Dato & tid: Torsdag d. 24. maj 2018 kl. 12.30-15.15
Sted: Forskningens Hus, Mødelokale 018, Sdr Skovvej 15, 9000 Aalborg, Danmark
Arrangør: DCCC/NEXT Bioinformatik/Klinisk Kræftforskningscenter, Aalborg Universitetshospital
Antal: 30 deltagere
Tilmeldingsfrist: 17. maj 2018 (først til mølle)
Tre seminarer af Richard Simon, tidligere direktør ved Biometric Research Program, the National Cancer Institute, USA
12:30 – 13:15 Finding and Targeting the Genomic Alterations which Drive Cancer Invasion
Cancers are thought to be caused by genomic alterations which disturb the normal mechanisms that control cell proliferation, intra-cellular interaction and immunologic surveillance. Sequencing of DNA from tumor genomes has been used as a tool for identifying the mutations which occur in human tumors. In this talk I will review the results of large sequencing studies as well as those of cancer disease association studies which are large case control studies to identify genomic polymorphisms associated with cancer phenotypes. I will discuss the algorithms that are used to distinguish driver mutations from passenger mutations and some attempts to construct phylogenic relationships of the sub-clones of individual tumors.
13:15 – 14.00 Basket Clinical Trials in Oncology
Most cancer drugs are today targeted to molecular alterations present in tumor cells regardless of the primary site or histology of the tumor. This has required the development of new designs and strategies for clinical development. In this talk I will review new clinical trial designs for conducting “histology agnostic” clinical trials in oncology. These designs include the Bayesian basket designs of Simon et al. as well as the frequentist design of Cunanan et al. We will also discuss changing paradigms for clinical development of new drugs possibly leading to multi-histology regulatory approvals.
As genomic tools have become available to identify the driver DNA alterations in tumors, treatment has become increasingly based on molecular phenotypes. This movement has been called personalized or precision medicine. In oncology it is driven mainly by the somatic changes in tumor DNA, not the inherited germ-line changes, although both can be important. The heterogeneous nature of tumors of the same primary site offers new challenges for therapeutics development and clinical trial design. Physicians have always known that cancers of the same primary site were different with regard to natural history and response to treatment. Today we have better tools for understanding these differences and using this knowledge to improve the development of drugs and the predictive biomarkers to guide their use. This approach provides the opportunity to tailor drugs to patients so that a greater portion of the treated population will benefit, the average benefit for the treated population will be larger, fewer patients will be exposed to the adverse effects of new regimens without benefit, clinical trials can be smaller and payers more likely to reimburse since the cost-benefit is greater.
Cunanan KM, Iasonos A, Shen R, Begg CB & Gonen M. 2017. An efficient basket trial design. Statistics in Medicine 36( 10): 1568-1579.
Cunanan KM, Gonen M, Shen R, et al. Basket Trials in Oncology: A Trade-Off Between Complexity and Efficiency. Journal of Clinical Oncology. 2017;35(3):271-273.
Simon R, Geyer S, Subramanian J, Roychowdhury S. (2016). The Bayesian basket design for genomic alteration driven phase II clinical trials, Seminars in Oncology 43:13-18.
Simon R. Genomic alteration based clinical trials in oncology. (2016). Annals of Internal Medicine 165:270-278.
Simon R. New designs for basket clinical trials in oncology. (2017). Journal of Biopharmaceutical Statistics 28:2, 245-255.
14:00 – 14.30 Kaffepause
14:30 – 15:15 Biomarker Driven Clinical Trial Designs in Oncology
Cancers are diseases of DNA disfunction and new diagnostic classification systems based on somatic genomic alterations are rapidly replacing traditional systems based on primary site and histology. A large proportion of the cancer drugs that have been approved by regulatory authorities in the past decade have an intended use for a restricted subset of patients. The intended use subset is often characterized by genomic de-regulation of a gene related to the molecular target of the drug. Much current drug development in oncology involves co-development of a companion in-vitro diagnostic test for selecting the subset of patients who are likely to benefit from the drug. The companion diagnostics are often based on DNA sequencing of patients' tumors. Progress in the development of effective drugs has increased in oncology. The progress has been based on use of non-traditional clinical trial designs such as enrichment designs in which a relatively narrow subset of patients is selected for randomization instead of the usual broad eligibility trials. Adaptive enrichment designs have been developed for settings where a single candidate predictive biomarker is not known a-priori. I will review some of the new phase III designs for biomarker driven clinical trials that have been developed and used in oncology.