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CLINICAL TRIALS OVERVIEW 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 Answer? 100 CHOP m-BACOD 80 ProMACE-CytaBOM MACOP-B Patients (%) 60 40 20 Adapted from Fisher. N Engl J Med. 1993;328:1002. 0 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 filed 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? Disadvantages • 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 treatment 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 design 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, 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) 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 1 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 effective 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) 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 Mantle cell lymphoma post idiotype vaccine 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 dimension) 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 Trial Sample size (N) of a preliminary trial (Phase IIA) required to rule out given levels of therapeutic effectiveness and Type II error Therapeutic effectiveness (%) Permissible 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 disease. Phase IV Phase III Compare New and Standard Treatments • Randomized • “New” Treatment Well Studied Randomization Stratification “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 Sampling 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 benefit 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 (DSMB) 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 effective 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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