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Ref Type Journal Article
PMID (34301750)
Authors Saleh MN, Patel MR, Bauer TM, Goel S, Falchook GS, Shapiro GI, Chung KY, Infante JR, Conry RM, Rabinowits G, Hong DS, Wang JS, Steidl U, Naik G, Guerlavais V, Vukovic V, Annis DA, Aivado M, Meric-Bernstam F
Title Phase 1 Trial of ALRN-6924, a Dual Inhibitor of MDMX and MDM2, in Patients with Solid Tumors and Lymphomas Bearing Wild-Type TP53.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol
Issue
Date 2021 Jul 22
URL
Abstract Text We describe the first-in-human dose-escalation trial for ALRN-6924, a stabilized, cell-permeating peptide that disrupts p53 inhibition by MDM2 and MDMX to induce cell cycle arrest or apoptosis in TP53 wild-type tumors.Two schedules were evaluated for safety, pharmacokinetics, pharmacodynamics, and anti-tumor effects in patients with solid tumors or lymphomas: In arm A, patients received ALRN-6924 by intravenous infusion once-weekly for 3 weeks every 28 days; arm B, was twice-weekly for 2 weeks every 21 days.Seventy-one patients were enrolled: 41 in arm A (0.16-4.4 mg/kg), 30 in arm B (0.32-2.7 mg/kg). ALRN-6924 showed dose-dependent pharmacokinetics and increased serum levels of MIC-1, a biomarker of p53 activation. The most frequent treatment-related adverse events were gastrointestinal side effects, fatigue, anemia, and headache. In arm A, at 4.4 mg/kg, dose-limiting toxicities (DLTs) were Grade 3 (G3) hypotension, G3 alkaline phosphatase elevation, G3 anemia, and G4 neutropenia in one patient each. At the maximum tolerated dose in arm A of 3.1 mg/kg, G3 fatigue was observed in one patient. No DLTs were observed in arm B. No G3/G4 thrombocytopenia was observed in any patient. Seven patients had infusion-related reactions; three discontinued treatment. In 41 efficacy-evaluable patients with TP53 wild-type disease across both schedules the disease control rate was 59%. Two patients had confirmed complete responses, two had confirmed partial responses, 20 had stable disease. Six patients were treated for >1 year. The recommended phase 2 dose was schedule A, 3.1 mg/kg.ALRN-6924 was well tolerated and demonstrated anti-tumor activity.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
TP53 wild-type Advanced Solid Tumor predicted - sensitive ALRN-6924 Phase I Actionable In a Phase I trial, treatment with ALRN-6924 in patients with advanced solid tumors and lymphomas resulted in a disease control rate of 59% (24/41), with 2 patients experiencing a complete response, 2 patients achieving a partial response, and 20 patients demonstrating stable disease (PMID: 34301750; NCT02264613). 34301750
TP53 wild-type colorectal cancer predicted - sensitive ALRN-6924 Case Reports/Case Series Actionable In a Phase I trial, ALRN-6924 treatment resulted in a partial response in a patient with colorectal cancer (PMID: 34301750; NCT02264613). 34301750
TP53 wild-type peripheral T-cell lymphoma predicted - sensitive ALRN-6924 Case Reports/Case Series Actionable In a Phase I trial, ALRN-6924 treatment in a patient with peripheral T-cell lymphoma resulted in a complete response (PMID: 34301750; NCT02264613). 34301750
TP53 wild-type Merkel cell carcinoma predicted - sensitive ALRN-6924 Case Reports/Case Series Actionable In a Phase I trial, ALRN-6924 treatment in a patient with Merkel cell carcinoma resulted in a complete response (PMID: 34301750; NCT02264613). 34301750
TP53 wild-type liposarcoma predicted - sensitive ALRN-6924 Case Reports/Case Series Actionable In a Phase I trial, ALRN-6924 treatment resulted in a partial response in a patient with liposarcoma (PMID: 34301750; NCT02264613). 34301750
TP53 wild-type lymphoma predicted - sensitive ALRN-6924 Phase I Actionable In a Phase I trial, treatment with ALRN-6924 in patients with advanced solid tumors and lymphomas resulted in a disease control rate of 59% (24/41), with 2 patients experiencing a complete response, 2 patients achieving a partial response, and 20 patients demonstrating stable disease (PMID: 34301750; NCT02264613). 34301750