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The antimetabolite 5-fluorouracil (5-FU) has been in use for more than 50 years, and oncology researchers are still trying to figure out how to maximize its potential. Low-dose continuous-infusion regimens have been tested for several years. More recently, several oral fluorinated pyrimidine pro-drugs of 5-FU have been developed.
UFT and eniluracil are two active oral drugs related to 5-FU, described at the Chemotherapy Foundation Symposium XVI, a meeting sponsored by the Mount Sinai School of Medicine and the Chemotherapy Foundation of New York. The goal in developing each of these was to find a drug which offered the convenience of oral delivery, but with fewer toxic effects than seen with conventional i.v. 5-FU regimens or with oral 5-FU alone.
UFT is a 5-FU pro-drug with high oral bioavailability. It is not new, but the introduction of oral leucovorin has renewed interest in oral UFT. Besides the convenience of an oral regimen, oral UFT/leucovorin might also be a safer regimen if it avoids the severe neutropenia seen with i.v. 5-FU.
Eniluracil may help resolve the 5-FU dilemma in a different way, by inhibiting the enzyme which appears to be responsible for much of oral 5-FU's toxicity. A preliminary report on a phase II trial of patients with advanced breast cancer at the M.D. Anderson Cancer Center, Houston, showed a response rate of approximately 25% in patients taking an oral regimen of eniluracil and 5-FU. Eniluracil prevents the degradation of 5-FU's precursor by inhibiting the enzyme dihyrdopyrimidine dehydrogenase (DPD). In preclinical data, inhibition of DPD prolongs 5-FU's half-life, thereby increasing its bioavailability.
Gabriel Hortobagyi, chairman of Breast Medical Oncology at M.D. Anderson, said DPD is found in the liver but also in the intestinal mucosa, which may be the major reason oral fluoropyrimidines have been so unpredictable in activity. He said a genetic deficiency of DPD can prevent oral 5-FU from being catabolized at the usual rate, producing toxic and potentially life-threatening serum levels of 5-FU.
Hortobagyi showed data based on the first large trial of eniluracil, in patients who had breast cancer that was refractory to both taxanes and anthracyclines. The phase II trial used oral eniluracil 10 mg/m2 plus oral 5-FU 1.0 mg/m2, given twice daily for four weeks out of every five. Treatment was continued until progression or toxicity. There were very few grade severe toxicities, he said, but severe effects did include malaise and fatigue. There was some myelosuppression and GI toxicity, but these were not clinically relevant, he said. Severe mucositis did not occur, as it can with capecitabine or continuous-infusion 5-FU.
There was a 10% response rate among the first 60 evaluable patients, all of whom were refractory to a taxane and to doxorubicin or epirubicin, and who were taking this regimen as second- or third-line therapy. Hortobagyi said another 25% of patients achieved a minor response or stable disease. Median duration of progression-free survival was 2.5 months, and the median duration for survival was 42 weeks.
Hortobagyi noted that his 10% response rate does not seem to compare with early response rates exceeding 50% in an ongoing European trial of oral eniluracil/5-FU as front-line therapy. He said researchers anticipate further data from that trial to get a more balanced view of this agent. But given its activity in patients refractory to drugs most active in treatment of breast cancer, Hortobagyi concluded that eniluracil needs to be evaluated in patients who are not yet resistant to those agents.
Coulter, SmithKline Agree to Develop Anti-B1 Antibody
Coulter Pharmaceutical of Palo Alto, CA, and SmithKline Beecham (SB) said they have signed an agreement to jointly commercialize Coulter's lead cancer therapy, I-131 Anti-B1 Antibody (iodine I 131 tositumomab), which is in late-stage development for the treatment of non-Hodgkin's lymphoma (NHL). The total agreement has a potential value of up to $132 million, plus shared profits and royalties, the companies said.
The agreement provides for an up-front payment of $41.5 million from SB to Coulter, including the purchase of $7.25 million in equity. In addition, a $15 million credit line will be provided. Coulter potentially will receive an additional $76 million in payments, based on completion of development milestones. Development expenses for I-131 Anti-B1 Antibody will be shared by both companies. The companies said they will jointly explore the potential of the I-131 Anti-B1 Antibody therapy for other indications.
Coulter and SB will jointly market I-131 Anti-B1 Antibody in the U.S. following regulatory approval, and the two companies will share profits equally. Outside the U.S., excluding Japan, Coulter has granted SB exclusive marketing and distribution rights in return for product royalties. SB will also have access to second-generation anti-CD20 compounds.
The U.S. FDA has designated I-131 Anti-B1 Antibody as a Fast-Track Product for which the agency will take appropriate actions to expedite development and review.
In a recent phase III trial for I-131 Anti-B1 Antibody in refractory non-Hodgkin's lymphoma (NHL), more patients experienced remissions with a single therapeutic dose of I-131 Anti-B1 Antibody compared to their last chemotherapy regimen and the I-131 Anti-B1 Antibody-induced remissions were of longer duration, the company said. The results of the trial were presented at the American Society of Hematology meeting in December by Mark Kaminski, associate professor of Internal Medicine at the University of Michigan Comprehensive Cancer Center and principal investigator for the clinical trial.
The phase III trial, which included 60 patients, sought to compare the duration of remission on I-131 Anti-B1 Antibody and the duration of remission on the patient's last chemotherapy, as assessed by a masked, randomized review of efficacy data by an independent panel of physicians. Of the 41 cases where response durations to chemotherapy and I-131 Anti-B1 Antibody were not equivalent, 32 patients (78%) experienced a longer duration of response to I-131 Anti-B1 Antibody compared to only nine patients (22%) who experienced a longer duration of response to prior chemotherapy (p < 0.001). The median duration of remission on I-131 Anti-B1 Antibody was 6.5 months, approximately doubling the 3.4-month median duration of remission patients experienced on their last chemotherapy. Currently, the longest duration of remission in this trial with the I-131 Anti-B1 Antibody is ongoing at 17.3 months.
"These results showing longer cancer remissions with a subsequent therapy are unprecedented when conventional chemotherapy is used in the treatment of low-grade and transformed low-grade NHL," said Kaminski. "In treating these patients, I would have expected a subsequent therapy to provide only about half of the benefit in terms of duration of remission compared to most recent therapy.
"To see reversal of the natural history of this disease with durations of remissions in I-131-Anti-B1 Antibody-treated patients approximately twice that of their prior therapy is extremely encouraging, particularly in this poor prognosis patient population who more than likely would not have responded to any other treatment," Kaminski said.
The company said the overall response rate, a secondary clinical endpoint, was significantly greater on I-131 Anti-B1 Antibody, with 39 of 60 patients (65%) responding to Anti-B1 Antibody compared to only 17 of 60 patients (28%) responding to prior chemotherapy (p < 0.001). In addition, 10 of 60 I-131 Anti-B1 Antibody-treated patients (17%) experienced a complete remission (or complete elimination of signs and symptoms of the disease) compared to only two of 60 patients (3%) who experienced a complete remission on prior chemotherapy (p = 0.011).
Side effects related to the I-131 Anti-B1 Antibody therapy included a decrease in blood counts which were reversible and generally self-limiting. A minority of these heavily pre-treated patients required support by blood cell transfusion or growth factor. A mild flu-like syndrome also was observed in some patients. Four patients developed human anti-mouse antibodies.
Hospitals Collaborate to Recruit Overseas Patients
Ten Philadelphia hospitals have formed a consortium to establish the area as a destination for international patients. The consortium, called Philadelphia International Medicine (PIM), includes Fox Chase Cancer Center, University of Pennsylvania Medical Center Children's Hospital, Thomas Jefferson University Hospital, Temple University Hospital, Pennsylvania Hospital, Christiana Care, Crozer-Keystone Health System, Wills Eye Hospital, and Moss Rehab Hospital.
PIM will coordinate physician consultations and patient support services with personnel at member institutions, as well as assist with travel arrangements, hotels, medical equipment rental and entertainment.
Hoechst, Rhône-Poulenc Rorer Plan to Merge Pharm and Agri Businesses
The German-based Hoechst AG and the French Rhône-Poulenc Rorer (RPR) announced plans to merge their pharmaceutical and agricultural businesses. The new company will be named Aventis, incorporated in France, and based in Strasbourg, the companies said. The companies said formation of the new company is a first step in a two-step process aimed at full merger of Hoechst and RPR and divestment of their remaining non-life sciences assets. The units that would be merged into Aventis had sales of $20 billion and a research and development budget of $3 billion in 1997.
Phase III Study of Angiogenesis Inhibitor to Begin
AEterna Laboratories Inc. of Sainte-Foy, Quebec, Canada, said it has signed a Clinical Trials Agreement (CTA) with the NCI for the launching of phase III trials using its angiogenesis inhibitor AE-941/Neovastat. The company also released details of the protocol for the first trial to be realized under the CTA, using AE-941/Neovastat in combination with chemotherapy and radiotherapy for the treatment of lung cancer.
The announcement follows the selection of AEterna by the NCI to perform phase III pivotal trials using AE-941/Neovastat. The NCI-sponsored trial will be a double-blind placebo-controlled study involving over 550 patients with non-operable non-small cell lung cancer. The patients will be administered standard chemotherapy and radiotherapy and randomized in two groups. One group will be administered AE-941/Neovastat and the other a placebo. The primary endpoint will be survival, with time to progression and quality of life as secondary endpoints.
The phase III study will involve over 40 hospitals and cancer centers in the U.S. and Canada. The principal investigators will be Roy Herbst of the M.D. Anderson Cancer Center for the U.S., and William Evans, of the Ottawa Regional Cancer Centre, for Canada. Enrollment is expected to begin in the second quarter of 1999 and the results should be available in 2001.
AE-941/Neovastat, AEterna's angiogenesis inhibitor to be used in this phase III trial, is a liquid cartilage extract which has been tested on over 450 patients with advanced cancer in the U.S. and Canada. In vivo and in vitro properties of AE-941/Neovastat include anti-MMP activity, antiendothelial cell proliferation activity, antitumor and antimetastatic activity alone or in combination with cytotoxic agent.
FDA Approvals and Applications: HER-2 DNA Probe Kit Approved for Detection
Vysis Inc. of Downers Grove, IL, said the FDA had approved its PathVysion HER-2 DNA Probe Kit for detection and quantifying the HER-2 gene in breast cancer patients. The kit is also under review for marketing in France by the Agence du Medicament.
The test utilizes the Vysis Fluorescence In Situ Hybridization technology, which enables it to directly detect both the HER-2 gene and the chromosome 17 on which the gene resides, the company said. Patients with more than two copies of chromosome 17 do not represent true amplification of the HER-2 gene. Thus, the ability to simultaneously detect chromosome 17 provides a built-in control to determine true amplification of the HER-2 gene. This added capability is unique to Vysis' patented technology, the company said. The Vysis test measures HER-2 status directly at the DNA level.
Actiq Cleared by the FDA
Anesta Corp. of Salt Lake City, UT said the FDA has cleared Actiq (oral transmucosal fentanyl citrate) for marketing for breakthrough cancer pain in patients with malignancies who are already receiving and who are tolerant to opioid therapy.
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