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  John Janik, M.D.
  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
Why Conduct a Trial if We Know the

                       80                                                            ProMACE-CytaBOM
        Patients (%)



                                 Adapted from Fisher. N Engl J Med. 1993;328:1002.
                             0      1              2            3             4            5       6
                                              Years After Randomization
  Types of Clinical Trials
 Treatment Trials
 Prevention Trials
 Screening Trials
 Diagnostic Trials
 Genetics Trials
 Quality of Life Trials
Treatment Trials
Prevention Trials
Screening Trials
 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
 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
History of the Development of Gleevec for the
Treatment of Chronic Myelogenous Leukemia
Imatinib (Gleevec)
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
Why Do a Clinical Trial?

  Evaluate New Drugs
     • Phase I - Safety
     • Phase II - Effectiveness
     • Phase III - Role in Treatment
Drug Development
100,000 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.
Why Do a Clinical Trial?

Optimize “Therapy”
   •   Explore New Drug Combinations
   •   Minimize Treatment Toxicity
   •   Which Types/Stages of Lymphoma
   •   When in Disease Natural History
Why Do a Clinical Trial?

 Other Benefits
    •   Expert Care
    •   State of the Art Treatment
    •   Patient Education
    •   Reduce Treatment Costs
Why Do a Clinical Trial?

    • Randomization to “lesser arm”
    • Unknown or Increased Toxicity
    • Increased Cost and Time
“Phases” of Clinical Trials
Phase I
Determine the relation
between toxicity and dose schedule of

Phase II
Phase III
Phase IV
              Phase I
 Determine the Safe Dose
    • Increase Dose in Patient Groups
    • Stop Escalating if too Toxic
    • Carefully Monitor all Toxicity
 Pharmacokinetics
 Effectiveness
 Experimental Endpoints
Phase I dose escalation scheme
Hazards of Alternative Phase I Designs
  Limitation of standard Phase I

Ethical – Many patients treated with
  subtherapeutic dose of agent

Efficiency – Modified Fibonacci scheme
  results in lengthy trials
       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
        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,
Phase I trials in general are started with a
  dose that is one tenth that of the LD10 in
  mice (or most sensitive species)
Safety and Number of Dose Levels in
 21 Trials (14 Agents) With Varying
            Starting Doses
                  # of Dose
                  Levels to
                 Reach MTD

Starting Dose*    Median      Range   # of Unsafe^   # of Unsafe^
                                          Trials        Agents
     0.1             7        4-14         0              0
     0.2             5        3-11         5              2
     0.3             3         2-9        11              6
Accelerated Dose Escalation
Modified Fibonacci escalation
  Dose Level   Percentage Increase Over
                 Previous Dose Level

      2                 100%

      3                  67%

      4                  50%

     5-X                 33%
           Accelerated Titration Design

Design   # of Pts.   Increments    Intrapatient    Stop/Switch Rule     # of Patients
 Type    Per Dose      Between      Escalation     Invoked for 1st or     Entered
          Level      Dose Levels                  Any Course Toxicity

 1A         3           40            No                 NA                 39
 2B         1           40            Yes              First*               24
 3B         1           100           Yes              First*               21
 4B         1           100           Yes               Any*                21
“Phases” of Clinical Trials
 Phase I
 Phase II
   Identify diseases in
    which the treatment is

 Phase III
 Phase IV
         Phase II

• Determine Effectiveness
   • Single or Limited Disease Types
   • Pharmacokinetics
   • Experimental Endpoints
    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)
CR (complete response) = disappearance of
  all target lesions
PR (partial response) = 30% decrease in the
  sum of the longest diameter of target
PD (progressive disease) = 20% increase in
  the sum of the longest diameter of target
SD (stable disease) = small changes that do
  not meet above criteria
Mantle cell lymphoma post idiotype
Proposed European Organization for Research and Treatment of
    Cancer criteria for assessment of response by FDG-PET

Progressive metabolic disease
   Increase of SUV >25%
   Visible increase of FDG uptake (>20% of longest
   Appearance of new focus
Stable metabolic disease
    Increase of SUV <25% or decrease <15%
    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;
   >25% after more than one treatment cycle
Complete metabolic response
   Complete resolution of FDG uptake
         [F-18] FDG -PET

4/1/03        5/6/03       8/5/03
FDG-PET predicts response to chemotherapy in lung cancer
FDG-PET predicts response to imatinib
  Patient Number Required for Phase II
   Sample size (N) of a preliminary trial (Phase IIA) required to rule
    out given levels of therapeutic effectiveness and Type II error

                    Therapeutic effectiveness (%)

Type II        5     10    15     20    25     30    35    40     45     50
error (beta)

5%             59    29    19     14    11     9      7     6     6      5

10%            4     22    15     11     9     7      6     5     4      4
“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

    Phase IV
             Phase III

 Compare New and Standard Treatments
   • Randomized
   • “New” Treatment Well Studied
“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.
          Phase IV

 “Post-Marketing” Studies
    • Expanded Treatment Groups
      Under studied groups (racial/gender)
      Long term benefit
      Long term risk
      Low frequency toxicity
Model systems
Tissue acquisition
 Differences Between Phase 0 & Phase
                1 Trials
                         Phase 1 Trial            Phase 0 Trial
                                               Establish a safe
                     Establish dose-           dose-range that
                     limiting toxicities and   modulates (or
Primary Endpoint
                     maximum tolerated         images) target for
                     dose                      use in subsequent
                                               definitive trials
                     Advanced incurable        May include
                     malignancy, after         patients with
Patient Population
                     failure of standard       indolent disease not
                     therapy                   requiring treatment
                     Usually at least 4        May be 2 weeks or
Washout Period
                     weeks                     less
Number of patients   Usually >20               10-15
Differences Between Phase 0 & Phase
               1 Trials
                         Phase 1 Trial         Phase 0 Trial
                                          Intended to achieve
                   Guided primarily by    desired drug
Dose Escalation
                   toxicity               exposure and/or
                                          target modulation

                   Multiple cycles until  Limited dosing (1-7
Duration of Dosing disease progression or days) (one cycle
                   unacceptable toxicity  only)

Evaluation for
Therapeutic        Yes                    No
 Differences Between Phase 0 & Phase
                1 Trials
                         Phase 1 Trial         Phase 0 Trial
                                            Biomarker assays
                    Not consistently        and/or imaging
                    performed. Most Phase   studies are
Biomarker Assays
                    1 trials do not         integrated to
                    emphasize PD markers    establish MOA in
                                            patient samples
                                            Serial tumor
                                            biopsies required to
Tumor Biopsies      Usually optional
                                            evaluate drug effect
                                            on target
Pharmacokinetic/Ph Samples are usually
armacodynamic      batched and analyzed at Real time
analysis           a later time point
   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
Protocol Development
●At 1 month the protocol concept in reviewed by an IND
holder cooperative group.
●At 2 months the protocol development is reviewed by a
department institutional scientific review.
●At 3 months the protocol is approved by the
Institutional review board (IRB) and FDA
●At 2 years, the clinical trial is monitoted by the IRB,
data safety and monitoring board, IND holder and FDA.
          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
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
Institutional Review Board

 Monitor data to ensure safety
    • Monitors Adverse Events
    • Data, Safety and Monitoring Boards
Unanticipated Problems
   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)
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
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
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
   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.
  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
   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
  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

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