Wilson H. Miller, MD Jewish General Hospital discusses an ASCO 2020 abstract entitled A phase Ib study of oral Chk1 inhibitor LY2880070 as monotherapy in patients with advanced or metastatic cancer.
LY2880070 (LY) is an orally administered, selective control-point kinase 1 (Chk1) adenosine triphosphate competitive inhibitor. LY blocks the response of the checkpoint, and inhibition of Chk1 results in apoptosis induced by mitotic catastrophe.
This two-part, open-label multicenter research investigates LY 's protection, pharmacokinetics (PK) and anti-tumor activity in patients with advanced or metastatic cancers. The main purpose of this research was to determine the maximum tolerated dose (MTD) for multiple escalating oral LY doses. The secondary objectives were to: 1) define the dose-limiting toxicity (DLT) and overall LY safety profile; 2) assess the LY PK; and 3) assess the LY anti-tumor function. Patients administered LY orally in two treatment arms in 21-day cycles: 1) A multiple ascending dose (MAD) arm in patients with normal / intermediate CYP2D6 metabolism; or 2) an arm with LY given as monotherapy to weak CYP2D6 metabolisers.
The MTD was 200 mg BID daily for normal / intermediate CYP2D6 metabolizers. Also with the use of anti-emetics, the 400 mg QD dose was not tolerated. BID administration (same daily total dose) nevertheless made LY tolerable. Vomiting, nausea, and exhaustion were primarily dose-limiting toxicities, and seemed to be associated with Cmax. The mean half-life was 5.35 hours (+ /- 2.3) BID dosing produced AUC maintenance (3271.4 h∙ng / mL 200 mg BID vs 3377.9 h∙ng / mL 400 mg QD) while Cmax (350.0 ng / mL 200 mg BID vs 691.9 ng / mL 400 mg QD) was reduced and Cmin was increased relative to QD dosing with the same total daily dose. Importantly, 200 mg LY BID administration resulted in a steady-state median Cmin remaining above the IC80 for 12 h / day and 24 h / day above the IC50. Five patients had the strongest SD response over a span of 6 cycles or more.
In a regular BID plan LY has been tolerated. You can modulate the toxicity profile by adjusting the dosing frequency from QD to BID when prescribing the same daily dosage. LY may be a possible combination treatment with DNA harmful agents. Study #: NCT02632448. This research is funded by the 1255 boul Esperas Pharma Inc .. # 1610 Robert-Bourassa, Montreal, Qc, H3B 3X3. Details on clinical trials: NCT02632448.