Alex's Lemonade Stand Foundation holds an annual Childhood Cancer Symposium in Philadelphia. It is designed to be an educational resource, providing families with the opportunity to learn about issues and topics of treatment and beyond, while meeting other families in a group setting. Registration is free and is open to all those touched by childhood cancer, including patients and their siblings. Hear from speaker Rochelle Bagatell, MD of Children's Hospital of Philadelphia as she discusses clinical trials and experimental treatments in childhood cancer cases. For more information on Alex's Lemonade Stand Foundation's childhood cancer resources, click here: http://www.AlexsLemonade.org

1. Ro Bagatell
June 26, 2010
ALSF Family Conference

2.  Systematic studies involving human beings
 Goal: generate knowledge that can be
applied to patients
 Two kinds of studies
 Observational
 Interventional

3.  GD2 –expressed on the surface of 99% of
neuroblastoma cells
 Also found on nerve, skin and brain tissue
 Earliest antibodies were generated from mice
(14G2A, 3F8)
 Ch14.18 is chimeric
 Lab work late 1970s to mid 1980s
 Investigational New Drug application process
begun in 1989

4.  Performed in late 1980s/early 1990s
 Goals of Phase I trials
◦ Primary objective: Determine the dose to be used
in future studies of a new agent
 Secondary objectives
 Study drug levels to determine how the body breaks down
the drug (Pharmacokinetics)
 Look for an early signal of activity of the agent
 Collect samples that may help explain the mechanism of
action of a drug

5.  Define the level of toxicity that would be
considered unacceptable
 Define eligibility
◦ “These are the healthiest patients”
◦ Washouts
 Provide guidance regarding management of
side effects
 Ensure uniform collection of information
 Safety and regulatory procedures

6.  Start low, go slow
 Initial dose based on preclinical studies or on
adult data
◦ Pediatric studies typically start at 75-80% of adult
doses
 Enroll 3-6 patients
 Monitor closely

7.  Every piece of toxicity data is important
◦ Detailed history
◦ Documentation of severity of complaints
◦ Laboratory observations
◦ Other monitoring studies
 Anti-GD2 antibody examples
◦ Pain – How severe? What pain medication was
required?
◦ Allergic reaction – How severe? What were the
components of this reaction? Was intensive care
management required?

8.  If first dose level is tolerated well, increase
 Assumption is that more is better
 Monitor next group of patients closely
◦ If serious toxicity is observed, may need to expand
the cohort
◦ For example, if 1of 3 patients has severe,
intractable pain – add 3 more patients to help sort
out whether this is bad luck or a pattern
◦ If no additional serious toxicity, continue to
escalate
◦ If more toxicity is seen, may need to de-escalate

9.  Lowest dose 10mg/m2
 Subsequent dose levels: 20, 50, 100, 200 mg/m2
 Pain
◦ Mild at lower dose levels; more significant at doses
above 50 mg/m2
 Other side effects
◦ Rash in 7/20 courses
◦ Fever in 8/20 courses
◦ Heart rate and BP changes
◦ Changes in body chemistries
◦ GI effects
◦ Fatigue, tingling sensations
Yu et al, JCO, 1998

10.  What kind of levels can be achieved?
◦ Peak
◦ Trough
 How long does the drug stick around?
◦ Half life
 Does the amount of drug seen by the body
increase as the dose is increased?
 Does the drug accumulate in the body over
time?

11.  What does the drug do to the body?
◦ Detection of biologic activity in tumor cells or
“surrogate tissues”
 For ch14.18 effects on the immune system
were an important topic
◦ Collected multiple serum samples to look for
effects on neuroblastoma cells
◦ Effects longer lasting at higher dose levels
◦ Activity increased in subsequent courses compared
to first course

12.  Emphasis on early, preliminary
 Beware of The Therapeutic Misconception
◦ Less than 1 of 10 agents studied in Phase I is
effective clinically
◦ Phase I is about dose determination
◦ Families choose Phase I studies because they have
HOPE, but the goal of a Phase I trial is dose
identification

13.  Response Ch14.18 14G2a
 Complete Response 0 1
 Partial Response 1 0
 Mixed Response 4 3
 Stable Disease 1 1
 Progressive Disease 4 10
 Not Evaluable 1 0
 Total 11 15
Yu AL et al, JCO,1998

14.  Lab data suggested that there may be more
activity against neuroblastoma if antibody is
combined with other agents that stimulate
the immune system
 Is it feasible to add these agents to ch14.18??
 Need a Pilot Study

15.  Pilot: 17 patients
 Monitor toxicity closely
 Stopping rules for toxicity
 This therapy is toxic, but it can be delivered
 9 patients with disease progression
 3 had stable disease
 5 had complete responses
◦ 3 later relapsed
◦ 2 remain without disease more than 15 years later

16.  Goals of a Phase II study
◦ Early assessment of activity
 Not a definitive study for drug licensing
 Tool for Go/No Go decision making
 The Therapeutic Misconception
 Improved understanding of toxicity
◦ All patients treated at same dose
◦ Larger number of patients, opportunity to better
understand toxicity
 Pharmacokinetics, Pharmacodynamics

17.  Overall study design
◦ Single arm
 Often 2 stage
◦ Randomized selection design
 Patient population
◦ All comers
◦ Specific disease, tumor biology, etc

18.  POG #9347 : A phase II study of combined use of
human-mouse chimeric anti-GD2 antibody and
GM-CSF in the treatment of recurrent
neuroblastoma
 What does a Phase II study entail?
 Protocol
◦ Eligibility, dose modification, study requirements
◦ Disease assessment
 Measurable vs Evaluable disease
 Timing of disease evaluations and why

19.  28 evaluable patients
 21 had progressive disease, 3 had stable
disease or a mixed response
 4 had partial or complete responses
Yu et al JCO, 1997

20.  Drug companies don’t always see it that way
 No financial interest in developing drugs for
childhood cancer
◦ Especially agents targeted specifically at molecules
specific for childhood tumors
 No drug company willing to take on
development and manufacture of ch14.18
 Eventually: NCI program to produce

21.  Could this be done in patients who have
undergone stem cell transplantation?
 Could ch14.18 be given with IL-2 and
Accutane (cis-RA)?
Ozkaynak et al: Ch14.18 + GM-CSF post-SCT, JCO 2000
Gilman et al: Ch14.18 + IL2+ GM-CSF + cis-RA post SCT, JCO 2009

22.  Compare a new treatment to standard
treatment, usually in randomized fashion
 Randomization
◦ If we knew which was better, there would be no
reason to do the study
◦ Prevent bias by taking decision about treatment for
a particular patient out of human hands
◦ Placebo controlled studies are rare in pediatric
oncology

23.  Typically performed in large, untreated
population
 Findings meant to be applicable to a wider
population of patients
◦ Eligibility criteria less restrictive
◦ A little more “wiggle room” regarding timing of
study treatments and evaluations
◦ Standardization still important
 Informed by data from previous studies
◦ Toxicity monitoring less intensive
◦ Patients/families can be more extensively informed
about prior experience

24.  Many variations in study design
 Factorial
 Crossover
 Stratified
 Stopping rules
◦ Toxicity
◦ Futility
◦ Success

25. COG ANBL0032: phase III trial design for high
risk neuroblastoma
Prior to ANBL0032:
High risk
Chemo- Stem cell
neuroblastoma Surgery
therapy transplant
at diagnosis
Within 100 days post transplant:
Cis-Retinoid acid
Enroll on ANBL0032:
Randomize
Cis-Retinoid acid
+ immunotherapy

26. Regimen A: standard therapy
Cis-RA x 2 weeks q 4 weeks X 6 courses
Schema
Course 1 Course 2 Course 3 Course 4 Course 5 Course 6
Ch14.18 Ch14.18 Ch14.18 Ch14.18 Ch14.18
GM-CSF IL2 GM-CSF IL2 GM-CSF
Cis-RA Cis-RA Cis-RA Cis-RA Cis-RA Cis-RA

27.  Patients randomized = 226

28. Or is this just the beginning?
 Study stopped early due to superiority of new
treatment
 Ch14.18 + cytokines is the new standard
therapy
•Need FDA licensing and a committed manufacturer
to ensure antibody supply
•Second generation antibodies
•Antibody + chemo
•Antibody + other immune modulators
•Use of antibody at other times during therapy

29.  A good idea
 A feasible treatment
 An active treatment
 Patients and parents interested in new
therapy
 Financial backing
 Persistence and patience
 A little bit of luck