Stopping rules employing response rates, time to progression, and early progressive disease for phase II oncology trials

BMC Medical Research Methodology

Greg R Pond²  John R Goffin¹ 

[1] McMaster University, Juravinski Cancer Centre, 699 Concession St., Hamilton, Ontario L8V 5C2, Canada;McMaster University, Ontario Clinical Oncology Group (OCOG), Juravinski Hospital G(60) Wing. 1st Floor, 711 Concession Street, Hamilton, Ontario L8V 1C3, Canada

关键词: time to progression;    stopping rules;    simulation;    response rate;    phase II trial;    early progressive disease;   

Others  :  1136932
DOI  :  10.1186/1471-2288-11-164

 received in 2011-06-12, accepted in 2011-12-12,  发布年份 2011

【 摘 要 】

Background

Response rate (RR), the most common early means of assessing oncology drugs, is not suitable as the sole endpoint for phase II trials of drugs which induce disease stability but not regression. Time to progression (TTP) may be more sensitive to such agents, but induces recruitment delays in multistage studies. Early progressive disease (EPD) is the earliest signal of time to progression, but is less intuitive to investigators, To study drugs with unknown anti-tumour effect, we designed the Combination Stopping Rule (CSR), which allows investigators to establish a hypothesis using RR and TTP, while the program also employs early progressive disease (EPD) to assess for drug inactivity during the first stage of study accrual.

Methods

A computer program was created to generate stopping rules based on specified error rates, trial size, and RR and median TTP of interest and disinterest for a two-stage phase II trial. Rules were generated for stage II such that the null hypothesis (H_nul) was rejected if either RR or TTP met desired thresholds, and accepted if both did not. Assuming an exponential distribution for progression, EPD thresholds were determined based on specified TTP values. Stopping rules were generated for stage I such that H_nul was accepted and the study stopped if both RR and EPD were unacceptable.

Results

Patient thresholds were generated for RR, median TTP, and EPD which achieved specified error rates and which allowed early stopping based on RR and EPD. For smaller proportional differences between interesting and disinteresting values of RR or TTP, larger trials are required to maintain alpha error, and early stopping is more common with a larger first stage.

Conclusion

Stopping rules are provided for phase II trials for drugs which have either a desirable RR or TTP. In addition, early stopping can be achieved using RR and EPD.

【 授权许可】

   
2011 Goffin and Pond; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Lee JJ, Liu DD: A predictive probability design for phase II cancer clinical trials. Clin Trials 2008, 5:93-106.
• [2]Booth B, Glassman R, Ma P: Oncology's trials. Nat Rev Drug Discov 2003, 2:609-610.
• [3]DiMasi JA, Grabowski HG: Economics of new oncology drug development. J Clin Oncol 2007, 25:209-216.
• [4]Yamanaka T, Okamoto T, Ichinose Y, Oda S, Maehara Y: Methodological aspects of current problems in target-based anticancer drug development. Int J Clin Oncol 2006, 11:167-175.
• [5]Anderson H, Hopwood P, Stephens RJ, Thatcher N, Cottier B, Nicholson M, Milroy R, Maughan TS, Bond MG, et al.: Gemcitabine plus best supportive care (BSC) vs BSC in inoperable non-small cell lung cancer - a randomized trial with quality of life as the primary outcome. British Journal of Cancer 2000, 83:447-453.
• [6]Burris H, Storniolo AM: Assessing clinical benefit in the treatment of pancreas cancer: gemcitabine compared to 5-fluorouracil. Eur J Cancer 1997, 33(Suppl 1):S18-S22.
• [7]Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, et al.: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007, 356:125-134.
• [8]Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, et al.: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008, 359:378-390.
• [9]El-Maraghi RH, Eisenhauer EA: Review of phase II trial designs used in studies of molecular targeted agents: outcomes and predictors of success in phase III. J Clin Oncol 2008, 26:1346-1354.
• [10]Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, et al.: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009, 45:228-247.
• [11]A'Hern RP, Ebbs SR, Baum MB: Does chemotherapy improve survival in advanced breast cancer? A statistical overview. Br J Cancer 1988, 57:615-618.
• [12]Graf W, Pahlman L, Bergstrom R, Glimelius B: The relationship between an objective response to chemotherapy and survival in advanced colorectal cancer. Br J Cancer 1994, 70:559-563.
• [13]Shanafelt TD, Loprinzi C, Marks R, Novotny P, Sloan J: Are chemotherapy response rates related to treatment-induced survival prolongations in patients with advanced cancer? J Clin Oncol 2004, 22:1966-1974.
• [14]Torri V, Simon R, Russek-Cohen E, Midthune D, Friedman M: Statistical model to determine the relationship of response and survival in patients with advanced ovarian cancer treated with chemotherapy. J Natl Cancer Inst 1992, 84:407-414.
• [15]Goffin J, Baral S, Tu D, Nomikos D, Seymour L: Objective responses in patients with malignant melanoma or renal cell cancer in early clinical studies do not predict regulatory approval. Clin Cancer Res 2005, 11:5928-5934.
• [16]Abou-Alfa GK, Schwartz L, Ricci S, Amadori D, Santoro A, Figer A, De Greve J, Douillard JY, Lathia C, Schwartz B, et al.: Phase II Study of Sorafenib in Patients With Advanced Hepatocellular Carcinoma. Journal of Clinical Oncology 2006, 24:4293-4300.
• [17]Cesano A, Lane SR, Poulin R, Ross G, Fields SZ: Stabilization of disease as a useful predictor of survival following second-line chemotherapy in small cell lung cancer and ovarian cancer patients. Int J Oncol 1999, 15:1233-1238.
• [18]Hotta K, Fujiwara Y, Kiura K, Takigawa N, Tabata M, Ueoka H, Tanimoto M: Relationship between response and survival in more than 50,000 patients with advanced non-small cell lung cancer treated with systemic chemotherapy in 143 phase III trials. J Thorac Oncol 2007, 2:402-407.
• [19]Lara PN Jr, Redman MW, Kelly K, Edelman MJ, Williamson SK, Crowley JJ, Gandara DR: Disease control rate at 8 weeks predicts clinical benefit in advanced non-small-cell lung cancer: results from Southwest Oncology Group randomized trials. J Clin Oncol 2008, 26:463-467.
• [20]Hotta K, Fujiwara Y, Matsuo K, Kiura K, Takigawa N, Tabata M, Tanimoto M: Time to progression as a surrogate marker for overall survival in patients with advanced non-small cell lung cancer. J Thorac Oncol 2009, 4:311-317.
• [21]Ratain MJ, Mick R, Schilsky RL, Siegler M: Statistical and ethical issues in the design and conduct of phase I and II clinical trials of new anticancer agents. J Natl Cancer Inst 1993, 85:1637-1643.
• [22]Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989, 10:1-10.
• [23]De Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, et al.: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000, 18:2938-2947.
• [24]Hanna N, Shepherd FA, Fossella FV, Pereira JR, De MF, von PJ, Gatzemeier U, Tsao TC, Pless M, Muller T, et al.: Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004, 22:1589-1597.
• [25]Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP, Vega-Villegas ME, Eng C, Steinhauer EU, Prausova J, et al.: EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol 2008, 26:2311-2319.
• [26]Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, Ou SH, Dezube BJ, Janne PA, Costa DB, et al.: Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010, 363:1693-1703.
• [27]Goffin JR, Tu D: Phase II stopping rules that employ response rates and early progression. J Clin Oncol 2008, 26:3715-3720.
• [28]Zee B, Melnychuk D, Dancey J, Eisenhauer E: Multinomial phase II cancer trials incorporating response and early progression. J Biopharm Stat 1999, 9:351-363.
• [29]Fleming TR: One-sample multiple testing procedure for phase II clinical trials. Biometrics 1982, 38:143-151.
• [30]Korn EL, Arbuck SG, Pluda JM, Simon R, Kaplan RS, Christian MC: Clinical trial designs for cytostatic agents: are new approaches needed? J Clin Oncol 2001, 19:265-272.
• [31]Dent S, Zee B, Dancey J, Hanauske A, Wanders J, Eisenhauer E: Application of a new multinomial phase II stopping rule using response and early progression. J Clin Oncol 2001, 19:785-791.
• [32]Dhani N, Tu D, Sargent DJ, Seymour L, Moore MJ: Alternate endpoints for screening phase II studies. Clin Cancer Res 2009, 15:1873-1882.
• [33]Gutierrez ME, Kummar S, Giaccone G: Next generation oncology drug development: opportunities and challenges. Nat Rev Clin Oncol 2009, 6:259-265.
• [34]Baruchel S, Sharp JR, Bartels U, Hukin J, Odame I, Portwine C, Strother D, Fryer C, Halton J, Egorin MJ, et al.: A Canadian paediatric brain tumour consortium (CPBTC) phase II molecularly targeted study of imatinib in recurrent and refractory paediatric central nervous system tumours. Eur J Cancer 2009, 45:2352-2359.
• [35]Gallagher DJ, Milowsky MI, Gerst SR, Ishill N, Riches J, Regazzi A, Boyle MG, Trout A, Flaherty AM, Bajorin DF: Phase II Study of Sunitinib in Patients With Metastatic Urothelial Cancer. Journal of Clinical Oncology 2010, 28:1373-1379.
• [36]Gordon MS, Hussey M, Nagle RB, Lara PN Jr, Mack PC, Dutcher J, Samlowski W, Clark JI, Quinn DI, Pan CX, et al.: Phase II Study of Erlotinib in Patients With Locally Advanced or Metastatic Papillary Histology Renal Cell Cancer: SWOG S0317. Journal of Clinical Oncology 2009, 27:5788-5793.
• [37]Schiller JH, Larson T, Ou SH, Limentani S, Sandler A, Vokes E, Kim S, Liau K, Bycott P, Olszanski AJ, et al.: Efficacy and safety of axitinib in patients with advanced non-small-cell lung cancer: results from a phase II study. J Clin Oncol 2009, 27:3836-3841.
• [38]Burzykowski T, Buyse M, Piccart-Gebhart MJ, Sledge G, Carmichael J, Luck HJ, Mackey JR, Nabholtz JM, Paridaens R, Biganzoli L, et al.: Evaluation of tumor response, disease control, progression-free survival, and time to progression as potential surrogate end points in metastatic breast cancer. J Clin Oncol 2008, 26:1987-1992.
• [39]Fleming TR, Rothmann MD, Lu HL: Issues in using progression-free survival when evaluating oncology products. J Clin Oncol 2009, 27:2874-2880.
• [40]Ratain MJ, Stadler WM: Clinical trial designs for cytostatic agents. J Clin Oncol 2001, 19:3154-3155.
• [41]Nandram B, Liu N, Choi JW, Cox L: Bayesian non-response models for categorical data from small areas: an application to BMD and age. Stat Med 2005, 24:1047-1074.
• [42]Collett D: Modelling Survival Data in Medical Research. Boca Raton: Chapman & Hall/CRC; 2003.
• [43]Lawless JF: Statistical Models and Methods for Lifetime Data. Hoboken: John Wiley and Sons; 2003.
• [44]Panageas KS, Smith A, Gonen M, Chapman PB: An optimal two-stage phase II design utilizing complete and partial response information separately. Control Clin Trials 2002, 23:367-379.