Cancer Clinical Trials in Cancer Clinical Trials in Special Populations Special Populations

Gregory H. Reaman, MDGregory H. Reaman, MD

Professor of PediatricsProfessor of Pediatrics

The George Washington University The George Washington University

School of Medicine and Health SciencesSchool of Medicine and Health Sciences

Chair, Children’s Oncology GroupChair, Children’s Oncology Group

What Makes Children What Makes Children (with cancer) Special?(with cancer) Special?

Vulnerable population with life-threatening diseaseVulnerable population with life-threatening disease General ethical principles that apply to research in General ethical principles that apply to research in

children embodied in Subpart D of Code of Federal children embodied in Subpart D of Code of Federal RegulationsRegulations

Risks must be justified by the anticipated benefitRisks must be justified by the anticipated benefit Benefit : Risk relationship at least as favorable as Benefit : Risk relationship at least as favorable as

current alternative therapiescurrent alternative therapies Risk-adapted clinical trialsRisk-adapted clinical trials

45 CFR46.405 – research involving greater than minor increase over minimal risk must offer the prospect of direct benefit.

VulnerabilityVulnerability

Developmental association with normal Developmental association with normal physiologyphysiology

Age and cognitive abilitiesAge and cognitive abilities Consent and assentConsent and assent ComplianceCompliance Dissonance at emancipationDissonance at emancipation

Progress in Pediatric Progress in Pediatric OncologyOncology

Success achieved through multi-center, multi-Success achieved through multi-center, multi-disciplinary clinical and applied researchdisciplinary clinical and applied research

Systematic application of the principles of Systematic application of the principles of evidence-based medicine to a national clinical evidence-based medicine to a national clinical trials infrastructuretrials infrastructure

Infrastructure strengthened by the unification Infrastructure strengthened by the unification of the pediatric cancer clinical trials groupsof the pediatric cancer clinical trials groups

Benefits of Pediatric Benefits of Pediatric Clinical Trial ParticipationClinical Trial Participation

Access to collective wisdom of leading experts Access to collective wisdom of leading experts in the fieldin the field

Access to state-of-the art therapies and Access to state-of-the art therapies and technologiestechnologies

Access to translational research and Access to translational research and discoveries-prognostic classification and risk-discoveries-prognostic classification and risk-adjusted therapyadjusted therapy

Access to late effects studiesAccess to late effects studies

The National Childhood Cancer The National Childhood Cancer Mortality Rate and the Pediatric Mortality Rate and the Pediatric

Cooperative GroupsCooperative Groups

19501950 19601960 19701970 19801980 19901990

22

44

66

88

( )( )

Annual USA Cancer Mortality Rate Children <15 Years

CCG

NWTSG

IRSG

CALGB Pediatric Division

SWOG Pediatric DivisionPOG

20002000

Mortality per

100,000, Age-

Adjusted

20052005

COG

Pediatric Cancer ResearchPediatric Cancer Research

Unique (academic medical center/hospital based vs. private Unique (academic medical center/hospital based vs. private practice) system of care delivery historically linked to highly practice) system of care delivery historically linked to highly effective clinical research modeleffective clinical research model

Enhanced requirement for correlative biologic investigations: Enhanced requirement for correlative biologic investigations: etiology, therapy development, target identification/validationetiology, therapy development, target identification/validation

Strong collaboration/integration with NCI-designated Strong collaboration/integration with NCI-designated Comprehensive and Clinical Cancer Centers and Intramural Comprehensive and Clinical Cancer Centers and Intramural ProgramsPrograms

Heterogeneity of diseases and biologic/molecular sub-Heterogeneity of diseases and biologic/molecular sub-classification (risk-group assessment) impact on study classification (risk-group assessment) impact on study accrual requirements and increased collaboration – COGaccrual requirements and increased collaboration – COG

Childhood Cancer Survival Childhood Cancer Survival DataData

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

ALL

AM

L

Hodgkin's

Non-H

odgkins

CN

S

Neuroblastom

a

Retinoblastom

a

Renal T

umors

Liver T

umors

Bone T

umors

Soft Tissue

Sarcomas

Germ

Cell

Tum

ors

1995-2001

1975-1995

Pediatric Cancer Pediatric Cancer Therapeutic ResearchTherapeutic Research

Future Progress from Biologic Discovery and Future Progress from Biologic Discovery and Translational ResearchTranslational Research

Genomics/Proteomics Molecular targets:Genomics/Proteomics Molecular targets:

– Drug discoveryDrug discovery

– Etiology/Genetic EpidemiologyEtiology/Genetic Epidemiology

– Prevention (Gene: Environment Prevention (Gene: Environment Interactions)Interactions)

Challenges in Pediatric Challenges in Pediatric Cancer ResearchCancer Research

Clinical Challenges in New Clinical Challenges in New Cancer Drug DevelopmentCancer Drug Development

Relatively low cancer incidence – unfavorable Relatively low cancer incidence – unfavorable market forcesmarket forces

Unique pediatric cancersUnique pediatric cancers Development (age – related)Development (age – related)

– Changes in organ function: absorption, Changes in organ function: absorption, distribution and clearancedistribution and clearance

Other pK and pD differencesOther pK and pD differences Optimism – Pediatric exclusivity – PREA - BPCAOptimism – Pediatric exclusivity – PREA - BPCA

Critical Criteria for Selecting Critical Criteria for Selecting New AgentsNew Agents

Novel mechanism of actionNovel mechanism of action Favorable toxicity profileFavorable toxicity profile pK considerations (e.g. pharmacologic pK considerations (e.g. pharmacologic

sanctuary sites)sanctuary sites) Measurable endpoints: correlation of pK and Measurable endpoints: correlation of pK and

outcomeoutcome

Prioritization of Agents for Prioritization of Agents for Pediatric DevelopmentPediatric Development

Sound rationaleSound rationale Compelling pre-clinical data (Compelling pre-clinical data ( in vivo, in vitro in vivo, in vitro

pediatricpediatric models) models) Preliminary adult experiencePreliminary adult experience Drug availability and long term development planDrug availability and long term development plan Disease-specific scientific agendaDisease-specific scientific agenda

The Adolescent and Young The Adolescent and Young Adult “Gap”Adult “Gap”

64% of “pediatric” cancer patients between 15-64% of “pediatric” cancer patients between 15-21 not seen at a pediatric center21 not seen at a pediatric center

60% of eligible patients age 15-21 are not 60% of eligible patients age 15-21 are not entered on open clinical trialsentered on open clinical trials

Age related survival differences (15-19, 19-21, Age related survival differences (15-19, 19-21, 21-25, 25-30) exist for nearly every cancer type 21-25, 25-30) exist for nearly every cancer type most commonly seen in children and most commonly seen in children and adolescents – ALL, Ewing, Rhabdomyosarcoma, adolescents – ALL, Ewing, Rhabdomyosarcoma, OsteosarcomaOsteosarcoma

Age-Specific PrognosisAge-Specific Prognosis

All All MalignanciesMalignancies

SEER 1999

Case 1Case 1

16 yo girl of African American/Mexican 16 yo girl of African American/Mexican American descentAmerican descent

3 year h/o: primary tumor in R pelvis 3 year h/o: primary tumor in R pelvis (synovial cell sarcoma) previously CR (synovial cell sarcoma) previously CR following Ifos/Adria, XRT, surgeryfollowing Ifos/Adria, XRT, surgery

Refused to come for multiple follow-up Refused to come for multiple follow-up appointments/scansappointments/scans

Case 1Case 1

Developed RLE swelling while incarcerated, Developed RLE swelling while incarcerated, presented to outside hospitalpresented to outside hospital

CT finally done within one week of CT finally done within one week of scheduled release datescheduled release date

Case 1Case 1

CT: massive abdominal tumor with CT: massive abdominal tumor with loculated fluid collections + multiple loculated fluid collections + multiple pulmonary metastasespulmonary metastases

Case 1Case 1

Physical exam: Physical exam:

– Thin female, in no distressThin female, in no distress

– Vitals normal, KPS 90% Vitals normal, KPS 90%

– Chest unremarkable Chest unremarkable

– Abdomen distended, mild discomfort on Abdomen distended, mild discomfort on palpation, firm RUQ but o/w soft with ?palpation, firm RUQ but o/w soft with ?fluid wavefluid wave

– Massive edema RLE to groin; 3+ pitting Massive edema RLE to groin; 3+ pitting LLE to kneeLLE to knee

Case 1Case 1

Counts normalCounts normal Coags normalCoags normal CMP normalCMP normal Room air oxygen sat 99-100%Room air oxygen sat 99-100% Pregnancy test negativePregnancy test negative Not on any medicationsNot on any medications

Would You Offer an Would You Offer an Early Phase Clinical Early Phase Clinical Trial to This Patient?Trial to This Patient?

Is this Patient a Candidate Is this Patient a Candidate for a Clinical Trial?for a Clinical Trial?

We don’t have great drugs for recurrent, We don’t have great drugs for recurrent, metastatic synovial sarcomametastatic synovial sarcoma

Disease is not resectableDisease is not resectable Performance status excellentPerformance status excellent Organ system function is excellentOrgan system function is excellent Ethnic groups and representation in clinical Ethnic groups and representation in clinical

trialstrials

Any Issues Here?Any Issues Here?

Patient is a minorPatient is a minor Patient represents an ethnic minorityPatient represents an ethnic minority Patient is a female of child-bearing potentialPatient is a female of child-bearing potential Patient/parent are not medically Patient/parent are not medically

sophisticatedsophisticated Adherence a challenge in pastAdherence a challenge in past

What Makes a Person Part What Makes a Person Part of a “Special Population”?of a “Special Population”?

AgeAge Race and ethnicityRace and ethnicity GenderGender IncomeIncome Insurance statusInsurance status

What ELSE?What ELSE?

Rural environmentRural environment Abilities/disabilitiesAbilities/disabilities

– PhysicalPhysical

– CognitiveCognitive

– EducationalEducational Sexual orientationSexual orientation Demographic and social characteristics that Demographic and social characteristics that

are different from the majorityare different from the majority

““Health Disparities”Health Disparities”

Unequal access to health care for segments Unequal access to health care for segments of a populationof a population

– inferior health outcomes inferior health outcomes

– unequal burden unequal burden morbiditymorbidity quality of lifequality of life survival survival

““The burden of cancer is too The burden of cancer is too often greater for the poor, often greater for the poor, ethnic minorities and the ethnic minorities and the

uninsured than for the uninsured than for the general population.”general population.”

NCI Center to Reduce Cancer Health Disparities

Let’s Go Through Let’s Go Through the Specific Issuesthe Specific Issues

Patient is a minorPatient is a minor

– Any track record for clinical trials in Any track record for clinical trials in pediatric oncology?pediatric oncology?

– Childhood cancer uniformly fatal in Childhood cancer uniformly fatal in 1950s/early 1960s1950s/early 1960s

– Overall survival data: >78%Overall survival data: >78%

– Most progress through multicenter clinical Most progress through multicenter clinical trialstrials

Toxicity and pKToxicity and pK

In some cases there are very legitimate In some cases there are very legitimate reasons to be concerned about toxicity reasons to be concerned about toxicity issuesissues

However, MTD usually higher in childrenHowever, MTD usually higher in children pK in children may or may not be similar to pK in children may or may not be similar to

adultsadults

– Teens>50 kg often very much like adultsTeens>50 kg often very much like adults

Recent HistoryRecent History

Phase I studies of IGF1 inhibitors (anti-IgF1r)Phase I studies of IGF1 inhibitors (anti-IgF1r) Not initially conceived with sarcomas as main Not initially conceived with sarcomas as main

target tumortarget tumor Patients with Ewings and other sarcomas with Patients with Ewings and other sarcomas with

objective responses in Phase Iobjective responses in Phase I Major shift in drug development programs in Major shift in drug development programs in

this areathis area

The LawThe Law

Pediatric Research Equity Act of 2003Pediatric Research Equity Act of 2003

– Provides legislative authority for FDA to require companies to do pediatric testing for drugs and biologics

Best Pharmaceuticals for Children Act Best Pharmaceuticals for Children Act (BPCA) and Pediatric Rule – provides (BPCA) and Pediatric Rule – provides patient exclusivity incentivepatient exclusivity incentive

Pharma a bit more anxious to acquire Pharma a bit more anxious to acquire pediatric data than previouslypediatric data than previously

If You Are Going If You Are Going to Enroll Minorsto Enroll Minors

Federal RegulationsFederal Regulations

– CFR Section 46, Subpart DCFR Section 46, Subpart D

– Intervention > minimal risk to child: Intervention > minimal risk to child:

must either be of DIRECT BENEFIT to child or must either be of DIRECT BENEFIT to child or

risk of intervention must be = that of available risk of intervention must be = that of available alternativealternative

– If research yields only generalizable knowledge If research yields only generalizable knowledge about child’s disease, must be only MINOR about child’s disease, must be only MINOR increase over minimal riskincrease over minimal risk

If You Are Going If You Are Going to Enroll Minorsto Enroll Minors

ConsentConsent– Parental consent for <18 year oldsParental consent for <18 year olds

Both parents for research without direct Both parents for research without direct benefitbenefit

– Age of majority state regulatedAge of majority state regulated– Adolescent assentAdolescent assent

– Child’s assentChild’s assentLocal Context Responsibility

Correlative Studies Correlative Studies in Minorsin Minors

Serial tumor biopsies of >minimal risk, no Serial tumor biopsies of >minimal risk, no direct benefitdirect benefit

– Not permitted unless making clinical Not permitted unless making clinical decisions for patient on the basis of your decisions for patient on the basis of your findingsfindings

– Not permitted **Not permitted **even if parent agrees**even if parent agrees** Use surrogate tissuesUse surrogate tissues

Reasonable Approaches Reasonable Approaches Other Than Other Than

Integrated TrialsIntegrated Trials If endpoint is MTD of cytotoxic agent:If endpoint is MTD of cytotoxic agent:

– Stepwise cohorts with minors enrolled one Stepwise cohorts with minors enrolled one dose level just behind adultsdose level just behind adults

– Two-part study with minor portion opening as Two-part study with minor portion opening as adult portion closesadult portion closes

If agent unlikely to have an MTDIf agent unlikely to have an MTD

– PK (or someday PD) based study for minorsPK (or someday PD) based study for minors

Patient is IncarceratedPatient is Incarcerated

Autonomy in PrisonsAutonomy in Prisons

– Are increased access to medical care + Are increased access to medical care + opportunities to interact during study-opportunities to interact during study-related activities undue inducement?related activities undue inducement?

45 CFR 46.305 and 45 CFR 46.306 45 CFR 46.305 and 45 CFR 46.306

– Only permits participation in studies with Only permits participation in studies with no > minimal riskno > minimal risk

Incarcerated PatientsIncarcerated Patients

““Early phase” clinical trials prohibitedEarly phase” clinical trials prohibited August 2006 IOM report August 2006 IOM report

– ““Prisoners have been exploited in the past, Prisoners have been exploited in the past, carrying a heavier burden of risks than the carrying a heavier burden of risks than the general population, however . . .. responsible general population, however . . .. responsible research has the potential of improving research has the potential of improving health and well being of prisoners . . ..” health and well being of prisoners . . ..”

Rec: Later phase trials could be possible as Rec: Later phase trials could be possible as long safeguards in effectlong safeguards in effect