Rationale for Developing New DrugsRationale for Developing New Drugs

• 25% of children with cancer will not survive 5 25% of children with cancer will not survive 5 yearsyears

• The acute toxicity of dose-intensive The acute toxicity of dose-intensive chemotherapy is life-threateningchemotherapy is life-threatening

• The long-term effects of cancer therapy can be The long-term effects of cancer therapy can be debilitating or life-threateningdebilitating or life-threatening– Growth delayGrowth delay– Cognitive effectsCognitive effects– Hormonal/reproductive problemsHormonal/reproductive problems– Permanent tissue/organ damagePermanent tissue/organ damage– Second cancersSecond cancers

Toxicity in IRS-IIIToxicity in IRS-III

Mild Moderate Severe Life-threatening Fatal

0

100

200

300

400

500

600

700

Mild Moderate Severe Life-threatening Fatal

0

100

200

300

400

500

600

700

Worst Degree of Any Toxicity (n=1062)Worst Degree of Any Toxicity (n=1062)No. of No. of

PatientsPatients

Severity of ToxicitySeverity of Toxicity

Clinical Drug DevelopmentClinical Drug Development

Separate Pediatric Clinical TrialsSeparate Pediatric Clinical Trials

• Developmental changes affect:Developmental changes affect:– Drug disposition (pharmacokinetics)Drug disposition (pharmacokinetics)

– Tissue/organ sensitivity (pharmacodynamics)Tissue/organ sensitivity (pharmacodynamics)

• Childhood cancers differ from adult cancersChildhood cancers differ from adult cancers– Tissue of originTissue of origin

– Pathogenesis (genetic alterations)Pathogenesis (genetic alterations)

– Disease manifestationsDisease manifestations

– Drug sensitivityDrug sensitivity

Pediatric Pediatric vsvs. Adult MTD (1970s). Adult MTD (1970s)

0 50 100 150 200

ICRF-187CyclocytidineDeazauridine

TeniposideMitoxantrone

BisantreneCarboplatin

DianhydrogalactitolZorubicin

DONChlorozotocin

Indicine N-oxideDiaziquone

0 50 100 150 200

ICRF-187CyclocytidineDeazauridine

TeniposideMitoxantrone

BisantreneCarboplatin

DianhydrogalactitolZorubicin

DONChlorozotocin

Indicine N-oxideDiaziquone

% Difference between Pediatric % Difference between Pediatric and Adult MTDand Adult MTD

MTDs in mg/mMTDs in mg/m22

Pediatric Pediatric vsvs. Adult MTD (1990s). Adult MTD (1990s)

-80 -60 -40 -20 0 20 40 60 80

9-cis Retinoic Acid

Piritrexim

Docetaxel

Irinotecan

Trimetrexate

CI-980

9-Aminocamptothecin

Topotecan

Vinorelbine

Temozolomide

Paclitaxel

Raltitrexed

-80 -60 -40 -20 0 20 40 60 80

9-cis Retinoic Acid

Piritrexim

Docetaxel

Irinotecan

Trimetrexate

CI-980

9-Aminocamptothecin

Topotecan

Vinorelbine

Temozolomide

Paclitaxel

Raltitrexed

% Difference between Pediatric % Difference between Pediatric and Adult MTDand Adult MTD

Clinical Anticancer Drug DevelopmentClinical Anticancer Drug DevelopmentDRUGSDRUGS

PATIENTSPATIENTS

Phase IPhase I

Phase IIIPhase III

Phase IIPhase II

NewlyNewlyDiagnosedDiagnosed

RelapsedRelapsed

RelapsedRelapsed

CuredCured

New AgentNew Agent

Too ToxicToo Toxic

Not EfficaciousNot Efficacious

InactiveInactive

Approved DrugApproved Drug

Docetaxel Phase I TrialsDocetaxel Phase I Trials

* <500/µL for >7 days was considered dose-limiting* <500/µL for >7 days was considered dose-limiting

Determinants of ChemotherapyDeterminants of Chemotherapy

• Selection of front line treatment regimenSelection of front line treatment regimen

– Tumor histologyTumor histology

– Stage of cancerStage of cancer

– Prognostic characteristicsPrognostic characteristics

• Studying activity of new agentsStudying activity of new agents

– Stratified by tumor histologyStratified by tumor histology

Molecularly-Targeted DrugsMolecularly-Targeted Drugs

• Specific for molecular target (e.g., mutant Specific for molecular target (e.g., mutant rasras) rather ) rather than histologythan histology– Patient treated based on presence of molecular lesion rather Patient treated based on presence of molecular lesion rather

than tumor histologythan tumor histology

– Phase II trials not stratified by histologyPhase II trials not stratified by histology

• Molecular pathogenesis of adult and childhood cancers Molecular pathogenesis of adult and childhood cancers differentdifferent

• Endpoint of dose finding (phase I) trials may be Endpoint of dose finding (phase I) trials may be blocking target rather than toxicityblocking target rather than toxicity

• Toxicity profile and dose-limiting toxicity may be Toxicity profile and dose-limiting toxicity may be different than for cytotoxic agentsdifferent than for cytotoxic agents