National Cancer Institutes Experimental Therapeutics Program NEx T

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National Cancer Institute’s Experimental Therapeutics Program (NEx. T) James H. Doroshow, M. D. Division

National Cancer Institute’s Experimental Therapeutics Program (NEx. T) James H. Doroshow, M. D. Division of Cancer Treatment and Diagnosis, NCI

Drug Development Programs: NCI & NIH Primarily a Contract-Based Program T 1 D RAID

Drug Development Programs: NCI & NIH Primarily a Contract-Based Program T 1 D RAID NIH DDG NIH RAID Pilot NIDDK NCI DCTD-CCR JDC DCTD RAID CCR DTP DCB CTEP DCCPS BTB BRB (BDP) CIP DSCB PRB DCP CDP NPB TPB DCEG RRP STB IDG ITB/GCOB NCDDG

Decentralized NCI Drug Development • Created inefficiencies (duplication of experimental work and/or mission) •

Decentralized NCI Drug Development • Created inefficiencies (duplication of experimental work and/or mission) • Fostered resource silos (staff with expertise in an area could be unintentionally excluded from a project) • Confused collaborators (which mechanisms most appropriate for entry of agent into the program? What resources available? ) • Confused staff (What projects had priority? What resources could be accessed? Who had decision making authority? )

NCI Experimental Therapeutics Program CHEMISTRY BIOLOGY CHEMICAL BIOLOGY NEx. T Program Imaging Rx’s CIP

NCI Experimental Therapeutics Program CHEMISTRY BIOLOGY CHEMICAL BIOLOGY NEx. T Program Imaging Rx’s CIP SPOREs RAID CCR Cancer Centers Lead Optimization Profiling Clinical Candidate Phase 0/1 DTP/CCR/Chemical Biology Medicinal Chemistry Teams DTP Pharmacology and Toxicology NCI Molecular Imaging Roadmap CTEP/RRP/CCR Discovery Development Clinical Investigation

NCI Experimental Therapeutics Program GOAL: Unified Discovery & Development A single pipeline for all

NCI Experimental Therapeutics Program GOAL: Unified Discovery & Development A single pipeline for all therapeutic development resources – One Pipeline, Many Points of Entry Targets INCLUDES Therapeutics • Investigational drugs • Investigational imaging agents • Academic & small biotech projects • NCI & NIH internal projects

NCI Experimental Therapeutics Program Current Strengths Particular strength: Proof-of-concept early phase therapeutic trials INCLUDES

NCI Experimental Therapeutics Program Current Strengths Particular strength: Proof-of-concept early phase therapeutic trials INCLUDES • Clinical pharmacodynamics • Rare tumors • Early phase investigational combination therapy

DCTD Early Drug Development: A Unique Niche NCI adds value to company and academic

DCTD Early Drug Development: A Unique Niche NCI adds value to company and academic collaborator molecules by expanding a drug’s development plan: • • • Pediatrics Organ Dysfunction New Doses/Schedules (Phase 1 consortium) Multidisciplinary (Brain, Head and Neck) Uncommon Tumors (utilizes the CTSU platform for neuroendocrine, hematologic, AIDS and molecularly defined subsets of common or uncommon tumors) • Radiation sensitization • Combinations of investigational agents

Targeted/Novel Agents under DCTD IND • EGFR/HER pathway: – – – Erlotinib (OSI Pharm)

Targeted/Novel Agents under DCTD IND • EGFR/HER pathway: – – – Erlotinib (OSI Pharm) Gefitinib (Astra. Zenaca) Cetuximab (Im. Clone) Trastuzumab (Genentech) Pertuzumab (Genentech) Lapatinib (GSK) • IGF-1 R : IMC-A 12 (Im. Clone) • MEK: AZD 6244 • m. TOR: CCI-779 (Wyeth) • Signal Transduction/Cell cycle – – • Anti-angiogenesis: − − − Bevacizumab (Genentech) VEGF Trap (Sanofi-Aventis) Medi 552 (Med. Immune) Sorafenib (Bayer) AZD 2127 (Astra. Zeneca) Cilengitide (EMD) • BCL-2 family: − AT-101 (Ascenta) − GX 15 -070 (Gemin X) − ABT-263 (Abbott) • HDAC inhibitors: − SAHA (Merck) − PXD 101 − Romidepsin (Gloucester) Flavopiridol Bryostatin UCN-01 • Proteasome/chaperone Sch 727965—CDK (Schering) − PS-341 (Millennium) • Other: − 17 -AAG (BMS) – Sunitinib (Pfizer) • Immune modulators and Vaccines – Dasatinib (BMS) − anti-CTLA-4 (Medarex) – FTI (R 115777) (J&J) − Vaccines – Imatinib (Novatis) – GDC-0449—Hedgehog (Genentech) • 105 INDs for investigational agents • > 80 collaborative agreements with pharmaceutical/biotech

Combinations of Investigational Targeted Agents inhibition of one target Linear target inhibition Parallel pathways

Combinations of Investigational Targeted Agents inhibition of one target Linear target inhibition Parallel pathways Targets Clinical trials Tumor types VEGF + VEGFR/raf BV + Sorafenib* RCC EGFR + EGFR TKI* C 225 + Erlotinib* Colon VEGF + m. TOR BV + CCI-779* RCC Sorafenib + CCI-779* Melanoma, GBM Her-2 + m. TOR* Trastuzumab + Everolimus Breast EGFR + m. TOR EGFR TKI + CCI-779* NSCLC, GBM Her-2 + CDK* Trastuzumab+flavopirid Breast ol* VEGR + EGFR* BV + C 225* Colon, Pancreatic BV + Erlotinib* Breast, SCCHN, RCC, etc VEGF + PDGF*/c-kit BV + Imatinib* Melanoma, GIST Her-2 + Her-1 Trastuzumab + gefitinib* Breast

Novel Approaches to Early Phase Personalized Trials Phase 0 Trial of ABT-888

Novel Approaches to Early Phase Personalized Trials Phase 0 Trial of ABT-888

NCI Experimental Therapeutics Program Current Strengths Particular strength: “Humanizing” Preclinical Systems INCLUDES • Mouse

NCI Experimental Therapeutics Program Current Strengths Particular strength: “Humanizing” Preclinical Systems INCLUDES • Mouse models • Pharmacodynamic assay development • Formulation • Imaging agents

Clinical Qualification of PD Assay: “Humanizing” Preclinical Models • “Clinical Readiness” of PD Assay:

Clinical Qualification of PD Assay: “Humanizing” Preclinical Models • “Clinical Readiness” of PD Assay: – Validated analytical performance – Therapeutically relevant in preclinical model • Clinical procedures for sample acquisition and handling • Storage transferability • Time frames achievable in clinical setting • Inter- and intratumoral variability • Stability of baseline • Minimum doses required for target effect • Suitability of surrogate tissues

Bortezomib (Velcade®): Industry/Government Collaboration DATE 1. 2. 3. 4. 5. 6. 7. 8. 9.

Bortezomib (Velcade®): Industry/Government Collaboration DATE 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. July 1995 August 1995 September 1995 January 1997 October 1997 April 97–March 98 December 1997 June 1998 December 1998 June 1999 July 1999 May 2000 March 2003 ACTION 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 30 Analogs Rec’d from Pro. Script In Vitro Activity Confirmed in NCI 60 Hollow Fiber Activity Determined Xenograft Activity Demonstrated Passed NCI DN 2 A Milestone NCI Stable Formulation Developed Pharmacokinetic Studies Conducted Toxicology Studies Initiated Passed NCI DN 3 Milestone Toxicology Studies Completed IND Filed 1 St NCI Clinical Trial Initiated (54) NCI Formulation Adopted by

Pre-Clinical Imaging Drugs and Technologies Agents for development • 18 F-d-cytidine • 11 C-acetate

Pre-Clinical Imaging Drugs and Technologies Agents for development • 18 F-d-cytidine • 11 C-acetate • 13 N-gemcitabine • 18 F-FLT • 11 C-SN-38 • 18 F-MISO • 11 C-AMT • 18 F-Galacto-RGD • 18 F-paclitaxel • 111 In-Herscan • 18 F-DCFBC • Gd-chelated albumin • 18 F • Her 2 Affibody 18 F-FES Synthesis and GMP Scale up (including radiolabeling) Imaging Feasibility: SAIC-F Small Animal Imaging Pre-clinical development (pharmacology and toxicology)

Pre-clinical Imaging Technologies Mouse with bilateral thigh SKOV 3 tumors (4+ Her 2) CT

Pre-clinical Imaging Technologies Mouse with bilateral thigh SKOV 3 tumors (4+ Her 2) CT – SPECT 111 In trastuzumab at 96 hrs Pre-clinical imaging for drug development by Small Animal Imaging Program. NCI Frederick

GMP Radiochemistry – Frederick

GMP Radiochemistry – Frederick

NCI Drug Discovery and Development: Future Chemical Biology Consortium target discovery through NCIsponsored clinical

NCI Drug Discovery and Development: Future Chemical Biology Consortium target discovery through NCIsponsored clinical trials IND-supporting preclinical studies Early clinical studies This initiative fills a critical gap in the NCI drug development pipeline Mission: Increase flow of early stage drug candidates from academia into NCI pipeline Unique Opportunity: Move all the way from target discovery to clinical trial

The Chemical Biological Consortium: A New NCI Initiative • • • • Burnham Institute

The Chemical Biological Consortium: A New NCI Initiative • • • • Burnham Institute Southern Research SRI International Vanderbilt Emory UCSF Univ. North Carolina Pittsburgh Univ. of Minnesota Georgetown NCI Intramural Chemical Biology NIH Chemical Genomics Center Affiliate Investigators

Chemical Biology Consortium Vision Why is CBC different? • • Builds on >50 yrs

Chemical Biology Consortium Vision Why is CBC different? • • Builds on >50 yrs of NCI experience in cancer drug development Not intended to replicate Pharma CBC members will submit own projects and take on those of other investigators Focus on bringing academic targets and molecules to patients Will not shy away from difficult targets Longer time horizon NCI committed to supporting CBC projects from inception through proof-of-concept, PD-driven clinical trials if milestones achieved: Only NCI could do this Inclusive involvement of CBC members in shared projects developed in parallel across consortium Discovery Risk • NCI Biotech Big Pharma Market Risk

Chemical Biology Consortium: Enabling Hit-to-Lead Discovery Lead Chemical Matter CHEMISTRY Roadmap Molecular Library Screening

Chemical Biology Consortium: Enabling Hit-to-Lead Discovery Lead Chemical Matter CHEMISTRY Roadmap Molecular Library Screening Centers BIOLOGY Chemistry / Biology Contracts Focused Analog Synthesis CCR/DTP/academic medicinal chemistry teams working closely with computational chemists Structure-based drug design Aggressive Compound Progression • Proprietary CBC Database housed at DCTD • In silico and in vitro ADME/Tox screening CRO Contracts: support external/internal chemistry efforts Program Focus: Cross-site “targeteers”, screeners and medicinal chemists working on high-priority targets in a team setting Integrated Program vs. Service-Driven Program

Leveraging NIH Road. Map Investment in Molecular Libraries Program Early Drug Discovery Partnership With

Leveraging NIH Road. Map Investment in Molecular Libraries Program Early Drug Discovery Partnership With the NIH Molecular Libraries Screening Centers and Comprehensive Chemical Biology Centers: The CBC will provide resources and expertise to interrogate novel targets, implement multi-platform assays (including genome-wide RNAi screens), and profile lead compounds discovered under NCI grant mechanisms including the Cancer Genome Atlas Project Team Chemistr y Hit Validation Assay Development Assay Implementation Compound Libraries Informatics Outreach/ PI project development Assay validation Compound management Compound registration Cherry picks Purification Assay optimization HTS operations Reconfirmation Analytical chemistry Follow-up assays Analog Purchase or Synthesis Assay development Offline robotic validation Online robotic validation Data normalization, curve fitting/ classification, SAR analysis Crystallography Hit Criteria Met? Adapted with permission from the NIH Chemical Genomics Center N Yes Cell-based assay and preclinical development

Multiple Entry Points into the CBC Exploratory Screen Development Target identification Screening/ Designed Synthesis

Multiple Entry Points into the CBC Exploratory Screen Development Target identification Screening/ Designed Synthesis Primary HTS Model Development and Target Validation Lead Development Parallel medicinal chemistry Candidate Seeking Optimal potency/ selectivity Biomarker validation Clinical Candidate Efficacy in pivotal in vivo models Small Animal Imaging Center Adapted with permission from the NIH Chemical Genomics Center

Purpose and Scope of CBC Consortium Agreement • CBC participants sign a Consortium Agreement.

Purpose and Scope of CBC Consortium Agreement • CBC participants sign a Consortium Agreement. This agreement details: – How CBC participants ensure timely entry of deliverable data into the database – How CBC participants manage IP ownership to ensure that other members of the consortium have adequate access to data for development – The preferred mechanism by which CBC participants manage joint inventions – CBC participant responsibilities to share research resources developed under the contract with the broader research community The Consortium Agreement addresses: Data Transfer Data Sharing Data Ownership

CBC Request for Proposal Extramural scientists encouraged to join the CBC and may propose

CBC Request for Proposal Extramural scientists encouraged to join the CBC and may propose targets, screens, or molecules for entry into the CBC pipeline https: //dctd. cancer. gov/nextapp or https: //dctd. cancer. gov/nextregistration

Intramural Participation in CBC Basic Discovery Science in Cancer, Immunology, Genetics/Genomics Molecular Biology, Chemistry,

Intramural Participation in CBC Basic Discovery Science in Cancer, Immunology, Genetics/Genomics Molecular Biology, Chemistry, Structural Biology + Molecular Discovery Program Chemical Biology Structural Biology Screening of Natural Products DISCOVERY NCI Drug Development Platform Governance Senior Management Committee External Advisory Groups NCI Drug Development Committee DEVELOPMENT NCI Drug Discovery Committee Target Lead Identification Optimization Profiling Chemical Biology Consortium Clinical Candidate Phase 0/I/II

NCI Experimental Therapeutics How to Govern a Unified Pipeline? • Transparency – Decisions (scientific

NCI Experimental Therapeutics How to Govern a Unified Pipeline? • Transparency – Decisions (scientific or resourcing) must be done through a formal process. Relevant staff must have access to decision making bodies • Accountability – Clearly establish roles and responsibilities and provide authority to carry out the decisions of the organizing body • Inclusiveness –The overarching structure must have buy-in from the NCI community, both extramural and intramural

2009 and Beyond: Moving Toward One NCI Pipeline— A Centralized Decision Body to Support

2009 and Beyond: Moving Toward One NCI Pipeline— A Centralized Decision Body to Support Discovery and Developmen Activities Anticipate ~20 -30 projects in the pipeline

A Unified Approach to NCI Experimental Therapeutics – One Pipeline—Multiple Inputs Discovery (SEP) Senior

A Unified Approach to NCI Experimental Therapeutics – One Pipeline—Multiple Inputs Discovery (SEP) Senior Management Committee Development (SEP) Strategic decisions & scientific merit Drug Discovery Committee Senior Advisory Committee Tactical decisions Inputs Drug Development Committee CBC Development PD Working Group Intramural Imaging Drugs CTEP Agents

Senior Management Committee – DCTD: Crowell – CCR: – OD: – OCG: – FFRDC:

Senior Management Committee – DCTD: Crowell – CCR: – OD: – OCG: – FFRDC: – SAIC-F: Doroshow, Tomaszewski, Collins, Wiltrout, Helman, Schneider Niederhuber Gerhard Reynolds Harris Provides strategic direction for the overall NEx. T Program

NEx. T Discovery Committee Membership 2 -year term of appointment Chairs: Yves Pommier and

NEx. T Discovery Committee Membership 2 -year term of appointment Chairs: Yves Pommier and DTP Chemistry Chief 1. 2. 3. 4. 5. 6. 7. 8. Barbara Mroczkowski Joseph Tomaszewski Jerry Collins Myrtle Davis-Millin Melinda Hollingshead Susan Holbeck Paul Grothaus DTP Chemistry Branch Chief 9. Steve Creekmore 10. Jim Tatum 11. Helen Chen or Malcolm Smith (CTEP) 1. Joel Schneider 2. Yves Pommier 3. Allan Weissmann 4. Terry van Dyke 5. Andy Byrd 6. Len Neckers 7. Pat Steeg 8. Barry O’Keefe 9. Pete Choyke 10. Ad hoc: Alex Wlodawer 11. Ad hoc: Don Bottaro

NEx. T Development Committee Membership 2 -year term of appointment Cmte Chair: Jerry Collins;

NEx. T Development Committee Membership 2 -year term of appointment Cmte Chair: Jerry Collins; Co-Chairs: Jeff Abrams and Lee Helman 1. James Doroshow 2. Joseph Tomaszewski 3. Barbara Mroczkowski 4. Jerry Collins 5. Myrtle Davis-Millin 6. Rao Vishnuvajjala 7. Jeff Abrams 8. Jamie Zweibel 9. Steve Creekmore 10. Paula Jacobs (Imaging) 11. Helen Chen 12. Percy Ivy 13. Malcolm Smith 1. Robert Wiltrout 2. Lee Helman 3. Howard Fine 4. Giuseppe Giaconne 5. Patricia Steeg 6. Shivaani Kummar 7. Marston Linehan 8. Stan Lipkowitz 9. Bill Dahut 10. Brad Wood-Director, NIH Center for Interventional Oncology

NEx. T Senior Advisory Committee (SAC) (Voting Members or Designee) Membership: – Co-Chairs: James

NEx. T Senior Advisory Committee (SAC) (Voting Members or Designee) Membership: – Co-Chairs: James Doroshow, Robert Wiltrout – DCTD: Joseph Tomaszewski, Barbara Mroczkowski – DTP: Jerry Collins, James Crowell – CIP: James Tatum, Paula Jacobs – CTEP: Jeff Abrams, Jamie Zweibel – CCR: resource Lee Helman, Michelle Performs allocation for. Bennett NEx. T Program

Success: What Will it Look Like? Transparent, Accountable, Inclusive, & Unified Hypothesis Generation Risk

Success: What Will it Look Like? Transparent, Accountable, Inclusive, & Unified Hypothesis Generation Risk Clinical Candidate Development Commercialization Po. C in 30% of Phase II trials Cumulative Investment Target Validation Target/ Assay Molecule Lead Preclinical Phase Development Discovery Optimization Development I II Phase III Registration Global Launch Optimization Lead Generation Risk

https: //dctd. cancer. gov/nextregistration CBC Implementation Team Heba Barazi Michelle Bennett Jason Cristofaro Mike

https: //dctd. cancer. gov/nextregistration CBC Implementation Team Heba Barazi Michelle Bennett Jason Cristofaro Mike Difilippantonio Gina Hayman Lee Helman Sanjay Malhotra Barbara Mroczkowski Ralph Parchment David Segal Shizuko Sei Tom Stackhouse Joe Tomaszewski Bob Wiltrout SAIC-Frederick