive infusion. They are pumped out of the cell by P-gp so that they cannot kill cancer cells. Only recently have researchers been able to detect this protein in cancer cells as well as in normal tissue. Now it is known that P-gp is expressed in multiple tissues throughout the body.
P-gp is expressed in the brain and participates in the blood-brain barrier, Dalton said. It also is distributed in the adrenal gland, proximal tubules of the kidney, columnar epithelial cells of the large intestine, biliary canaliculi of the liver and normal blood cells of bone marrow.
"P-glycoprotein is highly expressed in cytotoxic lymphocytes," Dalton said. This MDR protein is not highly expressed in newly diagnosed patients. As patients undergo chemotherapy, "the increase in P-gp is directly related to prior amounts of drugs, which is related to drug resistance clinically," he said. "The question is, can we reverse drug resistance with chemosensitizers by binding P-gp and inhibiting its function?" The intergroup multiple myeloma trial will be pivotal in understanding the relevance of P-gp, Dalton said.
The phase III study includes one of the new, less toxic P-gp inhibitors, PSC-833, in combination with vincristine, doxorubicin and dexamethasone versus VAD alone in patients with relapsing or refractory disease. Previous trials defined the optimum drug doses as oral PSC-833 4 mg/kg four times a day and infusions of vincristine 0.2 mg/day, doxorubicin 7 mg/m2/day and dexamethasone 40 mg/day. Patients will receive PSC-833 one day before and one day after four days of VAD infusion, or VAD alone, once a month for one year.
Myeloma is a good prototype disease to study drug resistance because "we can get tissue sequentially and more readily than with solid tumors," Dalton said. The results will be analyzed for response rates and duration of response.
"The trial will test the ability to eliminate P-gp in patients, and whether this has significant outcome on survival," Dalton said. "If P-gp is expressed, we have to deal with it, either by inhibiting its function with PSC-833 or by developing mechanisms of treatment that bypass P-gp, such as immune therapy using DNA vaccination and passive autoimmunity."
While only 6% of newly diagnosed multiple myeloma patients express P-gp, they have only a 10% remission rate, which means that numerous mechanisms of resistance are in effect, Dalton said. "P-glycoprotein is the most obvious because we know the most about it."
A new drug-resistance protein called LRP (for lung resistance protein) has been demonstrated to be overexpressed in drug-resistant myeloma patients, but whether the expression is the cause of drug resistance remains to be determined, he said. Initial studies indicate that LRP may be overexpressed in patients treated with chemosensitizers. However, these studies need to be confirmed, Dalton said.
The normal, physiologic programmed cell death pathway may not be functioning, and may be a major reason for drug resistance, he said.
FDA Market Approvals
Chiron Corp. of Emeryville, CA, has received FDA approval to market Proleukin (aldesleukin) for the treatment of metastatic melanoma, the company said.
Proleukin is an injectable recombinant form of the naturally occurring immunostimulator interleukin-2 (IL-2), the company said
The approval came less than a month after an advisory committee recommended approval of the therapy. The Oncologic Drugs Advisory Committee voted unanimously on December 19, 1997 to recommend approval of the drug. The supplemental Biological License Application for Proleukin was given priority review status after it was submitted to FDA in April, the company said.
In data presented to the FDA, Chiron reported 16% of 270 patients treated with Proleukin responded to the drug. The company said approximately half of the 16% remains alive over four years after treatment. Six percent of patients treated with Proleukin had a complete response, showing no signs of melanoma for two consecutive observations at least 28 days apart, the company said. Approximately 60% of the patients who achieved a complete response have remained in remission for more than five years with no further treatment, the company said.
Nearly all patients treated with Proleukin experienced serious toxicities, the company said. The majority of adverse events were fully reversible after stopping therapy, the company said.
Proleukin is currently marketed in the U.S., Europe, and Canada for the treatment of metastatic renal cell carcinoma, the company said.
QLT PhotoTherapeutics Inc. of Vancouver, BC, Canada, has received FDA marketing clearance for Photofrin (porfimer sodium) for injection, a photodynamic therapy for the treatment of early-stage, microinvasive lung cancer, the company reported.
FDA followed last year's recommendation by the Oncologic Drugs Advisory Committee to approve Photofrin for the treatment of microinvasive endobronchial non-small cell lung cancer in patients for whom surgery and radiation are contraindicated, and not for the treatment of endobronchial carcinoma in situ.
The company said FDA approval includes clearance for laser systems and a fiber optic used to activate Photofrin. The therapy is administered intravenously and activated by a non-thermal laser light at the tumor site. Necrotic tissue and exudate are removed two days later through a bronchoscope.
Photofrin, marketed exclusively in the U.S. by Sanofi Pharmaceuticals Inc. of New York, has been approved in the U.S. for the treatment of advanced-stage esophageal cancer.
NeoPath Inc. said an FDA advisory committee has unanimously recommended approval of the company's AutoPap System as a primary Pap smear screener.
The Hematology and Pathology Devices Advisory Panel voted to recommend FDA approval of NeoPath's pre-market approval submission, the company said.
The company said the PMA supplement requests approval to use the system as an initial Pap smear screener, identifying slides that may be archived as normal, and abnormal slides that should be manually screened.
Clinton Proposes $1.15 Billion Increase for NIH, Support for Cancer Research
President Clinton's budget proposal for fiscal 1999 will include a $1.15 billion, or 8.5%, increase for NIH over the current budget of $13.6 billion, the White House said.
In his State of the Union address, the President said increased funding for medical research would be a major component of his budget proposal.
"Tonight, as part of our gift to the millennium, I propose a 21st Century Research Fund for path-breaking scientific inquiry—the largest funding increase in history for the National Institutes of Health, the National Science Foundation, the National Cancer Institute," Clinton said in the January 27th address before both Houses of Congress. "I ask you to support this initiative, so ours will be the generation that finally wins the war against cancer, and begins a revolution in our fight against all deadly diseases."
President Clinton did not specify a dollar amount for the funding increase, but a White House background paper obtained by The Cancer Letter following the speech listed the $1.15 billion increase for NIH.
Larger Increases for NCI?
The proposed research fund would provide an increase of more than 50% for NIH over the next five years. "Under the President's proposal, the NIH will devote over $20 billion to biomedical research in 2003," the document said.
It could not be determined how the proposed research fund would be financed. Vice President Al Gore and Health and Human Services Secretary Donna Shalala were to provide further information on the fund. Sources said that at the briefing, Gore would announce that the President's budget includes a 10% increase in funding for cancer research, about 9% of which will be provided to NCI.
The Administration also will propose that funding for cancer research increase 65% over the next five years, beginning with fiscal 1999, for annual increases of 11%, sources said. The bulk of the funds would go to NCI to fund the "extraordinary opportunities" for cancer research in the Bypass Budget.
Coverage for Clinical Trials
In another apparent victory for advocates and researchers, the Administration bill is expected to propose that for the next three years the Health Care Finance Administration cover patient care costs for Medicare beneficiaries enrolled in NIH-sponsored cancer clinical trials.
The demonstration project would be reviewed after two and one-half years by Shalala in consultation with the National Cancer Policy Board. The project could be expanded to include other cancer clinical trials, as well as clinical trials in other diseases.
The demonstration project would cost an estimated $750 million over three years, sources said. The funds would come from the proposed legal settlement between 40 state Attorneys General and five tobacco companies.
In a gesture that appeared to be intended to emphasize the President's support for medical research, NIH Director Harold Varmus was one of 12 guests invited to sit in the VIP box with First Lady Hillary Clinton during the State of the Union address. Varmus sat between the First Lady and Tipper Gore.
Bill of Rights for Medical Consumers
In the speech, the President also outlined his support for a "Consumer Bill of Rights" that would allow patients enrolled in managed care to choose their own physicians.
"Medical decisions ought to be made by medical doctors, not insurance company accountants," President Clinton said.
"I urge this Congress to reach across the aisle and write into law a Consumer Bill of Rights that says this: You have the right to know all your medical options, not just the cheapest. You have the right to choose the doctor you want for the care you need. You have the right to emergency room care, wherever and whenever you need it. You have the right to keep your medical records confidential."
The President also described his proposal for legislation that would prohibit discrimination based on genetic information.
"We must continue to see that science serves humanity, not the other way around," Clinton said. "We must prevent the misuse of genetic tests to discriminate against any American."
President Clinton has previously supported legislation prohibiting insurers from using genetic information to change or deny coverage. Vice President Gore proposed legislation that would prohibit workplace discrimination.
Tobacco Price Proposal
The President proposed raising the price of cigarettes by $1.50 per pack over the next 10 years. Clinton's proposal would affirm the authority of the FDA to regulate tobacco products and impose penalties on tobacco companies that do not meet goals in reducing teen smoking. The proposal also would provide some financial relief to tobacco farmers for loss of income related to reduced smoking.
"Let's pass bipartisan, comprehensive legislation that will improve public health, protect our tobacco farmers, and change the way tobacco companies do business forever," Clinton said. "Let's do what it takes to bring teen smoking down."
Bristol-Myers Sues Immunex over Two Taxol Patents
Bristol-Myers Squibb Co. of Princeton, NJ, filed a suit against Immunex Corp. of Seattle, WA, claiming that Immunex infringed on two U.S. patents related to the drug Taxol (paclitaxel).
The suit, filed January 8, 1998 in U.S. District Court in New Jersey, follows FDA acceptance of an Abbreviated New Drug Application (ANDA) submitted by Immunex for a generic version of paclitaxel.
The Immunex application was accepted for review on October 7, 1997. Under FDA rules, the sponsor of the pioneer drug has 45 days after ANDA acceptance to bring patent infringement action against the sponsor of the generic. The ANDA, submitted in August by Immunex, claims that the BMS patents in question, U.S. Patents No. 5,641,803 and 5,670,537, are invalid and therefore not infringed by Immunex (Cancer Economics, December 1997).
The Bristol-Myers Squibb patents claim "methods for reducing hematologic toxicity in cancer patients undergoing Taxol treatment comprising parenterally administering an antineoplastically effective amount of about 135-175 mg/m2 Taxol over three hours."
Immunex said Bristol's complaint was anticipated when the ANDA was filed.
"The FDA is expected to continue its review of the Immunex ANDA," Immunex said in a statement. "Immunex will work cooperatively with FDA with the hope of providing women with breast cancer better access to therapy through competition from a pharmaceutical equivalent to Taxol."
Bristol is seeking a permanent injunction to keep Immunex from manufacturing, marketing, or selling paclitaxel in the U.S. for use in therapies that are covered by the Bristol patents. Bristol has also requested a court order to ensure that any approval of the Immunex generic will have an effective date later than August 3, 2012—the expiration date of the Bristol patents.
Patent infringement suits commonly occur following expiration of pioneer companies' market exclusivity. Even in cases when the pioneers' patent claims are ruled invalid, the time allotted for resolution of such disputes effectively becomes an extension of exclusivity for the pioneer.
Under FDA rules, the agency can be expected to withhold approval of the Immunex ANDA for 30 months, or until the suit is resolved. If the ANDA is approved after 30 months, Immunex will have the option of marketing the generic product whether or not the companies are still in litigation. However, this strategy entails considerable risk. If the suit is resolved in the pioneer's favor after the generic begins marketing its product, the pioneer would be able to seek damages.
In a related development, Bristol has filed a patent infringement complaint against Ben Venue Laboratories Inc. of Bedford, OH, and its Bedford Laboratories division. The complaint claims infringement on the same paclitaxel patents involved in the Immunex suit.
The complaint, filed December 17, 1997 in the U.S. District Court for New Jersey, is also in response to an ANDA recently accepted for review. According to the Bristol complaint, Ben Venue, through Bedford Laboratories, is seeking approval to market paclitaxel for injection in 6 mg/ml, 5 ml, and 16.7 ml vials. Bristol is seeking the same injunction and court order against Ben Venue as it is in the Immunex suit.
Bristol Myers-Squibb earned $3,205 million ($3.22 per share) for the year ended December 31, 1997, the company said. Last year, the company earned $2,850 million ($2.84 per share). The company said sales of Taxol increased 16%, to $941 million for the year.
Immunex said it lost $15.8 million ($0.40 per share) on revenues of $185.3 million for the year ended December 31, 1997. Last year, the company lost $53.6 million ($1.35 per share) and revenues $151.2 million.
OncorMed, Myriad Embroiled in Battles over Patent Rights
Two genetic testing companies are embroiled in legal battles over the patent rights related to the diagnostic and therapeutic applications of the BRCA 1 gene.
OncorMed Inc. of Gaithersburg, MD, and Myriad Genetics Inc. of Salt Lake City, UT, are each seeking permanent injunctions to bar the other from continuing to market tests for BRCA 1 mutations.
OncorMed holds a patent that covers a full-length coding sequence of BRCA 1. Myriad holds two patents for the mutations associated with the gene. Now, in three concurrent cases, the courts are being asked to sort through conflicting claims of patent infringement:
- In a complaint filed November 17, 1997, in the U.S. District Court for the District of Columbia, OncorMed claims that Myriad has infringed on U.S. Patent No. 5,654,155, "Consensus sequence of the human BRCA 1 gene," issued to OncorMed on August 5, 1997. The patent covers a full-length coding sequence of BRCA 1, and the therapeutic and diagnostic products and services associated with the sequence.
- In a complaint filed in the U.S. District Court in Utah December 2, 1997, Myriad claims that OncorMed has infringed on U.S. Patent No. 5,693,473. The patent, issued to Myriad December 2, covers 47 different BRCA 1 mutations, including 185delAG and 5382insC, the mutations most commonly found in people of Ashkenazi Jewish descent.
- In a third suit, filed January 20, 1998, in the U.S. District Court in Utah, Myriad claims that OncorMed infringed on U.S. Patent No. 5,709,999, issued to Myriad. The patent, issued earlier that day, covers a predisposition diagnostic test for specific mutations in the BRCA 1 gene.
"Every major gene can be expected to be associated with multiple patents, and BRCA 1 is no exception," OncorMed said in a statement. "We remain confident in the strength of our intellectual property position on the BRCA 1 gene and we intend to vigorously pursue our previously filed lawsuit against Myriad."
"In addition, we intend to aggressively defend against the claims made against OncorMed by Myriad," OncorMed said.
Myriad declined to comment on the suits.
SmithKline's Kytril Effective Antiemetic, Study Finds
SmithKline Beecham of Philadelphia said results of a multicenter study show that a single oral dose of Kytril tablets (granisetron hydrochloride) is as effective as intravenous ondansetron as an antiemetic for cancer patients undergoing moderately emetogenic chemotherapy.
Results of the study are published in the January issue of the Journal of Clinical Oncology.
The double-blind, randomized trial studied the effectiveness of Kytril tablets versus intravenous ondansetron in 1,085 patients treated with either cyclophosphamide or carboplatin. Half of the patients received two 1 mg tablets of Kytril orally one hour before chemotherapy, and the other half received 32 mg of ondansetron intravenously 30 minutes before chemotherapy. The company said 59% of patients receiving Kytril experienced no nausea or vomiting 24 hours after chemotherapy, compared to 58% of patients in the ondansetron arm. After 48 hours, 47% of patients in the Kytril arm of the study achieved total control, compared to 44% in the ondansetron arm, the company said.
The company said Kytril is the only oral antiemetic indicated for use with all chemotherapy agents. In November, FDA cleared Kytril tablets to be administered as a single 2 mg dose.
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