First imatinib trial: a pill that switched off the enzyme driving chronic myeloid leukaemia
In the first human study of imatinib, almost every patient with chronic-phase CML who had failed interferon regained normal blood counts, with mild side effects.
Phase 1 dose-escalation study of the ABL kinase inhibitor STI571 (imatinib) in 83 patients with chronic-phase CML in whom interferon alfa had failed. Doses of 25 to 1000 mg daily were tested and no maximum tolerated dose was reached. At 300 mg or more, complete haematological responses occurred in 53 of 54 patients, usually within four weeks, and cytogenetic responses in 29 of 54 (17 major). It was the first demonstration that a small molecule designed against a defined oncogenic kinase could control a human cancer, and became the template for targeted therapy.
- 83 patients with interferon-refractory chronic-phase CML; doses 25-1000 mg/day; no dose-limiting toxicity identified.
- Complete haematological response in 53 of 54 patients treated at 300 mg/day or more, typically within 4 weeks.
- Cytogenetic responses in 29 of 54 patients at 300 mg or more, 17 of them major (0-35% Ph-positive metaphases).
- Adverse events were mostly grade 1-2: nausea, myalgia, oedema and diarrhoea.
Druker's 2001 imatinib paper turned the idea of hitting a cancer's specific molecular engine into a working medicine. For people with CML it began the shift from a fatal disease treated with interferon or transplant to one managed with a daily tablet. It also set expectations, later tempered, that every cancer might have its own imatinib.
- Single-arm phase 1 with short follow-up and no survival data.
- Responses were haematological and cytogenetic; molecular monitoring came later.
- CML is unusually dependent on a single fusion kinase, which limits how far the model generalises.