The Oncologist, Vol. 1, No. 4, 240–243,
August 1996
© 1996 AlphaMed Press
ADVANCES IN CANCER TREATMENT: THE CHABNER SYMPOSIUM |
The Clinical Development of Paclitaxel: A Successful Collaboration of Academia, Industry and the National Cancer Institute
Ross C. Donehower
Division of Medical Oncology, Johns Hopkins Oncology Center, Baltimore, Maryland, USA
Correspondence: Ross C. Donehower, M.D., Division of Medical Oncology, Johns Hopkins Oncology Center, 600 North Wolfe Street, Baltimore, MD 21287-8936, USA. Telephone: 410-955-8838; Fax: 410-955-0125.
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ABSTRACT
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The successful development of paclitaxel as an important new antineoplastic agent with the potential to have an impact on a number of human cancers was possible as a result of significant contributions from individuals and groups with diverse areas of interest and expertise.
The advancement of paclitaxel through the preclinical and clinical evaluation which ultimately led to its approval, as well as surmounting the regulatory hurdles which were faced required the close collaboration of individual investigators at academic institutions, the pharmaceutical industry (Bristol-Myers Squibb) and the National Cancer Institute. The latter stages of this developmental effort can be viewed as a prime example of the potential of the Cooperative Research and Development Agreement mechanism to bring novel therapies to patients with serious illnesses in a timely fashion. It is also tangible evidence of the vision and perseverance of a number of members of the Division of Cancer Treatment under the direction of Dr. Bruce Chabner, in whose honor this symposium is given.
Key Words. Paclitaxel • Taxol® • Cytotoxicity • Tubulin • Cisplatin
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INTRODUCTION
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Paclitaxel (Taxol®) is among the most important new agents introduced for cancer therapy in the last several decades. It has shown activity against a broad range of human cancers and is being evaluated in a number of studies as a component of initial chemotherapy regimens for diseases such as ovarian cancer, breast cancer, lung cancer, head and neck cancer, etc., where the true effect on the natural history of these diseases can be assessed. Clearly, paclitaxel is not a panacea for advanced solid tumors, although great enthusiasm exists among clinical investigators for the role of this compound in the future. The path taken to arrive at the current prominence of paclitaxel in cancer therapy has not been simple and straightforward and a number of formidable challenges have been overcome. This brief review will highlight several of the major critical developments which have allowed the preclinical and clinical evaluation of this drug to come to fruition. The process has been one of basic scientific discovery, clinical tenacity and pharmaceutical and medicinal chemistry ingenuity. There has been continuing bidirectional flow of information from laboratory to clinic and effective collaboration between industry, academia and the NCI to complete this important task.
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DISCOVERY, ISOLATION AND IDENTIFICATION
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It would be possible to say that the development of paclitaxel took nearly 30 years, although the drug was not in full clinical development for much of that time. Paclitaxel was discovered as part of a National Cancer Institute program in which extracts of thousands of plants and natural products were screened for antineoplastic activity. In the early 1960s the crude extract of the bark of the Pacific yew, Taxus brevifolia, a slowly growing evergreen in the old growth forests of the Pacific northwest, was found to have cytotoxic activity against the KB cell in a preliminary screening evaluation. Later, in vivo activity against a number of preclinical models in use at the time was demonstrated, including the Walker 256 tumor, P1534 and L1210 leukemia models and B16 melanoma. The active component of the extract was isolated in pure form in 1969 and the structure demonstrated in 1971 by Wall, Wani and colleagues at Research Triangle Institute. The drug was finally selected for clinical trial in 1977 by the Division of Cancer Treatment (DCT), but despite its novel structure, enthusiasm for its development was muted and it was not initially felt to be a high-priority project. The preclinical activity was broad but not overly impressive and the compound was scarce and poorly soluble. Those factors suggested that the procurement and preparation of quantities sufficient for large-scale clinical development would be difficult.
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DESCRIPTION OF THE MECHANISM OF ACTION
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Preliminary morphologic and cytologic evidence had suggested that paclitaxel functioned as a mitotic inhibitor, superficially similar to what had been seen for vinca alkaloids. Interest in the drug increased significantly in 1979 when the laboratory of Susan Horwitz described its unique mechanism of cytotoxicity. Unlike other antimicrotubule drugs, such as the vinca alkaloids which induce the disassembly of microtubules, paclitaxel promotes the polymerization of tubulin. At concentrations of the drug which are readily achievable clinically, the drug inhibits disassembly and promotes the formation of excessively stable, dysfunctional microtubules which prevent normal cellular processes which depend on these structures from occurring. The microtubules formed are arranged in thick "bundles" or multiple mitotic asters with no obvious microtubule organizing centers. Cells exposed to paclitaxel are slowed in their traverse of the cell cycle and ultimately are arrested in G2 or M phases.
The binding site has been shown to be distinct from that for guanosine triphosphate, vinca alkaloids, colchicine, or podophyllotoxin and is present on the microtubule rather than tubulin dimers. The localization of the binding site to the N-terminal 31 amino acids of the beta subunit by Horwitz and her colleagues may be of value in the design of simpler molecules which retain the therapeutic effect of the parent compound.
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EARLY CLINICAL DEVELOPMENT
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Clinical trials of paclitaxel began in 1983 with a series of phase I trials at institutions around the country. However, before these studies could begin, the problem of the limited solubility of paclitaxel in aqueous media had to be resolved. The drug has no activity when given orally and is poorly soluble in water and other common vehicles used to formulate drugs for intravenous use. The drug is very soluble in a number of organic solvents, but precipitates when a saturated solution is comixed with water. A number of approaches were evaluated before settling on the Cremophor EL/alcohol vehicle including use of cosolvents, complexation, oil-water emulsions, and micellar solubilization. The latter approach using Cremophor as the surfactant for solubilizing the compound allowed dilution of the nearly saturated solution and proved ideal for clinical use from a pharmaceutical perspective. Although alternative formulations have been identified, no major change in the current clinical product has been made.
With this problem solved, the clinical trials began. The phase I trials demonstrated a series of characteristic toxicities, some of which required considerable effort to circumvent. Very early in its evaluation a high incidence of acute hypersensitivity reactions was observed approaching 25%-30% in some studies. These reactions were typically severe Type I events with dyspnea, bronchospasm, hypotension, uticaria, etc. The majority occurred on the first or second dose and began almost immediately on initiation of the infusions. Although the majority of patients recovered with vigorous support, one fatality occurred and the development of the drug was seriously threatened. Observations suggested that these reactions were possibly mediated by the direct release of histamine and other vasoactive substances in a manner similar to radiographic contrast agents. Although these reactions could have been caused by the Cremophor EL or the drug, the vehicle was felt to be responsible since it had been associated with similar reactions with other drugs such as cyclosporine A and Vitamin K. After a conference call of investigators and NCI staff a decision was reached on how to proceed, and the studies were completed using prolonged (24 h) infusions and a premedication regimen similar to that used for contrast agents. This was highly successful and the practice has continued almost unaltered to the present time, with an incidence of severe reactions of 1%-2%. This has also allowed the drug to be given as a more convenient 3 h outpatient infusion.
The principal dose-limiting toxicity is neutropenia, typically occurring on day 8-10 after treatment. Doses of 200-250 mg/m2 are typically given with G-CSF in clinical trials because of the incidence of febrile neutropenias. The most critical pharmacologic determinant of this toxicity appears to be the duration of plasma drug concentrations at a level higher than 0.05-0.1 µmol/l. This may explain the greater hematologic toxicity seen with longer infusions.
Other toxicities which have been commonly seen include alopecia, peripheral neuropathy, and transient myalgias. Possible cardiac toxicity was observed in earlier studies, but accumulated evidence suggests that this is not a major concern for most patients. Nausea, neucositis, diarrhea, or serious end organ damage have been rare.
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ANTITUMOR ACTIVITY
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The impressive antitumor activity which has been observed with paclitaxel in a broad range of cancers has been the subject of numerous reviews and monographs and will not be reviewed in detail here. Paclitaxel was initially approved by the FDA in 1992 for the treatment of women with refractory ovarian cancer on the basis of five phase II trials of paclitaxel as a single agent given over 24 h. These data were supplemented by the experience of the Treatment Referral Center program instituted by the DCT to make this agent available to women who were not candidates for ongoing clinical trials through cancer centers in the USA. The 22% response rate seen in this heavily pretreated, poor prognosis group of patients established the generalizability of the data from the clinical trials to the everyday practice of oncology. This unique program strongly demonstrated the desire and willingness of the NCI to make treatment advances observed in clinical trials rapidly available to patients. With the demonstration that paclitaxel and cisplatin could be safely combined, the Gynecologic Oncology Group placed this regimen in a phase III trial in untreated stage III-IV patients comparing it to the standard cyclophosphamide-cisplatin regimen. This bold move has yielded important results and has established a new standard for ovarian cancer treatment.
This excitement was rapidly duplicated in metastatic breast cancer where response rates near 60% were observed for previously untreated patients. Considerable activity is also observed in previously treated patients, although the response rates predictably decline as the number of prior regimens increase. Further development of paclitaxel in the treatment of breast cancer will involve defining its role in combination with other active agents and in earlier stages of disease, particularly the adjuvant setting.
A complete discussion of all the data regarding single agent activity of paclitaxel is beyond the scope of this symposium. However, the activity which has been observed in both small cell and non-small cell lung cancer by several groups has spawned phase III trials to compare combination chemotherapy with this agent to standard therapy. A similar emphasis is being given to paclitaxel in head and neck cancer, bladder cancer, esophageal cancer and several other diseases based on encouraging preliminary data.
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DEVELOPMENT OF A RENEWABLE SOURCE OF DRUG
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Despite the encouraging initial results with paclitaxel, its development was hampered by additional logistical problems. The source of paclitaxel is the bark of a small, slowly growing evergreen that yields only a small amount of the active compound. Unless a renewable, reliable source of the drug could be identified, supplying the amount of drug needed to treat patients would have been an unattainable goal. The issues to be confronted also included those of environmentalists who were concerned about the possible effects of ongoing harvests on natural habitat. To facilitate the dialogue regarding these issues, the NCI convened two workshops on Taxol® and Taxus in 1990 and 1992 bringing together botanists, medicinal chemists, as well as clinicians and basic scientists to discuss the importance of this new drug and possible solutions to the problem of supply. A number of initiatives that have helped to solve this vexing problem came out of these meetings. The limited supply also stimulated collaboration between government and private industry. In 1989 the NCI opened competition for a pharmaceutical partner and in 1991 a Cooperative Research and Development Agreement between NCI and Bristol-Myers Squibb was signed. Bristol-Myers received the marketing rights for paclitaxel and access to the data from ongoing and completed clinical trials. They also assumed responsibility for supplying paclitaxel for clinical trials and the compassionate use of TRC protocols as well as rapid development of a new drug application. Their success allowed tremendous expansion in the number of clinical trials which could be conducted and has contributed in a major way to the substantial database currently available. Initially, the supply came from bark, but more recently commercial drug has been produced by a partial synthetic process which utilizes a readily available precursor, 10-deacetyl baccatin III, which is found in abundance in needles, etc., of more abundant yew species. Several totally synthetic methods have been described, but at this time they are not utilized commercially. The major role may be in analog development.
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FUTURE DIRECTIONS
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A number of important questions remain to be evaluated before the full impact of paclitaxel in cancer therapy can be assessed. The first is to establish whether the high doses (250 mg/m2) utilized in many of the phase II trials with G-CSF are necessary to achieve antitumor activity. Several prospective trials have been designed to address this question. The second question will be to evaluate whether there are circumstances where prolonged infusions of 24 h to 96 h are advantageous over a more convenient 3 h outpatient regimen. Data in refractory ovarian cancer and breast cancer do not suggest a difference exists, but whether this can be extrapolated to other situations is not clear. The third factor will be to establish the optimal means in which paclitaxel can be combined with other active agents in diseases under study. Careful pharmacologic and toxicologic evaluation of combinations with doxorubicin, cisplatin, etc., have demonstrated clear drug interactions which impact on these decisions. Finally, the last question will be to evaluate paclitaxel as expeditiously as possible in clinical circumstances where meaningful prolongation of life, extended progression-free survival, or even cure might be possible. The recently reported study of McGuire et al. describing the results of the phase III trial in advanced ovarian cancer may be the first of a number of applications of this new agent which results in extended survival, not simply a transient radiographic response. Other potential areas where this might optimistically be seen include adjuvant therapy of breast cancer and combined modality therapy of cancers of the lung and upper aerodigestive tract.
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SUMMARY
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The successful development of paclitaxel was the result of diligence and hard work on the part of a number of investigators in academia, the pharmaceutical industry, and the National Cancer Institute. The role of the NCI in this process cannot be underestimated and this example, among others, should be considered when the future role of NCI in drug development is considered. The leadership of Dr. Bruce Chabner, whom we honor in this symposium, was critical in the success of this project. His leadership created an environment where talented people could work productively in a cooperative effort toward a common goal. His grasp of important scientific and clinical issues and the facility with which he related to both groups of investigators focused attention on the issues of crucial priority and allowed the work to progress to a successful conclusion.
Those of us who have had an opportunity to work closely with him during our training also are grateful for the nurturing environment, sound advice, scientific training and friendship which he offered to us so willingly and unselfishly.
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ADDITIONAL SUGGESTED READING
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The author apologizes to those investigators whose work is discussed here but not specifically referenced. Readers can find complete reference lists in the suggested readings.
1 Rowinsky EK, Donehower RC. Drug Therapy: Paclitaxel (Taxol®). N Engl J Med
1995;332:1004–1014.[Free Full Text]
2 Proceedings of the Second National Cancer Institute Workshop on Taxol® and Taxus. Monographs of the Journal of National Cancer Institute
1993;15:1–199.
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FOOTNOTES
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From Advances in Cancer Treatment: The Chabner Symposium. STEM CELLS 1996;14:25-28.
This article has been cited by other articles:
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A. C. Wolff, R. C. Donehower, M. K. Carducci, M. A. Carducci, J. R. Brahmer, Y. Zabelina, M. O. Bradley, F. H. Anthony, C. S. Swindell, P. A. Witman, et al.
Phase I Study of Docosahexaenoic Acid-Paclitaxel: a Taxane-Fatty Acid Conjugate with a Unique Pharmacology and Toxicity Profile
Clin. Cancer Res.,
September 1, 2003;
9(10):
3589 - 3597.
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Abstract
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