Special Populations in Cancer Clinical Trials

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Special Populations in Cancer Clinical Trials

• Ro Bagatell, MD

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Case 1

• 16 yo girl of African American/Mexican
  American/Native American descent
• 3 year h/o synovial sarcoma primary tumor in R
  pelvis previously CR following Ifos/Adria, XRT,
  surgery
• Refused to come for multiple follow-up
  appointments/scans

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Case 1

• Developed RLE swelling while incarcerated, seen
  by juvy pediatrician and CT ordered
• CT massive abdominal tumor with loculated fluid
  collections multiple pulmonary metastases

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Case 1

• Physical exam
• Thin female in chains, in no distress
• Vitals normal, KPS 90
• Chest unremarkable
• Abdomen distended, mild discomfort on palpation,
  firm RUQ but o/w soft with ?fluid wave
• Massive edema RLE to groin 3 pitting LLE to
  knee

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Case 1

• Counts normal
• Coags normal
• CMPNL normal
• Room air oxygen sat 99-100
• Pregnancy test negative
• Not on any medications

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Would You Offer an Early Phase Clinical Trial
to This Patient?
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Is this Patient a Candidate for a Clinical Trial?

• We dont have great drugs for recurrent,
  metastatic synovial sarcoma
• Disease is not resectable
• Performance status excellent
• Organ system function is excellent

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Any Issues Here?

• Patient is a minor
• Patient is incarcerated
• Patient is a person of color
• Patient is a female of child-bearing potential
• Patient/parent are not medically sophisticated
• Adherence a challenge in past

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Lets Go Through the Specific Issues

• Patient is a minor
• Any track record for clinical trials in pediatic
  oncology?
• Childhood cancer uniformly fatal in 1950s/early
  1960s
• Overall survival now gt75
• Most progress through multicenter trials
• Slavish adherence to protocols

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Adolescents as a Medically Underserved Population
Annual Change in 5-Year Relative Survival SEER
Data 1982-1997
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If Its About Biology . . .

• 16 yo with HCC
• 33 yo with Ewing Sarcoma
• 17 yo with AML
• 28 yo with osteosarcoma

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Toxicity and PK

• In some cases there are very legitimate reasons
  to be concerned about toxicity issues
• However, MTD often higher in children
• PK in children may or may not be similar to
  adults
• Teensgt50 kg often very much like adults

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The Law

• Pediatric Research Equity Act of 2003
• FDA can require companies to do pediatric testing
  for drugs and biologics
• Pharma a bit more anxious to acquire pediatric
  data c/w previously

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If You Are Going to Enroll Minors

• Federal Regulations
• CFR Section 46, Subpart D
• Intervention gt minimal risk to child
• must either be of DIRECT BENEFIT to child or
• risk of intervention must be that of available
  alternative
• If research yields only generalizable knowledge
  about childs disease, must be only MINOR
  increase over minimal risk

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If You Are Going to Enroll Minors

• Consent
• Parental consent for lt18 year olds
• Both parents for research without direct benefit
• Adolescent assent
• Childs assent

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Correlative Studies in Minors

• Serial tumor biopsies of gtminimal risk, no direct
  benefit
• Not permitted unless making clinical decisions
  for patient on the basis of your findings
• Not permitted even if parent agrees
• Use surrogate tissues

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Reasonable Approaches Other Than Integrated
Trials

• If endpoint is MTD of cytotoxic agent
• Stepwise cohorts with minors enrolled one dose
  level just behind adults
• Two-part study with minor portion opening as
  adult portion closes
• If agent unlikely to have an MTD
• PK (or someday PD) based study for minors

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Cancer-Specific SurvivalYoung People of Color
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Representation of People of Color in Clinical
Trials
Christian and Trimble, 2003
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Audience Participation

• Between 1999 and 2002, the percentage of black
  patients in Maryland accrued onto NCI sponsored
  cancer treatment trials
• Increased by 9 per year
• Increased by only 5 per year
• Remained the same each year
• Declined by 9 per year

Baquet et al, JCO, July 08
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NCI Cooperative Group Studies

• Enrollment on Cooperative Group trials for
  patients with breast, colorectal, lung and
  prostate cancers 2000-2002 reviewed
• Total participants overall increased
• Representation of minorities decreased

Murthy et al, 2004
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Barriers to Enrollment of Minorities on Clinical
Trials

• History
• Lack of understanding
• Awareness
• The Fear Factor
• Access
• Uneven/Unequal Recruitment

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Recruitment and Enrollment

• Compilation of results of 20 health care studies
  with data re consent rates by race
• Data re enrollment decisions of 70,000 patients

Wendler et al, PLoS Medicine, 2006
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(No Transcript)
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Enrolling When Low Literacy is an Issue

• Considered a vulnerable population
• Specific issues re witness and other safeguards
  per 21 CFR 50.27(b)(2) and 21 CFR 56.111(b)
• Beyond the regulations
• Alternative formats for educational/consent
  materials

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Taken Together . . .

• Its a lot of work to conduct clinical research
• Its even more work to conduct inclusive clinical
  research

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Why Bother?

• Basic clinical trials methodology study
  population should be representative of overall pt
  population to be useful in clinical
  decision-making
• How will we know how to treat our patients if we
  do not include them in our trials?
• Good Science

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Back to Case 1

• Released from Juvy
• Treated with Gem/Docetaxel
• Progressive disease
• What would you do next?