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Monday, 30 May 2011


  • Phase 1 : Human Pharmacology, (Dose finding)
  • Phase 2 : Therapeutic Exploratory (? anti-tumour activity)
  • Phase 3: Therapeutic action Confirmed and compared to standard
  • Phase 4 : Post launch
For classical Cytotoxics
  1. Dose escalation Phase 1 to determine Dose Limiting Toxicity (DLT) & Max Tolerated Dose (MTD)
  2. No-randomised Phase 2 to determine efficacy
  3. Phase 3 - for comparative effficacy
DLT -for example
  • neutrophil count <0.5 for 5 days associated with fever or infection
  • Platelet count <10 or bleeding
  • Other Grade 3 toxicity
  • Dose at which < or = 33% patients experience an unacceptable toxicity
Characteristics of a Phase 1 trial
  • Usually in patients with an advanced malignancy, refractory to standard therapies
  • Patients usually otherwise well
  • Start with a very cautious dose as determined from pre-clinical studies.
  • Starting dose (mg/M2) 1/10th of the LD10 (dose at which 10% of rodents die)
  • 1/3rd of minimal toxic dose in large animal studies
  • Minimise number of patients treated with sub-therapeutic doses. Escalate dose quickly if toxicity absent. Escalate slowly if toxicity present.
  • Example: Treat 3 pts with safe starting dose (as described above), increase dose if no toxicity. If toxicity in 1 patient add 3 more. Stop escalation when more than 33% pts have an unacceptable toxicity.
  • Modified Fibomaci Scheme: Start at 1/10th of LD10, then increase by 100% then 67%, then 50%, then 40%, then 33% thereafter (100--67--50--40--33). If the LD10 is accurate, should be 5-6 dose incriments.
  • PURPOSE: Estimate the recommended dose for later trials, study drug metabolism, elimination and side effects
  • LIMITATIONS: Chronic/cumulative toxicities not well assessed, uncommon toxicities missed, dose for Phase 2 may be conservative as Phase 1 patients often heavily pre-treated.
- Pt benefit is not the primary goal, but the trial dose need to have a therapeutic intent
- Low probability of response expected - approx 5%

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