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Originally published as JCO Early Release 10.1200/JCO.2004.03.918 on May 10 2004 © 2004 American Society of Clinical Oncology.
New Target, New Drug, Old ParadigmSidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD The last few years have witnessed the clinical development of many novel, so-called targeted anticancer agents. The clinical development of most of these drugs has been guided by traditional clinical research methods. With these approaches, some of these drugs have progressed from phase I to phase III trials, and fewer have eventually received regulatory approval based on evidence—sometimes rather limited—of patient benefit. Although these examples can be viewed as great successes, as indeed are any interventions that significantly decrease cancer suffering, their success does not mean that the clinical trial approaches used are optimal. In general, these processes are very slow and costly. Early dose-finding studies are still based on toxicity, despite many of the new agents' failure to exert linear dose-dependent toxicity effects. As a consequence, multiple different doses and schedules are explored in phase I and II studies, significantly complicating the design and conduct of large-scale, randomized trials. In many instances, the "go or no-go" decision is based on response rates, when these drugs in the laboratory induce growth arrest rather than tumor shrinkage. In addition, the interpretation of the biologic bases of the antitumor effects of these drugs has been superficial, leading to large developmental efforts in the wrong diseases. This is perhaps best exemplified by the development of the farnesyl transferase inhibitors designed to inhibit Ras signaling in patients with pancreatic cancer, on the basis that these tumors frequently have mutations in the ras gene.1 Importantly, no effort has been made to learn the biologic basis for success or failure, and the goal remains unselected patient populations, based on weak and arbitrary criteria, rather than the individual. In this issue of the Journal of Clinical Oncology is the first phase I clinical trial of CCI-779, an inhibitor of the mammalian target of rapamycin (mTOR) and a novel drug with a novel mechanism of action.2 This trial is a good example of the limitations of the traditional methodology of phase I clinical studies in the development of targeted agents. mTOR is a serine/threonine kinase (a member of the phosphatidyl inositol-3 (PI3K)-related kinases) that plays a pivotal regulatory role in multiple cellular functions, such as the transduction of proliferative signals by growth factors and the response of cells to nutrients. mTOR was discovered in part because of the existence of rapamycin, a naturally occurring inhibitor of mTOR. Rapamycin has been known for years to have unique biologic properties, including immunosuppressive, antifungal, and antiproliferative effects. Based on these features, rapamycin-like drugs have been developed as anticancer agents.3-5 In preclinical models, mTOR inhibitors exert tumor growth inhibition, induce apoptosis in selected models, and inhibit angiogenesis.6 CCI-779 is an ester of rapamycin selected for clinical development. The article by Raymond et al2 summarizes the results of one of the first two phase I clinical trials testing a weekly administration schedule of the drug. The design of this study is that of a classic phase I clinical and pharmacologic study, in which dose escalation was to be based on the continuous reassessment method. The principal objectives of the study were to determine the right dose for subsequent disease-oriented studies and to describe the toxicity and pharmacology of the agent. The main results indicate that CCI-779 is generally well tolerated, is mainly converted to rapamycin in blood, displays nonlinear kinetics, and results in antitumor effects. However, the study failed to determine the maximally tolerated dose due to a non-dose-related toxicity of the drug. The conclusions of the study are that the drug should be further developed, perhaps in diseases such as breast and renal cell cancer, based on one partial response observed in each of them, and that the optimal dose should be further explored in a flat-dosing fashion exploring a 10-fold dose range (25, 75, and 250 mg). This was precisely the approach followed in two subsequent randomized phase II studies in patients with breast and renal cell cancer.7,8 These studies confirmed the drug's activity, albeit modest, in these two diseases, but they failed to clarify the dose issue. Indeed, after more than 200 patients treated with CCI-779 on this particular schedule, the right dose remains an enigma. In parallel to the unprecedented number of new drugs and targets available, many cancer investigators have wondered whether this process can be optimized, and an increasing effort is being made in taking advantage of the existing technological resources to develop new drugs using more efficient approaches. This change in paradigm indeed applies to all phases of the drug-development process, from early-dose-finding studies to outcome-oriented late clinical trials. Key aspects of these efforts include the implementation of pharmacodynamic studies in dose-finding clinical trials, so that the right dose and schedule can be selected; the assessment of target inhibition in tumor tissues as a factor to determine whether a drug should be further developed; and the focused development of drugs in tumors types in which the target plays an important functional role. The clinical development of CCI-779 started in the late 1990s, when many of the ideas and concepts mentioned previously were still immature and not readily applicable to clinical trials. In addition, as correctly mentioned in the discussion by the authors, the study did not incorporate any biologic correlative end point because these assays were not available at the time of study commencement. Indeed, the two assays that have been published to measure the pharmacologic actions of rapamycin, including assessment of S6K kinase activity and 4EBP-1 phosphorylation, were developed when the drug was already in phase II studies.9,10 Subsequent retrospective efforts to incorporate these assays in additional dose-finding and pharmacodynamic studies have not been successful so far. The question now is: if we were to begin to develop this agent again, or a similar agent de novo, what could we do differently? The first important point is to do additional development-oriented preclinical work to address not only the classic questions regarding preclinical toxicity, efficacy, and pharmacology, but a second generation of questions about the pharmacodynamic effects of the drug and the context in which the drug is more likely to be effective. It is important that the answer have an executive rather than informative role and that it be used to design the clinical development. For mTOR inhibitors, many of these questions are now in the process of being answered. The pharmacodynamic effects of the drug can be measured by assessing the phosphorylation status of two of the key mTOR downstream mediators, 4EBP-1 and S6K.9,10 Some of these assays have been incorporated into clinical studies and used to select the dose of RAD001, another mTOR inhibitor.11 In addition, several studies have consistently indicated that mTOR inhibitors are more effective in tumors that depend on activation of the PI3K/Akt signaling pathway, such as those with mutation in the PTEN tumor suppressor gene.12-16 The importance of properly and rigorously validating of these assays, if they are to be used to make decisions, cannot be overemphasized. However, one of the main weaknesses of this approach is that the assays being used are not robust and validated enough. With proper planning at early stages, obtaining this information will not necessarily delay the clinical development, which is the most important goal. The second key aspect is how these studies are incorporated into the clinical development phase. For dose-finding and pharmacodynamic studies, the important questions are: does the drug hit the target, and at what dose? This requires testing the pharmacodynamic effects of the drug in tumor tissues and, consequently, obtaining serial tumor biopsies in these patients. Although this requirement adds additional complexity, it is feasible if properly planned. An approach that could be applicable to drugs such as mTOR inhibitors (for which normal tissues have been reasonably validated as surrogates for their pharmacodynamic actions) is to conduct a two-stage approach of "dose estimation" based on effects on normal tissues and "dose confirmation" based on effects on tumor tissues. This approach is based on the hypothesis that doses that do not exert pharmacodynamic effects in normal tissues will not do so in tumor tissues, so that the range of doses at which tumor biopsies are needed is greatly reduced. Failure to identify a dose that consistently hits the target as measured by a well-validated and robust test should probably be a "no go" decision point for a particular agent with a considerable saving of resources. Subsequent disease-oriented development needs to depart from the common "There is a response in phase I in disease X; let's do a phase II in that disease right away" approach and should instead direct the outcome-oriented studies to test the hypothesis that the drug works in a given biologic background selected from preclinical studies. For mTOR inhibitors, this means exploiting idea that these drugs have antitumor effects in tumors with activated Akt. In summary, the number of new targets and new drugs with potential as anticancer agents is increasing daily. In parallel, technological advances in areas such as genomics, proteomics, and functional imaging, to name a few, permit the interrogation of biologic questions in an unprecedented manner. In retrospect, it appears that the early development of CCI-779 could have been optimized by applying a more translational and hypothesis-driven approach, as exemplified by the process followed with similar drugs that came to the clinic just a few years later. The greatest challenge for clinical investigations in the next few years is to generate and implement clinical research methodology that really gets to the following critical points: (1) Does this drug work? (2) How do we need to use it for it to work? (3) Who is likely to benefit from it? Authors' Disclosures of Potential Conflicts of Interest The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Performed contract work within the last 2 years: Manuel Hidalgo, Wyeth. REFERENCES 1. Van Cutsem E, KP, Oettle H: Phase III trial comparing gemcitabine + R115777 (Zarnestra) versus gemcitabine + placebo in advanced pancreatic cancer (PC). Proc Am Soc Clin Oncol 21: 2002 (abstr 1430)
2. Raymond E, Alexandre J, Faivre S, et al: Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J Clin Oncol 22:2336–2347, 2004 3. Dancey, JE: Clinical development of mammalian target of rapamycin inhibitors. Hematol Oncol Clin North Am 16:1101–1114, 2002[CrossRef][Medline] 4. Sawyers CL: Will mTOR inhibitors make it as cancer drugs? Cancer Cell 4:343–348, 2003[CrossRef][Medline] 5. Hidalgo M, Rowinsky EK: The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene 19:6680–6686, 2000[CrossRef][Medline] 6. Huang S, Bjornsti MA, Houghton PJ: Rapamycins: Mechanism of action and cellular resistance. Cancer Biol Ther 2:222–232, 2003[Medline]
7. Atkins MB, et al: Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 22:909–918, 2004 8. Mita MM, Mita A, Rowinsky EK: Mammalian target of rapamycin: A new molecular target for breast cancer. Clin Breast Cancer 4:126–137, 2003[Medline]
9. Peralba JM, DeGraffenried L, Friedrichs W, et al: Pharmacodynamic evaluation of CCI-779, an inhibitor of mTOR, in cancer patients. Clin Cancer Res 9:2887–2892, 2003
10. Dudkin L, Dillins MB, Cheshire PJ, et al: Biochemical correlates of mTOR inhibition by the rapamycin ester CCI-779 and tumor growth inhibition. Clin Cancer Res 7:1758–1764, 2001
11. Boulay A, Zumstein-Mecker S, Stephan C, et al: Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res 64:252–261, 2004
12. Neshat MS, Melinghoff IK, Tran C, et al: Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci U S A 98:10314–10319, 2001
13. Podsypanina K, Lee RT, Politis C, et al: An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/– mice. Proc Natl Acad Sci U S A 98:10320–10325, 2001
14. Shi Y, Gera J, Hu L, et al: Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res 62:5027–5034, 2002
15. Noh WC, Mondesire WH, Peng J, et al: Determinants of rapamycin sensitivity in breast cancer cells. Clin Cancer Res 10:1013–1023, 2004 16. Yu K, Toral-Barza L, Discafani C, et al: mTOR, a novel target in breast cancer: The effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr Relat Cancer 8:249–258, 2001[Abstract]
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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