Spotlight On… The Investigational Drug Steering Committee

In June 2005, the Clinical Trials Working Group, a broadly constituted panel with experts from academic research institutions, community oncology practices, the pharmaceutical and biotechnology industries, cancer patient advocacy groups, and government agencies recommended a series of initiatives to strengthen NCI’s clinical trials enterprise for the 21st century. (http://integratedtrials.nci.nih.gov/ict/CTWG_report_June2005.pdf) One of these initiatives was the creation of the Investigational Drug Steering Committee (IDSC).

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 23 principal investigators of CTEPs Early Drug Development Program grants and contracts, representatives from the Cancer Cooperative Groups, a patient advocate, and experts in biostatics, radiation oncology, 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 agents and, ultimately, increase the predictive value of early phase trials, resulting in the design of more successful phase III trials.

To achieve these goals, the IDSC has formed 10 Task Forces (TFs). Three (Clinical Trial Design, Biomarkers, and Pharmacology) focus on scientific issues of importance to the early drug development community. The other 7 (Signal Transduction TF, Angiogenesis TF, Gap Analysis TF, Immunotherapy TF, PI3k, akt, and mTOR TF, Cancer Stem Cell Therapeutics TF, and DNA Repair and Apoptosis TF) make recommendations regarding new agents for CTEP’s portfolio.

The Clinical Trial Design TF is currently considering these topics

• Phase 2 Trial Design Strategies (Adaptive Design vs. Frequentist Model)
• Use of Phase 2 Historical Controls for Retrospective Analysis
• Tumor Measurement Analysis: waterfall plots, tumor burden and time
• Phase 2 Trial Design Issues Involving the Use of Progression Free Survival
• Adaptive phase I/II designs
• Phase I Endpoints – which are mandatory
• Biomarkers in Phase I?
• Imaging in Phase I?
• Combination studies in Phase I
• Required preclinical studies before Phase I
• Single agent activity versus activity of drug combinations

The Biomarkers TF is currently considering these topics as possible guidelines for use of biomarkers in early drug development studies

• Rationale supported by data showing relationship between biomarker & agent effects
• A specific hypothesis shows the “target was hit”
• PK/PD relationship & possible tumor drug concentrations should be compared to plasma studies of the pharmacology of the new agent.
• Provide data for assay selection & stability of marker under proposed conditions
• Provide technical performance characteristics such as reproducibility, accuracy, source variability, rationale for choice of reagents, and issues of timing and stability.
• Assay includes positive & negative controls, methods of scoring results & validation

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. Recommendations:

• 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 Angiogenesis TF has reviewed CTEP’s clinical development plans for Sorafenib and VEGF-Trap and concluded no changes were needed. It also made recommendations to CTEP regarding blood pressure management for VEGF Signaling Pathway Inhibitors. Experts in cardiovascular diseases and oncologists discussed toxicities of inhibitors of VEGF signaling, possible mechanisms of adverse events, areas for further research, and standardized management of toxicities in future clinical trials. A manuscript is in preparation.

The Signal Transduction TF made recommendations for studies to be included in CTEP’s new clinical development plans for IMC-A12, an inhibitor of the insulin-like growth factor receptor, which is involved in tumor cell proliferation. It also recommended that CTEP acquire examples of a new class of agents, cMet inhibitors, which block tumor cell growth, migration and invasion, and tumor angiogenesis. It is currently considering whether there is sufficient activity of JAK-Stat inhibitors against solid tumors for inclusion of these agents in CTEP’s portfolio.

The Immunotherapy Task Force is currently considering a development plan for IL-12, an agent which modulates T cell activity and may boost anti-tumor immunity. It will also make recommendations regarding the kinds of immune monitoring assays needed and assay qualifications needed to assess the impact of immunotherapeutic agents.

The PI3K/akt/mTOR TF has undertaken an analysis of temsirolimus, everolimus, deferolimus, and AP5373 and will make recommendations regarding diseases or drug combinations where additional studies are needed. The TF also will consider correlation of endocrinologic toxicities with response or other pharmacodynamic measures in the development of drugs in this class. It plans to recommend guidelines for patient eligibility, monitoring, and potential management of hyperlipidemia and hyperglycemia in studies of these drugs. Finally, it will recommend biomarker and imaging studies to be included with clinical studies of PI3K/Akt/mTOR agents.

The Cancer Stem Cell Therapeutics TF is among the most recently established TFs. It will consider agents in the embryonic signaling pathway (inhibitors of hedgehog, notch, smoothened) that could inhibit cancer stem and progenitor cells. It will also consider agents that affect the stem cell microenvironment. It will also make recommendations to NCI regarding the assays that are needed to evaluate cancer stem cells and measure the effectiveness of agents that affect cancer stem and progenitor cells.

The DNA Repair and Apoptosis TF is another recently constituted TF. It will review CTEP’s portfolio of agents that affect DNA repair such as the PARP inhibitor and make recommendations regarding the addition of new agents.