Biostatistics

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Biostatistics

• Dr. Larry Rubinstein,
• National Cancer Institute

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Phase 0 Trial Statistics for PD Assay

• Endpoints are PD assay, baseline (ideally, just
  before Tx) vs. post-Tx, in tumor tissue and in
  blood
• Baseline measures 1 pre-treatment tumor biopsy
  measurement and at least 3 pre-treatment blood
  measurements (ideally, taken over the baseline to
  post-Tx time span) per patient
• 1 post-Tx measurement used as primary endpoint
  for tumor and blood (at same time post-Tx)
• Declare significant Tx-related change, for an
  individual patient, for observed 2-fold change
  combined with 90 statistical confidence of a
  true difference (10 false positive rate)
• For blood this is 1.8 x intra-pt pre-Tx SD
• For tumor tissue this is 1.8 x inter-pt pre-Tx SD

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Minimal Phase 0 Trial Design

• Accrue 3 patients to each of the dose levels
• For either endpoint, tumor or blood, significant
  Tx-related response for a dose is defined as
  significant change for at least 2 patients out of
  the 3
• For a dose, if there is 80 likelihood of
  observing change at the patient level, there is
  90 power to detect significant response for the
  dose level
• There is an overall 6 false positive rate, for
  both endpoints combined, for a dose level with no
  biologic effect (because of the 10 false
  positive observed change at the patient level)

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Enhanced Phase 0 Trial Design

• There may be a need to detect a lower rate of
  response per dose leveluse a 2-stage design
• Accrue 3-5 patients per dose level, allowing for
  the expansion of a cohort to 5 patients if the
  results are not definitive for the initial 3
• Declare significant change, for an individual
  patient, for an observed 2-fold change combined
  with 95 statistical confidence of a true
  difference
• For tumor tissue this is 2.3 x inter-patient
  pre-Tx SD
• For blood this is 2.3 x intra-pt pre-Tx SD

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Enhanced Phase 0 Trial Design Details

• Accrue 3 patients to each dose level
• If a significant change is observed for exactly
  1 patient, for either endpoint, expand the dose
  to 5 patients
• For either endpoint, significant Tx-related
  response for a dose, for cohort size 3 or 5, is
  defined as significant change for at least 2 pts
• For a dose, if there is 60 likelihood of
  observing change at the patient level, there is
  89 power to detect significant response for the
  dose level
• There is an overall 4 false-positive rate, for
  both endpoints combined, for a dose level with no
  biologic effect (because of the 5 false-
  positive observed change at the patient level)

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The Next Speaker isDr. Holly Taylor