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Iodine-131 (131I) anti-B1 antibody has been shown to be a promising new agent for the treatment of chemotherapy-refractory low-grade and transformed low-grade non-Hodgkin's lymphoma (NHL), according to Mark Kaminski in a presentation at the annual meeting of the American Society of Hematology.
Administered to NHL patients who had been heavily pretreated with chemotherapy and had failed an anthracycline or anthracenedione-containing regimen, this novel radioisotope-labeled anti-B1 monoclonal antibody proved to be effective, safe, and relatively well tolerated, said Kaminski, of the hematology/oncology division, Simpson Memorial Institute, University of Michigan Medical School in Ann Arbor, Michigan.
Nearly one-third of these very difficult-to-treat patients achieved complete responses (CR), many of which are still ongoing in duration, he said.
A multicenter study evaluating the safety and efficacy of 131I anti-B1 antibody was carried out in 45 patients with chemotherapy-refractory low-grade and transformed NHL who had progressed within one year after completing their last chemotherapy regimen. Initially, these individuals received an infusion containing 450 mg of unlabeled anti-B1 antibody. This "cold" antibody was administered to prevent uptake of the radiolabeled antibody by circulating lymphocytes and lymphocytes resident in healthy organs, such as the spleen and liver. As a result, more of the active dose goes to the diseased cells. This was immediately followed by an infusion of 5 mCi of 131I anti-B1 antibody (35 mg) as a dosimetric dose.
After administration of the dosimetric dose, periodic whole-body gamma camera scans were obtained over one week to calculate the radioactive clearance. These data were used to calculate a patient-specific therapeutic dose of 131I anti-B1 antibody. This therapeutic dose was administered approximately one week after the dosimetric dose and also was preceded by an infusion of unlabeled antibody.
Thirty six persons received 75 cGy and nine received 65 cGy total body dose, with a mean activity of 88 mCi. Response was assessed at six weeks, 12 weeks, and then in 12-week intervals thereafter for up to two years. Endpoints included overall response rate, complete response rate, safety and tolerability, times to progression, duration of response, dosimetry methodology, and survival.
At 16.9+ months follow up, in the 45 patients with low grade (35) or transformed low grade (10) B-cell NHL, 27 persons responded, for a total response rate (CR + PR) of 60%, and 14 of the 45, or 31%, had a CR, Kaminski said. Another 15 people had stable disease (33%), and three went on to progressive disease (7%). Of the 19 (42%) people with bulky disease in the total patient population, 11 (60%) responded, with four (19%) having a CR. The median duration of CR is 13.6 months, with a range of 4.5 to 16.9+ months, Kaminski said. In the 14 persons with CR, 10 (71.4%) have CRs of ongoing duration.
Reversible hematological toxicity was the dose-limiting toxicity, with 4% (2/45) of the patients having absolute neutrophil counts less than 100/mm3, 11% (5/45) having platelet counts less than 10,000/mm3, and 4.4% (2/45) having hemaglobins lower than 6.5 g/dl. The nadir typically occurred at weeks five through seven, with recovery by weeks eight to 10. Non-hematological toxicities were transient and generally mild, with the most common events being fatigue, nausea, and fever. None of the 45 patients developed human anti-mouse antibodies at any time following treatment, as assessed by a centralized validated assay. 
FDA News:
Agency Provides "Tentative Approval" for IVAX Paclitaxel
The U.S. Food and Drug Administration upheld the Bristol-Myers Squibb Co. (BMS) orphan drug market exclusivity for Taxol as a treatment for Kaposi's sarcoma (KS).
Acting on an application from IVAX Corp., the agency gave a "tentative approval" for that company's paclitaxel drug, allowing the drug on the market no earlier than August 4, 2004, the expiration date of the BMS orphan drug exclusivity.
At first glance, the agency's decision December 26, 1997, gave something to everyone: IVAX received an approval, while BMS retained its market exclusivity for KS. Nonetheless, a tentative approval of the drug, trade name Paxene, may have value to IVAX, observers said.
IVAX is "exploring alternative strategies to market Paxene for KS in advance of the expiration of Taxol's orphan drug exclusivity," the company said in a statement. These strategies could include filing abbreviated New Drug Applications (NDAs) for breast or ovarian cancers, indications not protected by the Orphan Drug Act, or by filing additional NDAs for a generic version of the drug, IVAX said.
Treatment Approvals: Rituxan, Fareston
The FDA has issued marketing clearance for Rituxan (Rituximab), a single-agent monoclonal antibody therapy for the treatment of relapsed or refractory low-grade or follicular, CD20-positive B-cell non-Hodgkin's lymphoma.
Rituxan, previously known as the C2B8 antibody, is marketed by IDEC Pharmaceuticals Corp. of San Diego, CA, and Genentech Inc., of South San Francisco, CA, the companies said.
The companies said clinical trials, conducted at 31 U.S. sites, showed Rituxan, when used alone, showed a 48% overall response rate. Eighty of 166 patients experienced tumor shrinkage of 50% or greater following four weekly infusions, the companies said.
Rituxan is the first monoclonal antibody licensed in the U.S. for the treatment of cancer, the companies said.
In clinical studies, B cells returned to normal levels within several months after completion of treatment. Unlike the traditional four- to six-month chemotherapy regimen or high-dose radiation treatment, Rituxan can be administered in four infusions on an outpatient basis over a 22-day period, the companies said.
IDEC discovered Rituxan and developed the product in collaboration with Genentech, F. Hoffmann-La Roche Ltd. of Switzerland, and Zenyaku Kogyo Co. Ltd. of Japan, the companies said. IDEC and Genentech said they will co-promote Rituxan in the U.S. and will have shared responsibility for product manufacture. Roche will market Rituxan in the rest of the world, excluding Japan.
Fareston for Breast Cancer
Schering-Plough Corp. received FDA marketing clearance for Fareston (toremifene citrate) as a first-line treatment for metastatic breast cancer in post-menopausal women with estrogen receptor positive or unknown tumors, the company said.
Fareston is the first new antiestrogen treatment for breast cancer to receive FDA clearance in almost 20 years, the company said. The company said efficacy of the drug was shown through three clinical trials involving 1,526 patients who had no prior therapy for advanced breast cancer. The trials compared Fareston with tamoxifen. Results of the trials show similar response rates between Fareston and tamoxifen, with no statistically significant difference in median overall survival, the company said.
The company said a 60 mg, once-daily dose of Fareston can be considered a safe and effective alternative to tamoxifen as a non-steroidal estrogen blocker for metastatic breast cancer. Adverse events include tumor flare, hypercalcemia, and vaginal bleeding. Patients with a history of severe thromboembolic disease should not be treated with Fareston, and patients with bone metastases should be monitored closely for hypercalcemia while under treatment, the company said. One percent of patients in the studies discontinued treatment due to adverse events.
Schering-Plough has marketing rights to Fareston in the U.S. and Canada through an exclusive agreement with Orion Corp. of Finland.
Neumega Cleared for Thrombocytopenia
Genetics Institute Inc. of Cambridge, MA, has received FDA marketing clearance for Neumega (Oprelvekin) (rhIL-11), for the prevention of severe thrombocytopenia in patients undergoing chemotherapy for solid tumors or lymphoma, the company said. Genetics Institute is a subsidiary of American Home Products Corp. of Madison, NJ.
The company said clinical trials of Neumega showed the drug reduced the incidence of severe chemotherapy-induced platelet depletion, reduced the need for platelet transfusions, and reduced the number of platelet transfusions required.
Neumega is undergoing a pharmacokinetic study among children with chemotherapy-induced platelet depletion, the company said.
National Cancer Policy Board Advocates $2 Increase in Price of Cigarette Packs
The price of a pack of cigarettes must increase by $2 per pack to reduce the number of new smokers and encourage current smokers to quit, the National Cancer Policy Board said in a report recently released. The price increase should be incorporated into the proposed settlement between state attorneys general and tobacco companies, because Congress has never passed such a large increase in the federal excise tax on tobacco, the Board said.
The report, "Taking Action to Reduce Tobacco Use," is the Cancer Policy Board's first major policy statement since its formation last year by the Institute of Medicine and the National Research Council.
Revenues generated by a price increase should be used to support tobacco control programs, improve treatment for tobacco dependence, and for peer-reviewed research directed by NIH, the report said. "The nation needs a strategy to reduce the death and disability caused by use of tobacco products. There are only three basic ways to reduce the death toll: to prevent the initiation of tobacco use, to get current users to quit, and to reduce exposure to tobacco toxins," the report said.
Under the proposed tobacco settlement between 40 state attorneys general and five tobacco companies, the companies would make payments of up to $368.5 billion over 25 years.
The Federal Trade Commission estimates that tobacco companies would increase prices by about 62 cents a pack as a result of the payments, but an industry analysis estimated a price increase of 82 cents, the Board said. According to the Board, neither of the projected price increases would be enough to sufficiently reduce demand.
"The Board cannot resolve the uncertainty over how much tobacco prices will increase, the effect of price increases on consumption, or the additive effect of price on other tobacco control measures," the report said. "The Board believes, however, that the desired health goals should dictate tax rates or settlement payments, rather than the reverse.
"Fixing the tax rate or payment amount in advance, with no provisions for adjustments later in light of data about levels of consumption and the initiation of tobacco use among youths, invites failure to achieve public health goals," the Board wrote. "If tobacco consumption and initiation do not recede, taxes on tobacco products should be increased to further reduce demand."
The increases should be indexed to inflation, and the settlement should include a system of public health monitoring, the report said. If goals for reducing tobacco use by youth are not met, financial penalties should be placed on manufacturers based on the brands used disproportionately by youth, the report said. Tobacco use by youth has gone up in states with active tobacco control programs, though at rates lower than the national average, the Board said. Those states, however, have not had large tax increases.
In addition to a price increase, federal regulation of tobacco must be strengthened by giving the FDA the authority to regulate tobacco products, the Board said.
In 1996, the FDA enacted regulations on tobacco advertising and marketing to minors, but needs the broad authority to regulate the design and content of tobacco products, the Board said. "Congressional action would avoid wasteful and unnecessary litigation and would establish a strong political and legal foundation for future regulatory initiatives," the report said. "Congress must also appropriate funding to the FDA commensurate with its authority."
In its report, the Board also advocated that the U.S. government:
The text of the Policy Board's report is available at the following web address: http://www2.nas.edu/cancerbd/
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  J. S. Jacobson, S. B. Workman, and F. Kronenberg Research on Complementary/Alternative Medicine for Patients With Breast Cancer: A Review of the Biomedical Literature J. Clin. Oncol., February 1, 2000; 18(3): 668 - 668. [Abstract] [Full Text] [PDF]
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