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The U.S. Food and Drug Administration's Oncologic Drugs Advisory Committee recommended approval for Taxol (paclitaxel) Injection for sequential administration to doxorubicin-containing therapy for the adjuvant treatment of node-positive breast cancer.
In another action at its meeting Sept. 16-17, the committee recommended approval for UFT capsules in combination with leucovorin calcium tablets for the first-line treatment of metastatic colorectal cancer. Both the Taxol and UFT-leucovorin therapies are sponsored by Bristol-Myers Squibb Co.
The committee recommended against approval for:
Voting for approval of Taxol, ODAC disregarded the FDA staff contention that the data did not support approval for estrogen receptor-positive and progesterone receptor-positive patients.
The agency's skepticism was based on the analysis of a very large subset of data-about two-thirds of the total 3,121 patients involved in the intergroup trial led by Cancer and Leukemia Group B, the study that formed the foundation of the BMS application.
Though not prospectively defined and not statistically significant, the subset analysis data demonstrated no overall survival advantage and no disease-free survival advantage for women whose tumors were ER-positive and PR-positive, and who received tamoxifen. Women who fit into this category should be followed until the impact of the therapy becomes measurable, FDA recommended.
The agency recommended that the Taxol-doxorubicin regimen be approved for ER-negative and PR-negative patients.
Basing a recommendation on a subset analysis is an unusual position for FDA, agency officials acknowledged. However, the ER+/PR+ subset in this case was unusually large: 2,066 patients, two-thirds of the total enrollment, said Robert Temple, associate director for medical policy at the Office of Drug Evaluation I of the FDA Center for Drug Evaluation and Research.
"We are usually on the other side of this argument," Temple said at the ODAC meeting. "We are historically skeptical about subgroup analysis. I think the theme here is that this sort of grabs you by the hair more than most of them do. It's just that when you see two-thirds of the study with the hazard ratio of approximately one, you sort of have to say, what shall I do with it? I would consider this quite exceptional."
Overall, patients who received Taxol and doxorubicin had a 22 percent decrease in risk of relapse and a 3.6 percent increase in three-year disease-free survival. (The hazard ratio was 0.78).
After the investigators—and subsequently FDA—performed an analysis of the overall survival and disease-free survival data, they found that receptor negative patients who received Taxol and doxorubicin had a 34 percent decrease in risk of relapse, and a 10.5 percent difference in three-year disease-free survival. (The hazard ratio was 0.66).
By contrast, receptor-positive patients showed no difference in disease-free survival. In accordance with the protocol, nearly all receptor-positive women received tamoxifen after completing chemotherapy.
The CALGB-led intergroup trial was the largest adjuvant breast cancer study ever conducted.
"In a challenging disease like cancer, where ground-breaking advances are often made in only minor increments, this recommendation represents a major step forward for patients," Richard Schilsky, associate dean for clinical research, University of Chicago, and chairman of CALGB, said in a statement, "It is even more critical now that women with breast cancer are diagnosed and treated early to increase their chances of living disease free."
Schilsky, who is also the chairman of ODAC, did not take part in either the voting or the discussion of the application.
"[ODAC's] recommendation further supports the clinical benefit of Taxol," said Renzo Canetta, BMS vice president, clinical oncology. "This study which demonstrates Taxol improving survival in patients with early stage breast cancer illustrates why we remain committed to researching new applications and developing Taxol to its fullest potential."
Of the more than 180,000 women diagnosed with breast cancer each year in the U.S., approximately 40 percent are candidates for adjuvant therapy. 
Survivors, Supporters Light Candles, Curse The Darkness
An estimated 5,000 people gathered at the Lincoln Memorial in Washington, DC, on Sept. 25 to honor cancer survivors, commemorate those who died of cancer, and to call on the federal government to increase funding for cancer research and assure high-quality cancer care.
The event, Rays of Hope, hosted by the National Coalition for Cancer Survivorship and sponsored by the Sidney Kimmel Foundation for Cancer Research, also marked the anniversary of last year's march on Washington by cancer advocacy organizations.
Queen Noor of Jordan served as honorary chairman of the event, which featured a day of educational activities, speeches, and entertainment, culminating with a candle lighting ceremony.
"It matters little whether you live in a royal palace or a small apartment in Anacostia, our very vulnerability draws us together," Noor said. "We must work to overcome the taboos which even in this country and in many other countries still prevent people from acknowledging their condition and seeking out the proper medical care.
"By speaking out, together we can be an inspiring and transforming force in this long war against cancer, a force for hope," she said.
In a videotaped statement played at the vigil, Vice President Al Gore repeated his proposal of earlier this year to double federal funding for cancer research. "In the history of his dread disease, there has never been a more hopeful time," Gore said. "It seems now every week brings another stunning discovery. We are on the verge of translating the stunning advances we've seen in genetics into an explosive growth in the possibility of fighting and defeating this cruelest of diseases.
"For generations we have waged war against this awful disease. With hard work and dedication, we can be the generation that finally wins that war."
NCI Director Richard Klausner said researchers are making progress in treatment and prevention.
"Tonight we're here to light candles and we're here to curse the darkness, to curse the darkness of cancer, for it is by light that we will conquer cancer," Klausner said. "We have yanked cancer out of its dark closet, of isolated whispers and loneliness of the disease that not that many years ago, polite society wouldn't even talk about. But the path to cures can only be lit by research.
"As we enter the new millennium, we can truly say that change is imminent," Klausner said. "The revolution in molecular biology and genetics, along with the emergence of powerful new technologies are allowing us for the first time in human history to see the surface of the cells that go awry in cancer, to explain how tumor cells behave, to understand how this abnormal cell can prosper and invade the body's own defenses. This basic knowledge about the nature of cancer for the first time is giving us the tools to prevent and treat cancer more effectively.
"It takes real resources," Klausner said. "This is an extraordinarily wealthy and talented country. It's up to us. We can either move forward into the still unlit territories of cancer with a flickering and weak candle, or we can choose lasers and 100,000 megawatt bulbs, searchlights. It's our choice.
"We will look back on this time as the decade that we began to turn the tide on cancer."
Sidney Kimmel, chairman of Jones Apparel Group, urged President Clinton to propose a $10 billion increase for cancer research, and challenged Presidential candidates to support increased funding for research.
Former U.S. Surgeon General Antonia Novello encouraged physicians to communicate better with cancer patients. "Never forget that what is routine for us is not routine for patients," she said. Novello called for universal health insurance.
FDA Approves Pharmacia & Upjohn's Ellence, For Early Breast Cancer Treatment
Pharmacia & Upjohn (NYSE: PNU) of Peapack, NJ, said the U.S. Food and Drug Administration approved Ellence (epirubicin hydrochloride injection) as a component of adjuvant therapy following resection of early breast cancer that has spread to the lymph nodes under the arm.
The approval of Ellence is based on a clinical study showing a combination of drugs containing Ellence can reduce the risk of cancer recurrence and the risk of death significantly more than CMF in women with axillary-node-positive early breast cancer, the company said.
The study, conducted by the NCI of Canada Clinical Trials Group and published in the Journal of Clinical Oncology in August, 1998, estimated 62 percent of women with early-stage breast cancer treated with a drug combination containing Ellence (cyclophosphamide, epirubicin, fluorouracil, known as CEF) will survive relapse-free for five years, compared to 53 percent of women treated with CMF. The estimated overall survival at five years was 77 percent in the CEF arm and 70 percent in the CMF arm.
Side effects from Ellence are predictable and manageable and are similar to those observed with other chemotherapies used in this setting. The most common side effects include hair loss, nausea, vomiting, mouth sores, and a low white blood cell count, due to myelosuppression, which can be severe, the company said.
Onyx Plans Phase III Trial Of ONYX-015 For Head & Neck Cancer
Onyx Pharmaceuticals Inc. (Nasdaq: ONXX) of Richmond, CA, said FDA has agreed to a phase III clinical development plan for ONYX-015, a therapeutic virus product. The company said it plans to initiate a phase III trial that would combine the virus with chemotherapy in the treatment of recurrent head and neck cancer.
The trial is expected to begin later this year or early in 2000, the company said. The proposed trial will be a randomized two-arm study comparing intra-tumoral injection of ONYX-015 plus standard chemotherapy (5-flurouracil and Cisplatin) versus chemotherapy alone. The study will take place at more than 40 centers in the U.S. and Europe and will include 180 evaluable patients with recurrent head and neck cancer in each of the study arms, the company said.
The primary endpoints will be progression-free survival and durable tumor responses. Secondary endpoints will include patient quality of life measurements and overall survival.
The company said it plans to conduct another study in recurrent head and neck cancer patients who have failed chemotherapy. Patients who are randomized to the control arm of the above phase III study will have an opportunity to be treated with the combination of ONYX-015 and chemotherapy once their disease has progressed. The primary endpoint will be durable tumor response.
Onyx said 50 to 100 patients will be accrued on the second study. Results from the open-label, single-arm study will be included in the eventual licensing application as supportive efficacy and safety data.
In a phase II study of ONYX-015 plus 5-FU/Cisplatin therapy in head and neck cancer, 19 of 30 evaluable patients experienced regressions of greater than 50 percent in their injected tumors, with eight patients experiencing complete tumor regressions.
The data represent an overall response rate of 63 percent, compared to approximately 35 percent with chemotherapy alone. A complete response rate of 27 percent in the phase II study was also significantly higher than the complete response rate of less than 10 percent with chemotherapy alone.
The company said 17 percent of tumors injected in the phase II study have progressed over the six months following initial treatment. By comparison, progression occurred in 60 to 70 percent of tumors in prior multi-center studies using chemotherapy alone, based on standard Kaplan-Meier analysis. Treatment was generally well-tolerated, the company said.
Chemotherapy-related gastrointestinal symptoms and injection site pain were the most frequently reported adverse events, the company said.
ONYX-015 is a genetically modified adenovirus that has been shown in preclinical and clinical studies to replicate in and kill tumor cells deficient in p53 tumor suppressor gene activity.
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