CLINICAL TRIALS OVERVIEW

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CLINICAL TRIALS OVERVIEW
John Janik, M.D.
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What is a Clinical Trial?

• The Way We Make Progress Against Disease
• Research studies to find better ways to
  prevent, detect, or treat disease
• Help health care providers find ways to improve
  patient care

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Why Conduct a Trial if We Know the Answer?
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Types of Clinical Trials

• Treatment Trials
• Prevention Trials
• Screening Trials
• Diagnostic Trials
• Genetics Trials
• Quality of Life Trials

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Treatment Trials
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Prevention Trials
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Screening Trials
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The Drug Development and Approval Process

• 1. Early research and preclinical testing
• 2. IND application filed with FDA
• 3. Clinical trials (phases 1, 2, and 3)
• 4. NDA filed with FDA
• 5. FDA validates claim and approves drug

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Challenges in the development of new agents

• Only 10 of new molecular entities that enter
  late stage clinical trials are approved by the
  FDA for human use
• For new agents tested in patients with cancer the
  figures are lower approaching only 5 of agents
  for which an Investigational New Drug (IND) is
  filed

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History of the Development of Gleevec for the
Treatment of Chronic Myelogenous Leukemia
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Imatinib (Gleevec)
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Kaplan-Meier Estimates of the Rates of Event-free
Survival and Progression to the Accelerated Phase
or Blast Crisis of CML for Patients Receiving
Imatinib
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Why Do a Clinical Trial?

• Evaluate New Drugs
• Phase I - Safety
• Phase II - Effectiveness
• Phase III - Role in Treatment

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Drug Development100,000 drugs have anti-tumor
activity.In preclinical studies, animal studies
are done on 1,000 drugs and 100 drugs have
chemistry formulation. In clinical studies, 10,
5 and 1 are tested in phase I, Phase II and Phase
III clinical trials respectively.
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Why Do a Clinical Trial?

• Optimize Therapy
• Explore New Drug Combinations
• Minimize Treatment Toxicity
• Which Types/Stages of Lymphoma
• When in Disease Natural History

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Why Do a Clinical Trial?

• Other Benefits
• Expert Care
• State of the Art Treatment
• Patient Education
• Reduce Treatment Costs

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Why Do a Clinical Trial?

• Disadvantages
• Randomization to lesser arm
• Unknown or Increased Toxicity
• Increased Cost and Time

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Phases of Clinical Trials

• Phase I
• Determine the relation
• between toxicity and dose schedule of treatment
• Phase II
• Phase III
• Phase IV

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Phase I

• Determine the Safe Dose
• Increase Dose in Patient Groups
• Stop Escalating if too Toxic
• Carefully Monitor all Toxicity
• Pharmacokinetics
• Effectiveness
• Experimental Endpoints

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Phase I dose escalation scheme
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Hazards of Alternative Phase I Designs
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Limitation of standard Phase I design

• Ethical Many patients treated with
  subtherapeutic dose of agent
• Efficiency Modified Fibonacci scheme results in
  lengthy trials

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Alternative strategies for Phase I clinical
trials

• Higher initial starting doses
• Accelerated dose escalation
• Recruitment of only one patient per dose level
  until mild toxicity is observed
• Accrual then reverts to standard phase I design
  with accrual of three patients per dose level

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Starting dose levels for phase I studies

• Preclinical experiments define dose at which 10
  of mice die (LD10)
• Additional animal testing performed in another
  species to confirm toxicity (dog, monkey)
• Phase I trials in general are started with a dose
  that is one tenth that of the LD10 in mice (or
  most sensitive species)

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Safety and Number of Dose Levels in 21 Trials (14
Agents) With Varying Starting Doses
Expressed as a fraction of MELD10 Unsafe as
defined as requiring less than 4 dose escalations
to reach MTD
Eisenhauer, J Clin Oncol 18684, 2000
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Accelerated Dose Escalation Modified Fibonacci
escalation
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Accelerated Titration Design
Design reverts to 40 dose increments with 3-6
patients per dose level with the occurrence of
DLT or two occurrences of grade 2 toxicity
Eisenhauer, J Clin Oncol 18684, 2000
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Phases of Clinical Trials

• Phase I
• Phase II
• Identify diseases in which the treatment is
  effective
• Phase III
• Phase IV

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Phase II

• Determine Effectiveness
• Single or Limited Disease Types
• Pharmacokinetics
• Experimental Endpoints

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Criteria for Measuring Response to Treatment

• Lymphoma Cheson non-Hodgkin's Lymphomas
  International Working Group
• Solid tumor patients RECIST (Response Evaluation
  Criteria in Solid Tumors)

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RECIST

• CR (complete response) disappearance of all
  target lesions
• PR (partial response) 30 decrease in the sum
  of the longest diameter of target lesions
• PD (progressive disease) 20 increase in the
  sum of the longest diameter of target lesions
• SD (stable disease) small changes that do not
  meet above criteria

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Mantle cell lymphoma post idiotype vaccine
Before treatment
After treatment
MDX-CTLA4 3 mg/kg 6 weeks post treatment
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Proposed European Organization for Research and
Treatment of Cancer criteria for assessment of
response by FDG-PET

• Progressive metabolic disease    
• Increase of SUV gt25    
• Visible increase of FDG uptake (gt20 of longest
  dimension)    
• Appearance of new focus
• Stable metabolic disease   
•  Increase of SUV lt25 or decrease lt15 
•  No visible increase of the extent of FDG uptake
• Partial metabolic response    
• Reduction of a minimum of 15-25 of SUV after
  one treatment cycle
• gt25 after more than one treatment cycle
• Complete metabolic response    
• Complete resolution of FDG uptake

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F-18 FDG -PET
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FDG-PET predicts response to chemotherapy in lung
cancer
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FDG-PET predicts response to imatinib
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Patient Number Required for Phase II TrialSample
size (N) of a preliminary trial (Phase IIA)
required to rule out given levels of therapeutic
effectiveness and Type II errorTherapeutic
effectiveness ()
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Phases of Clinical Trials

• Phase I
• Phase II
• Phase III
• Determine if a new treatment is superior to
  standard treatment. Determine the effects of
  treatment relative to the natural history of the
  disease.
• Phase IV

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Phase III

• Compare New and Standard Treatments
• Randomized
• New Treatment Well Studied

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Randomization
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Stratification
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Phases of Clinical Trials

• Phase I
• Phase II
• Phase III
• Phase IV
• Post-FDA approval studies to further assess
  efficacy and toxicity. Evaluates long-term
  effects, including under represented populations.
  

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Phase IV

• Post-Marketing Studies
• Expanded Treatment Groups
• Under studied groups (racial/gender)
• Long term benefit
• Long term risk
• Low frequency toxicity

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Phase 0 validation
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Pharmacodynamics
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Compressing drug development
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Differences Between Phase 0 Phase 1 Trials
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Differences Between Phase 0 Phase 1 Trials
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Differences Between Phase 0 Phase 1 Trials
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Protocol Components

• A written guide to the treatment and research
  studies.
• Major Sections
• Study Objectives
• Background and Rationale
• Eligibility Criteria
• Study Design
• Research Tests
• Statistical Section
• Toxicity Reporting
• Pharmacy Information

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Protocol DevelopmentIt takes 1-6 months for a
protocol concept to be appoved by
Investigator/IND Holder Cooperative Group. It
takes 2-3 months for protocol development by the
Department Review, Institutional Scientific
Review . It takes 2-3 months for the protocol
approval by the IND holder, institutional review
board and FDA.It takes 2-6 years for clinical
trials monitored by the Investigator,Institutiona
l Review Board,Data Safety and Monitoring Board,
IND Holder, andFood and Drug Administration
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NCI Protocol Review

• Scientific review - Branch Review
• IRB - Institutional Review Board Ethical review
• RSC - Radiation Safety Committee Research
  related radiation review
• RAC - Recombinant DNA Advisory Committee Gene
  therapy review
• CTEP Sponsor for NCI supported studies of
  investigational agents
• FDA For investigator held INDs

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Institutional Review Board

• Protection of Human Subjects from
  Research Risks
• Risks are minimized and reasonable in relation to
  anticipated benefits
• Assess risks in relation to accepted practices
• Minimize risks sound research design
• Assess benefits to subjects
• Assess importance of knowledge that might
• reasonably be obtained

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Institutional Review Board

• Monitor data to ensure safety
• Monitors Adverse Events
• Data, Safety and Monitoring Boards
• (DSMB)

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Unanticipated Problems
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Other Safety Reviews

• Gene Therapy
• RAC Recombinant DNA Advisory Committee
• OBA Office of Biotechnology Activities
• Research-related Radiation
• Radiation Safety Committee
• Data Safety and Monitoring Board (DSMB)

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Food and Drug Administration

• To promote the public health by promptly and
  efficiently reviewing clinical research and
  taking appropriate action on the marketing of
  regulated products in a timely manner
• To ensure that human drugs are safe and effective

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Logistics of Clinical Trials

• Clinical Trial Venues
• Single v Multi-Institutional
• Phase I and II
• Cooperative Groups
• Phase III and IV
• Pharmaceutical
• Phase I-IV

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Barriers to Clinical Trials

• Annual Accrual
• Pediatrics 50
• Adults 3
• Barriers
• Physician Bias
• Time and cost
• Patient Bias
• Lack of education
• Guinea Pig syndrome
• Cost and time
• Insurance Denial

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Frequently Asked Questions

• Could I Receive Less Effective Treatment?
• Phase I- Usually restricted to patients who
• have received standard therapy
• Phase II- May be less or more effective
• Phase III- Compares a new but well studied
  regimen
• to standard care. Treatment could be more
  effective.

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Frequently Asked Questions

• Will the Research Be Placed Above my
• Well Being?
• No this should not happen. Investigators are
• obligated to put patient care above the
  study.
• However, confidence in your treating
  physician
• is essential.
• Conflict of interest should be addressed in the
  protocol and with the patients
• Studies are closely monitored PI, IRB, DSMB,
  FDA

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Frequently Asked Questions

• Will I receive a placebo?
• Most oncology trials do not give placebos. If
  you
• randomize to a less treatment arm, you will
  be told.
• A less treatment arm is only included when we
  do
• not know if more treatment is necessary.
• More treatment may be more toxic and no more
  effective
• Data Safety and Monitoring Boards closely monitor
  randomized studies

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Frequently Asked Questions

• How can I find Out About Clinical Trials?
• Ask your physician
• Resources
• Lymphoma Research Foundation
• National Cancer Institute
• Physicians Data Query (PDQ)
• Internet