Navigating the Clinical Trials System: NCI, CTEP, Pharma

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Navigating the Clinical Trials System NCI, CTEP,
Pharma

• Louis M. Weiner, MD
• Fox Chase Cancer Center

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Question 1
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TLR Agonists Induce Innate and Adaptive Immune
Responses
Schmidt, Nature Biotech. 24, 230 - 231 (2006)
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So, You Have a Great Idea!

• Toll Receptor 4 Agonists
• Stimulate immune response
• Potentiate chemotherapy effects in vitro and in
  vivo
• Enhance in vivo anti-tumor effects of an
  anti-HER2 monoclonal antibody
• Appear to be safe

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ANTITUMOR ACTIVITY OF TLR4 AGONIST WITH
TRASTUZUMAB
SCID mice D5-Her2 103 Cells Rx BIW, begin Day 1
Trastuzumab (8)
PBS (8)
E6020 (8)
TE6020 (7)
6/7 alive
1/8 alive
1200
800
Tumor volume, mm3
400
0
0
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Days after tumor challenge
S. Wang, I. Astsaturov
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Question 2
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Who Will Supply an Agent?

• Identify a Source of Trastuzumab (easy)
• Identify the Source of a TLR4 Agonist
• Approved drug? (not available)
• Make your own drug
• Pharma
• CTEP

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Make Your Own Drug

• Make the own drug in your lab (rarely possible)
• Start your own company
• Employ the NCI Rapid Access Intervention
  Development (RAID) Mechanism
• Apply for support/assistance to produce the agent
  
• Support may be for a specific step in the drug
  development process (i.e., toxicology,
  formulation) or for the entire process
• Expect 5 years from initial application to
  initiation of the clinical trial
• http//dtp.nci.nih.gov/docs/raid/raid_index.html

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Collaborate with Pharma

• Identify companies that are making the agents
  that interest you
• Determine who you should contact at these
  companies
• Does your idea lie in the companys critical path
  for drug approval?
• If so, there is a chance your idea is already
  being tested
• If not, the company may not be interested in
  risking adverse outcomes that damage the approval
  process
• Contact representatives and begin dialogue
  regarding your concept and the availability of
  the reagent

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Collaborate with Pharma

• Your interests and those of pharma are unlikely
  to be perfectly aligned!
• Everyone wants to do well and do good
• You
• Want to acquire knowledge
• Want to lay a foundation for continued
  development of your (perhaps only) major focus
• Want to advance your career
• Pharma
• Needs to develop a product
• Needs to know quickly if this (one of perhaps
  many of their) agent(s) has a chance to be
  successful

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Question 3
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Companies in the race to bring TLRs to market
Schmidt, Nature Biotech. 24, 230 - 231 (2006)
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Work with the NCI

• Cancer Therapy Evaluation Program
• http//ctep.cancer.gov/
• Recent Solicitations
• GX16-070 (small molecule bcl-2 inhibitor)
• AZD6244 (MEK1/2 inhibitor)
• Pertuzumab Cetuximab
• Reovirus Serotype 3
• Dasatinib
• VEGF Trap
• GW786034 (multi-targeted TKI)
• Sunitinib Phase II trials
• AZD0530 (non-receptor TKI inhibitor)
• E7389 (Halochondrin analogue)
• MLN518 (multi-targeted TKI Phase II)
• SGN30 (anti-CD30 antibody)

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Work with the NCI

• Cancer Therapy Evaluation Program
• http//ctep.cancer.gov/
• Recent Solicitations
• GX16-070 (small molecule bcl-2 inhibitor)
• AZD6244 (MEK1/2 inhibitor)
• Pertuzumab Cetuximab
• Reovirus Serotype 3
• Dasatinib
• VEGF Trap
• GW786034 (multi-targeted TKI)
• Sunitinib Phase II trials
• AZD0530 (non-receptor TKI inhibitor)
• E7389 (Halochondrin analogue)
• MLN518 (multi-targeted TKI Phase II)
• SGN30 (anti-CD30 antibody)
• No TLR4 Agonist

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Now What?

• Be flexible!
• Are you interested in a specific drug, or are you
  interested in using a drug to test a concept?
• Are there other agents that may reproduce key
  attributes of your TLR4 agonist?
• TLR7 agonists (e.g., imiquimod)
• TLR9 agonists (e.g., CpG ODN)
• Cytokines (e.g., IL-21)
• Approach companies, CTEP with alternate ideas
  that will help you address your key concept.

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Case 2

• Your mentor is invited to participate in a Phase
  II clinical trial of a new TLR9 agonist in
  combination with taxol carboplatin in patients
  with advanced NSCLC, and offers you an
  opportunity to be the lead investigator in your
  institution

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Question 4
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Remember

• You are a contractor to the company
• You are expected to deliver timely study
  activation and patient accrual
• Assignment of authorship will be based on patient
  accrual and other, political factors
• Your exciting correlative studies are unlikely to
  be incorporated into the study plan

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Case 3

• CTEP releases a L0I for a Phase II trial of a
  TLR9 agonist in combination with radiation
  therapy for esophageal cancer
• Your institution sees 15 patients per year who
  might qualify for such a study
• You have developed an assay that measures
  induction of immune responses to MUC-1 (a
  glycoprotein antigen)
• This assay might be used as an exploratory
  biomarker of TLR9 activation of the immune
  response
• Should you respond to the LOI?

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Why Not?

• A study that cannot be completed (e.g., low
  patient accrual) is useless, even if the
  rationale is sound and the supporting science is
  superb
• LOI unlikely to be accepted by CTEP except as a
  multi-institutional study
• Distinctions from pharma-based study
• Longer gestation period
• More investigator input into study design
• Easier to add exploratory scientific endpoints to
  the study

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Good Luck!