A Phase I Trial of CHIR-258, a Multitargeted RTK Inhibitor, in Acute Myeloid Leukemia (AML).

Background: CHIR-258 is an orally active small molecule receptor tyrosine kinase (RTK) inhibitor which exhibits potent single digit nanomolar inhibitory activity against multiple RTKs involved in tumor growth and angiogenesis (IC₅₀ <=10 for VEGFR, PDGFR, FGFR, C-KIT, and FLT-3). Approximately 30% of AML patients have a FLT-3 mutation (ITD-internal tandem duplication or catalytic domain) which drives the malignant process and confers a worse prognosis. Additionally, the inhibition of the angiogenesis component of the disease could be beneficial in all cases. Preclinical data have shown FLT3 ITD models to be ~25 fold more sensitive than FLT3 WT (Menezes, et al, Blood 2005). Our hypothesis was that AML blasts carrying FLT-3 mutations would be exquisitely sensitive to CHIR-258, but that there may also be activity against patients with wild type (wt) FLT-3.

Methods: CHIR-258 was administered orally to adult patients with relapsed/refractory AML on a 7 on/7 off schedule followed by continuous daily dosing for 28 days (1 cycle). Subsequent 28-day cycles of continuous dosing were permitted. Pharmacokinetic (PK) and pharmacodynamic (PD) assessments were serially performed and drug tolerability assessed.

Results: As of May 2005 8 patients have been treated in 2 (50mg and 100 mg) cohorts of 3–6 patients [median age: 62 years (range: 46–72), sex: 4M/4F, median prior relapses = 1 (range: 1–3), FAB subtypes: M₁–1, M₂–2, M₅–1, M₆–2, unclassifiable-1, no information-1] Five patients remain on study with a median number of treatment cycles=3 (range=1–11). There have been no DLTs to date. Dose escalation to 200 mg has been tolerated and accrual continues. Drug related adverse events include fatigue, anorexia, nausea/vomiting, and headache and were generally mild (CTC G1-2). Of the 8 patients treated, 1 had FLT-3 ITD mutation and 7 were wt for ITD and D835. A patient with AML-M6 with wt FLT-3 continues with stable disease after 11 cycles of therapy and was dose escalated from 50mg to 100mg after 8 cycles. The patient with FLT-3 ITD mutation treated at the 100mg dose had near complete clearing of blasts from marrow and peripheral blood. This patient later died due to a presumed fungal infection, not attributed to CHIR-258. Plasma exposure and Cmax increase proportionally across the dose range, and Cmax at the 100mg dose level is in the range where antitumor activity was seen in a preclinical oncogene addicted tumor models for FLT-3 ITD AML (MV4;11).

Conclusions: CHIR-258 has demonstrated activity in relapsed refractory patients with AML, both with a FLT-3 mutation and wt FLT-3. Accrual continues at the 200mg dose cohort and updated data will be presented at the meeting.