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Biometric Research Program (BRP)

Dr. Lawrence Rubinstein

Mathematical Statistician, Biostatistics Branch


Lawrence Rubinstein received a Ph.D. in mathematical statistics from the Univ. of Maryland (1978). He has been in the Biometrics Research Program, NCI since 1985. He has published in a variety of areas relating to both clinical and pre-clinical studies. He helped to define methods for determining the required sample size in phase 3 studies. He has been involved in developing new designs for phase 0 trials and phase 1 trials and defining appropriate designs for phase 2 trials. He was involved with establishing and updating the RECIST response criteria, and participated in a 10-year review of phase 1 trial risks and benefits. He participated in the development of the in-vitro assay analysis tools used for the NCI human tumor cell line screen, and was responsible for statistical analyses that determined the degree of correlation between in-vitro and in-vivo results, for that screen, and phase 2 clinical results. His current responsibilities involve primary statistical review and advising capacities on NCI/CTEP clinical studies, helping to design and analyze NCI/DCTD pre-clinical and early clinical studies, as well as service on data monitoring committees, national clinical trials steering committees, and statistical liaison responsibilities with national cancer clinical trials organizations. He is on the editorial boards of CCR and JNCI.

Research Interests

Design, monitoring and analysis of clinical trials; pre-clinical drug screening and developmental clinical trials; gynecologic, gastrointestinal, and central nervous system cancer.

Selected Publications:

Therasse, P, Arbuck, SG, Eisenhauer, EA, Wanders, J, Kaplan, RS, Rubinstein, L Verweij, J, van Glabbeke, M, van Oosterom, A, Christian, MC, Gwyther, SG, New guidelines to evaluate the response to treatment in solid tumors, JNCI, 92:205-16, 2000.

Rubinstein, LV, Therapeutic studies, in Kramer, B.S. and Allegra, C.J. (eds.), Understanding Clinical Trials, Hematology/Oncology Clinics of North America. W.B. Saunders Co.,14(4):849-876, 2000.

Johnson, JI, Decker, S, Zaharevitz, D, Rubinstein, LV, Schepartz, SA, Venditti, JM, Kalyandrug, S, Arbuck, SG, Christian, M, Sausville, EA, Correlations between the National Cancer Institute USA, pre-clinical models and drug activity in human clinical trials, British Journal of Cancer, 84(10):1424-31, 2001.

Rubinstein LV and Simon RM: Phase I clinical trial design. In Budman, Calvert, Rowinsky, (eds.), Handbook of Anticancer Drug Development, Elsevier, Amsterdam, 297-308, 2003.

Hunsberger, SA, Rubinstein, LV, Dancey, J, Korn, EL, Dose escalation trial designs based on a molecularly targeted endpoint, Statistics in Medicine, 24:2171-2181, 2005.

Horstmann, E, McCabe, MS, Grochow, L, Yamamoto, S, Rubinstein, L, Budd, T, Shoemaker, D, Emanuel, EJ, Grady, C, Risks and benefits of phase 1 oncology research: Evaluating response rates and toxicities 1991-2002, New England Journal of Medicine, 352:895-904, 2005.

Rubinstein, LV, Korn, EL, Freidlin, B, Hunsberger, SA, Ivy, SP, Smith, MA, Randomized phase 2 design issues and a proposal for phase 2 screening trials, Journal of Clinical Oncology, 23:7199-7206, 2005.

Kummar, S, Kinders, R, Rubinstein, L, Parchment, RE, Murgo, AJ, Collins, J, Pickeral, O, Low, J, Steinberg, SM, Gutierrez, M, Yang, S, Helman, L, Wiltrout, R, Tomaszewski, JE and Doroshow, JH, Compressing drug development timelines in oncology using phase '0' trials, Nature Reviews Cancer 7, 131-139, 2007.

Rubinstein, L, Dancey, J, Korn, E, Smith, M, and Wright, J, Early average change in tumor size in a phase 2 trial: efficient endpoint or false promise?, Jour of the National Cancer Inst 99, 1422-23, 2007.

Kinders, R, Parchment, RE, Ji, J, Kummar, S, Murgo, AJ, Gutierrez, M, Collins, J, Rubinstein, L, Pickeral, O, Steinberg, SM, Yang, S, Hollingshead, M, Chen, A, Helman, L, Wiltrout, R, Simpson, M, Tomaszewski, JE and Doroshow JH, Phase 0 clinical trials in cancer drug development: From FDA guidance to clinical practice, Molecular Interventions 7, 325-334, 2008.

Kummar, S, Rubinstein, L, Kinders, R, Parchment, RE, Gutierrez, M, Murgo, AJ, Ji, J, Mroczkowski, B, Pickeral, O, Simpson, M, Hollingshead, M, Yang, S, Helman, L, Wiltrout, R, Collins, J, Tomaszewski, JE, Doroshow, JH, Phase 0 clinical trials: conceptions and misconceptions, The Cancer Journal 14, 133-137, 2008.

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), European Journal of Cancer 45, 228-247, 2009.

Dancey, J, Dodd, LE, Ford, R, Kaplan, R, Mooney, M, Rubinstein, L, Schwartz, LH, Shankar, L, Therasse, P, Recommendations for the assessment of progression in randomized cancer treatment trials, European Journal of Cancer 45, 281-289, 2009.

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, European Journal of Cancer 45, 290-299, 2009.

Rubinstein, L, Crowley, J, Ivy, P, LeBlanc, M, Sargent, D, Randomized phase II designs, Clinical Cancer Research 15, 1883-1890, 2009.

Sill, M and 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, ed. Peace, K., Chapman-Hall, p. 15-69, 2009.

Kummar, S, Kinders, R, Gutierrez, M, Rubinstein, L, Parchment, RE 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, Journal of Clinical Oncology, 27:2705-2711, 2009.

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, Clinical Cancer Research, 16: 1764-69, 2010.

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, Clinical Cancer Research, 16: 1726-36, 2010.

Rubinstein, L, Steinberg, S, Kummar, S, Kinders, R, Parchment, R, Murgo, A, Tomaszeweski, J, Doroshow, J, Statistics of phase 0 designs, Statistics in Medicine 20, 1072-1076, 2010.

Rubinstein, L, LeBlanc, M, Smith, M, More randomization in phase II trials: necessary but not sufficient, Journal of the National Cancer Institute 103: 1075-1077, 2011.

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, Clinical Trials, 9: 385-395, 2012.

Gupta, S, Boerner, SA, Alqwasmi, A, Hunsberger, S, Rubinstein, L, Royds, R, Ivy, Lorusso, P, Meta-analysis of the relationship between increasing dose and clinical benefit in phase 1 trials of molecularly targeted agents, Journal of the National Cancer Institute, 104: 1860-1866, 2012.

Chen, HX, Rubinstein, LV, Shankar, LK, Abrams, JS, Are we ready for the 10% solution, The Oncologist, 19: 439-440, 2014.

Rubinstein, L, Phase II design: history and evolution, Chinese Clinical Oncology, 3:48-59, 2014.

Kummar, S, Williams, M, Lih, C-J, Polley, EC, Chen, AP, Rubinstein, LV, Zhao, Y, Simon, RM, Conley, BA, Doroshow, JH, Application of Molecular Profiling in Clinical Trials for Refractory Cancers, Journal of the National Cancer Institute, 107, 2015.

Gilbert, G, Rubinstein, L, Lesser, G, Creating Clinical Trial Designs that Incorporate Clinical Outcome Assessments, Neuro-Oncology, 18 (suppl 2): ii21-25, 2016.

Kummar, S, Do, K, Coyne, G O, Chen, A, Ji, J, Rubinstein, L, Doroshow, JH, Establishing Proof of Mechanism: Assessing Target Modulation in Early-phase Clinical Trials, Seminars in Oncology, 43(4), 446-452, 2016.

Massett, HA, Mishkin, G, Rubinstein, L, Ivy, P, Denicoff, A, Godwin, E, DiPiazza, K, Bolognese, J, Zwiebel, J, Abrams, J, Challenges Facing Early Phase Trials Sponsored by the National Cancer Institute: An Analysis of Corrective Action Plans to Improve Accrual, Clinical Cancer Research, 22(22), 5408-16, 2016.

Holbeck, SL, Camalier, R, Crowell, J, Govindharajulu, J, Hollingshead, M, Hose, M, Polley, E, Rubinstein, L, Schweikart, K, Srivastava, A, Svetlik, P, Wilsker, D, Collins, JM, and Doroshow, JH, The National Cancer Institute ALMANAC: A Comprehensive Screening Resource for the Detection of Anticancer Drug Pairs with Enhanced Therapeutic Activity, Cancer Research, 77(13), 3564-3576, 2017.

Mehnert, JM, Monjazeb, AM, Beerthuijzen, JMT, Collyar, D, Rubinstein, L, Harris, LN, The challenge for development of valuable immune-oncology biomarkers, Clinical Cancer Research, 23(17), 4970-4979, 2017.

Seidman, AD, Bordeleau, L, Fehrenbacher, L, Barlow, WE, Perlmutter, J, Rubinstein, L, Wedam, SB, Hershman, DL, Hayes, JF, Butler, LP, Smith, ML, Regan, MM, Beaver, JA, Amiri-Kordestani, L, Rastogi, P, Zujewski, JA, Korde, LA, NCI Breast cancer steering committee working group report on meaningful and appropriate endpoints for clinical trials in metastatic breast cancer, JCO, 36: 3259-3268, 2018.

Lynce, F, Blackburn, MJ, Cai, L, Wang, H, Rubinstein, L, Harris, P, Isaacs, C, Pohlmann, PR, Characteristics and outcomes of breast cancer patients enrolled in the National Cancer Institute Cancer Therapy Evaluation Program sponsored phase I clinical trials, Breast Cancer Research and Treatment, 168:35-41, 2018.

Evans, DM, Fang, J, Silvers, T, Delosh, R, Laudeman, J, Ogle, C, Reinhart, R, Selby, M, Connelly, J, Harris, E, Krushkal, J, Rubinstein, L, Doroshow, JH, Collins, JM, Teicher, BA, Exposure Time versus Cytotoxicity for Anticancer Agents, Cancer Chem and Pharmac, Cancer Chem and Pharm, 84(2): 359-371, 2019.

Hirakawa, A, Sudo, K, Yonemori, K, Kinoshita, F, Kobayashi, Y, Okuma, HS, Kawachi, A, Tamura, K, Fujiwara, Y, Rubinstein, L, Takebe, N, A comparative study of longitudinal toxicity of cancer drug treatments, Clin Pharmac and Ther, 106(4): 803-809, 2019.

Armstrong, TS, Dirven, L, Arons, D, Bates, A, Chang, S, Coens, C, Espinasse, C, Gilbert, MR, Jenkinson, D, Kluetz, P, Mendoza, T, Rubinstein, L, Sul, J, Weller, M, Wen, P, Vandenbent, M, Taphoorn, M, Glioma Patient Reported Outcome Assessment in Clinical Care and Research: A RANO Collaborative Report, The Lancet Oncology, 21(2): e97-103, 2020.

Lee, YC, Wang, L, Kohn, EC, Rubinstein, L, Ivy, SP, Harris, P, Lheureux, S, Evaluation of toxicities related to novel therapy in clinical trials for patients with gynaecologic cancers, Cancer, 126(10): pp. 2139-2145, 2020.

Armstrong, TS, Dirven, L, Arons, D, Bates, A, Chang, S, Coens, C, Espinasse, C, Gilbert, MR, Jenkinson, D, Kluetz, P, Mendoza, T, Rubinstein, L, Sul, J, Weller, M, Wen, P, Vandenbent, M, Taphoorn, M, Glioma Patient Reported Outcome Assessment in Clinical Care and Research: A RANO Collaborative Report, The Lancet Oncology, 21(2): e97-103, 2020.

Kunos, CA, Rubinstein, L, Capala, J, McDonald, MA, Phase 0 Radiopharmaceutical-Agent Clinical Development, Frontiers in Oncol, 10:1310, 2020.

Flaherty, KT, Gray, R, Chen, A, Li, S, Patton, D, Hamilton, SR, Williams, PM, Mitchell, E, Iafrate, AJ, Sklar, J, Harris, LN, McShane, LM, Rubinstein, L, Sims, D, Routbort, M, Coffey, B, Fu, T, Zwiebel, J, Little, R, Marinucci, D, Catalano, R, Magnan, R, Kibbe, W, Weil, C, Tricoli, J, Alexander, B, Kumar, S, Schwartz, GK, Meric-Bernstam, F, Lih, C-J, McCaskill-Stevens, W, Calmi, P, Takebe, N, Datta, V, Arteaga, C, Abrams, J, Comis, RL,* O'Dwyer, P, Conley, BA, NCI-MATCH Team, Molecular Analysis for Therapy Choice (NCI-MATCH ) Trial: Lessons for Genomic Trial Design, JNCI: 112(10), 1021-1029, 2020.

Flaherty, KT, Gray R, Chen, A, Li, S, McShane, LM, Patton, D, Hamilton, SR, Williams, PM, Iafrate, AJ, Sklar, J, Mitchell, E, Harris, LN, Sims, DJ, Coffey, B, Fu, T, Routbort, M, Zwiebel, J, Rubinstein, L, Little, R, Arteaga, C, Comis, RL, Abrams, J, O'Dwyer, PJ, Conley, BA, for the NCI-MATCH team, Molecular Landscape and Actionable Alterations in a Genomically-Guided Cancer Clinical Trial: NCI-MATCH (Molecular Analysis for Therapy Choice), J of Clin Oncol, 38(33): 3883-3894, 2020.

Chen, AP, Kummar, S, Moore, N, Rubinstein, LV, Zhao, Y, Williams, PM, Palmisano, A, Sims, D, O'Sullivan Coyne, G, Rosenberger, C, Simpson, M, Raghav, KPS, Meric-Bernstam, F, Leong, S, Waqar, S, Foster, J, Polley, E, Simon, R, Konate, M, Das, B, Karlovich, C, Lih, C-J, Piekarz, R, and Doroshow, JH, Molecular Profiling-Based Assignment of Cancer Therapy (NCI-MPACT): A Randomized Multicenter Phase 2 Trial, JCO Precis Oncol, 5: 133-144, 2021.

Yang, SX, Hollingshead, M, Rubinstein, L, Nguyen, D, Larenjeira, A, Kinders, R, Difilippantonio, M, Doroshow, JH, TET2 and DNMT3A Mutations and Exceptional Response to 4'-Thio-2'-Deoxycytidine in Human Solid Tumor Models, J of Hem and Oncol, 14:83, 2021.

Dirven, L, Vos, ME, Walbert, T, Armstrong, TS, Arons, D, Bates, A, van den Bent, MJ, Blakeley, J, Brown, P, Bulbeck, H, Chang, SM, Coens, C, Espinasse, C, Gilbert, MR, Grant, R, Jalali, R, Jenkinson, D, Kluetz, P, Leeper, H, Mendoza, T, Nayak, L, Oliver, K, Reijneveld, JC, Rhun, EL, Rubinstein, L, Weller, M, Wen, PY, Taphoorn, MJB, Systematic review on the use of patient-reported outcome measures in brain tumor studies: part of the Response Assessment in Neuro-Oncology Patient Reported Outcome (RANO-PRO) initiative, Neuro-Oncology Practice 8(4), 417-425, 2021.

Dr. Lawrence Rubinstein

Office Address:
Room 5W106
9609 Medical Center Dr
Rockville, MD 20850

Contact Information:
Tel: (240) 276-6026
Fax: (240) 276-7888