# Presentation: 593902

## Children’s Oncology GroupPhase 1/Pilot Consortium

**Gregory Reaman, MD**
**Children’s Oncology Group**

**Notes:**
Good afternoon. I would like to highlight areas of our proposal for the Developmental Therapeutics program of the Children’s Oncology Group.

## COG Phase 1/Pilot Consortium

**Our mission is to identify and develop effective new agents for children and adolescents with cancer, through scientifically rational and efficient clinical and laboratory research. **

## Challenges in Pediatric Drug Development

**Limited patient numbers due to the success of front-line therapy**
**Integration of new agents into standard curative but toxic regimens**
**Application of molecularly targeted drugs to childhood cancer**

## Children’s Oncology Group

**Disease  Committees**
**Discipline Committees**
**Scientific Committees**

## Children’s Oncology Group

**Children’s Oncology Group**

**Disease  Committees**
**Discipline Committees**
**Scientific Committees**

**Developmental Therapeutics Committee**

## Phase 1 Accomplishments

**Phase 1 Accomplishments**

**Phase 1 Trials**
**29 completed studies**
**17 open studies**

## Recently Completed Phase 1 Trials

**Cytotoxics**
**Topotecan**
**Irinotecan**
**Rebeccamycin**
**Gemcitabine**
**ZD1694**
**Temozolomide**
**Doxil**
**ET-743**

**Modulating Agents**
**PSC-833**
**O6-BG**
**Signal Transduction**
**STI-571**
**Biologics**
**ch14.18 + IL-2**
**9-*****cis-*****RA**
**4-HPR**

## COG Phase 1/Pilot Consortium

**For childhood cancer, a consortium of highly qualified institutions is a necessary and optimal mechanism for accruing a sufficient number of patients to perform phase 1 trials and pilot studies efficiently.**

## COG Phase 1/Pilot Consortium

**Building the Consortium**
**Operations & Statistics**
**Current Status**
**Scientific Approach**

## Membership

**Children’s Hospital - Boston**
**Children's Hospital - Seattle**
**Children's Hospital - Pittsburgh**
**Children's Hospital - D.C. **
**Children’s Hospital - LA**
**Children’s Hospital Cincinnati**
**Children’s Hospital - Philadelphia**
**Children’s Hospital - Oregon**
**Columbia Presbyterian**
**Hopital Sainte-Justine**
**Hospital for Sick Children**

**Riley Children’s Hospital **
**Mayo Clinic and Foundation**
**Pediatric Oncology Branch, NCI**
**St. Jude Children's Research Hospital Memphis****	**
**Stanford University **
**SUNY at Syracuse****	**
**Texas Children's Cancer Center **
**University of Minnesota **
**Mississippi Children's Hospital**
**Texas Southwestern Medical School****	**

## Membership

**Institutions accrued > 90 patients/year to CCG/POG/COG phase 1 trials during 1998-2000***
**Estimate a minimum of 120 patients per year to COG phase 1 studies during initial year of grant cycle**

- *Limited protocol availability

## Expertise

**Drug development expertise**
**Pharmacology **
**Biological correlates**
**Phase 1 & 2 trial design & performance**
**Regulatory oversight**
**FDA/OHRP/NIH**
**IND requirements**
**Industry requirements**

**Monitoring**
**Toxicity**
**Reporting requirements**
**Specimen acquisition**
**Pharmacology Labs**
**Biology Labs **

## Organizational Structure

**Operations Center**

**Anita Khayat**

**OC Coordinator**

**Disease Committee**

**Chairs**

**Protocol Development**

**S. Berg - Chair**

**Pharmacology**

**M.Ames - Chair**

**Biology**

**P. Houghton - Chair**

**DVL Committee**

**Steering & Prioritization**

**Committee**

**DVL Scientific**

**Committee**

**DVL Leadership**

**P Adamson- P.I./Chair**

**S. Blaney - Vice Chair**

**Statistics/Data Center**

**R. Sposto-SDC Coordinator**

**J. Kepner-RDC Director**

**Organizational Structure**

## COG Phase 1/Pilot Consortium

**Building the Consortium**
**Operations & Statistics**
**Current Status**
**Scientific Approach**

## Study Coordination and Monitoring

**Managed by Research/Data Coordinator**
**Tight control over treatment slot allocation (through RDE)**
**Monitors data errors and delinquencies**
**Schedules formal reviews at landmark times **
**Coordinates specimen/image submission, and capture results of assay/review**

**Notes:**
Have to talk about how we are able to coordinate in such a large number of institutions.

## Study Coordination and Monitoring

**Detailed reports of accrual and toxicity**
**Distributed weekly to study chair & DVL chair/co-chair**
**Reviewed on weekly leadership call**
**At key decision points **
***e.g.***** escalation, de-escalation, expansion**
**Conference call between study chair, DVL chair/co-chair, SDC Coordinator, staff**
**Make decision, or identify deficiencies that prevent decision**
**Rapidly correct (through RDE) and reschedule**

## Rapid acquisition of high quality data

**Remote Data Entry (RDE) system**
**Comprehensive study databases**
**Concurrent and retrospective data screening with electronic feedback**

## Quality Control/Quality Assurance

**Integrated throughout OC/SDC operations**
**Clear and complete protocols**
**Careful design of data collection screens**
**RDE concurrent and retrospective error checking**
**Formal study/data review by committee **
**Audits by OC/SDC/Theradex**

## Statistical design, analysis, and reporting

**Design of Phase I studies**
**Standard phase I design when appropriate **
**Newer agents require innovative designs**
**PK guided designs **
**Surrogate endpoints**
**Design of pilot studies**
**Depends on agent (e.g. cytostatic)**
**Balance precision with timeliness of results**

**Notes:**
Talk about the issue of pilot studies in terms of adding new agents to cytotoxic agents.  
Peter will talk about specific other applications

## COG Phase 1/Pilot Consortium

**Building the Consortium**
**Operations & Statistics**
**Current Status**
**Scientific Approach**

## Recently Opened/Approved Phase I Studies

**Signal Transduction**
**ZD1839 (*****EGF-R*****)**
**Genasense (*****bcl-2*****)**
**R115777 (*****FTI*****)**
**Cytotoxics**
**PS-341 (*****Proteosome*****)**
**Depsipeptide (*****HDAC*****)**
**Flavopiridol (*****Cell cycle*****)**

**Biologics**
**huCh14.18-IL-2 (*****GD2*****)**
**Ibritumomab (*****CD20Ytrium*****) **
**Modulating Agents**
**Decitabine (*****Demethylating*****)**

**Notes:**
For our first specific aim, we plan to study a diverse array of new agents in phase 2 trials. Summarized here are agents currently or soon to be under investigation in COG phase 1 trials. Signal transduction inhibitors such as the EGR receptor pathway inhibitor ZD 1839, novel cytotoxic agents including the proteosome inhibitor PS341, and monoclonal antibodies such as the Ytrium conjugated anti-CD52 will move forward into phase 2 trials during the upcoming grant cycle. 

## Pilot Trials

**Integration with current therapy **
**Combinations of new agents**
**Combinations of modulating agents with standard cytotoxics**
**Dose escalation/refinement of novel regimens**
**Targeted drug exposures**

## Pilot Trials

**Signal transduction inhibitors + cytotoxics**
**Gleevec (STI-571)**
**ZD1839**
**Genasense + cytotoxics**
**Monoclonal antibodies + cytotoxics**
**PS-341 combinations**
**Decitabine combinations**

## COG Phase 1/Pilot Consortium

**Building the Consortium**
**Operations & Statistics**
**Current Status**
**Scientific Approach**

## Clinical Pharmacology Studies

**Pharmacogenetics**

**Pharmacodynamics**

**Clinical Pharmacology Studies**

**Pharmacokinetics**

**Notes:**
Clinical pharmacology studies will be extended from those performed during phase 1 trials into phase 2 trials. The triad of pharmacokinetics, pharmacogenetics, and pharmacodynamics are critically important components of the pediatric cancer drug development process. In phase 2 trials we will have the opportunity to relate phenotypic data defined as drug exposure determined by pharmacokinetics and drug response or pharmacodynamics, to emerging pharmacogenetic data, an approach that will form the foundation for the future individualization of drug therapy.

## Pharmacokinetics

**Scaling adult doses based solely on BSA ignores developmental changes**
**Volume of distribution**
**Drug clearance & metabolism**
**Developmental changes in drug disposition can alter tolerance and efficacy **

**Notes:**

the "old standards" for kids vs adults include...age-dependent clearance of busulfan, shorter half-life for cyclophosphamide, greater clearance of methotrexate in young children.  And, a # of investigational agents that didn't survive (e.g. indicine N-oxide in a CCG study), etc.

## Pharmacokinetics

**Define drug disposition in children**
**Correlate pharmacokinetic parameters with demographics and outcomes**
**Develop limited sampling methods to allow for on-going phenotyping in phase 2 and 3 trials**

## Pharmacogenetics

**Drug responses are determined by multiple factors including**
**Drug metabolism**
**Drug transport**
**Drug interactions with molecular targets**

**Methodologies**
**Allele-specific restriction fragment length polymorphism (RFLP) assays**
**GeneScan detection**
**TaqMan**
**CYP SNP Chips**

**Drug metabolism**

**Notes:**
The rationale for performing pharmacogenetic studies during phase 2 trials is based upon the knowledge that drug responses are determined by multiple factors  which have genetically determined influences including
Drug transport
Drug metabolism
Drug interactions with molecular targets
Our initial studies will focus on polymorphisms in drug metabolizing enzymes. 

Methodologies we will use include  
Furthermore, we are fortunate to have the support and expertise of Dr. Richard Weinshiboum, the discoverer of the TPMT polymorphism at Mayo, to help lead our research efforts in this field.

## Prioritization - Current Status

**Criteria for pediatric phase I development**
**Safety and activity in adults**
**Pre-clinical data**
**Prioritization primarily occurs **_**following**_** completion of broad-based pediatric phase II testing**

**Notes:**
An important challenge we must address when discussing childhood cancer drug development is how we are to prioritize among the rapidly increasing number of agents entering into the adult cancer drug development pipeline, as we are constrained by a limited number of patients available for phase 1 and 2 study.
Hhisotrically studied majority of classes of agents in development

Currently, the criteria... 

## NCI-CTEP Development Pipeline

**NCI-CTEP Development Pipeline**

## Prioritization - Future Goal

**To move toward a more rational method of drug prioritization through an improved understanding of tumor biology and the molecular mechanism(s) of drug action.**

**Notes:**
Our future goal therefore is

## COG Phase 1/Pilot Consortium

**Development of novel therapeutic agents by the consortium will form the foundation for future advances in the care of children with cancer by providing more effective, more targeted, and less toxic therapy.**