DRUG DEVELOPMENT 2

• 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

MTD

• 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.

PHASE 1 ETHICS

- Pt benefit is not the primary goal, but the trial dose need to have a therapeutic intent

- Low probability of response expected - approx 5%