Taxotere Development and Approval

Like most cancer drugs, Taxotere has a long and somewhat complex history of discovery, testing, development, and approval. Taxotere is actually the brand name of a chemical compound known in the medical community as docetaxel. Therefore, in most studies and trials concerning the drug, it will be referred to as docetaxel.

Development from Paclitaxel

Taxotere is actually a variation of the chemical compound known as paclitaxel, which is marketed under the brand names Taxol and Abraxane. Paclitaxel was first isolated from the bark of the Pacific yew tree in 1967, but interest in its unique ability to fight cancer was not ignited until 1978 when its specific mechanism of action was discovered. In 1992, naturally derived paclitaxel was approved by the Food and Drug Administration (FDA) for use in metastatic ovarian cancer that does not respond to normal chemotherapy, and demand for the drug increased. After renewed efforts, the compound was synthetically produced in 1994, opening up the possibility for widespread production and use that would not be dependent on the natural, finite resource of slow-growing yew trees.

As paclitaxel was gaining popularity, researchers started to wonder how variations of the original compound would work against cancer. They asked themselves, essentially, if the drug could be improved through manipulation of certain atoms. Scientists thus performed rapid screenings of many compounds that were closely related to the original formulation and found a stable compound with slight variations from paclitaxel. They named it docetaxel.

Early testing showed that docetaxel worked the same way as paclitaxel, by binding with essential structural bodies in cells called “microtubules” and preventing them from multiplying during cell division. In fact, docetaxel seemed to work better in certain ways. It had a higher affinity for the microtubules, meaning that it would bond effectively more often. In addition, in some tests, docetaxel seemed to be infiltrating the cell at higher rates, meaning that more of the drug could enter the cell to begin its work. These two indications suggested that the drug might actually be more effective than the original. The preclinical research also showed docetaxel's antitumor potential for many different kinds of human tumors.

The First Clinical Trial

After preclinical research, if a drug seems to have a good chance of treating a specific illness or disorder, a sponsor, usually a drug company, can file an Investigational New Drug application to the FDA. In the case of Taxotere, the drug company Aventis Pharmaceuticals, Inc sponsored the application and the clinical trials so that they could develop the drug commercially. The application must include the preclinical research including any information available on toxicity and animal testing, the drug's process of manufacture, test results on the chemical compound's stability, and detailed protocols surrounding the proposed phases of testing. If approved, this application allows the company to begin testing the drug's effectiveness on people instead of only on animals and cell cultures.

The effectiveness of chemotherapy drugs is often cancer-specific and may sometimes even be specific to certain stages or varieties of one kind of cancer. Therefore, drugs must be thoroughly tested in patients that display cancer that is as identical as possible. For example, Taxotere went through its first set of clinical trials in the late 1990s, and was finally approved in 1999 by the FDA, but only for “the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior platinum-based chemotherapy.”

Testing for NSCLC

Aventis Pharmaceuticals, Inc. first tested Taxotere for use in the treatment of non-small cell lung cancer (NSCLC), most likely because it was the most common cause of cancer-related deaths in the US. All new drugs are tested in four phases to ensure that the substance is safe and reliable for widespread use. In phase one, the drug is tested on small groups of people to observe the limits of safe dosing and evaluate its toxicity, including major side effects.

In the first Phase I clinical trial, side effects that limited the dosage for the drug included mucositis and neutropenia. Mucositis is an inflammation of the mucous membranes found within the digestive tract, which can cause infections and/or ulcers anywhere from the mouth to the anus. It is a common side effect of chemotherapy treatments. Neutropenia refers to a low white blood cell count which also leaves the body vulnerable to infection.

After Phase I for the development of Taxotere, researchers advised that the dosing schedule for Phase II should be 100 mg per square meter of a patient's body surface, administered intravenously over a period of 1 hour every three weeks. This dose was designed to ideally balance the side effects of the drug and reduce toxicity while maximizing the drug's potential. Four Phase II studies encompassing 40 patients each, for a total of 160 patients experiencing advanced non-small cell lung cancer, were completed in 1998. The conclusion to a statistical analysis and summary of the four trials revealed that, on average, the drug extended life by a median of 9.2 months (although response rate varied). The drug, therefore, entered Phase III testing.

Generally, Phase III testing is much more expansive and includes a wide variety of ages, genders, and ethnicities in order to obtain data for diverse populations. They are also often randomized, meaning that doctors do not choose whether or not to administer the new treatment to a patient or continue with standard treatment; rather, the treatment is randomly assigned, usually by a computer. The FDA may approve a drug while it is in Phase III testing, as it can take many years to complete. If drugs fail, they do so most often in Phase II when their effectiveness in real-world scenarios is put to the test. Taxotere was tested in Phase III on 373 patients to confirm the results of Phase II. While the results were generally confirmed by the end of the study, with higher rates of survival than the previously accepted treatment, the dose was reduced to 75 milligrams from the original 100.

Phase IV testing occurs after the drug is made generally available and is comprised of thousands of volunteers. Survey-like studies are completed as the drug is implemented in larger communities, and they are done to evaluate the long-term effectiveness and possible undiscovered side effects associated with the drug.

After much testing, Taxotere was approved for non-small cell lung cancer in patients that had previously undergone platinum-based chemotherapy treatment regimens in 1999. In 2002, it was additionally approved for NSCLC patients who had tumors which were unresectable through surgery, as a primary chemotherapy option, meaning that platinum-based chemotherapy was no longer necessary as a prerequisite for taking Taxotere.

Expanding Taxotere's Uses

After the initial extensive process of approval, the drug was tested for effectiveness on many different kinds of cancer to possibly expand its market. FDA approvals for other uses came relatively quickly after the hurdle of the first set of clinical trials involving non-small cell lung cancer.

Development for Prostate Cancer

In order to expand the drug's approved use, Aventis Pharmaceuticals, Inc. sponsored another large-scale randomized clinical trial, similar to the kinds of trials generally undertaken for Phase III testing. The trial included 1006 patients with a specific kind of prostate cancer at different treatment centers around the globe. The patients were randomly given one of three treatments: Taxotere and the steroid prednisone once weekly, Taxotere and prednisone once every three weeks, or mitoxantrone and prednisone, which was the former standard of treatment for patients with this kind of prostate cancer.

Researchers found that the most effective treatment was the administration of Taxotere and prednisone once every three weeks. In fact, this treatment added, on average, about two and a half more months of life to a patient's prognosis than the former standard of care.

In May of 2004, the FDA, therefore, approved Taxotere “in combination with prednisone for the treatment of metastatic, androgen-independent (hormone-refractory) prostate cancer.” This means that treatment of the drug can only be administered with the steroid prednisone (to reduce the side effects of Taxotere) and only to patients who are suffering from prostate cancer which has not been responsive to hormone therapy and which is spreading through the body.

Development for Breast Cancer

Only a few months later, in August of 2004, Taxotere by injection was additionally approved for use in breast cancer patients who were suffering from a version of the disease which can be operated on surgically but has spread to the lymph nodes, or glands near the armpit. This spreading means that it is more likely that the breast cancer will return and continue to spread after surgery, so chemotherapy is often used as an “adjuvant” therapy. Adjuvant therapies support surgery and discourage the relapse of the disease.

In order to gain approval for the drug's application in this situation, a randomized trial of 1491 women with “node-positive operable breast cancer” was conducted. Some women were selected to receive the current standard of care, which included a three-part series of chemotherapy drugs, starting with doxorubicin and followed by fluorouracil and cyclophosphamide. The other women randomly received a new set of three drugs which included doxorubicin and cyclophosphamide, with Taxotere administered one hour after.

The rate of disease-free survival for patients who received the series containing Taxotere was significantly higher when the results were evaluated 55 months after administration, making this regimen the new standard of care for node-positive breast cancer patients after surgery.

Development for Gastric Cancer

In March 2006, Taxotere was approved for the treatment of yet another kind of cancer. Gastric, or stomach, cancers are almost always adenocarcinomas, meaning that they begin in cells which produce a fluid, such as mucus. In advanced stages of gastric adenocarcinoma, patients may now be prescribed a combination of Taxotere, cisplatin, and fluorouracil if they have not undergone other chemotherapy for advanced disease.

Researchers again conducted a randomized trial which included 457 patients who were suffering from this stage of gastric cancer. Some of the patients were simply given cisplatin and fluorouracil, while others were given the same drugs with the addition of Taxotere. The trial's organizer's studied the amount of time between the administration of the drug and the progression of the disease in the patient, called time-to-progression or TTP.

The time-to-progression in the patients who received Taxotere in addition to the other two chemotherapy drugs was significantly higher (a difference of around 2 months). It may be important to note, however, that patients who underwent the treatment with Taxotere experienced much higher toxicity or severe side effects. The drug, however, was approved.

Development for Head and Neck Cancer

There have been two distinctive trials to evaluate the appropriateness of Taxotere to treat head and neck cancer. First, a study involving 358 patients with inoperable, locally advanced squamous cell carcinoma of the head and neck (SCCHN). Similar to the study done on Taxotere and gastric cancer, one group received only the previous standard of treatment, cisplatin, and fluorouracil, while the other group received Taxotere injections first, followed by cisplatin and fluorouracil. Radiation was administered to patients whose cancer had not progressed four to seven weeks after the completion of chemotherapy, and surgery was permitted in the trial as needed.

Patients who received the Taxotere in addition to the other drugs had, on average, three more months of progression-free survival than the control group. The FDA approved the use of Taxotere for this kind of cancer, SCCHN, in October of 2006.

Taxotere Today

Because of its success in combating so many different kinds of cancer, researchers are still exploring the new kinds of uses to which this drug might be put in the future. In addition, studies and clinical trials continue to hone the combinations of drugs, radiation, and surgery in different cancers which correctly balance each technique for the best chances of survival or slowed progression of the disease. Today, Sanofi, a French multinational pharmaceutical company (the fifth largest in the world) markets and manufactures the world's Taxotere. Docetaxel, the active compound in Taxotere, is also marketed as Docefrez by Sun Pharma Global.

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