3787 - A Phase I study of XZP-3287, a novel oral CDK4/6 Inhibitor, administered on a continuous dosing schedule, in patients with advanced solid tumours

Background

XZP-3287 is a novel selective inhibitor of cyclin-dependent kinases 4/6 (CDK 4/6). Preclinical data suggested a comparable antitumor activity with Palbociclib and Abemaciclib, and a more favourable safety profile of mild myelosupression. A continuous dosing schedule (28days/cycle) is adopted in this first-in-human study to achieve sustained target inhibition.

Methods

The study is designed as an accelerated titration followed by a standard 3 + 3 dose escalation. Eligible patients are those with locally advanced or metastatic solid tumours, and who have progressed despite of refractory to standard therapy or no standard-of-care therapy is available.

Results

16 subjects were enrolled in this study by April 1, 2019. The DLT evaluation in 320mg QD dose group was completed. No DLT or drug related serious adverse event (SAE) was observed from 20mg QD to 320mg QD dose groups. The drug related adverse events (AE) were mainly CTCAE grade 1 and 2, and reversible. Drug-related AEs (≥10%) were diarrhea (31.3%), leucopenia (31.3%), blood creatinine increased (25%), anemia (18.8%), neutropenia (18.8%), vomiting (18.8%), ALT increased (12.5%), thrombocytopenia (12.5%), blood alkaline phosphatase increased (12.5%) and hyperuricaemia (12.5%). Myelosuppression was observed from 160mg QD level. A negative correlation was showed between the AUC/C_max of steady state and the maximum percentage decrease from baseline of neutrophil/platelet counts (r=-0.57 to-0.48), which was consistent with pharmacological effects of CDK4/6 inhibition. Furthermore, clinical activity was observed at low and not yet optimal dose levels. Among 7 efficacy evaluable subjects, 3 achieved SD , and 4 experienced PD. 1 SD patient in 240mg QD dose group had sustained SD for over 8 months and the target lesions was reduced by 23.7% from baseline which previously treated by chemotherapy, The latest data (Apr.30.) showed that, all the 3 patients in 320mg QD dose group achieved SD (2 patients exhibited tumor shrinkage by 10.9% and 8.3% respectively). These data will be update at annual meeting.

Conclusions

This study demonstrated that single-agent XZP-3287 was well tolerated and showed the CDK4/6 inhibition activity in human.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Xuanzhu Biopharmaceutical Ltd.

Funding

Xuanzhu Biopharmaceutical Ltd.

Disclosure

All authors have declared no conflicts of interest.