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Molecular Targets in Cancer Drug Development PowerPoint Presentation

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Description : Check out this medical PowerPoint presentation titled "Molecular Targets in Cancer Drug Development: Access to Precision Medicine for Children with Cancer" by Gregory H. Reaman, MD.

This medical PowerPoint presentation is about access to precision medicine for children with cancer.

Cancer drug development aims to identify and target molecular pathways that are disrupted in cancer cells, with the goal of improving treatment outcomes and reducing side effects. Precision medicine is a tailored approach to cancer treatment that takes into account the unique molecular characteristics of an individuals tumor to guide therapy.

Access to precision medicine for children with cancer is important because pediatric cancers can have different molecular profiles than adult cancers, and may require different treatments. However, drug development for children with cancer has historically been limited due to challenges in conducting clinical trials in this population.

One strategy to improve access to precision medicine for children with cancer is through the development of targeted therapies that are designed to inhibit specific molecular targets that are important for cancer growth and survival. For example, drugs that target the fusion protein EML4-ALK have been shown to be effective in treating children with a rare form of lung cancer known as ALK-positive non-small cell lung cancer.

Another strategy is to develop drugs that can be used across different types of cancer, regardless of the specific molecular alterations present in the tumor. For example, immunotherapies such as checkpoint inhibitors that target the immune systems response to cancer cells have shown promise in treating a variety of different cancers.

To improve access to precision medicine for children with cancer, it is important to continue to invest in research to identify new molecular targets and develop targeted therapies, as well as to increase the availability of clinical trials that include pediatric patients. Additionally, there is a need to increase awareness and education among healthcare providers and families about the benefits of precision medicine in pediatric oncology.

Tags : Cancer Drug Development, Precision Medicine for Children with Cancer, pharmaceuticals, pharmaceuticals PowerPoint presentations

Published on : Jun 23, 2023 | Views : 1302 | Downloads : 4

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Slide 1-

Molecular Targets in Cancer Drug Development: Access to Precision Medicine for Children with Cancer Gregory H. Reaman, M.D. Associate Director for Pediatric Oncology, Oncology Center of Excellence Associate Director, Oncology Sciences Office of Hematology and Oncology Products, OND, CDER
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Cancer Drug Development for Children and Adolescents Well recognized, long-standing challenges- biologic, societal, economic Widely leverages adult drug discovery/development- limited opportunities for extrapolation and limited pre-clinical testing in pediatric models Impact of legislative initiatives which support pediatric drug development has been markedly less obvious in Oncology than in other clinical areas. Accepted off label use as part of standard of care and clinical research- delayed pediatric evaluations Improved outcomes for children with cancer lead to misperception of the unmet clinical need for new drugs. Unique practice model- integration of clinical research and management provides obvious opportunity to facilitate drug development. Lag in evolution of cancer drug development paradigm in pediatrics www.fda.gov
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Evolving Landscape of Oncology Drug Development Evolutionary Paradigm shift: Human genome (2003) – wide-spread availability of NGS Genomic and proteomic interrogation of individual cancers screened for specific molecular abnormalities for which “highly specific” targeted agents are developed Resulted in the creation of multiple rare subsets(defined by molecular phenotype) of previously common cancers and reconsideration of taxonomy Transformative: NSCLC, Melanoma, Myeloma, AML Tissue/histology agnostic development
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Evolution of Identification of Genomic Alterations in Lung Adenocarcinoma 2009 2004 2014 1984 - 2003 No known genotype EGFR No known genotype
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Challenges with “old paradigm” 5 EGFR ROS1 KRAS MET p53 Platinum doublet Platinum doublet + drug X HIGH RISK PHASE 3 FAILURE OR CLINICALLY SMALL EFFECT ALK Targeted Therapy Large, Clinically Meaningful Effect 1% Prevalence of even common tumors: Number needed to screen > 100 patients need to reduce screen failure rate 1 drug/ 1 biomarker per trial unsustainable Need common multi-analyte platform(s) Need Rapid Learning/ Failure/ Confirmation Challenges with “new paradigm” ALK N=800-1200 N=100-200
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Precision Medicine and Oncology Drug Development Precision oncology requires novel study platforms for evaluating new targeted therapies Multiple new targeted agents (including same in class) Platform studies: Master Protocols Combinations Standard control arms Centralized biomarker platforms Efficiency in setting of small populations (rare subsets) Precision cancer medicine: targeted therapy selection by identifying key gene variants.
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Frequency of cytogenetic subtypes of pediatric ALL. Charles G. Mullighan Hematology 2012;2012:389-396 ©2012 by American Society of Hematology
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Ph-like ALL Genetic Stratification for COG ALL Trials. Sarah K. Tasian et al. Blood 2017;130:2064-2072 ©2017 by American Society of Hematology
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Opportunities for Pediatrics Embryonal solid tumors with low mutation frequency Genetic and epigenetic evidence base for driver gene mutations differ between adult and pediatric cancers Multiple demonstrations of actionable gene aberrations in pediatric tumors provide suggest that inhibition of the same molecular targets may result in vulnerability of select childhood cancers Insufficient/delayed development opportunities for children require a paradigm shift in approaches to early pediatric evaluation of potentially promising new agents Paradigm shift necessitates amendment to current legislation to accelerate timelines. www.fda.gov
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Somatic mutations in the pediatric pan-cancer cohort S N Gröbner et al. Nature 555, 321–327 (2018) doi:10.1038/nature25480
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Potentially druggable events in pediatric cancers S N Gröbner et al. Nature 555, 321–327 (2018) doi:10.1038/nature25480
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15 U.S. Legislation and Pediatric Drug Development PREA Drugs and biologics Mandatory studies Requires studies only on indication(s) under review Orphan indications exempt from studies Pediatric studies must be labeled BPCA Drugs and biologics Voluntary studies with incentive Studies relate to entire moiety and may expand indications Studies may be requested for orphan indications Pediatric studies must be labeled www.fda.gov
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Pediatric Tumors are Different…but not always Mano, AACR Cancer Discovery June, 2012, 16 Adult tumor types Pediatric tumor types Children do not get NSCLC, but some pediatric tumors have ALK activation  targetability with ALK inhibitors? NSCLC: non small cell lung cancer RMC: renal medullary cancer NBL: neuroblastoma IMT: inflammatory myofibroblastic tumor ALCL: anaplastic large cell lymphoma
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RACE for Children Act: Changing the Paradigm Incorporated as Title V Sec. 504 of the FDA Reauthorization Act (FDARA), enacted August 18, 2017 Requires evaluation of new molecularly targeted drugs and biologics “intended for the treatment of adult cancers and directed at a molecular target substantially relevant to the growth or progression of a pediatric cancer.” Amends PREA: requirement for pediatric assessment based on MoA rather than clinical indication. Molecularly targeted pediatric cancer investigation: dosing, safety and preliminary efficacy to inform potential pediatric labeling.” Elimination of orphan exemption for pediatric studies for cancer drugs directed at relevant molecular targets. www.fda.gov
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Molecular Target Definition A molecule in human cells (normal or malignant) that is intrinsically associated with a particular disease process such as etiology, progression, and/or drug resistance. To be referred to as a target, there must be evidence that by addressing the target with a small molecule, biologic product, or other intervention, a desired therapeutic effect is produced resulting in the alteration of the disease process
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Statutory Requirements for FDA Establish with NCI, update regularly, and post on FDA website a list of “relevant” targets (1 year) Establish and post a list of targets (non-relevant) leading to waivers of pediatric studies (1 year) Work with NCI, Pediatric Subcommittee of ODAC, PeRC, investigators, sponsors, experts, and advocates on implementation and required studies Convene an open public meeting to generate/finalize lists (1 year) Issue guidance on implementation (2 years) www.fda.gov
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Framework* for Defining Relevance Presence of target in one or more pediatric cancers- not prevalence-dependent Target function- etiology, drug resistance, lethality Non-clinical evidence- general and pediatric-specific Adult clinical experience Predictive/response biomarkers availability Accessibility for immunotherapy-directed targets Therapeutic agent available/in development Focus on accelerating appropriate initial pediatric evaluations early in development timeline not increasing number of pediatric phase 1 studies *Multi-stakeholder workshop sponsored by FoCR
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Target Lists Statutory requirement to address regulatory uncertainty for Industry and guide ( not dictate) decision-making re. early evaluation of a specific agent as an amended PREA requirement through the iPSP process Designation as relevant neither an absolute nor exclusive requirement for decisions related to pediatric evaluation: studies of new products may be required if directed at a target not on the list and waivers may be justified for products directed at targets considered relevant Not envisioned to restrict authority or flexibility Relevant molecular targets- independent of agent and/or biomarker availability Candidate Target List constructed by OCE with NCI and input from international content experts; reviewed in a open public meeting Published, peer-reviewed literature, abstracts, public databases No pre-specified minimum evidence base www.fda.gov
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Molecular Targets Relevant Molecular Targets Targets Associated with Specific Gene Abnormalities Targets Associated with Cell Lineage Determinants Targets on Normal Immune Cells and/or Cellular Components of the Tumor Microenvironment Targets Associated with Pathways/ Functional Mechanisms of Cancer Cells Non-relevant Molecular Targets Leading to Waivers https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/OCE/ucm544641.htm
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Pediatric Cancer Platform Trial NCI-COGS Pediatric MATCH Following slides: courtesy of Dr. Nita Seibel, NCI
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Update on NCI-COG Pediatric Molecular Analysis for Therapy Choice (MATCH) APEC1621 Study A phase 2 precision medicine cancer trial Co-developed by the Children’s Oncology Group and the National Cancer Institute June 2, 2018
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What is Pediatric MATCH?
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NCI-COG Pediatric MATCH To determine whether matching certain drugs in children and adolescents whose tumors have specific gene abnormalities will effectively treat their cancer, regardless of the cancer type This is a signal-finding trial; treatments that show promise can advance to larger, more definitive trials
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Pediatric MATCH Screening Protocol APEC1621SC Screening registration children and adolescents with advanced cancers Tissue biopsy Tumor testing using validated single platform, with immunohistochemistry (IHC) for PTEN, SMARCB1, SMARCA4, RB No treatment assignment Drug C Drug D Drug E Drug F Drug H Yes, treatment assignment Tumor gene abnormality matching to a trial arm? Drug E Drug A Drug B Drug G Drug J DrugI
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NCI Pediatric MATCH SubprotocolsIn Development
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NCI Pediatric MATCH Subprotocols
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The Future Full implementation of FDARA Sec. 504- August, 2020 Expansion of pediatric pre-clinical testing in progress Prioritization of which new targeted agents for pediatric assessment by Industry and academic investigator community Global coordination and collaboration
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