The National Cancer Institute’s NExT Program

The National Cancer Institute’s
NExT Program
Michael J. Difilippantonio, Ph.D.
Program Manager for Therapeutic and Diagnostic
Initiatives, DCTD, NCI
October 02, 2012
Objectives
• Division of Cancer Treatment and Diagnosis
(DCTD), NCI
• The NCI Experimental Therapeutics (NExT)
Program
• The Application and Review Process
Division of Cancer Treatment and
Diagnosis (DCTD), NCI
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Biometrics Research Branch (BRB)
Cancer Diagnosis Program (CDP)
Cancer Imaging Program (CIP)
Cancer Therapy Evaluation Program (CTEP)
Developmental Therapeutics Program (DTP)
Radiation Research Program (RRP)
Translational Research Program (TRP)
Office of Cancer Complimentary and
Alternative Medicine (OCCAM)
FDA Approved Therapeutics Developed with
Assistance from the NCI in Last Decade
Year
Agents
Role of NCI
Mechanism of Support
2010
Sipuleucel (Provenge®)
RAID project
National Cooperative Drug
Discovery Grant
2010
Eribulin (Halaven®)
Natural product discovery; screening;
formulation of clinical product; efficacy
testing; clinical candidate selection; firstin-human trial
DCTD/DTP Frederick labs;
2009
Pralatrexate (Folytin®)
RAID project; NCI produced GMP bulk
drug
DCTD/DTP contract
resources for production of
GMP quality bulk drug
2009
Romidepsin /
Depsipeptide (Istodax®)
Developed safe human dosing schedule
in large animals; PK and Tox; produced
drug for clinical trials; conducted first-inhuman trials in NIH CC
DCTD/DTP pharmacology
and toxicology and drug
production
2007
Topotecan (Hycamtin®)
2004
Cetuximab (Erbitux®)
Produced first lots for imaging and
chimeric clones
DTP Contracts; Cooperative
Drug Discovery Grant
2004
5-Azacytidine (Vidaza®)
Pre-clinical molecular pharmacology;
produced pre-clinical and clinical drug
supply; conducted pivotal trial
DTP Contracts; Frederick
2003
Bortezomib (Velcade®)
Extensive analog screening; MOA and PD
studies; PK & Tox; clinical formulation
DCTD/DTP Frederick labs;
formulation, PK, Tox
2000
Temozolomide
(Temodar®)
Scale up synthesis and clinical
formulation
DCTD/DTP bulk drug and
formulation contracts
Selected NCI/CTEP-sponsored Group Trials Contributing to FDAapproved Indications for New Oncology Agents in Last Decade
Year
Agents
Group
Company
2007
Lapatininb (Tykerb®)
Deoxycoformycin (Pentostatin®)
NCCTG, CALGB,
Intergroup
2006
Dasatinib (Sprycel®)
Sunitinib (Sutent®)
Pegaspargase (Oncaspar®)
SWOG, Intergroup
ECOG, Intergroup
BMS
Pfizer
Enzon
2005
Lenalidomide (Revlimid®)
Nelarabine (Arranon®)
Sorafenib (Nexavar®)
ECOG, Intergroup
COG, CALGB
ECOG, Intergroup
Celgene
GSK
Bayer / Onyx
2004
5-Azacytidine (Vidaza®)
Bevacizumab (Avastin®)
Erlotinib (Tarceva®)
Taxotere (Doxetaxol®)
CALGB
ECOG. Intergroup
NCCTG, Intergroup
SWOG
Celgene
Genetech
Genentech / OSI
Sanofi-Aventis
2002
Oxaliplatin (Eloxitin®)
NCCTG, Intergroup
Sanofi-Aventis
2001
Imatinib mexylate (Gleevec®)
Letrozole (Femara®)
COG, SWOG
NCIC, Intergroup
2000
Arsenic trioxide (Trisenox®)
CALGB
GSK
Bedford Labs
Novartis
Novartis
Cell Therapeutics
What’s NExT?
Transformation of the NCI Therapeutics Pipeline
Cancer
Centers
NIH Roadmap
Biotech &
Pharma
RO1/PO1
SPORE
MLPCN
Intramural
Imaging / IDG
DDG
RAID
The NCI Experimental Therapeutics (NExT) Pipeline:
Target discovery through early stage clinical trials
Exploratory
Screen
Development
Screening/
Designed
Synthesis
Drug Discovery
Lead
Development
Candidate
Seeking
Clinical
Candidate
Early Development
Phase 0 / I
Trials
Phase II/III
Trials
Registration
Full Development
Harmonize Activities into Single Pipeline
Post
Launch
NExT Governance
NOT A GRANT PROGRAM
• Clear path to clinic/patient benefit
• Provides access to NCI resources and drug
development expertise
• Integrates a variety of prior decentralized and
uncoordinated programs
• Simple application
• PI has project involvement
A Unique Partnership with the NCI to Facilitate
Oncology Drug Discovery and Development
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Complete development of an orphan drug
Exploratory screen development and optimization
Preclinical development for molecularly targeted agents
Develop formulation and manufacture GMP grade drug
to conduct IND-enabling pre-clinical and clinical studies
• A pharmacodynamic assay or imaging technique to
determine if an agent is modulating its target
• Proof-of-concept or first-in-human studies
• Other resources to support drug discovery and
development
NExT Resources Currently Support
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Investigational drugs, biologics and NP’s
Investigational imaging agents
Academic, biotech and pharma projects
HTS, Hit-to-Lead, Lead Optimization, Clinical
Candidate, Phase 0, 1 and 2 clinical trials
NOT basic research
August 2009
Chemical Biological Consortium (CBC)
Mission
Dramatically increase the flow of early-stage drug
candidates into the DCTD therapeutics pipeline by
leveraging knowledge from innovative research and
discoveries made at leading academic institutions and
biotechnology companies
And
Provide the extramural community the opportunity to
participate in a highly collaborative drug discovery
partnership with the NCI
Chemical Biological Consortium (CBC)
• Comprehensive Chemical Biology Screening Centers (4)
 Identify targets, develop assays and adapt these assays to HTS
platforms, screen numerous compounds against a variety of
different assays each year, and provide Structure- Activity
Relationship (SAR) analysis
• Specialized Application Centers (3)
 Provide expertise and experience in specific technologies needed
to successfully develop and implement complex and technically
difficult assays that may not be amenable to HTS
• Chemical Diversity Centers (4)
 Capable of applying medicinal and synthetic chemistry to
advance hits to lead status
Chemical Biological Consortium (CBC)
University of
Minnesota
Chemical
Diversity Center
The Fragment
Discovery Center
(FDC at UCSF)
The University of
Pittsburgh
Chemical
Diversity Center
(UP-CDC)
The University of
Pittsburgh
Specialized
Application Center
VT
NH
MA
RI
CT
NJ
DE
SRI International
The NIH
Chemical
Genomics Center
(NCGC)
DC
Georgetown
University
Medical Center
Sanford Burnham
Institute
Vanderbilt
Institute of
Chemical Biology
Southern
Research
Emory Chemical
Biology
Discovery Center
North Carolina
Comprehensive
Chemical Biology
Center
Gain early access to enabling, leading-edge
translational technologies and tools
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PK/PD Modeling
Tox/Safety Pharmacology
GMP Scale-Up
Imaging supported by Cancer Imaging Program
Development and validation of PD assays during preclinical stages is
supported by the Pharmacodynamics Assay Development &
Implementation Section (PADIS) and during clinical stages by the National
Clinical Target Validation Laboratory (NCTVL).
• Clinical Assay Development Program (CADP) development and validation
of clinical assays (including diagnostic).
• Currently sponsors over 100 INDs
• Approx. 11,000 registered investigators at over 3,300
institutions
• Over 750 active protocols
• 150-250 new protocols/year
• Approx. 30,000 patients accrued/year
• Over 80 collaborative agreements (CRADAs, CTAs, and CSAs)
with pharmaceutical companies (Collaborators)
• Concept application – 5 pages
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Background
Hypothesis
Research strategy
Specific request to NCI
Justification
Uniqueness
• Appendices
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IP Information
Current and pending support
PI biosketch
Other Documentation as appropriate
• This selection is based on the following criteria.
– Scientific Merit
– Feasibility
– NCI Mission
– Novelty
– Clinical Need
Scoring:
1 = Exceptional
3 = Excellent
6 = Satisfactory
9 = Poor
• Special consideration to unmet needs in therapeutic
oncology, including "undruggable" targets, orphan
malignancies, and pediatric cancer
External
Input
Internal
Scientific
Decisions
Resource
Allocation
Senior Advisory
Committee (SAC)
http://next.cancer.gov/
Cycle Open for Submission
Submission Deadline
January 15, 2013
February 15, 2013
May 15, 2013
September 15, 2013
June 15, 2013
October 15, 2013
NCI next or next at NCI
Applications from Academic, Non-Profit, Biotech, Pharma or
Government sector through 9/2011
Total Applications (Total 235)
Top Tier (Total 40)
• Applications – SEP members and Federal employees
are subject to Confidentiality in relation to NExT
Applications. COI conditions do apply.
• CDA’s (Confidential Disclosure Agreements) –
Necessary when brining in non-NExT staff and outside
experts for additional review.
• Collaborative Agreements – A variety of mechanisms
necessary to memorialize interactions between the
applicant and the NExT program, will vary based on
stage/type of project. (CBC Participant’s agreement,
MTA, CTA, Collaborative Agreement, CRADA).
NExT Pipeline – Phase and Agreement Types
Chemical Biology Consortium
target discovery through lead
compound
CBC Consortium Agreement
Formerly RAID and
DDG – “Mid-phase
projects
CTEP – Sponsored
Clinical Trials
“NExT MTA”, CDA’s,
MTA’s
CTA’s, CRADA’s and
CSA’s subject to
CTEP IP Option
Associated Agreement
Slide Graphic courtesy of Barbara Mroczkowski
Early Stage - CBC
• Utilizes the CBC Agreement mechanism
– The advantage of this system is that all work can
be done under a single agreement that includes
provisions for confidentiality
– The disadvantage is that no tangible Intellectual
Property rights or options can be conferred under
this agreement, making it unsuitable for late stage
development
Mid Stage Projects – Lead Compound
through Phase 0/1
• NExT MTA
• “Not-to-file” language in these agreements for NCI
internal studies
• Non-SAIC Contractors have language in their
contracts wherein they are required to offer the first
option to negotiate an exclusive or non-exclusive
license
• SAIC contractors subject to third party language
described in the DEC
Late Stage Projects – CTEP Sponsored
Clinical Trials
• Utilizes CRADA’s, CTA’s and CSA’s to bring in agents for clinical
studies
• IP terms for both NCI use and for cooperative group trials
(CTEP IP Option), new language may have some reach
through on downstream inventions.
• CTA’s – quicker but many collaborators dislike them due to
the lack of IP terms on NCI inventions (IP Option still applies),
we may not bring in money under a CDA either (other than
direct payments to contractors
• CRADA’s – time consuming but allows the NCI to bring in
funding support from Collaborators and offer licensing rights
to the Collaborator
Question
Can the applicant get his/her HTS results back and
then submit, for example, an R01 application based
on these hits? Can he/she establish commercialsponsored research agreements supporting the
project further in his/her laboratory, or does the NExT
program have “rights” to the project indefinitely?
Answer
A PI may leave with his/her project and forego any
further use of NExT resources; however, the NCI
retains the right to continue with the project
independently if it so chooses:
“Materials generated by the CBC will also be defined
deliverables and be available to the government for
use and future development.”
“Yes” to both submitting R01 applications and
establishing commercial agreements.
Question
To what extent is the project’s originating PI
involved? Who decides the scope of work to be
performed within NExT and the “exit point” for the
project from the NExT program?
Can the PI influence these decisions?
Answer
The PI is an integral member of the Project Team.
As a PI you are privy to all information related to
your project as it moves through the various Stage
Gates into the clinic. As part of the project team,
you oversee the scientific direction of the project
to ensure that it stays on course to meet key
milestones.
External SEPs in conjunction with NCI
Committees will monitor project progress through
Stage Gates and will prioritize projects in the NCI
pipeline.
Receptor targeted optical agent for tumor
margin detection – request to NCI
• Optimize the protein-dye reaction: time,
temperature, ratios
• Verify targeting in vitro and in vivo
• Establish purity - >95% mass and optical purity
• Evaluate stability, formulation
• Transfer to biologics GMP contractor
• IND directed toxicology
• Assistance with IND filing
Therapeutic with imaging
• Protein drug totally species specific
• No meaningful toxicology possible
• NCI project team determined that imaging first
would best protect human subjects
– Much lower dose
– Biodistribution to determine off-target
• NCI prepared chelates for PET and SPECT
– Stability, dosimetry, in vitro bioactivity
• FDA negotiation on - going
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