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Originally published as JCO Early Release 10.1200/JCO.2007.13.7810 on November 5 2007 © 2007 American Society of Clinical Oncology.
Have We Forgotten the Purpose of Phase III Studies?Division of Hematology-Oncology, The Ohio State University, Columbus, OH Experimental design of cancer therapeutics involves well-accepted phases designed to establish safe dosing, assess efficacy, and determine relative effectiveness compared with standard regimens. Phase I testing allows identification of tolerable dosing and an administration schedule that is followed by phase II testing in a specific disease to examine safety and early efficacy. If acceptable toxicity and efficacy is observed in phase II testing, development may proceed down two different pathways to obtain regulatory approval for marketing within the United States. One pathway involves performance of phase III study(s) comparing the respective new agent with the accepted standard treatment. This randomized phase III design provides the best opportunity to examine patient benefit with respect to improvement in remission duration, survival, and disease symptoms along with early and late toxicities associated with each treatment. The second pathway is most appropriate for use in conditions where no good standard or alternative therapy exists. These single-arm phase II studies are of sufficient size to adequately assess patient safety and provide evidence of patient benefit. However, this nonrandomized design lacks a control comparison, thereby introducing biases that can overestimate the benefit of the therapeutic agent. As a consequence of these limitations, regulatory approval for marketing of drugs using this latter pathway is limited to patients for whom no good alternative therapy exists. When an agent is approved for marketing through this secondary provisional pathway, a confirmatory phase III study demonstrating patient benefit is generally required to attain full approval of the agent. Each of these pathways of drug approval is important for patients with cancer. Understanding these principles is important to the genesis of the trial reported by Hillmen et al1 in this issue of the Journal of Clinical Oncology. Alemtuzumab is a humanized antibody directed at the CD52 antigen. CD52 is expressed on normal immune cells (B lymphocytes, T lymphocytes, dendritic cells, monocytes, natural-killer cells, and eosinophils) and select B-cell and T-cell malignancies including chronic lymphocytic leukemia (CLL).2,3 Initial development of this agent was pursued as an immunosuppressive agent for autoimmune diseases and transplant, but was associated with unacceptable toxicity from immune suppression. Clinical studies in relapsed and refractory CLL, T-cell prolymphocytic leukemia, and select other malignancies demonstrated clinical activity in patients without bulky lymph nodes.4-6 As one might expect, these studies confirmed significant resultant immune suppression. Development of alemtuzumab ceased for a short period, but was again reinitiated focusing on an area of medically unmet need, fludarabine-refractory CLL. A pivotal nonrandomized phase II study was initiated targeting this patient group that was considered successful as measured by a 33% response rate and improvement in disease-related symptoms, establishing patient benefit.7 A large majority of fludarabine-refractory CLL patients have bulky lymph nodes and compromised performance status based on their advanced disease. Unfortunately, patients with bulky lymph nodes and poor performance status (Eastern Cooperative Oncology Group [ECOG] performance status 2 or greater) had poor responses to alemtuzumab. On the basis of this pivotal CAM211 study and other previous work, alemtuzumab received accelerated approval for marketing by the US Food and Drug Administration (FDA) in 2001. The on-label use of alemtuzumab since this time has been limited because of the small proportion of fludarabine-refractory CLL patients having features that predict benefit to therapy (eg, good performance status, nonbulky lymph nodes). Contingent on the provisional approval of alemtuzumab was implementation of a confirmatory study demonstrating alemtuzumab's clinical benefit in a select population of patients with good performance and nonbulky lymph nodes. CAM307, described in this issue of the JCO, is the culmination of this regulatory requirement. However, does it answer the question that every practicing hematologist caring for CLL patients will ask? Does this trial really represent a step forward for the treatment of CLL? The CAM307 trial includes 297 previously untreated, but symptomatic, patients who were equally randomly assigned between alemtuzumab as dosed in the CAM211 trial and chlorambucil (40 mg/m2 day 1, every 28 days). The overall response rate, complete response rate, and minimal residual disease elimination rate were significantly superior for alemtuzumab compared with chlorambucil. Alemtuzumab treatment had a longer median time to requirement of alternative therapy. Another tantalizing finding was a significantly higher response in the high-risk genomic patients with del(11q22.3) and del(17p13.1).8,9 All in all, this appears to be a promising study that could change the therapeutic approach applied to patients with CLL who are symptomatic and have not yet received any therapy for their disease. Indeed, it would seem that this answers our previous question. We look to change our approach to disease treatment on the basis of the results of such phase III studies. Unfortunately, CAM307 does not fulfill this primary goal of a phase III study. Why are these results of less impact in how we care for patients with CLL? Most importantly, during the time period of this study's enrollment, work by Rai et al in 2000 established an advantage of fludarabine over chlorambucil as the backbone of CLL therapy.10 This was followed by three phase III studies that have shifted the standard of care for CLL toward the use of combination therapy with fludarabine and cyclophosphamide (FC) for young patients.11-13 Additionally, for this same group of young patients, phase II studies using chemoimmunotherapy including rituximab have shown great promise,14-16 and a large phase III study of FC versus FC + rituximab has completed enrollment, and results are anticipated within the next year. In this younger population, the resultant paradigm shift of CLL standard treatment appears to support fludarabine-based combination therapy, which was not employed in the CAM307 study. For older patients (> 70 to 75 years of age), the standard therapy is less clear, with chlorambucil still being an acceptable first-line therapy. The large recently published Medical Research Council (MRC) phase III study demonstrated that chlorambucil, fludarabine, and FC does not work as well for patients with high-risk genomic features including those with del(11q22.3) and del(17p13.1).17 From this, one could infer that alemtuzumab therapy might find its place as first-line therapy for elderly patients with emphasis on those with high-risk genomic features. However, on the basis of the limitations outlined below with the CAM307 study, such an approach can not be routinely advocated from the data presented in this study. Indeed, although alemtuzumab in the CAM307 trial met the positive clinical end point of the study of improving progression-free survival, there remain several limitations. Most importantly, median progression-free survival for each group (alemtuzumab, 14.7 months; chlorambucil, 11.7 months) is disappointing, being less than that observed in all of the randomized US, German, and MRC phase III studies published during the last decade. The benefit observed with alemtuzumab compared with chlorambucil in high-risk del(17p13.1) and del(11q22.3) patients is significant with respect to response, but progression-free survival is not significantly different and is very short (median, 9.4 months). Finally, the long-term consequence of alemtuzumab therapy in terms of immune suppression and influence on survival will likely not be determined given the article's statement that "further information on overall survival is not expected." This is disappointing, given that 84% of patients are currently alive on the study, with a short median follow-up of 24.6 months. Many investigators might eventually become amendable to using alemtuzumab earlier in the treatment of CLL if a survival advantage emerged with long-term follow-up demonstrating the absence of increased secondary malignancies, Richter's transformation, and unusual late opportunistic infections. As the study is currently designed, these answers will never be reported. In summary, the results of this trial offer little advance for defining new treatment approaches for CLL relevant to routine practice. The exception to this is perhaps the small patient niche area of the elderly CLL with del(11q22.3) or del(17p13.1) without bulky lymph node disease. Moving forward, what can be learned from the CAM307 phase III trial? First of all, it should be emphasized that we believe that the current accelerated phase II approval process available for new therapies that meet unmet needs should remain a viable option for regulatory approval of new drugs. This pathway provides patients without additional therapeutic options rapid access to new effective agents. Where change may be needed is in planning the confirmatory phase III studies that follow. The CAM307 investigators should be commended for inclusion of genomic studies and careful monitoring that provide the 2-year safety profile outlined in this study. The results are well described, audited, and likely highly reproducible. Unfortunately, though, they are not results that will move the field of CLL therapy forward. Given the relative complexity and cost of phase III studies, future confirmatory studies, such as CAM307, that are required by regulatory agencies might be pursued through industry-supported, FDA-accepted cooperative group studies that embody a group of disease experts' opinion of where the new therapy has the best opportunity to work and eventually be used. These studies should include extended follow-up to address both survival end points and long-term survivorship issues related to late treatment-associated complications and disease-related morbidities. Such an approach will still require compromise among all parties involved, but ensures that drug development resources are used to advance outcomes for the disease in which they are applied. A good example of this approach is that being applied with the confirmatory phase III study of gemtuzumab ozogamicin added to induction and consolidation therapy in acute myeloid leukemia that is currently being pursued by the US Intergroup (S0106). If an additional lesson derived from CAM307 generates a new approach to how confirmatory phase III registration studies are pursued following accelerated approval, a major advance will always be attributed to this trial. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Joseph M. Flynn, John C. Byrd Administrative support: Joseph M. Flynn, John C. Byrd Collection and assembly of data: Joseph M. Flynn Data analysis and interpretation: Joseph M. Flynn, John C. Byrd Manuscript writing: Joseph M. Flynn, John C. Byrd Final approval of manuscript: Joseph M. Flynn, John C. Byrd REFERENCES
1. Hillmen P, Skotnicki AB, Robak T, et al: Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol 25:5553-5555, 2007 2. Treumann A, Lifely MR, Schneider P, et al: Primary structure of CD52. J Biol Chem 270:6088-6099, 1995 3. Rodig SJ, Abramson JS, Pinkus GS, et al: Heterogeneous CD52 expression among hematologic neoplasms: Implications for the use of alemtuzumab (CAMPATH-1H). Clin Cancer Res 12:7174-7179, 2006 4. Osterborg A, Dyer MJ, Bunjes D, et al: Phase II multicenter study of human CD52 antibody in previously treated chronic lymphocytic leukemia: European Study Group of CAMPATH-1H treatment in chronic lymphocytic leukemia. J Clin Oncol 15:1567-1574, 1997[Abstract] 5. Pawson R, Dyer MJ, Barge R, et al: Treatment of T-cell prolymphocytic leukemia with human CD52 antibody. J Clin Oncol 15:2667-2672, 1997 6. Alinari L, Lapalombella R, Andritsos L, et al: Alemtuzumab (Campath-1H) in the treatment of chronic lymphocytic leukemia. Oncogene 26:3644-3653, 2007[CrossRef][Medline] 7. Keating MJ, Flinn I, Jain V, et al: Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: Results of a large international study. Blood 99:3554-3561, 2002 8. Grever MR, Lucas DM, Dewald GW, et al: Comprehensive assessment of genetic and molecular features predicting outcome in patients with chronic lymphocytic leukemia: Results from the US Intergroup Phase III Trial E2997. J Clin Oncol 25:799-804, 2007 9. Byrd JC, Gribben JG, Peterson BL, et al: Select high-risk genetic features predict earlier progression following chemoimmunotherapy with fludarabine and rituximab in chronic lymphocytic leukemia: Justification for risk-adapted therapy. J Clin Oncol 24:437-443, 2006 10. Rai KR, Peterson BL, Appelbaum FR, et al: Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 343:1750-1757, 2000 11. Eichhorst BF, Busch R, Hopfinger G, et al: Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood 107:885-891, 2006 12. Flinn IW, Neuberg DS, Grever MR, et al: Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. J Clin Oncol 25:793-798, 2007 13. O'Brien S, Moore JO, Boyd TE, et al: Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 25:1114-1120, 2007 14. Keating MJ, O'Brien S, Albitar M, et al: Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol 23:4079-4088, 2005 15. Schulz H, Klein SK, Rehwald U, et al: Phase 2 study of a combined immunochemotherapy using rituximab and fludarabine in patients with chronic lymphocytic leukemia. Blood 100:3115-3120, 2002 16. Byrd JC, Rai K, Peterson BL, et al: Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: An updated retrospective comparative analysis of CALGB 9712 and CALGB 9011. Blood 105:49-53, 2005 17. Catovsky D, Richards S, Matutes E, et al:, Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): A randomised controlled trial. Lancet 370:230-239, 2007[CrossRef][Medline] Related Article
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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