rationale for developing new drugs 25% of children with cancer will not survive 5 years25% of...
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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