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Larry Rubinstein - One of the best experts on this subject based on the ideXlab platform.

  • Design of phase i combination Trials recommendations of the Clinical Trial Design task force of the nci investigational drug steering committee
    Clinical Cancer Research, 2014
    Co-Authors: Channing J Paller, Penelope Ann Bradbury, Lesley Seymour, Larry Rubinstein, Percy S Ivy, Patricia Lorusso, Laurence H Baker, Erich Huang, Deborah Collyar, Susan Groshen
    Abstract:

    Anticancer drugs are combined in an effort to treat a heterogeneous tumor or to maximize the pharmacodynamic effect. The development of combination regimens, while desirable, poses unique challenges. These include the selection of agents for combination therapy that may lead to improved efficacy while maintaining acceptable toxicity, the Design of Clinical Trials that provide informative results for individual agents and combinations, and logistic and regulatory challenges. The phase I Trial is often the initial step in the Clinical evaluation of a combination regimen. In view of the importance of combination regimens and the challenges associated with developing them, the Clinical Trial Design (CTD) Task Force of the National Cancer Institute Investigational Drug Steering Committee developed a set of recommendations for the phase I development of a combination regimen. The first two recommendations focus on the scientific rationale and development plans for the combination regimen; subsequent recommendations encompass Clinical Design aspects. The CTD Task Force recommends that selection of the proposed regimens be based on a biologic or pharmacologic rationale supported by Clinical and/or robust and validated preClinical evidence, and accompanied by a plan for subsequent development of the combination. The Design of the phase I Clinical Trial should take into consideration the potential pharmacokinetic and pharmacodynamic interactions as well as overlapping toxicity. Depending on the specific hypothesized interaction, the primary endpoint may be dose optimization, pharmacokinetics, and/or pharmacodynamics (i.e., biomarker). Clin Cancer Res; 20(16); 4210–7. ©2014 AACR .

  • the Design of phase ii Clinical Trials testing cancer therapeutics consensus recommendations from the Clinical Trial Design task force of the national cancer institute investigational drug steering committee
    Clinical Cancer Research, 2010
    Co-Authors: Lesley Seymour, Larry Rubinstein, Percy S Ivy, Laurence H Baker, David R Spriggs, Mark J Ratain, Daniel J Sargent, Michael Le Blanc, David J Stewart, John Crowley
    Abstract:

    The optimal Design of phase II studies continues to be the subject of vigorous debate, especially studies of newer molecularly targeted agents. The observations that many new therapeutics "fail" in definitive phase III studies, coupled with the numbers of new agents to be tested as well as the increasing costs and complexity of Clinical Trials, further emphasize the critical importance of robust and efficient phase II Design. The Clinical Trial Design Task Force (CTD-TF) of the National Cancer Institute (NCI) Investigational Drug Steering Committee (IDSC) has published a series of discussion papers on phase II Trial Design in Clinical Cancer Research. The IDSC has developed formal recommendations about aspects of phase II Trial Design that are the subject of frequent debate, such as endpoints (response versus progression-free survival), randomization (single-arm Designs versus randomization), inclusion of biomarkers, biomarker-based patient enrichment strategies, and statistical Design (e.g., two-stage Designs versus multiple-group adaptive Designs). Although these recommendations in general encourage the use of progression-free survival as the primary endpoint, randomization, inclusion of biomarkers, and incorporation of newer Designs, we acknowledge that objective response as an endpoint and single-arm Designs remain relevant in certain situations. The Design of any Clinical Trial should always be carefully evaluated and justified based on characteristic specific to the situation.

  • 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 national cancer institute investigational drug steering committee
    Clinical Cancer Research, 2010
    Co-Authors: Percy S Ivy, Lillian L Siu, Elizabeth Garrettmayer, Larry Rubinstein
    Abstract:

    The goals and objectives of phase 1 Clinical Trials are changing to include further evaluation of endpoints such as molecular targeted effects, in addition to dose-toxicity profile of the investigational agent. Because of these changes in focus, the National Cancer Institute and Investigational Drug Steering Committee's Task Force on Clinical Trial Design met to evaluate the most efficient ways to Design and implement early Clinical Trials with novel therapeutics. Clinical approaches discussed included the conventional 3 + 3 cohort expansion phase 1 Design, multi-institutional phase 1 studies, accelerated titration Designs, continual reassessment methods, the study of specific target patient populations, and phase 0 studies. Each of these approaches uniquely contributes to some aspect of the phase 1 study, with all focused on dose and schedule determination, patient safety, and limited patient exposure to ineffective doses of investigational agent. The benefit of labor-intensive generation of preliminary biomarker evidence of target inhibition, as well as the value of molecular profiling of the study population, is considered. New drug development is expensive and the failure rate remains high. By identifying patient populations expected to respond to the study agent and tailoring the treatment with a novel drug, investigators will be one step closer to personalizing cancer treatment. The "fail early and fast" approach is acceptable if the appropriate patient population is evaluated in the phase 1 Trial. The approaches outlined in this overview address the merits, advantages, disadvantages, and obstacles encountered during first in human studies.

Percy S Ivy - One of the best experts on this subject based on the ideXlab platform.

  • Design of phase i combination Trials recommendations of the Clinical Trial Design task force of the nci investigational drug steering committee
    Clinical Cancer Research, 2014
    Co-Authors: Channing J Paller, Penelope Ann Bradbury, Lesley Seymour, Larry Rubinstein, Percy S Ivy, Patricia Lorusso, Laurence H Baker, Erich Huang, Deborah Collyar, Susan Groshen
    Abstract:

    Anticancer drugs are combined in an effort to treat a heterogeneous tumor or to maximize the pharmacodynamic effect. The development of combination regimens, while desirable, poses unique challenges. These include the selection of agents for combination therapy that may lead to improved efficacy while maintaining acceptable toxicity, the Design of Clinical Trials that provide informative results for individual agents and combinations, and logistic and regulatory challenges. The phase I Trial is often the initial step in the Clinical evaluation of a combination regimen. In view of the importance of combination regimens and the challenges associated with developing them, the Clinical Trial Design (CTD) Task Force of the National Cancer Institute Investigational Drug Steering Committee developed a set of recommendations for the phase I development of a combination regimen. The first two recommendations focus on the scientific rationale and development plans for the combination regimen; subsequent recommendations encompass Clinical Design aspects. The CTD Task Force recommends that selection of the proposed regimens be based on a biologic or pharmacologic rationale supported by Clinical and/or robust and validated preClinical evidence, and accompanied by a plan for subsequent development of the combination. The Design of the phase I Clinical Trial should take into consideration the potential pharmacokinetic and pharmacodynamic interactions as well as overlapping toxicity. Depending on the specific hypothesized interaction, the primary endpoint may be dose optimization, pharmacokinetics, and/or pharmacodynamics (i.e., biomarker). Clin Cancer Res; 20(16); 4210–7. ©2014 AACR .

  • the Design of phase ii Clinical Trials testing cancer therapeutics consensus recommendations from the Clinical Trial Design task force of the national cancer institute investigational drug steering committee
    Clinical Cancer Research, 2010
    Co-Authors: Lesley Seymour, Larry Rubinstein, Percy S Ivy, Laurence H Baker, David R Spriggs, Mark J Ratain, Daniel J Sargent, Michael Le Blanc, David J Stewart, John Crowley
    Abstract:

    The optimal Design of phase II studies continues to be the subject of vigorous debate, especially studies of newer molecularly targeted agents. The observations that many new therapeutics "fail" in definitive phase III studies, coupled with the numbers of new agents to be tested as well as the increasing costs and complexity of Clinical Trials, further emphasize the critical importance of robust and efficient phase II Design. The Clinical Trial Design Task Force (CTD-TF) of the National Cancer Institute (NCI) Investigational Drug Steering Committee (IDSC) has published a series of discussion papers on phase II Trial Design in Clinical Cancer Research. The IDSC has developed formal recommendations about aspects of phase II Trial Design that are the subject of frequent debate, such as endpoints (response versus progression-free survival), randomization (single-arm Designs versus randomization), inclusion of biomarkers, biomarker-based patient enrichment strategies, and statistical Design (e.g., two-stage Designs versus multiple-group adaptive Designs). Although these recommendations in general encourage the use of progression-free survival as the primary endpoint, randomization, inclusion of biomarkers, and incorporation of newer Designs, we acknowledge that objective response as an endpoint and single-arm Designs remain relevant in certain situations. The Design of any Clinical Trial should always be carefully evaluated and justified based on characteristic specific to the situation.

  • 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 national cancer institute investigational drug steering committee
    Clinical Cancer Research, 2010
    Co-Authors: Percy S Ivy, Lillian L Siu, Elizabeth Garrettmayer, Larry Rubinstein
    Abstract:

    The goals and objectives of phase 1 Clinical Trials are changing to include further evaluation of endpoints such as molecular targeted effects, in addition to dose-toxicity profile of the investigational agent. Because of these changes in focus, the National Cancer Institute and Investigational Drug Steering Committee's Task Force on Clinical Trial Design met to evaluate the most efficient ways to Design and implement early Clinical Trials with novel therapeutics. Clinical approaches discussed included the conventional 3 + 3 cohort expansion phase 1 Design, multi-institutional phase 1 studies, accelerated titration Designs, continual reassessment methods, the study of specific target patient populations, and phase 0 studies. Each of these approaches uniquely contributes to some aspect of the phase 1 study, with all focused on dose and schedule determination, patient safety, and limited patient exposure to ineffective doses of investigational agent. The benefit of labor-intensive generation of preliminary biomarker evidence of target inhibition, as well as the value of molecular profiling of the study population, is considered. New drug development is expensive and the failure rate remains high. By identifying patient populations expected to respond to the study agent and tailoring the treatment with a novel drug, investigators will be one step closer to personalizing cancer treatment. The "fail early and fast" approach is acceptable if the appropriate patient population is evaluated in the phase 1 Trial. The approaches outlined in this overview address the merits, advantages, disadvantages, and obstacles encountered during first in human studies.

Lesley Seymour - One of the best experts on this subject based on the ideXlab platform.

  • Design of phase i combination Trials recommendations of the Clinical Trial Design task force of the nci investigational drug steering committee
    Clinical Cancer Research, 2014
    Co-Authors: Channing J Paller, Penelope Ann Bradbury, Lesley Seymour, Larry Rubinstein, Percy S Ivy, Patricia Lorusso, Laurence H Baker, Erich Huang, Deborah Collyar, Susan Groshen
    Abstract:

    Anticancer drugs are combined in an effort to treat a heterogeneous tumor or to maximize the pharmacodynamic effect. The development of combination regimens, while desirable, poses unique challenges. These include the selection of agents for combination therapy that may lead to improved efficacy while maintaining acceptable toxicity, the Design of Clinical Trials that provide informative results for individual agents and combinations, and logistic and regulatory challenges. The phase I Trial is often the initial step in the Clinical evaluation of a combination regimen. In view of the importance of combination regimens and the challenges associated with developing them, the Clinical Trial Design (CTD) Task Force of the National Cancer Institute Investigational Drug Steering Committee developed a set of recommendations for the phase I development of a combination regimen. The first two recommendations focus on the scientific rationale and development plans for the combination regimen; subsequent recommendations encompass Clinical Design aspects. The CTD Task Force recommends that selection of the proposed regimens be based on a biologic or pharmacologic rationale supported by Clinical and/or robust and validated preClinical evidence, and accompanied by a plan for subsequent development of the combination. The Design of the phase I Clinical Trial should take into consideration the potential pharmacokinetic and pharmacodynamic interactions as well as overlapping toxicity. Depending on the specific hypothesized interaction, the primary endpoint may be dose optimization, pharmacokinetics, and/or pharmacodynamics (i.e., biomarker). Clin Cancer Res; 20(16); 4210–7. ©2014 AACR .

  • early phase oncology Clinical Trial Design in the era of molecularly targeted therapy pitfalls and progress
    Clinical investigation, 2011
    Co-Authors: Penelope Ann Bradbury, John Hilton, Lesley Seymour
    Abstract:

    Oncology drug development has seen a shift from the development of cytotoxic chemotherapy to that of molecularly targeted agents. Different mechanisms of action and toxicity profiles may mean that traditional oncology Trial Designs are no longer optimal for the development of these agents. Furthermore, the wealth of agents that are being developed, coupled with a constrained research environment has increasingly highlighted the need for efficient Clinical Trial Design, both to filter agents as well as to advance promising agents rapidly into Clinical development. We review the adaptations to traditional Phase I and II Clinical Trial Design that are hoped to address some of the current challenges of drug development for oncology therapeutics.

  • the Design of phase ii Clinical Trials testing cancer therapeutics consensus recommendations from the Clinical Trial Design task force of the national cancer institute investigational drug steering committee
    Clinical Cancer Research, 2010
    Co-Authors: Lesley Seymour, Larry Rubinstein, Percy S Ivy, Laurence H Baker, David R Spriggs, Mark J Ratain, Daniel J Sargent, Michael Le Blanc, David J Stewart, John Crowley
    Abstract:

    The optimal Design of phase II studies continues to be the subject of vigorous debate, especially studies of newer molecularly targeted agents. The observations that many new therapeutics "fail" in definitive phase III studies, coupled with the numbers of new agents to be tested as well as the increasing costs and complexity of Clinical Trials, further emphasize the critical importance of robust and efficient phase II Design. The Clinical Trial Design Task Force (CTD-TF) of the National Cancer Institute (NCI) Investigational Drug Steering Committee (IDSC) has published a series of discussion papers on phase II Trial Design in Clinical Cancer Research. The IDSC has developed formal recommendations about aspects of phase II Trial Design that are the subject of frequent debate, such as endpoints (response versus progression-free survival), randomization (single-arm Designs versus randomization), inclusion of biomarkers, biomarker-based patient enrichment strategies, and statistical Design (e.g., two-stage Designs versus multiple-group adaptive Designs). Although these recommendations in general encourage the use of progression-free survival as the primary endpoint, randomization, inclusion of biomarkers, and incorporation of newer Designs, we acknowledge that objective response as an endpoint and single-arm Designs remain relevant in certain situations. The Design of any Clinical Trial should always be carefully evaluated and justified based on characteristic specific to the situation.

John Crowley - One of the best experts on this subject based on the ideXlab platform.

  • the Design of phase ii Clinical Trials testing cancer therapeutics consensus recommendations from the Clinical Trial Design task force of the national cancer institute investigational drug steering committee
    Clinical Cancer Research, 2010
    Co-Authors: Lesley Seymour, Larry Rubinstein, Percy S Ivy, Laurence H Baker, David R Spriggs, Mark J Ratain, Daniel J Sargent, Michael Le Blanc, David J Stewart, John Crowley
    Abstract:

    The optimal Design of phase II studies continues to be the subject of vigorous debate, especially studies of newer molecularly targeted agents. The observations that many new therapeutics "fail" in definitive phase III studies, coupled with the numbers of new agents to be tested as well as the increasing costs and complexity of Clinical Trials, further emphasize the critical importance of robust and efficient phase II Design. The Clinical Trial Design Task Force (CTD-TF) of the National Cancer Institute (NCI) Investigational Drug Steering Committee (IDSC) has published a series of discussion papers on phase II Trial Design in Clinical Cancer Research. The IDSC has developed formal recommendations about aspects of phase II Trial Design that are the subject of frequent debate, such as endpoints (response versus progression-free survival), randomization (single-arm Designs versus randomization), inclusion of biomarkers, biomarker-based patient enrichment strategies, and statistical Design (e.g., two-stage Designs versus multiple-group adaptive Designs). Although these recommendations in general encourage the use of progression-free survival as the primary endpoint, randomization, inclusion of biomarkers, and incorporation of newer Designs, we acknowledge that objective response as an endpoint and single-arm Designs remain relevant in certain situations. The Design of any Clinical Trial should always be carefully evaluated and justified based on characteristic specific to the situation.

Laurence H Baker - One of the best experts on this subject based on the ideXlab platform.

  • Design of phase i combination Trials recommendations of the Clinical Trial Design task force of the nci investigational drug steering committee
    Clinical Cancer Research, 2014
    Co-Authors: Channing J Paller, Penelope Ann Bradbury, Lesley Seymour, Larry Rubinstein, Percy S Ivy, Patricia Lorusso, Laurence H Baker, Erich Huang, Deborah Collyar, Susan Groshen
    Abstract:

    Anticancer drugs are combined in an effort to treat a heterogeneous tumor or to maximize the pharmacodynamic effect. The development of combination regimens, while desirable, poses unique challenges. These include the selection of agents for combination therapy that may lead to improved efficacy while maintaining acceptable toxicity, the Design of Clinical Trials that provide informative results for individual agents and combinations, and logistic and regulatory challenges. The phase I Trial is often the initial step in the Clinical evaluation of a combination regimen. In view of the importance of combination regimens and the challenges associated with developing them, the Clinical Trial Design (CTD) Task Force of the National Cancer Institute Investigational Drug Steering Committee developed a set of recommendations for the phase I development of a combination regimen. The first two recommendations focus on the scientific rationale and development plans for the combination regimen; subsequent recommendations encompass Clinical Design aspects. The CTD Task Force recommends that selection of the proposed regimens be based on a biologic or pharmacologic rationale supported by Clinical and/or robust and validated preClinical evidence, and accompanied by a plan for subsequent development of the combination. The Design of the phase I Clinical Trial should take into consideration the potential pharmacokinetic and pharmacodynamic interactions as well as overlapping toxicity. Depending on the specific hypothesized interaction, the primary endpoint may be dose optimization, pharmacokinetics, and/or pharmacodynamics (i.e., biomarker). Clin Cancer Res; 20(16); 4210–7. ©2014 AACR .

  • the Design of phase ii Clinical Trials testing cancer therapeutics consensus recommendations from the Clinical Trial Design task force of the national cancer institute investigational drug steering committee
    Clinical Cancer Research, 2010
    Co-Authors: Lesley Seymour, Larry Rubinstein, Percy S Ivy, Laurence H Baker, David R Spriggs, Mark J Ratain, Daniel J Sargent, Michael Le Blanc, David J Stewart, John Crowley
    Abstract:

    The optimal Design of phase II studies continues to be the subject of vigorous debate, especially studies of newer molecularly targeted agents. The observations that many new therapeutics "fail" in definitive phase III studies, coupled with the numbers of new agents to be tested as well as the increasing costs and complexity of Clinical Trials, further emphasize the critical importance of robust and efficient phase II Design. The Clinical Trial Design Task Force (CTD-TF) of the National Cancer Institute (NCI) Investigational Drug Steering Committee (IDSC) has published a series of discussion papers on phase II Trial Design in Clinical Cancer Research. The IDSC has developed formal recommendations about aspects of phase II Trial Design that are the subject of frequent debate, such as endpoints (response versus progression-free survival), randomization (single-arm Designs versus randomization), inclusion of biomarkers, biomarker-based patient enrichment strategies, and statistical Design (e.g., two-stage Designs versus multiple-group adaptive Designs). Although these recommendations in general encourage the use of progression-free survival as the primary endpoint, randomization, inclusion of biomarkers, and incorporation of newer Designs, we acknowledge that objective response as an endpoint and single-arm Designs remain relevant in certain situations. The Design of any Clinical Trial should always be carefully evaluated and justified based on characteristic specific to the situation.