A phase I dose-escalation study of the MDM2-p53 antagonist BI 907828 in patients (pts) with advanced solid tumors.

3016 Background: BI 907828, a highly potent and orally administered MDM2-p53 antagonist, showed antitumor efficacy in vivo, especially in TP53 wild-type MDM2-amplified de-differentiated liposarcoma (DDLPS) patient-derived xenografts and syngeneic models. Methods: NCT03449381 is a phase I study of BI 907828 in pts with solid tumors. The objectives of the dose-escalation part were to determine the maximum tolerated dose (MTD) based on the frequency of pts with dose-limiting toxicities (DLTs) during cycle 1, determine the recommended dose for expansion, and evaluate the safety and tolerability of two dosing schedules: BI 907828 given on day 1 of 21-day cycles (Arm A) or days 1 and 8 of 28-day cycles (Arm B). Dose escalation was guided by a Bayesian logistic regression model. The secondary objectives include pharmacokinetics (PK), pharmacodynamics and antitumor activity. Results: At January 15, 2021, 54 pts with advanced solid tumors (median of 2 lines of prior systemic therapies; range 0–11) were treated with BI 907828 (Arm A, 29 pts, dose range 10–80 mg; Arm B, 25 pts, dose range 5–60 mg). In Arm A, 5 pts experienced DLTs in cycle 1, including one Grade (Gr) 3 Nausea and one Gr 3 Thrombocytopenia at 45 mg, one Gr 3 Enterocolitis at 60 mg, and one Gr 4 Neutropenia and one Gr 4 Thrombocytopenia at 80 mg. In Arm B, 3 DLTs were reported: one Gr 4 Thrombocytopenia at 45 mg, one Gr 4 Neutropenia associated with Gr 4 Thrombocytopenia, and one Gr 3 Neutropenia at 60 mg. The most common Gr 3/4 treatment-related adverse events (AEs) were Thrombocytopenia (28.6%), Neutropenia (10.7%) and Nausea (10.7%) in Arm A, and Thrombocytopenia (16.6%) and Neutropenia (12.5%) in Arm B. Preliminary PK data indicate that BI 907828 reaches Tmax at 4–6 h. Mean plasma exposures (Cmax and AUC0-inf) increased with dose. The geometric mean (gMean) Clearance/F was 5–19 mL/min and the gMean apparent volume of distribution was 23–57 L. The gMean half-lives estimated after the 1st dose were 26–55 h. Inter-patient variability in exposure was moderate. An increase in the target engagement biomarker GDF-15 in plasma was observed. The mean fold-change from baseline ranged from 8 to 49. Antitumor activity was seen in both schedules. In Arm A, a confirmed PR was seen in 2 pts with MDM2-amplified LPS (one PR lasted > 2 years) and SD in 17 pts. In Arm B, 2 pts had PR (one confirmed in MDM2-amplified LPS and one not yet confirmed in MDM2-amplified pancreatic adenocarcinoma) and 14 had SD. Of note, 5 of 10 pts with DDLPS were progression-free for ≥9 months. Conclusions: BI 907828 showed a manageable safety profile, favorable PK properties and early signs of efficacy, especially in MDM2-amplified tumors. With both dosing regimens, DLTs were Neutropenia and Thrombocytopenia. Non-hematologic AEs, mainly gastrointestinal, were mostly low-grade and not dose-limiting. The MTD of 60 mg in Arm A (day 1 of 21-day cycles) and 45 mg in Arm B (days 1 and 8 of 28-day cycles) are awaiting confirmation. Clinical trial information: NCT03449381.

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