Phase 0 clinical trial of the poly (ADP-ribose) polymerase inhibitor ABT-888 in patients with advanced malignancies. Kummar, S., Kinders, R., Gutierrez, M. E., Rubinstein, L., Parchment, R. E., Phillips, L. R., Ji, J., Monks, A., Low, J. A., Chen, A., Murgo, A. J., Collins, J., Steinberg, S. M., Eliopoulos, H., Giranda, V. L., Gordon, G., Helman, L., Wiltrout, R., Tomaszewski, J. E., & Doroshow, J. H. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 27(16):2705–2711, June, 2009. doi abstract bibtex PURPOSE: We conducted the first phase 0 clinical trial in oncology of a therapeutic agent under the Exploratory Investigational New Drug Guidance of the US Food and Drug Administration. It was a first-in-human study of the poly (ADP-ribose) polymerase (PARP) inhibitor ABT-888 in patients with advanced malignancies. PATIENTS AND METHODS: ABT-888 was administered as a single oral dose of 10, 25, or 50 mg to determine the dose range and time course over which ABT-888 inhibits PARP activity in tumor samples and peripheral blood mononuclear cells, and to evaluate ABT-888 pharmacokinetics. Blood samples and tumor biopsies were obtained pre- and postdrug administration for evaluation of PARP activity and pharmacokinetics. A novel statistical approach was developed and utilized to study pharmacodynamic modulation as the primary end point for trials of limited sample size. RESULTS: Thirteen patients with advanced malignancies received the study drug; nine patients underwent paired tumor biopsies. ABT-888 demonstrated good oral bioavailability and was well tolerated. Statistically significant inhibition of poly (ADP-ribose) levels was observed in tumor biopsies and peripheral blood mononuclear cells at the 25-mg and 50-mg dose levels. CONCLUSION: Within 5 months of study activation, we obtained pivotal biochemical and pharmacokinetic data that have guided the design of subsequent phase I trials of ABT-888 in combination with DNA-damaging agents. In addition to accelerating the development of ABT-888, the rapid conclusion of this trial demonstrates the feasibility of conducting proof-of-principle phase 0 trials as part of an alternative paradigm for early drug development in oncology.
@article{kummar_phase_2009,
title = {Phase 0 clinical trial of the poly ({ADP}-ribose) polymerase inhibitor {ABT}-888 in patients with advanced malignancies},
volume = {27},
issn = {1527-7755},
doi = {10.1200/JCO.2008.19.7681},
abstract = {PURPOSE: We conducted the first phase 0 clinical trial in oncology of a therapeutic agent under the Exploratory Investigational New Drug Guidance of the US Food and Drug Administration. It was a first-in-human study of the poly (ADP-ribose) polymerase (PARP) inhibitor ABT-888 in patients with advanced malignancies.
PATIENTS AND METHODS: ABT-888 was administered as a single oral dose of 10, 25, or 50 mg to determine the dose range and time course over which ABT-888 inhibits PARP activity in tumor samples and peripheral blood mononuclear cells, and to evaluate ABT-888 pharmacokinetics. Blood samples and tumor biopsies were obtained pre- and postdrug administration for evaluation of PARP activity and pharmacokinetics. A novel statistical approach was developed and utilized to study pharmacodynamic modulation as the primary end point for trials of limited sample size.
RESULTS: Thirteen patients with advanced malignancies received the study drug; nine patients underwent paired tumor biopsies. ABT-888 demonstrated good oral bioavailability and was well tolerated. Statistically significant inhibition of poly (ADP-ribose) levels was observed in tumor biopsies and peripheral blood mononuclear cells at the 25-mg and 50-mg dose levels.
CONCLUSION: Within 5 months of study activation, we obtained pivotal biochemical and pharmacokinetic data that have guided the design of subsequent phase I trials of ABT-888 in combination with DNA-damaging agents. In addition to accelerating the development of ABT-888, the rapid conclusion of this trial demonstrates the feasibility of conducting proof-of-principle phase 0 trials as part of an alternative paradigm for early drug development in oncology.},
language = {eng},
number = {16},
journal = {Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology},
author = {Kummar, Shivaani and Kinders, Robert and Gutierrez, Martin E. and Rubinstein, Larry and Parchment, Ralph E. and Phillips, Lawrence R. and Ji, Jiuping and Monks, Anne and Low, Jennifer A. and Chen, Alice and Murgo, Anthony J. and Collins, Jerry and Steinberg, Seth M. and Eliopoulos, Helen and Giranda, Vincent L. and Gordon, Gary and Helman, Lee and Wiltrout, Robert and Tomaszewski, Joseph E. and Doroshow, James H.},
month = jun,
year = {2009},
keywords = {Administration, Oral, Aged, Antineoplastic Agents, Benzimidazoles, Biological Availability, Biopsy, Clinical Trials, Phase I as Topic, Dose-Response Relationship, Drug, Enzyme Inhibitors, Feasibility Studies, Female, Humans, Leukocytes, Mononuclear, Male, Middle Aged, Neoplasms, Poly(ADP-ribose) Polymerase Inhibitors, Research Design, Treatment Outcome},
pages = {2705--2711},
}
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It was a first-in-human study of the poly (ADP-ribose) polymerase (PARP) inhibitor ABT-888 in patients with advanced malignancies. PATIENTS AND METHODS: ABT-888 was administered as a single oral dose of 10, 25, or 50 mg to determine the dose range and time course over which ABT-888 inhibits PARP activity in tumor samples and peripheral blood mononuclear cells, and to evaluate ABT-888 pharmacokinetics. Blood samples and tumor biopsies were obtained pre- and postdrug administration for evaluation of PARP activity and pharmacokinetics. A novel statistical approach was developed and utilized to study pharmacodynamic modulation as the primary end point for trials of limited sample size. RESULTS: Thirteen patients with advanced malignancies received the study drug; nine patients underwent paired tumor biopsies. ABT-888 demonstrated good oral bioavailability and was well tolerated. Statistically significant inhibition of poly (ADP-ribose) levels was observed in tumor biopsies and peripheral blood mononuclear cells at the 25-mg and 50-mg dose levels. CONCLUSION: Within 5 months of study activation, we obtained pivotal biochemical and pharmacokinetic data that have guided the design of subsequent phase I trials of ABT-888 in combination with DNA-damaging agents. In addition to accelerating the development of ABT-888, the rapid conclusion of this trial demonstrates the feasibility of conducting proof-of-principle phase 0 trials as part of an alternative paradigm for early drug development in oncology.","language":"eng","number":"16","journal":"Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology","author":[{"propositions":[],"lastnames":["Kummar"],"firstnames":["Shivaani"],"suffixes":[]},{"propositions":[],"lastnames":["Kinders"],"firstnames":["Robert"],"suffixes":[]},{"propositions":[],"lastnames":["Gutierrez"],"firstnames":["Martin","E."],"suffixes":[]},{"propositions":[],"lastnames":["Rubinstein"],"firstnames":["Larry"],"suffixes":[]},{"propositions":[],"lastnames":["Parchment"],"firstnames":["Ralph","E."],"suffixes":[]},{"propositions":[],"lastnames":["Phillips"],"firstnames":["Lawrence","R."],"suffixes":[]},{"propositions":[],"lastnames":["Ji"],"firstnames":["Jiuping"],"suffixes":[]},{"propositions":[],"lastnames":["Monks"],"firstnames":["Anne"],"suffixes":[]},{"propositions":[],"lastnames":["Low"],"firstnames":["Jennifer","A."],"suffixes":[]},{"propositions":[],"lastnames":["Chen"],"firstnames":["Alice"],"suffixes":[]},{"propositions":[],"lastnames":["Murgo"],"firstnames":["Anthony","J."],"suffixes":[]},{"propositions":[],"lastnames":["Collins"],"firstnames":["Jerry"],"suffixes":[]},{"propositions":[],"lastnames":["Steinberg"],"firstnames":["Seth","M."],"suffixes":[]},{"propositions":[],"lastnames":["Eliopoulos"],"firstnames":["Helen"],"suffixes":[]},{"propositions":[],"lastnames":["Giranda"],"firstnames":["Vincent","L."],"suffixes":[]},{"propositions":[],"lastnames":["Gordon"],"firstnames":["Gary"],"suffixes":[]},{"propositions":[],"lastnames":["Helman"],"firstnames":["Lee"],"suffixes":[]},{"propositions":[],"lastnames":["Wiltrout"],"firstnames":["Robert"],"suffixes":[]},{"propositions":[],"lastnames":["Tomaszewski"],"firstnames":["Joseph","E."],"suffixes":[]},{"propositions":[],"lastnames":["Doroshow"],"firstnames":["James","H."],"suffixes":[]}],"month":"June","year":"2009","keywords":"Administration, Oral, Aged, Antineoplastic Agents, Benzimidazoles, Biological Availability, Biopsy, Clinical Trials, Phase I as Topic, Dose-Response Relationship, Drug, Enzyme Inhibitors, Feasibility Studies, Female, Humans, Leukocytes, Mononuclear, Male, Middle Aged, Neoplasms, Poly(ADP-ribose) Polymerase Inhibitors, Research Design, Treatment Outcome","pages":"2705–2711","bibtex":"@article{kummar_phase_2009,\n\ttitle = {Phase 0 clinical trial of the poly ({ADP}-ribose) polymerase inhibitor {ABT}-888 in patients with advanced malignancies},\n\tvolume = {27},\n\tissn = {1527-7755},\n\tdoi = {10.1200/JCO.2008.19.7681},\n\tabstract = {PURPOSE: We conducted the first phase 0 clinical trial in oncology of a therapeutic agent under the Exploratory Investigational New Drug Guidance of the US Food and Drug Administration. It was a first-in-human study of the poly (ADP-ribose) polymerase (PARP) inhibitor ABT-888 in patients with advanced malignancies.\nPATIENTS AND METHODS: ABT-888 was administered as a single oral dose of 10, 25, or 50 mg to determine the dose range and time course over which ABT-888 inhibits PARP activity in tumor samples and peripheral blood mononuclear cells, and to evaluate ABT-888 pharmacokinetics. Blood samples and tumor biopsies were obtained pre- and postdrug administration for evaluation of PARP activity and pharmacokinetics. A novel statistical approach was developed and utilized to study pharmacodynamic modulation as the primary end point for trials of limited sample size.\nRESULTS: Thirteen patients with advanced malignancies received the study drug; nine patients underwent paired tumor biopsies. ABT-888 demonstrated good oral bioavailability and was well tolerated. Statistically significant inhibition of poly (ADP-ribose) levels was observed in tumor biopsies and peripheral blood mononuclear cells at the 25-mg and 50-mg dose levels.\nCONCLUSION: Within 5 months of study activation, we obtained pivotal biochemical and pharmacokinetic data that have guided the design of subsequent phase I trials of ABT-888 in combination with DNA-damaging agents. In addition to accelerating the development of ABT-888, the rapid conclusion of this trial demonstrates the feasibility of conducting proof-of-principle phase 0 trials as part of an alternative paradigm for early drug development in oncology.},\n\tlanguage = {eng},\n\tnumber = {16},\n\tjournal = {Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology},\n\tauthor = {Kummar, Shivaani and Kinders, Robert and Gutierrez, Martin E. and Rubinstein, Larry and Parchment, Ralph E. and Phillips, Lawrence R. and Ji, Jiuping and Monks, Anne and Low, Jennifer A. and Chen, Alice and Murgo, Anthony J. and Collins, Jerry and Steinberg, Seth M. and Eliopoulos, Helen and Giranda, Vincent L. and Gordon, Gary and Helman, Lee and Wiltrout, Robert and Tomaszewski, Joseph E. and Doroshow, James H.},\n\tmonth = jun,\n\tyear = {2009},\n\tkeywords = {Administration, Oral, Aged, Antineoplastic Agents, Benzimidazoles, Biological Availability, Biopsy, Clinical Trials, Phase I as Topic, Dose-Response Relationship, Drug, Enzyme Inhibitors, Feasibility Studies, Female, Humans, Leukocytes, Mononuclear, Male, Middle Aged, Neoplasms, Poly(ADP-ribose) Polymerase Inhibitors, Research Design, Treatment Outcome},\n\tpages = {2705--2711},\n}\n\n","author_short":["Kummar, S.","Kinders, R.","Gutierrez, M. 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