Tibremciclib

Tibremciclib (BPI-16350) is a novel potent selective inhibitor of cyclin-dependent kinase 4 and 6 (CDK4/6). This phase I, first-in-human study assessed the tibremciclib monotherapy and combined with fulvestrant in advanced breast cancer (ABC).

This open-label, phase I study (NCT03791112) comprised dose escalation (phase Ia) and expansion (phase Ib). In phase Ia, Chinese patients with advanced solid tumors received tibremciclib monotherapy (50-500 mg orally once daily). Based on the tolerability and preliminary antitumor activity from phase Ia, two dose cohorts (300 or 400 mg orally once daily) were selected in phase Ib to combine with fulvestrant in patients with hormone receptor (HR)-positive/human epidermal growth receptor 2 (HER2)-negative ABC who failed endocrine therapy. The primary endpoints were safety and tolerability, and secondary endpoints included pharmacokinetics (PK) and antitumor activity.

In phase Ia, 24 patients with advanced tumors (23 ABC and 1 abdominal liposarcoma) received tibremciclib monotherapy, while in phase Ib, 78 patients with HR-positive/HER2-negative stage IV ABC received tibremciclib plus fulvestrant, with a median age of 56.0 (range 26-66) years and 53.5 (range 33-71) years, respectively. In phase Ia, one dose-limiting toxicity (grade 3 blood creatinine increased) occurred at 500 mg and the maximum tolerated dose was not reached. In phase Ib, the recommended phase II dose (RP2D) was tibremciclib 400 mg plus fulvestrant 500 mg. Frequently reported treatment-emergent adverse events of any grade were grade 1-2 blood creatinine increased, hypertriglyceridemia, and anemia. PK demonstrates dose proportionality, a half-life of ∼35.9-51.1 h, and no drug-drug interaction with fulvestrant. In phase Ia, one patient achieved partial response (PR), with a confirmed objective response rate (ORR) of 4.2% and a disease control rate (DCR) of 70.8%. In phase Ib, 42 patients achieved PR, with an ORR of 53.8% and a DCR of 87.2%.

Tibremciclib monotherapy or combined with fulvestrant was well tolerated with the RP2D set at 400 mg plus fulvestrant 500 mg. PK was consistent with dose proportionality. Both regimens showed preliminary antitumor activity in patients with HR-positive/HER2-negative ABC, supporting further evaluation in a phase III study (NCT05433480).