# Presentation: 097222

## 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 Trials**
**Quality 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

**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

**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

**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) 

**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

**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%	

**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

**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)

** **
**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 

**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**

## Mantle cell lymphoma post idiotype vaccine

- 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**

## [F-18]FDG-PET

**[F-18]FDG-PET**

**Notes:**
These finding were confirmed on FDG that at baseline had extensive adenopathy, spleen and bone invovlement but only mild nodeal uptake after one treatment and evidecne of CR at the time when we adminstered her 4th treatment with 15 mCi.

## Survivor curve

- Copyright ©2005 American Association for Cancer Research

**Kelloff, **

**Survivor curve**

## 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

**Phase II**
**Phase III**
**Phase IV**

**Phases of Clinical Trials **

## “Post-Marketing” Studies    
  Expanded Treatment Groups  
Under studied groups (racial/gender)
Long term benefit
Long term risk
Low frequency toxicity

**  ****Expanded Treatment Groups  **
**Under studied groups (racial/gender)**
**Long term benefit**
**Long term risk**
**Low frequency toxicity**

**Phase IV **

## History of the Development of Gleevec for the Treatment of Chronic Myelogenous Leukemia

**1960**

**1973**

**1990s**

**2001**

**History of the Development of Gleevec for the Treatment of Chronic Myelogenous Leukemia**

## Imatinib (Gleevec)

**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

**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**

**Notes:**
Figure 2. 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. At 60 months, the estimated rate of event-free survival was 83%. At that time, 93% of the patients had not progressed to the accelerated phase or blast crisis. The following were considered events: death from any cause during treatment, progression to the accelerated phase or blast crisis, loss of a complete hematologic response, loss of a major cytogenetic response, or an increasing white-cell count. The number of patients with events and the number of patients available for analysis are shown.

## Drug Phases

**Drug Phases**

**Notes:**
Serial baseline blood samples can be obtained before the administration of the drug to establish the baseline for the measurement of post-drug effects. Tumour biopsies could be obtained once a target level of drug is achieved in the plasma, or some evidence of biological effect is observed in peripheral blood mononuclear cells (PBMCs), to avoid unnecessary biopsies.

## Study Drug

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

**Study Drug**

**Notes:**
Serial baseline blood samples can be obtained before the administration of the drug to establish the baseline for the measurement of post-drug effects. Tumour biopsies could be obtained once a target level of drug is achieved in the plasma, or some evidence of biological effect is observed in peripheral blood mononuclear cells (PBMCs), to avoid unnecessary biopsies.

## Drug Development

**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 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 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.

**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 Objectives
Background and Rationale 
Eligibility Criteria
Study Design
Research Tests
Statistical Section
Toxicity Reporting 
Pharmacy Information 

**  ****Major Sections  **
**Study Objectives**
**Background and Rationale **
**Eligibility Criteria**
**Study Design**
**Research Tests**
**Statistical Section**
**Toxicity Reporting **
**Pharmacy Information **

**Protocol Components **

## Protocol Development 

**Protocol Concept**

**Stage**

**Review/Approval**

- Investigator/IND Holder
- Cooperative Group

**Protocol Development**

- Department Review
- Institutional Scientific Review

- IND Holder
- Institutional Review Board
- Food and Drug Administration

**Protocol Approval **

**Clinical Trial **

**Monitoring**
- Investigator
- Institutional Review Board
- Data Safety and Monitoring Board
- IND 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 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

**Branch Review – Internal review **
**PRMC - Protocol Review and Monitoring Committee – Scientific 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**

## 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

**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 Therapy**
**RAC Recombinant DNA Advisory Committee**
**OBA 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
   Pharmaceutical
Phase I-IV

**  ****Single v Multi-Institutional **
** ****Phase I and II**
**  ****Cooperative Groups  **
**Phase III  and IV**
**   ****Pharmaceutical**
**Phase I-IV**

**Logistics of 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

**  ****Pediatrics: 50% **
**  ****Adults: 3% **
**Barriers   **** **** **
**  ****Physician Bias**
**Time and cost**
**  ****Patient Bias**
**Lack 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. 

**  ****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

**     ****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 

**  ****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 **

## 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 **

## How can I find Out About Clinical Trials?       
  Ask your physician 
  Resources 
Lymphoma Research Foundation 
National Cancer Institute
Physicians Data Query (PDQ)  
Internet

**  ****Ask your physician **
**  ****Resources **
**Lymphoma Research Foundation **
**National Cancer Institute**
**Physicians Data Query (PDQ)  **
**Internet**

**Frequently Asked Questions **