Clinical Trials in Oncology by changcheng2


									Clinical Trials in Oncology

          Kyle Holen, MD
       Associate Professor
   University of Wisconsin

               CPT-1, CPT-2,
               CPT-3, etc. to
From Bench to Bedside
      Types of Clinical Trials
      Preclinical Testing and Toxicology
      Phase I trials
      Phase II trials
      Phase III trials
      Phase IV trials
      Funding mechanisms/initiating
       clinical trials
      Regulatory bodies and ethical
       conduct of clinical trials
Types of Clinical Trials
     Treatment trials
       – An analysis of new treatments or
       – An analysis of what is the most effective treatment
     Prevention trials
       – May include treatments or changes in lifestyle
       – For patients who do not have cancer
       – “agent” trials or “action” trials
     Early-detection/screening trials
       – Ie, colonoscopy, mammo, pap smear
     Diagnostic trials
       – How can new tests or procedures identify cancer more
         accurately and at an earlier stage?
     Quality-of-life/supportive care trials
Preclinical Testing and Toxicology
   Drug screening
    – 60 Human tumor cell lines
    – Lung, colon, breast, ovary, leukemia,
      melanoma, etc.
    – Mouse tumors
    – Human tumor xenografts
Preclinical Testing and Toxicology

HepG2 Cells Treated with ZM 336372 at Day 9
     Control Media        25uM ZM336372
Preclinical Testing and Toxicology

                           HepG2 MTT assay



               0.800                                    CM+DMSO
                                                        25uM ZM
               0.600                                    50uM ZM
                                                        100uM ZM


                       0   2    4          6   8   10
Preclinical Testing and Toxicology
 File for Patent
 ZM336372
    – WARF:014US
    – P04267US
Preclinical Testing and Toxicology
   Toxicology
    – Goals
      • Determine safe starting doses
      • Determine safe schedules
    – FDA requirement
      • LD10 dose for 2 species, if discrepency,
        then a third
      • Histopathology for all animals
Phase I Studies
 Also called “dose finding” studies
 All tumor types enrolled
 Starting dose – 1/10 of the LD10 in
  the most sensitive species
Phase I Studies
   Dose Escalation
    – Fibonacci, Italian
    – 0, 1, 1, 2, 3, 5, 8, 13, 21, 34, 55,
      89, 144
    – Some plants branch in such a
      way that they always have a
      Fibonacci number of growing
      points; flowers often have a
      Fibonacci number of petals,
      pine cones and pineapples
      have a Fibonacci number of
Phase I Studies
    Fibonacci Escalation
    Level             Dose
    1                 1/10 LD10
    2                 2x Level 1
    3                 3x Level 1
    4                 5x Level 1
    5                 8x Level 1
    6                 13x Level 1
Phase I Studies
   Accelerated Escalation
    – Assumes that we will see mild toxicities
      first, and can then adjust the escalation
    – Dose is doubled successively until
      grade 1 or 2 toxicity observed
    – Then a Fibonacci-type escalation is
Phase I Studies
   Accelerated escalations
    – In favor of accelerated designs
      • Fewer patients required
      • Fewer patients treated at potentially
        ineffective low doses
      • Less time
    – Against accelerated designs
      • Increased risks of toxic dosing
Phase I Studies
    Goals:
     – Evaluate toxicities
         • All side effects are graded and recorded
     – Evaluate the highest dose that can be administered safely –
       the “MTD” or the maximum tolerated dose
    MTD
     – Defined as the highest dose where less than 2 of 6 patients
       have a DLT
    DLT
     – Dose limiting toxicity, or a side effect that is considered severe
       enough to limit the escalation of the dose.
     – Ie, severe nausea, diarrhea, fatigue or neutropenia with fever.
       Usually grade 3 non-heme toxicity or grade 4 heme toxicity.
Phase I studies
   Any benefit to patients?
    – Average of 10.6% response rate
       • Novel agents – 4.4%, combinations with at least one
         approved agent – 17.8%*
    – Higher for approved drug combinations
    – Lower for never tested drugs
   University of Chicago study
    – Why did you enroll in a phase I study?
       • 85% answered “possible therapeutic benefit”

       *Horstman, et al. NEJM 2005; 352: 895 - 904
Phase II Studies
   Estimation of efficacy
    – Usually in one tumor type
   Further clarification of toxicities
    – Often times a larger number of patients
      than phase I studies
   Feasibility of administration
Phase II studies
   Two-stage Simon Design
    – Design where a small number of patients are
      tested in the first stage.
    – An early stopping rule is set where the trial is
      stopped to further accrual if the number of
      successes are less than expected.
    – If the early stopping rule is not met, accrual
      continues and you can better define the
    – Designed to limit the number of patients that
      may receive a drug that is ineffective
Phase II studies
 The endpoint is usually response rate
 Overall response rate is defined as partial
  response (PR) plus complete response
 Response is define by RECIST
    – Calculate the sum of the longest diameters of
      each tumor at baseline
    – Compare the sum at baseline with the sum at
      the first scan post treatment
    – >30% reduction = PR, >20% growth =
      progression, otherwise considered stable
Phase II studies
   Randomized phase II studies
    – Compare response as endpoint
    – Compare toxicity as an endpoint
    – Underpowered to show statistically
      significant differences between the
      arms, particularly in regards to overall
Phase III studies
 Generally compares a new treatment
  to a standard therapy/no therapy
 Randomized
    – May be blinded, single vs. double
 Endpoint usually survival
 Large numbers of patients required
 Multiple centers are usually required
Phase III studies
   Statistical considerations
    – Smaller effects mean larger trials
       • 50% increase in survival, n = 350
       • 25% increase in survival, n = 1125
    – Fewer events mean larger trials
       • Time to relapse – 2 years, n = 520 for
         disease free survival
       • Survival – 4 years, n = 870 for overall
Phase III studies
   Superiority Trial
    – Confidence intervals give you a range
      of plausible values
    – Confidence interval must not cross 1.0
   Equivalence Trial
    – Confidence interval must not cross
      clinically significant difference between
Phase IV Studies
 Post marketing studies to further
  examine toxicities in a larger patient
 Performed after FDA approval
Funding Mechanisms/Initiating
   Initiating clinical trials
    – Starts with an idea, then converted to a letter
      of intent (LOI)
    – Letter of intent written to sponsor of the trial
   Sponsors
    – Government (NIH through cooperative groups
      or grants)
    – Industry (through pharmaceutical companies)
    – Non-profit (through grants, such as ACS)
    – Occasionally university or other support
Funding Mechanisms/Initiating
      LOI is approved
      Write protocol
       –   Background
       –   Objectives/endpoints
       –   Eligibility
       –   Treatment plan
            • Dose modifications
       –   Measurement of effect
       –   Study parameters
       –   Drug formulation
       –   Statistics
       –   Data safety and monitoring plan
       –   Informed consent
      Protocol is approved by sponsor
      Regulatory bodies
FDA Approval Process
   After phase I trials
    – There are enough data to support
      further study with a phase 2 trial
    – Further research will be discontinued
      because the agent was not safe
FDA Approval Process
   After phase II trials
    – There are enough data to support
      further study with a phase 3 trial
    – Further research will be discontinued
      because the agent was not safe or
FDA Approval Process
   After phase III trials
    – Researchers look at the data and decide
      whether the results have medical
    – Researchers will inform the medical
      community and the public of the trial
      results – peer review
FDA Approval Process
   Sponsor of the trial then applies to
    the FDA
    – IND required prior to phase I trials
    – NDA required after phase III trials prior
      to FDA approval
    – 16 years average from preclinical
      testing to FDA approval
Regulation and Ethical Conduct
   Ethical Disasters
    – Nazi Doctors
       • Lead to Nuremberg code (1947) and established
         informed consent
    – Tuskegee study
       • Prompted the formation of IRBs via the National
         Research act of 1974, releasing the Belmont Report
    – Human radiation experiments
       • Created the Advisory Committee on Human
         Radiation experiments (1994)
Regulation and Ethical Conduct
   Selected guidelines on ethics:
    – Nuremberg code
       • Set the standard for informed consent
    – National Research Act of 1974
       • Created the National Commission for the Protection of
         Human Subjects of Biomedical and Behavioral Research
       • Commission laid the ground work for 45 C.F.R. 46
       • Also released the Belmont Report in 1978
       • These reports essentially protected at risk classes of
         patients (prisoners, pregnant women, children, mental
         disability, etc.) and required IRBs for all research funded
         by the federal government
    – In 1991, 45 CFR 46 was adopted by 16 federal agencies
      and called the “Common Rule”
Regulation and Ethical Conduct
   Nuremburg code (1947)
    – Participants must give voluntary consent
    – There must be no reasonable alternatives to conducting the
    – The results have a basis in bioligical knowledge
    – The procedures should avoid suffering
    – There is no expectation of death or disability
    – Benefits (to individual or society) outweigh risks
    – The subjects are protected against injury or death
    – The study is conducted by qualified scientists
    – The subject can stop at will
    – The investigator is obliged to stop the invesitigation if injury is
Regulation and Ethical Conduct
       The Belmont report
        – Respect for people
        – Individuals as autonomous agents
        – Special protection for children and
          mentally impaired
       Beneficence
        – Do no harm
        – Maximize benefits and minimize harm
       Justice
Regulation and Ethical Conduct
   Protective mechanisms for patients
    – Established by the Common Rule
    – All research reviewed by an IRB
    – Researchers must obtain informed
    – Institutional assurances of compliance
Regulation and Ethical Conduct
   Protective measures for clinicians
    – All clinicians must comply with Good
      Clinical Practice (GCP) guidelines
    – Offers protection for human subjects in
      clinical trials
    – Ensures accuracy and reliability of data
    – Recognized as standard operating
Regulation and Ethical Conduct
   GCP compliance includes:
    – Rights and safety of subjects not
    – Trained staff manages study
    – Careful documentation
    – Strict adherence to protocol
Regulation and Ethical Conduct
   GCP procedures:
    – Obtaining informed consent
    – Documenting case histories
    – Maintaining good records
    – Reporting adverse events
Regulation and Ethical Conduct
   Seven requirements for ethical research:
    –   Social/scientific value
    –   Scientific validity
    –   Fair subject selection
    –   Favorable risk/benefit ratio
    –   Independent review
    –   Informed consent
    –   Respect for subjects
Regulation and Ethical Conduct
   Two major review processes:
    – Scientific review
      • Reviews the scientific merit of the research
    – Institutional review
      • Reviews for GCP
Regulation and Ethical Conduct
   Institutional Review Board (IRB)
    – Reviews subject recruitment and enrollment
    – Ensures equitable selection of subjects
    – Makes sure there are adequate provisions to
      protect patient privacy
    – Confirms subject safety by reviewing the data
      and safety monitoring plan
    – Safeguards to protect vulnerable patients from
      coercion or undue influence
Barriers to Clinical Trials
   "Only 3 percent of adult cancer
    patients in the United States
    participate in clinical trials - far fewer
    than the number needed to answer
    the most pressing cancer questions
Barriers to Clinical Trials
   Barriers to Health Care Professionals
    – Lack of awareness of appropriate clinical
    – Unwillingness to "lose control" of a person's
    – Belief that standard therapy is best.
    – Belief that referring to and/or participating in a
      clinical trial adds an administrative burden.
    – Concerns about the person's care or how the
      person will react to the suggestion of clinical
      trial participation.
Barriers to Clinical Trials
   Barriers to General Public
    –   Lack of awareness of clinical trials.
    –   Lack of access to trials.
    –   Fear, distrust, or suspicions of research.
    –   Practical or personal obstacles.
    –   Insurance or cost problems
    –   Unwillingness to go against personal
        physician's wishes.
Barriers to Clinical Trials
   Barriers to Racially or Ethnically Diverse
    – Long-standing fear, apprehension, and
    – Doctors may not mention clinical trials as an
    – People from various cultural or ethnic
      backgrounds may hold values and beliefs that
      may be different than those of Western
    – Language or literacy barriers
    – Additional access problems confront many
Barriers to Clinical Trials
    Cost Barriers
     – Patient care costs
       • Trials request the insurance company
         pay for “standard of care” health care
       • CT Scans, standard blood work, MD
         visits, etc.
Barriers to Clinical Trials
   Cost Barriers
    – Research costs
       • Can be very expensive, depending on study between
         $5 – 10,000/patient plus agent
       • Includes: data collection and management, research
         physician and nurse time, analysis of results ,
         clinical laboratory tests and x-rays, particularly if
         more are needed above “standard of care”
       • The cost of the agent being tested is usually not a
         barrier if the agent is not FDA approved
       • Most of the time, research costs and investigational
         agent costs are covered by the sponsor
Barriers to Clinical Trials
   Cost Barriers
    – Wisconsin passed a law in 2006 that
      requires insurance companies to pay
      for “standard” costs associated with
      clinical trials
                              Preclincial Testing 1980’s
Camptothecin 11

  FDA approval 4/20/2000
                                Phase I 1990, named
                             Irinotecan (Camptosar®)

        Phase III CRC 2000

                             Phase II NSCLC 1992,
                              Phase II CRC 1993

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