A phase I trial of pevonedistat in combination with ruxolitinib for the treatment of myelofibrosis

A phase I trial of pevonedistat in combination with ruxolitinib for the treatment of myelofibrosis

Janus kinase 2 (JAK2) inhibitors such as ruxolitinib have become standard-of-care therapy for patients with myeloproliferative neoplasms (MPNs); however, activation of alternate oncogenic pathways including nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) has limited durable res...

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Bibliographic Details
Published in:Therapeutic advances in hematology Vol. 15; p. 20406207241237607
Main Authors: Kong, Tim, Gaudin, Nicole, Gordon, Karyn, Cox, Maggie J, Zhou, Amy W, Oh, Stephen T
Format: Journal Article
Language:English
Published: England SAGE Publications 01-01-2024
SAGE Publishing
Subjects:
Brief Report
clinical trial
myeloproliferative neoplasms
NFκB
MLN4924
ruxolitinib
JAK2
pevonedistat
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Summary:Janus kinase 2 (JAK2) inhibitors such as ruxolitinib have become standard-of-care therapy for patients with myeloproliferative neoplasms (MPNs); however, activation of alternate oncogenic pathways including nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) has limited durable response as single-agent therapy. With the rationale of targeting both pathways, we conducted a phase I dose escalation trial of pevonedistat in combination with ruxolitinib for the treatment of patients with myelofibrosis (NCT03386214). The primary objective was to assess the safety and tolerability of combination therapy with additional objectives of treatment efficacy and alterations of biomarkers. There were no dose-limiting toxicities observed with most adverse events being limited to grades 1/2. In secondary measures, anemia response was observed in two patients. Pro-inflammatory cytokines and iron parameters were longitudinally assessed, which revealed suppression of interleukin-6 and interferon-gamma in a dose-dependent manner across a subset of patients. These results suggest that combination therapy targeting both JAK2 and NFκB may hold clinical merit for MPN patients.
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ISSN:2040-6207
2040-6215
DOI:10.1177/20406207241237607