Contributed by Dr. Larry Rubinstein
Dr. Larry Rubinstein conducts research on the statistical issues of pre-clinical and early clinical drug development. He has worked DTP and CTEP staff to evaluate new drug combinations in vitro and in vivo. He has helped to develop and implement an in vitro screening methodology, with Dr. Freidlin and DTP staff, for testing the combined effect of adding a new agent to an established agent. He has helped analyze in vivo pediatric combination studies, with Dr. Malcolm Smith of CTEP and Children’s Oncology Group (COG) staff.
Dr. Rubinstein has provided statistical leadership to the NCI phase 0 clinical trials working group, made up of DCTD and CCR staff. He developed innovative statistical designs to assess pharmacodynamic endpoints for phase 0 protocols in general, for the NCI phase 0 PARP inhibitor trial in particular, and for the NCI randomized phase 1 indenoisoquinolone trial. As statistician for these trials, he is collaborating on the management and analysis, in particular, the analysis of the molecular assay endpoints, and in the publication of methodology and results.
Dr. Rubinstein has helped to develop and evaluate new designs for phase 1 and phase 2 clinical studies. He has collaborated in a review of the use and performance of accelerated titration phase 1 designs and has helped to develop innovative dual-endpoint designs to enable evaluation in phase 2 trials of new agents for which both tumor response rate and PFS are important. He is collaborating with Drs. Hunsberger and Lorusso (Wayne State University) to analyze the relation between dose and response in a large collection of phase 1 trials. He is also collaborating with Dr. Hunsberger to evaluate by simulation the possible advantages of attempting to “borrow strength” between multiple arms of a phase 2 trial, defined by histology or molecular characteristics, which are meant to be evaluated separately, rather than compared. He has participated in investigations concerning the advisability of blinded independent central review of PFS in phase 2 and phase 3 studies.
Dr. Rubinstein has been actively involved with the international collaborative effort to update the original RECIST (Response Evaluation Criteria In Solid Tumors) publication. He has been especially active in working with the new NCI/extramural national steering committees mandated by the Clinical Trials Working Group, as well as with many of the numerous associated task forces. He is the NCI statistician for both the GI and the gynecologic cancer steering committees, providing statistical leadership in the development of new national phase 3 trial concepts. He is also the NCI statistician for the investigational drug steering committee, and provides statistical leadership to its clinical trials design task force, helping to plan and participating in national workshops, and publishing the recommendations and results.
Bogaerts J, Ford R, Sargent D, Schwartz LH, Rubinstein L, Lacombe D, Eisenhauer EA, Verweij J, Therasse P, RECIST Working Party. Individual patient data analysis to assess modifications to the RECIST criteria. Eur J Cancer 2009:45;248-60. http://www.ncbi.nlm.nih.gov/pubmed/19095437
Dancey J, Dodd LE, Ford R, Kaplan R, Mooney M, Rubinstein L, Schwart, LH, Shankar L, Therasse P. Recommendations for the assessment of progression in randomized cancer treatment trials. Eur J Cancer 2009:45; 281-89. http://www.ncbi.nlm.nih.gov/pubmed/19097775
Dodd LE, Korn EL, Freidlin B, Rubinstein LV, Dancey J, Jaffe CC, Mooney MM. Onsite image evaluations and independent image blinded reads: Close cousins or distant relatives? Reply. J Clin Oncol 2009:27;2104-05. http://jco.ascopubs.org/content/27/12/2104.full
Dodd LE, Korn EL, Freidlin B, Dancey J, Jaffe CC, Mooney MM, Rubinstein LV. Are onsite image evaluations the solution or are we trading one problem for another? Reply. J Clin Oncol 2009:27: e263-4. http://www.ncbi.nlm.nih.gov/pubmed/19901131
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). Eur J Cancer 2009:45;228-47. http://www.ncbi.nlm.nih.gov/pubmed/19097774
Ford R, Schwartz L, Dancey J, Dodd L, Eisenhauer EA, Gwyther S, Rubinstein L, Sargent D, Shankar L, Therasse P, Verweij J. Lessons learned from independent central review. Eur J Cancer 2009:45;268-274.
Heath EI, LoRusso PM, Ivy SP, Rubinstein L, Christian MC, Heilbrun LK. Theoretical and practical application of traditional and accelerated titration phase I clinical trial designs: The Wayne State University experience. J Biopharm Stat 2009:19; 414-23. http://www.ncbi.nlm.nih.gov/pubmed/19384685
Ivy P, Siu L, Garrett-Mayer E, Rubinstein L. Approaches to phase 1 clinical trial design focused on safety, efficiency and selected patient populations: A report from the Clinical Trial Design Task Force of the NCI IDSC. Clin Cancer Res 2010:16;1726-36. http://www.ncbi.nlm.nih.gov/pubmed/20215542
Kinders RJ, Hollingshead M, Lawrence S, Ji J, Tabb B, Bonner WM, Pommier Y, Rubinstein L, Parchment RE, Tomaszewski J, Doroshow JH, and the National Cancer Institute Phase 0 Clinical Trials Team. Development of a validated immunofluorescence assay for γH2AX as a pharmacodynamic marker of topoisomerase inhibitor activity. Clin Cancer Res 2010:16;5447-57. http://www.ncbi.nlm.nih.gov/pubmed/20924131
Kummar S, Kinders R, Gutierrez M, Rubinstein L, Parchment R, Phillips LR, Ji J, Monks A, Low J, Chen A, Murgo AJ, Collins J, Steinberg S, Eliopoulos H, Giranda VL, Gordon G, Helman L, Wiltrout R, Tomaszewski JE, Doroshow JH, and the NCI Phase 0 Working Group. Phase 0 clinical trial of the Poly (ADP-ribose) Polymerase (PARP) inhibitor ABT-888 in patients with advanced malignancies. J Clin Oncol 2009:27;2705-11. http://www.ncbi.nlm.nih.gov/pubmed/19364967
Kummar S, Chen A, Ji J, Reid JM, Jia L, Weil M, Speranza G, Murgo AJ, Kinders R, Wang L, Parchment RE, Carter J, Stotler H, Rubinstein L, Hollingshead M, Melillo G, Tomaszewski JE, Doroshow JH. Phase I study of ABT-888 in combination with topotecan hydrochloride in adults with refractory solid tumors and lymphomas. Cancer Res (Submitted).
Houghton PJ, Morton CL, Gorlick R, Lock RB, Carol H, Reynolds CP, Kang MH, Maris JM, Keir ST, Kolb EA, Wu J, Watkins AE, Billups CA, Rubinstein L, Smith MA. Stage 2 combination testing of rapamycin with cytotoxic agents by the Pediatric Preclinical Testing Program. Mol Cancer Ther 2010:9;101-12. http://www.ncbi.nlm.nih.gov/pubmed/20053767
Nguyen D, Zajac-Kaye M, Rubinstein L, Voeller D, Tomaszewski JE, Kummar S, Chen AP, Pommier Y, Doroshow JH, Yang S. Genome-wide identification and validation of molecular pathways implicated in response to poly(ADP-ribose) polymerase inhibition plus DNA damaging agent. Mol Cancer Ther (Submitted).
Rubinstein L, Crowley J, Ivy P, LeBlanc M, Sargent D. Randomized phase II designs, Clin Cancer Res 2009:15;1883-90. http://www.ncbi.nlm.nih.gov/pubmed/19276275
Rubinstein L, Steinberg S, Kummar S, Kinders R, Parchment R, Murgo A, Tomaszeweski J, Doroshow J. Statistics of phase 0 designs. Stat Med 2010:29;1072-76. http://www.ncbi.nlm.nih.gov/pubmed/20419759
Rubinstein L. Phase 0 trials. In: Handbook of Statistics in Clinical Oncology, 3rd edition. Crowley J, ed. 2011. (In press).
Sargent DJ, Rubinstein L, Schwartz L, Dancey JE, Gatsonis C, Dodd LE, Shankar LK. Validation of novel imaging methodologies for use as cancer clinical trial endpoints. Eur J Cancer 2009:45;290-99. http://www.ncbi.nlm.nih.gov/pubmed/19091547
Seymour L, Ivy P, Sargent D, Spriggs D, Baker L, Rubinstein L, Ratain M, LeBlanc M, Stewart D, Crowley J, Groshen S, Humphrey J, West P, Berry D. The design of phase II clinical trials testing cancer therapeutics: Consensus recommendations from the clinical trials task force and the investigational drug steering committee. Clin Cancer Res 2010:16;1764-69. http://www.ncbi.nlm.nih.gov/pubmed/20215557
Sill M, Rubinstein L. Design (and monitoring) of clinical trials with time-to-event endpoints. In: Design, Summarization, Analysis & Interpretation of Clinical Trials with Time-To-Event Endpoints. Peace K, ed. Norwell, MA: Kluwer Academic Publishers;2009.
Sill M, Rubinstein L, Litwin S, Yothers G. A method for utilizing bivariate efficacy outcome measures to screen agents for activity in 2-stage phase 2 clinical trials. Stat Med (Submitted).
Wang LH, Pfister TD, Parchment RE, Kummar S, Rubinstein L, Evrard YA, Gutierrez ME, Murgo AJ, Tomaszewski JE, Doroshow JH, Kinders RJ. Monitoring drug-induced γH2AX changes as a pharmacodynamic biomarker in individual circulating tumor cells. Clin Cancer Res 2010:16;1073-84. http://www.ncbi.nlm.nih.gov/pubmed/20103672
Yang SX, Kummar S, Steinberg SM, Murgo AJ, Gutierrez M, RubinsteinL, Nguyen D, Kaur G, Chen AP, Giranda VL, Tomaszewski JE, Doroshow JH, the NCI Phase 0 Working Group. Immunohistochemical detection of poly(ADP-ribose) polymerase inhibition by ABT-888 in patients with refractory solid tumors and lymphoma. Cancer Biol Ther 2009:8;2004-09. http://www.ncbi.nlm.nih.gov/pubmed/19823047
Richard Simon, D.Sc., leads the Biometric Research Program and is chief of the Computational & Systems Biology Branch. Dr. Simon holds a doctoral degree in Applied Mathematics & Computer Science from Washington University in St. Louis, MO. More…