Ro Bagatell        June 26, 2010ALSF Family Conference
   Systematic studies involving human beings   Goal: generate knowledge that can be    applied to patients   Two kinds ...
   GD2 –expressed on the surface of 99% of    neuroblastoma cells   Also found on nerve, skin and brain tissue   Earlie...
   Performed in late 1980s/early 1990s   Goals of Phase I trials    ◦ Primary objective: Determine the dose to be used  ...
   Define the level of toxicity that would be    considered unacceptable   Define eligibility    ◦ “These are the health...
   Start low, go slow   Initial dose based on preclinical studies or on    adult data    ◦ Pediatric studies typically s...
   Every piece of toxicity data is important    ◦   Detailed history    ◦   Documentation of severity of complaints    ◦ ...
   If first dose level is tolerated well, increase   Assumption is that more is better   Monitor next group of patients...
   Lowest dose 10mg/m2   Subsequent dose levels: 20, 50, 100, 200 mg/m2   Pain    ◦ Mild at lower dose levels; more sig...
   What kind of levels can be achieved?    ◦ Peak    ◦ Trough   How long does the drug stick around?    ◦ Half life   D...
   What does the drug do to the body?    ◦ Detection of biologic activity in tumor cells or      “surrogate tissues”   F...
   Emphasis on early, preliminary   Beware of The Therapeutic Misconception    ◦ Less than 1 of 10 agents studied in Pha...
   Response              Ch14.18             14G2a   Complete Response       0                   1   Partial Response  ...
   Lab data suggested that there may be more    activity against neuroblastoma if antibody is    combined with other agen...
   Pilot: 17 patients   Monitor toxicity closely   Stopping rules for toxicity   This therapy is toxic, but it can be ...
   Goals of a Phase II study    ◦ Early assessment of activity      Not a definitive study for drug licensing      Tool...
   Overall study design    ◦ Single arm      Often 2 stage    ◦ Randomized selection design   Patient population    ◦ A...
   POG #9347 : A phase II study of combined use of    human-mouse chimeric anti-GD2 antibody and    GM-CSF in the treatme...
   28 evaluable patients   21 had progressive disease, 3 had stable    disease or a mixed response   4 had partial or c...
   Drug companies don’t always see it that way   No financial interest in developing drugs for    childhood cancer    ◦ ...
   Could this be done in patients who have    undergone stem cell transplantation?   Could ch14.18 be given with IL-2 an...
   Compare a new treatment to standard    treatment, usually in randomized fashion   Randomization    ◦ If we knew which...
   Typically performed in large, untreated    population   Findings meant to be applicable to a wider    population of p...
   Many variations in study design      Factorial      Crossover      Stratified   Stopping rules    ◦ Toxicity    ◦ ...
COG ANBL0032: phase III trial design for highrisk neuroblastoma Prior to ANBL0032:     High risk                     Chemo...
Regimen A: standard therapyCis-RA x 2 weeks q 4 weeks X 6 coursesSchema Course 1   Course 2   Course 3   Course 4   Course...
   Patients randomized = 226
Or is this just the beginning?   Study stopped early due to superiority of new    treatment   Ch14.18 + cytokines is the...
   A good idea   A feasible treatment   An active treatment   Patients and parents interested in new    therapy   Fin...
Childhood Cancer Symposium -- Clinical Trials and Experimental Treatments
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Childhood Cancer Symposium -- Clinical Trials and Experimental Treatments

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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

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  • IGF1 inhibitors as an example
  • 1. SPACE ADDED AFTER “mAb” in second “bullet”2. GM-CSF/IL2 changed to GM-CSF + IL23. Last bullet added
  • Childhood Cancer Symposium -- Clinical Trials and Experimental Treatments

    1. 1. Ro Bagatell June 26, 2010ALSF Family Conference
    2. 2.  Systematic studies involving human beings Goal: generate knowledge that can be applied to patients Two kinds of studies  Observational  Interventional
    3. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 17.  Overall study design ◦ Single arm  Often 2 stage ◦ Randomized selection design Patient population ◦ All comers ◦ Specific disease, tumor biology, etc
    18. 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. 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. 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. 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. 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. 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. 24.  Many variations in study design  Factorial  Crossover  Stratified Stopping rules ◦ Toxicity ◦ Futility ◦ Success
    25. 25. COG ANBL0032: phase III trial design for highrisk 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. 26. Regimen A: standard therapyCis-RA x 2 weeks q 4 weeks X 6 coursesSchema 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. 27.  Patients randomized = 226
    28. 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 manufacturerto ensure antibody supply•Second generation antibodies•Antibody + chemo•Antibody + other immune modulators•Use of antibody at other times during therapy
    29. 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

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