Journal of Clinical Oncology, Vol 20, Issue 22
(November), 2002: 4478-4484
© 2002 American Society for Clinical Oncology
Randomized Discontinuation Design: Application to Cytostatic Antineoplastic Agents
By Gary L. Rosner,
Walter Stadler,
Mark J. Ratain
From the Cancer and Leukemia Group B Statistical Office and Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and Section of Hematology/Oncology, Department of Medicine, Committees on Cancer Biology, and Clinical Pharmacology, and Cancer Research Center, The University of Chicago, Chicago, IL.
Address reprint requests to Gary L. Rosner, ScD, Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 447, Houston, TX 77030-4009; email: glr{at}odin.mdacc.tmc.edu
PURPOSE: Propose a phase II study design to evaluate the activity of a putative cytostatic agent, acknowledging heterogeneity of tumor growth rates in the population of patients.
METHODS: In the setting of renal cell carcinoma, some patients’ tumors will grow slowly naturally. An appropriate design has to distinguish antiproliferative activity attributable to the novel agent from indolent disease. We propose a randomized discontinuation design that initially treats all patients with the study agent (stage 1) and then randomizes in a double-blind fashion to continuing therapy or placebo only those patients whose disease is stable (stage 2). This design allows the investigators to determine if apparent slow tumor growth is attributable to the drug or to selection of patients with naturally slow-growing tumors.
RESULTS: By selecting a more homogeneous population, the randomized portion of the study requires fewer patients than would a study randomizing all patients at entry. The design also avoids potential confounding because of heterogeneous tumor growth. Because the two randomly assigned treatment groups each comprise patients with apparently slow growing tumors, any difference between the groups in disease progression after randomization is more likely a result of the study drug and less likely a result of imbalance with respect to tumor growth rates. Stopping rules during the initial open-label stage and the subsequent randomized trial stage allow one to reduce the overall sample size. Expected average tumor growth rate is an important consideration when deciding the duration of follow-up for the two stages.
CONCLUSION: The randomized discontinuation design is a feasible alternative phase II study design for determining activity of possibly cytostatic anticancer agents.
 CiteULike  Complore  Connotea  Del.icio.us  Digg  Facebook  Reddit  Technorati  Twitter What's this?
This article has been cited by other articles:
|
|
|
|
 
T. B. Dorff, A. Goldkorn, and D. I. Quinn
Review: Targeted therapy in renal cancer
Therapeutic Advances in Medical Oncology,
November 1, 2009;
1(3):
183 - 205.
[Abstract]
[PDF]
|
|
|
|
|
|
|
P. Fu, A. Dowlati, and M. Schluchter
Comparison of Power Between Randomized Discontinuation Design and Upfront Randomization Design on Progression-Free Survival
J. Clin. Oncol.,
September 1, 2009;
27(25):
4135 - 4141.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. M.G. Larkin, E. L.S. Kipps, C. J. Powell, and C. Swanton
Review: Systemic therapy for advanced renal cell carcinoma
Therapeutic Advances in Medical Oncology,
July 1, 2009;
1(1):
15 - 27.
[Abstract]
[PDF]
|
|
|
|
|
|
|
R. L. Wahl, H. Jacene, Y. Kasamon, and M. A. Lodge
From RECIST to PERCIST: Evolving Considerations for PET Response Criteria in Solid Tumors
J. Nucl. Med.,
May 1, 2009;
50(Suppl_1):
122S - 150S.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Rubinstein, J. Crowley, P. Ivy, M. LeBlanc, and D. Sargent
Randomized Phase II Designs
Clin. Cancer Res.,
March 15, 2009;
15(6):
1883 - 1890.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Dhani, D. Tu, D. J. Sargent, L. Seymour, and M. J. Moore
Alternate Endpoints for Screening Phase II Studies
Clin. Cancer Res.,
March 15, 2009;
15(6):
1873 - 1882.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. A. Adjei, M. Christian, and P. Ivy
Novel Designs and End Points for Phase II Clinical Trials
Clin. Cancer Res.,
March 15, 2009;
15(6):
1866 - 1872.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. M. Hartford, A. A. Desai, L. Janisch, T. Karrison, V. M. Rivera, L. Berk, J. W. Loewy, H. Kindler, W. M. Stadler, H. L. Knowles, et al.
A Phase I Trial to Determine the Safety, Tolerability, and Maximum Tolerated Dose of Deforolimus in Patients with Advanced Malignancies
Clin. Cancer Res.,
February 15, 2009;
15(4):
1428 - 1434.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. K. Daugherty, M. J. Ratain, E. J. Emanuel, A. T. Farrell, and R. L. Schilsky
Ethical, Scientific, and Regulatory Perspectives Regarding the Use of Placebos in Cancer Clinical Trials
J. Clin. Oncol.,
March 10, 2008;
26(8):
1371 - 1378.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. H. El-Maraghi and E. A. Eisenhauer
Review of Phase II Trial Designs Used in Studies of Molecular Targeted Agents: Outcomes and Predictors of Success in Phase III
J. Clin. Oncol.,
March 10, 2008;
26(8):
1346 - 1354.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Dowlati and P. Fu
Is Response Rate Relevant to the Phase II Trial Design of Targeted Agents?
J. Clin. Oncol.,
March 10, 2008;
26(8):
1204 - 1205.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. A. Garcia
Small Molecules: Big Changes in the Cancer Treatment Paradigm
Journal of Pharmacy Practice,
February 1, 2008;
21(1):
17 - 35.
[Abstract]
[PDF]
|
|
|
|
|
|
|
B. J. Lange, F. O. Smith, J. Feusner, D. R. Barnard, P. Dinndorf, S. Feig, N. A. Heerema, C. Arndt, R. J. Arceci, N. Seibel, et al.
Outcomes in CCG-2961, a Children's Oncology Group Phase 3 Trial for untreated pediatric acute myeloid leukemia: a report from the Children's Oncology Group
Blood,
February 1, 2008;
111(3):
1044 - 1053.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. M. Skolnik, J. S. Barrett, B. Jayaraman, D. Patel, and P. C. Adamson
Shortening the Timeline of Pediatric Phase I Trials: The Rolling Six Design
J. Clin. Oncol.,
January 10, 2008;
26(2):
190 - 195.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. M. Stadler
Tumor Burden Endpoints and Phase II Clinical Trial Design
ASCO Educational Book,
January 1, 2008;
2008(1):
89 - 93.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. C. Michaelis and M. J. Ratain
Phase II Trials Published in 2002: A Cross-Specialty Comparison Showing Significant Design Differences between Oncology Trials and Other Medical Specialties
Clin. Cancer Res.,
April 15, 2007;
13(8):
2400 - 2405.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. M. Stadler
The randomized discontinuation trial: a phase II design to assess growth-inhibitory agents
Mol. Cancer Ther.,
April 1, 2007;
6(4):
1180 - 1185.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Stadler
Chromosomes, Hypoxia, Angiogenesis, and Trial Design: A Brief History of Renal Cancer Drug Development
Clin. Cancer Res.,
March 15, 2007;
13(6):
1630 - 1633.
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. H. Johnson
Targeted therapies in combination with chemotherapy in non-small cell lung cancer.
Clin. Cancer Res.,
July 15, 2006;
12(14):
4451s - 4457s.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Ratain, T. Eisen, W. M. Stadler, K. T. Flaherty, S. B. Kaye, G. L. Rosner, M. Gore, A. A. Desai, A. Patnaik, H. Q. Xiong, et al.
Phase II Placebo-Controlled Randomized Discontinuation Trial of Sorafenib in Patients With Metastatic Renal Cell Carcinoma
J. Clin. Oncol.,
June 1, 2006;
24(16):
2505 - 2512.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Ratain, A. A. Miller, H. L. McLeod, A. P. Venook, M. J. Egorin, and R. L. Schilsky
The cancer and leukemia group B pharmacology and experimental therapeutics committee: a historical perspective.
Clin. Cancer Res.,
June 1, 2006;
12(11):
3612s - 3616s.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Gray, J. Manola, S. Saxman, J. Wright, J. Dutcher, M. Atkins, M. Carducci, W. See, C. Sweeney, G. Liu, et al.
Phase II Clinical Trial Design: Methods in Translational Research from the Genitourinary Committee at the Eastern Cooperative Oncology Group.
Clin. Cancer Res.,
April 1, 2006;
12(7):
1966 - 1969.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Sleijfer, C. Seynaeve, and J. Verweij
Using Single-Agent Therapy in Adult Patients with Advanced Soft Tissue Sarcoma Can Still Be Considered Standard Care
Oncologist,
November 1, 2005;
10(10):
833 - 841.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Freidlin and R. Simon
Evaluation of Randomized Discontinuation Design
J. Clin. Oncol.,
August 1, 2005;
23(22):
5094 - 5098.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. J. Lee and L. Feng
Randomized Phase II Designs in Cancer Clinical Trials: Current Status and Future Directions
J. Clin. Oncol.,
July 1, 2005;
23(19):
4450 - 4457.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. M. Stadler, G. Rosner, E. Small, D. Hollis, B. Rini, S. D. Zaentz, J. Mahoney, and M. J. Ratain
Successful Implementation of the Randomized Discontinuation Trial Design: An Application to the Study of the Putative Antiangiogenic Agent Carboxyaminoimidazole in Renal Cell Carcinoma--CALGB 69901
J. Clin. Oncol.,
June 1, 2005;
23(16):
3726 - 3732.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. G. Hilsenbeck
Statistical Issues in Early Phase Trials
Am. Assoc. Cancer Res. Educ. Book,
April 1, 2005;
2005(1):
98 - 100.
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. A. Sausville
Indifferently Pursued or Unowned Drugs: Who Should Lead Where Companies Do Not Tread?
J. Clin. Oncol.,
March 20, 2005;
23(9):
1796 - 1798.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Ratain and S. G. Eckhardt
Phase II Studies of Modern Drugs Directed Against New Targets: If You Are Fazed, Too, Then Resist RECIST
J. Clin. Oncol.,
November 15, 2004;
22(22):
4442 - 4445.
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. G. Roberts Jr, T. J. Lynch Jr, and B. A. Chabner
The Phase III Trial in the Era of Targeted Therapy: Unraveling the "Go or No Go" Decision
J. Clin. Oncol.,
October 1, 2003;
21(19):
3683 - 3695.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. K. Rowinsky
Challenges of Developing Therapeutics That Target Signal Transduction in Patients With Gynecologic and Other Malignancies
J. Clin. Oncol.,
May 15, 2003;
21(90100):
175s - 186.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
