Background: Salivary gland carcinoma is a rare tumor that accounts for 6% of all head and neck cancers. This histologically and anatomically heterogeneous malignant tumor type is largely resistant to platinum and other chemotherapies but commonly has wild-type TP53 based on next-generation sequencing analysis. Alrizomadlin is a novel, orally active, small molecular agent that binds to MDM2, restoring p53 tumor suppressor function and inducing apoptosis in tumor cells retaining wild-type p53. Preliminary clinical evidence suggests promising antitumor activity and a favorable safety profile for alrizomadlin in the treatment of solid tumors (Rasco 2019). Methods: This US multicenter open-label trial is evaluating alrizomadlin with or without platinum chemotherapy in adults with histologically documented wild-type TP53 salivary gland carcinoma, including primary or metastatic lesions, an ECOG performance status 0-1, and a life expectancy of at least 12 weeks. In addition, subjects need to have measurable disease by computed tomography according to RECIST v1.1, with radiographic disease progression within the prior 12 months, high-grade status with or without metastases, and/or not amenable to curative treatment. An initial randomized phase (Part 1) will be followed by a single-arm phase (Part 2). Treatment arms include a cycle length of 21 days, and the study is using a time-to-event continual reassessment method. In Part 1 (42 patient target), patients are randomly allocated (in a 1:2 ratio) to one of two arms: single-agent alrizomadlin at a starting dose of 150 mg (Arm A) or at a starting dose of 150 mg with concomitant IV carboplatin administered at starting AUC = 4.5 (Arm B). Based on overall response rate (ORR; complete or partial response after Cycle 2) and safety profile, the most promising treatment arm will be advanced to Part 2, which has a target enrollment of 20 patients. Study endpoints are (1) dose-limiting toxicity (DLT), which is defined by the rate of drug-related grade ≥ 3 adverse events (by NCI CTCAE v5.0) over the first 2 cycles (6 weeks) of study treatment; (2) maximum tolerated dose based on these DLTs; and (3) ORR by RECIST v1.1 observed at up to 12 months. As of January 27, 2021, 11 of 42 patients had been enrolled in Part 1. Internal study identifier APG-115SG101. Clinical trial registration: NCT03781986. Clinical trial information: NCT03781986