# Presentation: 071720

## Prioritizing New Agents for Pediatric Oncology Evaluation

- Malcolm A. Smith, MD, PhD
- Cancer Therapy Evaluation Program
- National Cancer Institute
- May 2007

## How Are New Agents Prioritized for Evaluation in Children with Cancer?

- Novel mechanism of action
- Pre-clinical data model systems
- High levels of activity in adult pre-clinical models
- Activity against pediatric models (e.g., rhabdomyosarcoma xenograft)
- High degree of activity observed in trials in adult patients

## Why Is Prioritizing Targeted Therapies so Important??

- Old approaches to improving outcome are not sufficient
- Maximum treatment intensities have been reached for patients with high risk diagnoses
- Outcome improvements have slowed for some diagnoses
- The opportunity costs of picking the wrong new agents for definitive evaluations
- “Costs” to individual patients
- The loss of 5 to 10 years of opportunity for improving outcome, which may occur if agents that are ineffective are selected for definitive evaluations.

## Number of Phase 3 Trials Initiated in past 20 Years for Selected Childhood Cancers

- Ewing sarcoma
- INT-0091 (1988)
- INT-0154 (1995)
- AEWS0031 (2001)
- AEWS0531 (2008)
- High Risk Neuroblastoma
- POG-8741 (1987)
- CCG-3891 (1991)
- POG-9340/42 (1993)
- A3973 and ANBL0032 (2001)
- ANBL0532 (2007)
- Rhabdomyosarcoma
- IRS-III (1984)
- IRS-IV (1991)
- IRS-V (1999)
- ARST0531 (2006)

## Why Has the Task Been So Challenging??

- Relatively small patient populations make it difficult to obtain reliable answers about the effectiveness of new treatments
- The menu of molecularly targeted agents is large and is driven by adult cancer drug development
- Most agents have some rationale for pediatric evaluation, but available preclinical data have often been fragmentary for the role of the agents in modulating growth/survival of specific childhood cancers
- No uniformly accepted standards for prioritizing agents for evaluation

## Examples of New Agents under Investigation (or recently studied) for Children with Cancer

| AGENT | MOLECULAR TARGET |
| --- | --- |
| Bortezomib | Proteasome |
| 17-AAG | Heat shock protein 90 |
| Erlotinib & gefitinib | EGF receptor |
| Vorinostat & depsipeptide | Histone deacetylase |
| Lapatinib | EGF receptor & ErbB-2 |
| Bevacizumab & AZD2171 & VEGF Trap | VEGF pathway |
| Sunitinib & sorafenib | Multi-targeted kinase |
| Decitabine | Demethylating agent |
| Ispinesib | KSP inhibitor |
| Campath-1H | CD52 |
| Epratuzumab | CD22 |
| Dasatinib | Src-Abl inhibitor |
| Imatinib | Bcr-Abl & other tyrosine kinases |
| IMC-A12, R1507, SCH 717454, etc. | IGF-1R |
| Everolimus, temsirolimus | mTOR |
| Lenalidomide (Revlimid) | Angiogenesis & others |

## How to Keep Focus of Pediatric Drug Development “child focused”??

- Agents developed by pharmaceutical sponsors for adult cancers may (or may not) have limited relevance in the pediatric setting.
- A more systematic preclinical data driven prioritization process for introducing novel agents into the pediatric oncology setting may help to ensure that selection of agents for pediatric evaluation remains a “child focused” process

## Relevant Data for Prioritizing an Agent for Pediatric Evaluation

- RNA and protein expression pattern consistent with the oncogenic role of the agent’s putative target
- Genetic evidence in childhood cancers for oncogenic role for putative target
- Genetic evidence in preclinical models for oncogenic role for the putative target
- Agents directed against the putative target show in vitro activity within relevant concentration ranges in appropriate cell line models
- Agents directed against the putative target show in vivo activity against relevant preclinical models
- Adult activity of agent and number of agents in class already being studied in the pediatric setting

**Notes:**
RNA and protein expression pattern consistent with putative role of candidate target  
Genetic evidence in human cancers for oncogenic role for gene as indicated by one or more of the following:
Activation of the gene/gene product by translocation, mutation, or amplification 
Inactivation of a negative regulatory element of the gene/gene product by translocation, mutation or amplification.
Genetic evidence in preclinical models
Increased expression/activity of the gene/gene product leads to growth/tumorigenesis
Decreased expression/activity of the gene/gene product leads to decreased growth/tumorigenesis
In vivo evidence of activity in relevant preclinical models for an agent directed against the gene or its gene product
In vitro evidence of selective activity for an agent directed against the gene or its gene product
RNA and protein expression pattern consistent with putative role of candidate target  
Genetic evidence in human cancers for oncogenic role for gene as indicated by one or more of the following:
Activation of the gene/gene product by translocation, mutation, or amplification 
Inactivation of a negative regulatory element of the gene/gene product by translocation, mutation or amplification.
Genetic evidence in preclinical models
Increased expression/activity of the gene/gene product leads to growth/tumorigenesis
Decreased expression/activity of the gene/gene product leads to decreased growth/tumorigenesis
In vivo evidence of activity in relevant preclinical models for an agent directed against the gene or its gene product
In vitro evidence of selective activity for an agent directed against the gene or its gene product

## IGF-1 Receptor in Ewing Sarcoma

## IGF-1 Receptor in Ewing Sarcoma

**Ewing sarcoma xenograft EW5**

## Building upon Molecular Characterization Discoveries in the Childhood Cancer Setting

- A novel oncogenic fusion gene is found in the majority of pilocytic astrocytomas (AACR 2008)
_*David T W Jones*_, *Sylvia Kocialkowski*, *Lu Liu*, *Danita Pearson*, *L. Magnus Backlund*, *Koichi Ichimura*, *V. Peter Collins*. University of Cambridge, Cambridge, United Kingdom, Karolinska Institute, Stockholm, Sweden
- The novel rearrangement produces an in-frame fusion gene encoding the kinase domain of B-Raf coupled to the N-terminus of a previously uncharacterized gene
- The fusion has constitutive kinase activity
- The alteration was not present in > 200 WHO Grade III/IV astrocytomas

## Building upon Molecular Characterization Discoveries in the Childhood Cancer Setting

- Identification of ALK as the major neuroblastoma predisposition gene (Mosse, et al. AACR 2008)
- Heritable mutations in the tyrosine kinase domain of the ALK proto-oncogene are the major genetic determinants of familial neuroblastoma,
- Somatically acquired alterations in this gene also occur frequently (~10% of high-risk cases)and may contribute to a more aggressive clinical phenotype.
- ALK is strong candidate target for evaluating in a subset of children with high-risk neuroblastoma.

## Relevant Data for Prioritizing an Agent for Pediatric Evaluation

- RNA and protein expression pattern consistent with the oncogenic role of the agent’s putative target
- Genetic evidence in childhood cancers for oncogenic role for putative target
- Genetic evidence in preclinical models for oncogenic role for the putative target
**Agents directed against the putative target show***** in vitro***** activity within relevant concentration ranges in appropriate cell line models**
**Agents directed against the putative target show***** in vivo***** activity against relevant preclinical models**
- Adult activity of agent and number of agents in class already being studied in the pediatric setting

**Notes:**
RNA and protein expression pattern consistent with putative role of candidate target  
Genetic evidence in human cancers for oncogenic role for gene as indicated by one or more of the following:
Activation of the gene/gene product by translocation, mutation, or amplification 
Inactivation of a negative regulatory element of the gene/gene product by translocation, mutation or amplification.
Genetic evidence in preclinical models
Increased expression/activity of the gene/gene product leads to growth/tumorigenesis
Decreased expression/activity of the gene/gene product leads to decreased growth/tumorigenesis
In vivo evidence of activity in relevant preclinical models for an agent directed against the gene or its gene product
In vitro evidence of selective activity for an agent directed against the gene or its gene product
RNA and protein expression pattern consistent with putative role of candidate target  
Genetic evidence in human cancers for oncogenic role for gene as indicated by one or more of the following:
Activation of the gene/gene product by translocation, mutation, or amplification 
Inactivation of a negative regulatory element of the gene/gene product by translocation, mutation or amplification.
Genetic evidence in preclinical models
Increased expression/activity of the gene/gene product leads to growth/tumorigenesis
Decreased expression/activity of the gene/gene product leads to decreased growth/tumorigenesis
In vivo evidence of activity in relevant preclinical models for an agent directed against the gene or its gene product
In vitro evidence of selective activity for an agent directed against the gene or its gene product

## Setting the Bar for Declaring Success

- Does the in vivo experiment below indicate activity against an intracranial xenograft model for glioblastoma?  24 days to event for controls and 29 for treated animals (Mol Cancer Ther 2007;6(3). 2007)
- Setting an appropriate bar for declaring a “hit” for in vivo testing is critical:
- Lowest bar is “significant difference” between control and treated groups, and progressive disease often meets this bar
**More relevant bar in pediatric oncology is** **tumor regression and “cures”**

## Tumor Regression Is the Gold Standard in Pediatrics

**Rh28 (alveolar rhabdomyosarcoma) response to vincristine**

**ALL-17 (B-precursor ALL) response to vincristine**

## Tumor Regression Is the Gold Standard in Pediatrics

- Cyclophosphamide single agent activity against PPTP *in vivo* panel.
- Comparable activity being observed for novel agents against selected tumor panels.
- Testing results available at _[http://](http://pptp.stjude.org/)__[pptp.stjude.org](http://pptp.stjude.org/)_

## Preclinical Data Driven Prioritization of Combinations for Evaluation

- Single agent activity generally prompts incorporation of agent into regimen with standard therapy.
- Rituximab for adult and pediatric NHL
- What if agent has limited single agent activity?
- Preclinical demonstration of potentiation of activity of standard agents
- Preclinical demonstration of synergistic effects in vitro with in vivo confirmation of supra-additive effects at tolerable doses

## Rh18

- Combination Treatment with Rapamycin and Cytoxan

- Rh30

## Relevant Data for Prioritizing an Agent for Pediatric Evaluation

- RNA and protein expression pattern consistent with the oncogenic role of the agent’s putative target
- Genetic evidence in childhood cancers for oncogenic role for putative target
- Genetic evidence in preclinical models for oncogenic role for the putative target
- Agents directed against the putative target show in vitro activity within relevant concentration ranges in appropriate cell line models
- Agents directed against the putative target show in vivo activity against relevant preclinical models
**Adult activity of agent and number of agents in class already being studied in the pediatric setting. **

**Notes:**
RNA and protein expression pattern consistent with putative role of candidate target  
Genetic evidence in human cancers for oncogenic role for gene as indicated by one or more of the following:
Activation of the gene/gene product by translocation, mutation, or amplification 
Inactivation of a negative regulatory element of the gene/gene product by translocation, mutation or amplification.
Genetic evidence in preclinical models
Increased expression/activity of the gene/gene product leads to growth/tumorigenesis
Decreased expression/activity of the gene/gene product leads to decreased growth/tumorigenesis
In vivo evidence of activity in relevant preclinical models for an agent directed against the gene or its gene product
In vitro evidence of selective activity for an agent directed against the gene or its gene product
RNA and protein expression pattern consistent with putative role of candidate target  
Genetic evidence in human cancers for oncogenic role for gene as indicated by one or more of the following:
Activation of the gene/gene product by translocation, mutation, or amplification 
Inactivation of a negative regulatory element of the gene/gene product by translocation, mutation or amplification.
Genetic evidence in preclinical models
Increased expression/activity of the gene/gene product leads to growth/tumorigenesis
Decreased expression/activity of the gene/gene product leads to decreased growth/tumorigenesis
In vivo evidence of activity in relevant preclinical models for an agent directed against the gene or its gene product
In vitro evidence of selective activity for an agent directed against the gene or its gene product

## Drug Development Pyramid

## Clinical Trial “Niches” in Pediatric Sarcoma Setting

- Relapsed, multiple
- Single agent or multi-agent phase 2
- Phase 1
- Recurrence 1st  (or 2nd)
- Multi-agent single arm phase 2 / pilot (multi-agent)
- Multi-agent randomized phase 2 (selection design or “screening” design)
- Potential for single agent “window” evaluation prior to multi-agent therapy
- Newly diagnosed, metastatic
- Single arm pilot (multi-agent)
- 30-60 patients per year
- Newly diagnosed, localized
- Phase 3, most often with concurrent randomization
- 50-150 patients per year (depending upon how patient population is “risk categorized”)

## Conclusions

- A more systematic preclinical data driven prioritization process may help ensure that selection of agents for pediatric evaluation remains a “child focused” process.
- Relevant data to use for prioritization include:
- RNA and protein expression pattern consistent with the oncogenic role of the agent’s putative target
- Genetic evidence in childhood cancers for oncogenic role for putative target
- Genetic evidence in preclinical models for oncogenic role for the putative target
- Agents directed against the putative target show in vitro activity within relevant concentration ranges in appropriate cell line models
- Agents directed against the putative target show in vivo activity against relevant preclinical models
- Adult activity of agent and number of agents in class already being studied in the pediatric setting
- By assembling relevant preclinical datasets for agents entering pediatric evaluation today, the prioritization process may be able to be refined and improved in the coming years.