Directory of Drugs Therapeutic Area Updates
Neoplasms
The National Cancer Institute reports that new cancer cases and cancer
death have continued to decline for the past decade. While this is good
news, cancer remains the second leading cause of death in the United
States after cardiovascular disease. In 1999, there were almost 550,000
deaths secondary to cancer. Of the 1.2 million new cancers estimated
to have occurred in 2001, more than half of all these cancers were from
one of four sites: breast, colon/rectum, lung and prostate. The total
economic burden of cancer in the United States was estimated at $180
billion for the year 2000. Some statistics available from the National
Cancer Institute include:
|
Condition |
Percentage of all cancers |
Estimated number of cases (2001) |
Estimated mortality (2001) |
|
Breast Cancer |
16.3% |
193,700 |
40,600 |
|
Prostate Cancer |
14.8% |
198,100 |
30,500 |
|
Lung Cancer |
13.2% |
169,500 |
157,400 |
|
Colorectal Cancer |
11.6% |
135,400 |
56,700 |
Of the more than 700 oncology clinical trials in the field of cancer, almost 40% are specifically for cancers of the breast, prostate, lung or colorectal. For just breast cancer, more than 15 clinical trials are in or have completed phase III testing. The drugs in these phase III trials are in one of the following categories:
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Aromatase inhibitors/inactivators: In this category, Letrozole (Femara/Novartis) and Exemestane (Aromasin/Pharmacia) are both FDA approved for the management of breast cancer; they are in phase III trials to show efficacy as adjuvant therapy and as preventive therapy in breast cancer, respectively.
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Estrogen antagonists: Lasofoxifene (Pfizer) and Fulvestrant (Faslodex/Astrazeneca) are both estrogen receptor blockers being evaluated for the prevention and management of breast cancer, respectively.
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Biphosphonates: Ibandronate (Bonviva/Hoffman-LaRoche) and minodronate (Yamanouchi Pharmaceutical) are both in phase III trials for breast cancer. Since 25% of patients with breast cancer develop skeletal metastases, biphosphonates are an important component in breast cancer therapy. They may also have a role in preventing cancer therapy-induced osteoporosis and bone metastasis; clinical trials evaluating the role of biphosphonates are therefore particularly important in guiding treatment strategies for subjects with breast and other cancers that metastasize to bone.
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Recently approved and novel chemotherapeutic agents: Gemcitabine (Gemzar/Eli Lilly), Doxorubicin (in new liposomal formulations), Docetaxel (Taxotere), tesmilifene (YM Biosciences), and tariquidar (QLT) are all in phase III trials for breast cancer. Of particular interest is Tesmilifene. This drug is an intracellular histamine antagonist being developed as a chemopotentiator for the treatment of malignant solid tumors. The compound is cytotoxic to tumor cells and cytoprotective to the gut and bone marrow progenitor cells. Studies have indicated its ability to augment in vivo anti-tumor activity of cytotoxic drugs routinely used in the treatment of cancer, such as doxorubicin, cyclophosphamide, 5-fluorouracil (5-FU), cisplatin, and mitoxantrone. Interim analysis of data from a North American phase II pilot study in hormone refractory metastatic prostate cancer has shown promising results. Tesmilifene has also completed phase III trials for treatment of metastatic breast cancer.
- Vaccination strategies, monoclonal antibodies and compounds that bind to over-expressed tumor antigens. Examples of this include a phase III trial of Herceptin (already approved for breast cancer expressing HER2) in early stage breast cancer, ZD 1839 (Iressa/AstraZeneca) that binds to the epidermal growth factor receptor (EGFR) and inhibits tyrosine kinase, Theratrope (Biomira) vaccine that induces an immune response against the cancer-associated antigen Sialyl Tn (STn), and bevacizumad (Avastin/Genentech), a humanized antibody to vascular endothelial growth factor (VEGF). Over-expression of these tumor antigens (particularly, HER2 and VEGF) seems to have independent prognostic significance. Therapies to down-regulate these proteins may demonstrate an important survival advantage in subjects with breast cancer.
For prostate cancer, there are more than 60 clinical trials evaluating various treatment strategies. Many of these trials are evaluating newer ways of antagonizing gonadotropin-releasing hormone to achieve clinical castration and suppress tumor growth. Suppression of androgen production is the initial treatment of advanced prostate cancer, but most men with metastases will develop disease progression. Subjects with hormone refractory prostate cancer (HRPC) have a median survival of about 18 months. No therapy has yet demonstrated a survival advantage. Combination chemotherapy is being used in subjects with failure of primary androgen deprivation. These include agents that block signal transduction, inhibit growth factor receptors, prevent tumor angiogenesis, stimulate apoptosis and induce immunity against tumor-specific antigens.
An anti-angiogenesis compound under evaluation for prostate cancer in
a phase III trial is Atrasentan (Abbott Laboratories). Atrasentan blocks
the action of a potent substance in the body (endothelin-A). This substance
is a strong constrictor of blood vessels, and it also stimulates cell
proliferation. By preventing the action of endothelin-A, it is thought
that blood vessel and cancer cell growth will be slowed or halted altogether.
In initial trials involving late-stage metastatic prostate cancer, Atrasentan
decreased the level of serum PSA and pain resulting from cancerous spread
to the bone. Immunotherapy against the prostate specific antigen (PSA),
the primary tumor antigen expressed on prostate cancer cells, is also
being evaluated in two phase III trials. The first of these trials uses
a dendritic ex-vivo cell therapy, where dendritic cells are removed from
a subject, pulsed with PSA and re-injected. Early clinical trials demonstrated
that these dendritic cells (Provenge/Dendreon) were safe and well tolerated
and induced an immune response in subjects with prostate cancer. A second
trial with a similar product (DCVax-prostate/Northwest Biotherapeutics)
showed disease stabilization in subjects with late-stage prostate cancer.
For lung cancer, there are at least 80 ongoing clinical trials, one fourth
of which are in phase III. Lung cancer is the major cause of death from
cancer accounting for more than 30% of cancer deaths in men and 25% in
women. Both small cell and non-small cell lung cancers are already metastatic
in more than two thirds of subjects at the time of diagnosis. The five-year
survival rates for lung cancer are a dismal 15%. Newer drugs with single-agent
anti-tumor activity (for example, gemcitabine, paclitaxel, docetaxel,
vinorelbine, irinotecan and topotecan) are being added to conventional
regimens with evidence of modest tumor response and survival.
In the area of colorectal cancer, metastatic cancer response rates with fluorouracil-based regimens are about 25% when combined with newer agents such as irinotecan and oxaliplatin, response rates improve to more than 50% in some subjects. However, that still leaves many subjects who experience the side effects of chemotherapy without benefit for resistant cancer. There are about 60 clinical trials at present for colorectal cancer; most of these are in phase I and phase II testing.
Of the trials currently in phase III testing, five are evaluating anti-tumor antigen therapies. The first is testing an anti-cancer monoclonal antibody (CEAVac/Titan Pharmaceuticals) that targets the carcinoembryonic antigen on colorectal tumor cells. Early phase I/II results of CEAVac in subjects with colorectal cancer suggested a positive clinical effect, with nine of 15 subjects continuing without disease. The second vaccine trial is evaluating OncoVax which is an autologous vaccine designed to provoke an immune response against cancer cells. It is designed for post-surgical use for the treatment of stage II and III colon cancer. The vaccine is specifically prepared for each recipient using his or her surgically removed tumor. Trials conducted in Europe have shown this product to produce a significant reduction in recurrence of colon cancer. OncoVax is currently marketed in some European countries. A phase III study in Europe is currently evaluating the effectiveness of the vaccine in stage III colon cancer. Intracel is planning a trial of OncoVax for stage III cancer in the United States.
The third trial is evaluating Gastrimmune (Aphton). Gastrimmune is a therapeutic vaccine that neutralizes specific gastrin hormones (G17 & Gly-extended G17). The drug is in phase III trials for the treatment of cancers of the gastrointestinal tract, including gastric cancer and colorectal cancer. The fourth trial is evaluating an antibody to the epidermal growth factor receptor (EGFR). IMC-C225 (Erbitux/ImClone Systems) is a highly specific chimerized monoclonal antibody that binds to EGFR. This binding inhibits tumor growth by interfering with the effects of EGFR activation, including tumor invasion and metastases, cell repair and angiogenesis. ImClone submitted a rolling BLA to the FDA in November 2001 for the treatment of irinotecan-refractory colorectal cancer. Phase III trials are also being conducted with Erbitux in colorectal cancer subjects. In addition, the drug is in phase II and III trials in combination with standard cancer therapies for the treatment of colorectal, pancreatic, head and neck, and non-small-cell lung cancer.
Finally, Bevacizumab (Avastin/Genentech) is a humanized antibody to vascular endothelial growth factor (VEGF). The drug functions as an angiogenesis inhibitor, and it is being tested in various combinations with fluorouracil, leucovorin calcium and irinotecan. In October 2001, Genetech reported that a preliminary analysis of a phase II kidney cancer trial showed that the pre-specified efficacy endpoint had been reached and recruitment could be stopped. These results, in addition to data from phase II colorectal and breast cancer trials, confirm Avastin's anti-angiogenic activity and support the drug's use in future trials. Phase III trials are now under way in subjects with colorectal and breast cancer.
Two other drugs are in phase III trials for colorectal cancer:
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Trimetrexate glucuronate (NeuTrexin/MedImmune) is already approved in 13 countries for the management of moderate-to-severe pneumocystis carinii pneumonia. NeuTrexin works by disrupting DNA, RNA, and protein synthesis, causing cell death. It is being tested in combination with leucovorin in phase III trials for the treatment of colorectal cancer.
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Oxaliplatin (Eloxatine/Sanofi-Synthelabo) is a third-generation cisplatin analogue. This drug is being evaluated in the United States as a second- and third-line treatment in combination with 5-fluorouracil for advanced metastatic colorectal cancer.
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