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MDM2 Inhibition with Alrizomadlin (APG-115) in TP53 wild-type salivary gland cancers: a phase I clinical trial
Alexander T Pearson1,2, Jameel Muzaffar3, Kedar Kirtane3
1University of Chicago Cancer Center, Chicago, IL, USA.
Abstract:
Preclinical studies have evaluated murine double minue 2 (MDM2) inhibitors as a treatment for adenoid cystic carcinoma (ACC), but clinical trials are lacking. This phase I trial (NCT03781986) assesses the safety and antitumor activity of an oral MDM2 inhibitor, alrizomadlin (APG-115), +/- carboplatin in TP53 wild type unresectable recurrent/metastatic salivary gland cancers (R/M SGC) with a planned 1:1 randomization to carboplatin chemotherapy. The co-primary endpoints are determination of dose-limiting toxicity (DLT) and response rate (RR) for alrizomadlin monotherapy +/- carboplatin. Secondary endpoints include safety, survival, and RR by tumor histology. After enrollment of 4 patients to combination therapy, the trial was modified to a single arm study of alrizomadlin monotherapy due to excess toxicity. 1 DLT was seen in the combination arm, all patients had ≥ G3 treatment related adverse events (TRAE). 37 patients were enrolled to alrizomadlin monotherapy. 3 DLTs were encountered, 67% of patients had ≥ G3 TRAE. The RR was 15% with median progression free survival 10.5 months. These findings demonstrate encouraging tolerability of alrizomadlin monotherapy with antitumor activity in patients with TP53 wild type SGC, especially ACC.
Insights
This Phase I trial investigated alrizomadlin, a murine double minute 2 (MDM2) inhibitor, for salivary gland cancers. Alrizomadlin monotherapy showed tolerable safety and antitumor activity in patients with TP53 wild type tumors.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Adenoid cystic carcinoma (ACC) and other salivary gland cancers (SGC) often harbor wild-type TP53, making them potential candidates for MDM2 inhibition.
- Preclinical data suggested MDM2 inhibitors could be effective against SGC, but clinical evidence was lacking.
Purpose of the Study:
- To assess the safety and antitumor activity of alrizomadlin, an oral MDM2 inhibitor, in patients with unresectable recurrent/metastatic TP53 wild-type SGC.
- To determine dose-limiting toxicity (DLT) and response rate (RR) for alrizomadlin monotherapy and in combination with carboplatin.
Main Methods:
- A Phase I clinical trial (NCT03781986) initially planned a 1:1 randomization to alrizomadlin +/- carboplatin.
- The trial was modified to a single-arm study of alrizomadlin monotherapy due to excess toxicity in the combination arm.
- Co-primary endpoints were DLT and RR; secondary endpoints included safety and survival.
Main Results:
- The combination arm was stopped early due to excess toxicity (1 DLT, all patients experienced Grade ≥3 TRAEs).
- In the alrizomadlin monotherapy arm (37 patients), 3 DLTs were observed, and 67% experienced Grade ≥3 TRAEs.
- The overall response rate (RR) for alrizomadlin monotherapy was 15%, with a median progression-free survival of 10.5 months.
Conclusions:
- Alrizomadlin monotherapy demonstrated encouraging tolerability and antitumor activity in patients with TP53 wild-type SGC, particularly ACC.
- These findings support further investigation of alrizomadlin as a monotherapy for this patient population.
