Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research			2021 Jul 22	5236-5247	Clin Cancer Res

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	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	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
MDM2 amp TP53 wild-type	Advanced Solid Tumor	predicted - sensitive	ALRN-6924	Phase I	Actionable	In a Phase I trial, treatment with ALRN-6924 resulted in a disease control rate of 71% (5/7) in advanced solid tumors patients with wild-type TP53 and MDM2 amplification (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
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	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	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