Docstoc

Clinical Trials in Oncology

Document Sample
Clinical Trials in Oncology Powered By Docstoc
					Clinical Trials in Oncology




          Kyle Holen, MD
       Associate Professor
   University of Wisconsin
Japan
Camptotheca
Acuminata
Camptothecin


               Derivatives:
               CPT-1, CPT-2,
               CPT-3, etc. to
               CPT-11
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
               1.400

               1.200

               1.000
                                                        CM
  Absorbance




               0.800                                    CM+DMSO
                                                        25uM ZM
               0.600                                    50uM ZM
                                                        100uM ZM
               0.400

               0.200

               0.000
                       0   2    4          6   8   10
                                    Days
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
      mathematician
    – 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
      petals
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
      employed
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
      efficacy.
    – 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
  (CR)
 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
      survival.
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
         survival
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
      groups
Phase IV Studies
 Post marketing studies to further
  examine toxicities in a larger patient
  population.
 Performed after FDA approval
Funding Mechanisms/Initiating
trials
   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
trials
      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
      effective
FDA Approval Process
   After phase III trials
    – Researchers look at the data and decide
      whether the results have medical
      importance
    – 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
      experiment
    – 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
      likely
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
      consent
    – 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
      procedures
Regulation and Ethical Conduct
   GCP compliance includes:
    – Rights and safety of subjects not
      compromised
    – 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
    quickly."
Barriers to Clinical Trials
   Barriers to Health Care Professionals
    – Lack of awareness of appropriate clinical
      trials.
    – Unwillingness to "lose control" of a person's
      care.
    – 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
    Populations
    – Long-standing fear, apprehension, and
      skepticism
    – Doctors may not mention clinical trials as an
      option
    – People from various cultural or ethnic
      backgrounds may hold values and beliefs that
      may be different than those of Western
      medicine
    – Language or literacy barriers
    – Additional access problems confront many
      people.
Barriers to Clinical Trials
    Cost Barriers
     – Patient care costs
       • Trials request the insurance company
         pay for “standard of care” health care
         costs
       • 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

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:15
posted:1/14/2012
language:
pages:52