Clinical Trials and Novel Therapies

Ro BagatellJune 26, 2010

ALSF Family Conference

Systematic studies involving human beings

Goal: generate knowledge that can be applied to patients

Two kinds of studies Observational Interventional

What are Clinical Trials?

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

Clinical Trials Case Study

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

14G2a and ch14.18 Phase I Studies

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

Phase I Protocols

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

Dose determination

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?

Toxicity monitoring

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

Dose escalation

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

Ch14.18 dose escalation

Yu et al, JCO, 1998

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?

Pharmacokinetics

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

Pharmacodynamics

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

Response

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

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

What next for ch14.18?

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

Ch14.18 + GM-CSF

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

Phase II

Overall study design◦ Single arm

Often 2 stage◦ Randomized selection design

Patient population◦ All comers◦ Specific disease, tumor biology, etc

Phase II Design Considerations

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

Phase II

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

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

Maybe there’s something to this . .

Could this be done in patients who have undergone stem cell transplantation?

Could ch14.18 be given with IL-2 and Accutane (cis-RA)?

More Pilot Data

Ozkaynak et al: Ch14.18 + GM-CSF post-SCT, JCO 2000Gilman et al: Ch14.18 + IL2+ GM-CSF + cis-RA post SCT, JCO 2009

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

Phase III study

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

Phase III Studies

Many variations in study design Factorial Crossover Stratified

Stopping rules◦ Toxicity◦ Futility◦ Success

Phase III Studies

COG ANBL0032: phase III trial design for high risk neuroblastoma

Prior to ANBL0032:

Within 100 days post transplant:

Chemo-therapy

Surgery Stem cell transplant

High risk neuroblastoma

at diagnosis

Enroll on ANBL0032:Randomize

Cis-Retinoid acid

Cis-Retinoid acid + immunotherapy

Regimen B: immunotherapy

Regimen A: standard therapy

Cis-RA x 2 weeks q 4 weeks X 6 courses

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

Schema

Patients randomized = 226

Phase III Study of ch14.18

Study stopped early due to superiority of new treatment

Ch14.18 + cytokines is the new standard therapy

End of ch14.18 storyOr is this just the beginning?

•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

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

What does it take to bring a new treatment forward?

Questions??