CLINICAL TRIALS OVERVIEW

John Janik, M.D.

What is a Clinical Trial?

“Clinical trials are research studies in which people help doctors find ways to improve health and cancer care. Each study tries to answer scientific questions and to find better ways to prevent, diagnose, or treat cancer.”

CancerTrials (NCI)

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

Challenges in the Development of New Agents

Why Do a Clinical Trial?

What are the Challenges• Lymphoma Incidence is Rising

• Over 40 Different Types and Rising!

• Treatment Dependent on Stage and Prior Therapy

• Overwhelming New Treatment Options

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 Antitumor Activity • 1,000 Drugs work in Animal Studies• 100 Drugs have Proper Chemistry Formulation• 10 Drugs pass Phase I Clinical Trials • 5 Drugs pass Phase II Clinical Trials• 1 Drug passes Phase III Clinical Trials

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

Types of Clinical Trials

Treatment Trials

Prevention Trials

Screening Trials

Diagnostic Trials

Genetics TrialsQuality of Life Trials

“Phases” of Clinical Trials

Phase I

Phase II

Phase III

Phase IV

Determine the relation

between toxicity and dose schedule of treatment

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

Limitation of standard Phase I trial design

Ethical – Many patients treated with subtherapeutic dose of agent

Efficiency – Modified Fibonacci scheme results in lengthy trials

Alternatives for phase I clinical trial design

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

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)

Starting dose levels for phase I studies

Starting Median Range Unsafe Trials Unsafe Agents

0.1 7 4-14 0 0

0.2 5 3-11 5 2

0.3 3 2-9 11 6

Safety and Number of Dose Levels in 21 Trials (14 Agents) With Varying

Starting Doses

Dose Level Percentage Increase Over Previous Dose Level

1

2 100%

3 67%

4 50%

5-X 33%

Accelerated Dose Escalation Modified Fibonacci escalation

Design (# of PaPts. Increments Intrapatient Stop/ # of

Type Per Dose Between Escalation Switch Patients

Level) Dose Levels Rule Entered

1A 3 40 No NA 39

2B 1 40 Yes First* 24

3B 1 100 Yes First* 21

4B 1 100 Yes Any* 21

Accelerated Titration Design

Clinical Phases of Clinical Trials include Phase I, Phase

II, Phase III and Phase IV

●Phase I

●Phase II

●Phase III

●Phase IV

Phase II

• Determine Effectiveness • Single or Limited Disease Types

• Pharmacokinetics

• Experimental Endpoints

Lymphoma Cheson non-Hodgkin's Lymphomas International Working Group

Solid tumor patients RECIST (Response Evaluation Criteria in Solid Tumors)

Criteria for Measuring Response to Treatment

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

RECIST

MDX-CTLA4 3 mg/kg 6 weeks post treatment

Before treatment After treatment

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

4/1/03 5/6/03 8/5/03

[F-18]FDG-PET

Copyright ©2005 American Association for Cancer Research

Kelloff,

Survivor curve

Copyright ©2005 American Association for Cancer Research

Survivor curve

If the level of therapeutic effectiveness is 10%, 29 patients are required to et a

permissible type II error of 5%.

If the type II error is 10%, 22 patients are required.

“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

Phase I Phase II Phase III Phase IV

Phases of Clinical Trials

“Post-Marketing” Studies • Expanded Treatment Groups

Under studied groups (racial/gender)Long term benefitLong term riskLow frequency toxicity

Phase IV

1960 1973

1990s 2001

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

Drug Phases

Kummar et al., Nat Rev Cancer 7:131-9,2007

Study Drug

Drug Development

Differences Between Phase 0 & Phase 1 Trials . ●The primary endpoint established dose limiting toxicities and maximum tolerated dose.Whereas a phase 0 Trial establishes a safe dose-reange for use in subsequent definitive trials. ●The patient population is advanced incurable malignancy in Phase I trials where in a phase 0 trial patients with indolent disease not requireing treatment may be utilized.●The Washout Period is 4 weeks in a phase I trial but 2 weeks in a Phase 0 Trial. ●The Number of patients is usally >20 in a phase I but 12 in a phase 0 trial.

Differences Between Phase 0 & Phase 1 Trials . ●The biomarker assays are not consistently performed in a phase I trial whereas they are integrated into a phase O trial. ●Tumor biopsies are optional in a phase I trial whereas serial tumor biopsies are performed in a phase 0 trial. ●Pharmacokinetic/pharmacodynamic analysis are performed on time in a phase 0 trial whereas they are performed later in a phase I trial.

Differences Between Phase 0 & Phase 1 Trials . ●The dose escalation in a Phase I Trial is guided primarily by toxicity, whereas the desire to achieve a drug concentration is emphasized in phase 0. ●The duration of dosing is multiple cycles in a Phase I Trial whereas limited dosing occurs in a Phase 0 Trial. ●Both the phase I and phase 0 trial evaluate therapeutic benefit.

A written guide to the treatment and research studies.

• Major Sections Study ObjectivesBackground and Rationale Eligibility CriteriaStudy DesignResearch TestsStatistical SectionToxicity Reporting Pharmacy Information

Protocol Components

Protocol Development

Protocol Concept

Stage Review/Approval

Investigator/IND HolderCooperative Group

Protocol DevelopmentDepartment Review

Institutional Scientific Review

IND HolderInstitutional Review Board

Food and Drug AdministrationProtocol Approval

Clinical Trial Monitoring

InvestigatorInstitutional Review Board

Data Safety and Monitoring BoardIND Holder

Food and Drug Administration

1-6 Months

Time Line

2-3 Months

2-3 months

2-6 years

NCI Protocol Review Branch Review – Internal review PRMC - Protocol Review and Monitoring Committee – Scientific reviewIRB - Institutional Review Board – Ethical reviewRSC - Radiation Safety Committee – Research related radiation reviewRAC - Recombinant DNA Advisory Committee – Gene therapy reviewCTEP – Sponsor for NCI supported studies of investigational agents FDA – For investigator held INDs

NCI Protocol Review and Monitoring Committee (PRMC)

Provide prospective scientific review of NCI intramural clinical trials

Identify high priority trials

Mandate of the NIH for all intramural protocols

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)

Other Safety Reviews

Gene TherapyRAC Recombinant DNA Advisory CommitteeOBA Office of Biotechnology Activities

Research-related Radiation Radiation Safety Committee

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

Clinical Trial Venues • Single v Multi-Institutional

Phase I and II• Cooperative Groups

Phase III and IV

• PharmaceuticalPhase I-IV

Logistics of Clinical Trials

Annual Accrual • Pediatrics: 50% • Adults: 3%

Barriers • Physician Bias

Time and cost

• Patient BiasLack of education“Guinea Pig” syndrome Cost and time

• Insurance Denial

Barriers to Clinical Trials

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 effectiveData Safety and Monitoring Boards closely monitor

randomized studies

Frequently Asked Questions

Frequently Asked Questions

Why Conduct a Trial if We Already Know Which Treatment is More Effective?

• Very unwise to conclude superiority of a new treatment without a proper study

Diffuse Large B-cell Lymphomas

Adapted from Fisher. N Engl J Med. 1993;328:1002.

Pat

ien

ts (

%)

Years After Randomization

100

80

60

40

20

00 1 2 3 4 5 6

CHOPm-BACODProMACE-CytaBOMMACOP-B

How can I find Out About Clinical Trials? • Ask your physician • Resources

Lymphoma Research Foundation National Cancer InstitutePhysicians Data Query (PDQ) Internet

Frequently Asked Questions