The Investigational Drug Steering Committee (IDSC) was established following recommendations by the Clinical Trials Working Group (CTWG). The IDSC was created to collaborate with NCI in the design and prioritization of early phase drug development trials with agents for which CTEP holds an IND. IDSC members include the Principal Investigators of CTEPs Experimental Therapeutics Clinical Trail Network (ETCTN), representatives from the each of the Cooperative Groups that comprise the National Clinical Trial Network (NCTN), a patient advocate, and Subject Matter Experts in drug development, radiation oncology, clinical pharmacology, clinical immunology, clinical trial design, omics, biostatistics and imaging.
The goals of the IDSC are to enhance strategic input, increase the transparency and openness of the trial design and prioritization process, achieve optimal phase I and phase II trial designs for the most promising new investigational agents and, ultimately, increase the predictive value of early phase trials, resulting in the design of more successful phase III trials.
The IDSC has reviewed and provided scientific input into the Clinical Development Plans of 32 new investigational agents within the CTEP portfolio:
|ABT-263||bcl2, BH3 mimetic||2009|
|AMG386||Ang 1 / 2 Inhibitor||2010|
|MLN-8237||Aurora kinase A||2010|
|TRC-105||mAb to CD105||2011|
|Cabozantinib (XL-184)||c-MET; VEGFR2||2011|
|Nivolumab and MK-3475||Anti-PD-1||2013|
|BMN-673||PARP 1 and 2||2013|
To facilitate its goals the IDSC currently has 4 Task Forces (TFs). The Clinical Trial Design TF, Biomarkers TF, and Pharmacology TF focus on scientific issues of importance to the early drug development community. The Immunotherapy TF provides recommendations regarding potential new immunotherapeutic agents to be added to CTEP’s portfolio.
The Clinical Trial Design TF has developed or is in the process of developing recommendations for the following topics:
Phase 2 Trial Design Strategies
Use of Phase 2 Historical Controls for Retrospective Analysis
Recommendations for Phase 1/2 Trial Design
Adaptive Phase I/2 Trial designs
Biomarkers in Phase I/2 Trials
Recommendations for combinational agent Trials
Robustness of preclinical studies required for Phase I Trials
Single agent activity versus drug combinations activity
Expansion Cohort Recommendations
In looking at novel clinical trial designs, the Clinical Trial Design TF convened a Phase I Workshop that covered optimal planning, design, and conduct of Phase I studies of new therapeutics; approaches to Phase I design focusing on safety, efficiency and selected patient populations; and guidelines for the development and incorporation of biomarker studies in early clinical trials of novel agents. The findings of this Workshop led to several opinion publications in 2010 in Clinical Cancer Research. In addition, a series of Phase II opinion papers were published in Clinical Cancer Research in 2009. More recently the Clinical Trial Design TF published a paper in Clinical Cancer Research on Phase I agent combinations and recommendations.
The Biomarker TF developed guidelines for incorporation of biomarkers into early-phase clinical trials. The TF reviewed biomarker trials, peer-reviewed literature, and NCI and FDA guidance documents, and conducted a survey of investigators to determine practices and challenges to executing biomarker studies in clinical trials of new drugs in early development. Based on these efforts, the TF published a paper entitled “Development and Incorporation of Biomarker Studies in Early Clinical Trials of Novel Agents” Clinical Cancer Research in 2010). This paper provides standard definitions and categories of biomarkers, and lists recommendations to sponsors and investigators for biomarker incorporation into such trials. In addition, in 2014 the Biomarker TF worked with the Clinical Trial Design TF to develop a Workshop titled “Design of Biomarker Driven Phase II Cancer Treatment Clinical Trials Workshop.” The goal of this workshop was to optimize the design of phase II oncology trials that incorporate predictive biomarkers and the objectives were to:
To review the basic framework and justification for predictive biomarkers in phase II trials.
To review trial designs that have been used in phase II trials that have attempted to evaluate predictive biomarkers and their strengths and weakness.
To consider the regulatory and statistical issues for phase II trials with predictive biomarkers.
To present trial designs based on simulation studies from real clinical trial data.
To develop recommendations regarding when and how to incorporate predictive biomarkers into phase II trials.
The Pharmacology TF considers topics related to what needs to be known about agents before they are tested in patients and how to determine whether the drug is having the desired effect. The Pharmacology TF has made the following recommendations to the NCI:
NCI should set up cross-validation of analytical chemical assays used to quantitate drugs in CTEP-sponsored studies when more than one laboratory is performing the analytical chemical assays in support of those clinical studies.
NCI should provide blinded quality control samples and collate the data submitted by the laboratories that analyze samples for cross-validation.
Pediatric formulations of drugs tested in adults should be developed for testing in children when appropriate.
The Immunotherapy TF has put together an adoptive immunotherapy white paper on the adoptive transfer of immune effector cells against metastatic melanoma, which is a clinically promising and complex procedure. The TF put together recommendations on adoptive therapy and developed a multi-institution Phase II trial, which was adequately powered, randomized, and controlled, with a central facility for cell growth. Pharma is currently conducting a study based on the Immunotherapy TF white paper. The white paper was titled "White Paper on Adoptive Cell Therapy for Cancer with Tumor-Infiltrating Lymphocytes: A Report of the NCI CCCT Subcommittee on Adoptive Cell Therapy" and was published in Clinical Cancer Research in 2011.
The IDSC convened interdisciplinary expert panels to review the pathophysiologies of hyperlipidemia and hyperglycemia induced by mTOR pathway inhibitors and cardiac toxicities such as hypertension, left ventricular dysfunction, heart failure, and myocardial ischemia and infarction associated with antiangiogenic therapies. These expert panels summarized the incidences of these toxicities in the current literature, provided recommendations for clinical trial screening and monitoring criteria, and provided management guidance and therapeutic goals upon occurrence of these toxicities. The Cardiovascular Toxicities Panel published guidelines for management of cardiac toxicity in patients receiving vascular endothelial growth factor signaling pathway inhibitors in the American Heart Journal. The other IDSC expert panel published guidelines on management of metabolic effects (hyperlipidemia and hyperglycemia) associated with anticancer agents targeting the PI3K-Akt-mTOR (PAM) pathway in the Journal of Clinical Oncology in 2012. These publications raise awareness of these adverse events to enable their early recognition, regular monitoring and timely intervention in clinical trials.
Another of the IDSC’s accomplishments is the focused educational sessions at CTEP Early Drug Development meetings, which occur twice a year. Many of the educational sessions have focused on drugs that were either in the CTEP portfolio or about to enter the portfolio to help educate investigators prior to solicitation of LOIs for these agents. These sessions are listed below:
Wnt educational session (Cancer Stem Cell TF)
Phase II recommendations (Clinical Trial Design TF)
Biomarker TF recommendations (Biomarker TF)
Autophagy (DNA Repair TF)
JAK-STAT educational session (Signal Transduction)
c-Met educational session (Signal Transduction)
ALK educational session (Signal Transduction)
Targeted Resistance educational session (Signal Transduction)
The IDSC has published 32 manuscripts during the last several years. The manuscripts focus on Phase I and II clinical trial design, management of drug-related toxicities, and management of common cardiovascular toxicities, as well as hyperglycemia and hyperlipidemia. Selected publications are listed below:
Adjei AA, Christian M, Ivy P. Novel designs and end points for phase II clinical trials. Clin Cancer Res 2009; 15(6):1866-72.
Amaravadi RK, Lippincott-Schwartz J, Yin XM, Weiss WA, Takebe N, Timmer W, et al. Principles and Current Strategies for Targeting Autophagy for Cancer Treatment. Clin Cancer Res 2011; 17(4):654-666.
Busaidy NL, Farooki A, Dowlati A, Perentesis JP, Dancey JE, Doyle LA, et al. Management of metabolic effects associated with anticancer agents targeting the PI3K-Akt-mTOR pathway. J Clin Oncol 2012; 30(23):2919-28.
Dancey JE, Dobbin KK, Groshen S, Jessup JM, Hruszkewycz AH, Koehler M, et al. Guidelines for the development and incorporation of biomarker studies in early clinical trials of novel agents. Clin Cancer Res 2010; 16(6):1745-55.
Dhani N, Tu D, Sargent DJ, Seymour L, Moore MJ. Alternate endpoints for screening phase II studies. Clin Cancer Res 2009; 15(6):1873-82.
Forster MD, Saijo N, Seymour L, Calvert H. Performing phase I clinical trials of anticancer agents: perspectives from within the European union and Japan. Clin Cancer Res 2010; 16(6):1737-44.
Hewitt SM, Badve SS, True LD. Impact of preanalytic factors on the design and application of integral biomarkers for directing patient therapy. Clin Cancer Res 2012; 18(6):1524-30.
Ivy SP, Siu LL, 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 national cancer institute investigational drug steering committee. Clin Cancer Res 201016(6):1726-36.
LaBarge MA. The difficulty of targeting cancer stem cell niches. Clin Cancer Res 2010; 16(12):3121-9.
LoRusso PM, Boerner SA, Seymour L. An overview of the optimal planning, design, and conduct of phase I studies of new therapeutics. Clin Cancer Res 2010; 16(6):1710-8.
Maitland ML. Cardiovascular toxicity of new agents. Clin Adv Hematol Oncol 2008;6(9):657-9.
Maitland ML, Bakris GL, Black HR, Chen HX, Durand JB, Elliott WJ, et al. Initial assessment, surveillance, and management of blood pressure in patients receiving vascular endothelial growth factor signaling pathway inhibitors. J Natl Cancer Inst 2010;102(9):596-604.
McShane LM, Hunsberger S, Adjei AA. Effective incorporation of biomarkers into phase II trials. Clin Cancer Res 2009; 15(6):1898-905.
Merchant AA, Matsui W. Targeting Hedgehog--a cancer stem cell pathway. Clin Cancer Res 2010; 16(12):3130-40.
Meshinchi S, Hunger SP, Aplenc R, Adamson PC, Jessup JM. Lessons learned from the investigational device exemption review of Children's Oncology Group trial AAML1031. Clin Cancer Res 2012; 18(6):1547-54.
O'Brien CA, Kreso A, Jamieson CH. Cancer stem cells and self-renewal. Clin Cancer Res 2010; 16(12):3113-20.
Pannuti A, Foreman K, Rizzo P, Osipo C, Golde T, Osborne B, et al. Targeting Notch to target cancer stem cells. Clin Cancer Res 2010; 16(12):3141-52.
Philip PA, Chansky K, Rubinstein L, LeBlanc M, Seymour L, Ivy SP, et al. Historical Controls for Metastatic Pancreatic Cancer: Benchmarks for Planning and Analyzing Single Arm Phase II Trials. Clin Cancer Res 2014.
Poste G, Carbone DP, Parkinson DR, Verweij J, Hewitt SM, Jessup JM. Leveling the playing field: bringing development of biomarkers and molecular diagnostics up to the standards for drug development. Clin Cancer Res 2012; 18(6):1515-23.
Rubinstein L, Crowley J, Ivy P, Leblanc M, Sargent D. Randomized phase II designs. Clin Cancer Res 2009; 15(6):1883-90.
Sargent DJ, Taylor JM. Current issues in oncology drug development, with a focus on Phase II trials. J Biopharm Stat 2009; 19(3):556-62.
Schilsky RL, Doroshow JH, Leblanc M, Conley BA. Development and use of integral assays in clinical trials. Clin Cancer Res 2012; 18(6):1540-6.
Seymour L. Controversies in the Design of Phase II Clinical Trials. Clinical Advances in Hematology & Oncology 2010; 8(2):95-97.
Seymour L, Ivy SP, Sargent D, Spriggs D, Baker L, Rubinstein L, et al. 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. Clin Cancer Res 2010; 16(6):1764-9.
Shankar LK, Van den Abbeele A, Yap J, Benjamin R, Scheutze S, Fitzgerald TJ. Considerations for the use of imaging tools for phase II treatment trials in oncology. Clin Cancer Res 2009; 15(6):1891-7.
Takebe N, Ivy SP. Controversies in cancer stem cells: targeting embryonic signaling pathways. Clin Cancer Res 2010; 16(12):3106-12.
Weber JS, Atkins MB, Hwu P, Radvanyi L, Sznol M, Yee C. White Paper on Adoptive Cell Therapy for Cancer with Tumor Infiltrating Lymphocytes: a report of the CTEP Subcommittee on Adoptive Cell Therapy. Clin Cancer Res 2011.
Williams PM, Lively TG, Jessup JM, Conley BA. Bridging the gap: moving predictive and prognostic assays from research to clinical use. Clin Cancer Res 2012; 18(6):1531-9.