A CRUK first-in-human phase I trial of LY3143921, a novel CDC7 inhibitor, in patients with advanced solid tumors.
Authors: Gallagher Peter F. , Naylor Gregory , Bashir Saira , Yan Xiangfei , Burke David , Plummer Elizabeth Ruth , Evans T.R. Jeffry , Coyle Victoria M. , Clive Sally , McGuigan Lesley , Heinzmann Kathrin , Halbert Gavin , Veal Gareth , Tiplady Eleanor , Barnett Shelby , Yalla Krishna , Brook Sue , Dobbs Nicola , Wilson Richard H. 
Published: June 2022

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Background: CDC7, a protein with key roles in regulating cell-cycle progression is often over-expressed in malignant cells, particularly those with TP53 mutations. LY3143921, an orally administered ATP-competitive CDC7 inhibitor, demonstrated favorable pre-clinical anti-cancer activity in colorectal cancer (CRC) and squamous non-small cell lung cancer (sqNSCLC), particularly in TP53 mutant models. Methods: Phase Ia (dose escalation) recruited patients (pts) with advanced solid tumors enriched for malignancies associated with TP53 mutation. Pts received LY3143921 OD or BD continuously on a 21-day schedule, using an accelerated 3+3 escalation design, starting at 30 mg OD. Phase Ib recruited pts with CRC or sqNSCLC treated continuously at RP2D, or pts with other advanced tumors treated at RP2D on days 1-3 every 7 days. Radiological assessment was performed every 2 cycles initially. Pts in phase Ib could consent to pre- and on-treatment skin +/- tumor biopsies. Primary objectives: assess safety/tolerability and determine MTD and RP2D of LY3143921. Secondary objectives: evaluate preliminary efficacy and pharmacokinetic (PK) profile of LY3143921. Exploratory objective: correlate efficacy to baseline molecular/genetic alterations, including TP53 mutation and measure markers including pMCM2 in pre- and on- treatment tumor and skin samples. Results: 68 pts were recruited and 67 treated (38 phase Ia, 29 phase Ib). Most frequent drug-related CTCAEs (all grades): nausea (75%), orthostatic hypotension (50%), vomiting (47%), fatigue (45%) & diarrhea (44%). Grade 3-4 LY3143921 related AEs occurred in 17 pts. In phase Ia 8 DLTs occurred in 5 pts (G3 nausea, vomiting, fatigue & hyponatraemia and G2 diarrhea, anorexia & lethargy). RP2D was 360 mg BD (continuous non-fasted dosing schedule). 37 pts were evaluable for radiological response with no complete or partial responses seen, and stable disease (SD) was observed in 24 pts (65%). In phase Ia 3 pts achieved long term SD of 1, 2.5 and 3+ years duration. For evaluable pts treated in phase Ib, SD was seen in 8/12 CRC pts, 1/2 sqNSCLC pts and 2/2 pts treated with the intermittent schedule (median duration 15 weeks, range 6-18+). 2 pts remain on-study. Recruitment ceased due to lack of radiological response according to RECIST. Dose-dependent increases in LY3143921 exposure (Cmax & AUC0-24) were seen. IHC analyses of skin biopsies demonstrated reductions in pMCM2, indicating on-target activity of LY3143921. Pre-clinical testing of combination with standard of care agents is ongoing. Additional PD and PK data will be presented. Conclusions: LY3143921 is well tolerated, exhibits dose-dependent increases in plasma exposure and demonstrates evidence of target inhibition. Significant monotherapy clinical activity was not observed; further analyses should investigate potential predictive response biomarkers and rational combination approaches. Clinical trial information: NCT03096054.