Early Clinical Trial Design Recommendations in Oncology Based on Overall Success across ...

204 Pages·2017·3.55 MB·English

Early Clinical Trial Design Recommendations in Oncology
Based on Overall Success across Phases I, II, and III
Dissertation
Presented in Partial Fulfillment of the Requirements for the Degree
Doctor of Philosophy in the Graduate School of The Ohio State
University
By
Amy S. Ruppert Stark, M.A.S.
Graduate Program in Biostatistics
The Ohio State University
2017
Dissertation Committee:
Dr. Abigail Shoben, Advisor
Dr. Rebecca Andridge
Dr. John Byrd
Dr. Jason Hsu
(cid:13)c Copyright by
Amy S. Ruppert Stark
2017
Abstract
Conventionally, drug development has spanned three distinct phases, and the
success rate for experimental drugs across phases has been less than 15% (Hay,
Thomas, Craighead, Economides, and Rosenthal, 2014). Despite increased options
for nonstandard early phase designs, lack of familiarity and a perceived increase in
complexity have been barriers to their use. Herein, we provide early phase design
recommendations for standard and nonstandard designs, considering the trade-offs
between performance, design complexity, and ease of implementation. We focus
on overall success rate as a performance measure, which quantifies the ability to
recognize a favorable drug across phases.
Phase I, II, and III trials were simulated for clinical scenarios defined by eight
toxicity profiles and two nondecreasing efficacy profiles. Early results showed that
correctly selecting the maximum tolerated dose (MTD) greatly impacted overall
success rates. Hence, we primarily evaluated phase I dose-finding designs, including
the rule-based standard 3+3 design, the CCD, BOIN, mTPI, and mTPI-2 interval
designs, and the model-based CRM design. Phase I designs were followed by Simon’s
optimal phase II design and a randomized group sequential phase III design. A
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seamless phase I/II SEARS design, integrating toxicity and efficacy data, was also
considered.
Based on our results, we make the following recommendations for design selection
when data informing the shape of the dose-toxicity curve exist. If a large jump in
toxicity between dose levels is expected, we recommend the standard 3+3 design,
which more often recognized when the MTD had been exceeded and resulted in
the highest overall success rates. If gradually increasing toxicity is expected, we
recommend a nonstandard design other than the CRM. Nonstandard designs were
more aggressive in dosing decisions and MTD estimation than the standard 3+3
design and resulted in higher overall success rates, but the CRM was too aggressive
and most frequently overestimated the MTD. If fairly constant and safe toxicity is
expected, we recommend the BOIN or CRM designs, which escalated to the highest
dose level most frequently and had superior overall success rates. If in addition
to a constant and safe toxicity profile, multiple dose levels with favorable efficacy
are expected, we recommend a phase I/II SEARS design, which had higher overall
success rates and more frequent selection of the lowest dose level with highest efficacy
compared to separate phase I and II designs. A phase I/II SEARS design is also
recommended if an unconventional nonmonotonic toxicity profile is expected, since
overall success rates were 2-3 times higher than when separate phase I and II designs
were used.
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Without data informing the shape of the dose-toxicity curve, we recommend
nonstandard phase I designs with a modified excessive toxicity rule that more easily
eliminates dose levels due to safety concerns. With this modification, the MTD
overestimation error decreased and overall success rates were similar or higher with
nonstandard designs versus the standard 3+3 design. Among nonstandard designs,
we recommend the modified CCD and BOIN designs, since both perform well and
are as transparent and simple as the standard 3+3 design to implement.
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To my husband Greg and our daughter Emma.
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Acknowledgments
I would like to acknowledge my advisor, Dr. Abby Shoben, for her time and
encouragement that she showed over the past five years. I have grown in multiple
areas as a statistical researcher due to her continual guidance. I would like to
acknowledge Drs. Jason Hsu, Stan Lemeshow, John Byrd, and Rebecca Andridge for
serving on my candidacy and dissertation committees. Additionally, I acknowledge
Drs. Doug Wolfe and Rebecca Andridge for coaching me through the first two
qualifying exams of my program. I acknowledge Drs. Steve MacEachern, Doug
Critchlow, Elizabeth Stasney, and Raj Nagaraja, all who said they were not only
happy to see me pursue a PhD but also that I was capable of obtaining it. Those
words, spoken in passing, kept me going through the years and were invaluable.
I especially want to thank my family and friends for their love and support.
Thank you Greg and Emma for being so patient and allowing me to take the time
needed to complete this chapter in my life. Thank you Greg for motivating me and
believing in me even when I wanted to throw in the towel. Thank you to my parents
and my sister for being positive throughout these many years of schooling.
I am thrilled to celebrate this achievement with all of you, without whom this
winding road would have been ever more bumpy.
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Vita
October 8, 1976 ............................Born - Columbus, Ohio, U.S.A.
Education
1999 .......................................B.S. Secondary Education,
Miami University
Oxford, OH
2002 .......................................M.A.S. Statistics,
The Ohio State University
Columbus, OH
Professional Experience
1999-2000 ..................................Assistant Editor-Mathematics,
Glencoe/McGraw-Hill Publishing
Columbus, OH
2001 .......................................Summer Research Intern,
Battelle Memorial Institute
Columbus, OH
2002-2007 ..................................Research Specialist,
Comprehensive Cancer Center
The Ohio State University
Columbus, OH
2007-2010 ..................................Sr. Consulting Research Statistician,
Center for Biostatistics
The Ohio State University
Columbus, OH
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2010-present ...............................Research Specialist,
Division of Hematology
The Ohio State University
Columbus, OH
Publications
Research Publications
Woyach, J.A., Ruppert, A.S., Guinn, D., Lehman, A.M., Blachly, J.S., Lozanski,
A., Heerema, N.A., Zhao, W., Coleman, J., Jones, D., Abruzzo, L., Gordon, A.,
Mantel, R., Smith, L.L., McWhorter, S., Davis, M., Doong, T.J., Ny, F., Lucas, M.,
Chase, W., Jones, J.A., Flynn, J.M., Maddocks, K.J., Rogers, K.A., Jaglowski, S.M.,
Andritsos, L.A., Awan, F.T., Blum, K.A., Grever, M.R., Lozanski, G., Johnson,
A.J., and Byrd, J.C. (2017). BTKC481S-mediated resistance to ibrutinib in chronic
lymphocytic leukemia. Journal of Clinical Oncology, 35(13):1437-1443.
Miller, C.R., Ruppert, A.S., Fobare, S., Chen, T.L., Liu, C., Lehman, A.M.,
Blachly, J.S., Zhang, X., Lucas, D.M., Grever, M.R., Tallman, M.S., Flinn, I.W.,
Rassenti, L.Z., Kipps, T.J., Sampath, D., Coombes, K.R., and Hertlein, E.K. (2017).
The long noncoding RNA, treRNA, decreases DNA damage and is associated with
poor response to chemotherapy in chronic lymphocytic leukemia. Oncotarget,
8(16):25942-25954.
Bond, D., Huang, Y., Ruppert, A.S, Walker, A.R., Dotson, E.K., Roddy, J.,
Blum, K.A., and Christian, B.A. (2017). Retrospective analysis of bendamustine
and rituximab use in indolent and mantle cell non-Hodgkin lymphoma based on
initial starting dose. Leukemia & Lymphoma, 58(7):1589-1597.
Haverkos B.M., Huang Y., Gru A., Pancholi P., Freud A.G., Mishra A., Ruppert,
A.S., Baiocchi, R.A., and Porcu P. (2017). Frequency and clinical correlates of
elevatedplasmaEpstein-BarrvirusDNAatdiagnosisinperipheralT-celllymphomas.
International Journal of Cancer, 140(8):1899-1906.
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Ranganathan, P., Ngankeu, A., Zitzer, N.C., Leoncini, P., Yu, X., Casadei, L.,
Challagundla, K., Reichenbach, D.K., Garman, S., Ruppert, A.S., Volinia, S.,
Hofstetter, J., Efebera, Y.A., Devine, S.M., Blazar, B.R., Fabbri, M., and Garzon,
R. (2017). Serum miR-29a is upregulated in acute graft-versus-host disease and
activates dendritic cells through TLR binding. Journal of Immunology,
198(6):2500-2512.
Flinn, I.W., Ruppert, A.S., Harwin, W., Waterhouse, D., Papish, S., Jones, J.A.,
Hainsworth, J., and Byrd, J.C. (2016). A phase II study of two dose levels of
ofatumumab induction followed by maintenance therapy in symptomatic, previously
untreated chronic lymphocytic leukemia. American Journal of Hematology,
91(10):1020-1025.
Chen, T.L., Gupta, N., Lehman, A.M., Ruppert, A.S., Yu, L., Oakes, C.C.,
Claus, R., Plass, C., Maddocks, K.J., Andritsos, L.A., Jones, J.A., Lucas, D.M.,
Johnson,A.J.,Byrd,J.C.,andHertlein,E.(2016). Hsp90inhibitionincreasesSOCS3
transcript and regulates migration and cell death in chronic lymphocytic leukemia.
Oncotarget, 7(19):28684-28696.
Oakes, C.C., Seifert, M., Assenov, Y., Gu, L., Przekopowitz, M., Ruppert, A.S.,
Wang,Q.,Imbusch,C.D.,Serva,A.,Koser,S.D.,Brocks,D.,Lipka,D.B.,Bogatyrova,
O., Weichenhan, D., Brors, B., Rassenti, L., Kipps, T.J., Mertens, D., Zapatka, M.,
Lichter, P., Do¨hner H., Ku¨ppers, R., Zenz, T., Stilgenbauer, S., Byrd, J.C., and
Plass, C. (2016). DNA methylation dynamics during B cell maturation underlie a
continuum of disease phenotypes in chronic lymphocytic leukemia. Nature Genetics,
48(3):253-264.
Rogers, K.A., Ruppert, A.S., Bingman, A., Andritsos, L.A., Awan, F.T., Blum,
K.A., Flynn, J.M., Jaglowski, S.M., Lozanski, G., Maddocks, K.J., Byrd, J.C.,
Woyach, J.A., and Jones, J.A. (2016). Incidence and description of autoimmune
cytopenias during treatment with ibrutinib for chronic lymphocytic leukemia.
Leukemia, 30(2):346-350.
Mikhail, S., Lustberg, M.B., Ruppert, A.S., Mortazavi, A., Monk, P., Kleiber, B.,
Villalona-Calero, M., and Bekaii-Saab, T. (2015). Biomodulation of capecitabine by
paclitaxelandcarboplatininadvancedsolidtumorsandadenocarcinomaofunknown
primary. Cancer Chemotherapy and Pharmacology, 76(5):1005-1012.
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