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...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
SAGE Publishing
2024-03-01
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| Series: | Therapeutic Advances in Hematology |
| Online Access: | https://doi.org/10.1177/20406207241237607 |
| _version_ | 1797263303210172416 |
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| author | Tim Kong Nicole Gaudin Karyn Gordon Maggie J. Cox Amy W. Zhou Stephen T. Oh |
| author_facet | Tim Kong Nicole Gaudin Karyn Gordon Maggie J. Cox Amy W. Zhou Stephen T. Oh |
| author_sort | Tim Kong |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-25T00:10:52Z |
| format | Article |
| id | doaj.art-0a734db388e74aec9b92f27dfac3ac37 |
| institution | Directory Open Access Journal |
| issn | 2040-6215 |
| language | English |
| last_indexed | 2024-04-25T00:10:52Z |
| publishDate | 2024-03-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Therapeutic Advances in Hematology |
| spelling | doaj.art-0a734db388e74aec9b92f27dfac3ac372024-03-13T13:03:26ZengSAGE PublishingTherapeutic Advances in Hematology2040-62152024-03-011510.1177/20406207241237607A phase I trial of pevonedistat in combination with ruxolitinib for the treatment of myelofibrosisTim KongNicole GaudinKaryn GordonMaggie J. CoxAmy W. ZhouStephen T. OhJanus 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.https://doi.org/10.1177/20406207241237607 |
| spellingShingle | Tim Kong Nicole Gaudin Karyn Gordon Maggie J. Cox Amy W. Zhou Stephen T. Oh A phase I trial of pevonedistat in combination with ruxolitinib for the treatment of myelofibrosis Therapeutic Advances in Hematology |
| title | A phase I trial of pevonedistat in combination with ruxolitinib for the treatment of myelofibrosis |
| title_full | A phase I trial of pevonedistat in combination with ruxolitinib for the treatment of myelofibrosis |
| title_fullStr | A phase I trial of pevonedistat in combination with ruxolitinib for the treatment of myelofibrosis |
| title_full_unstemmed | A phase I trial of pevonedistat in combination with ruxolitinib for the treatment of myelofibrosis |
| title_short | A phase I trial of pevonedistat in combination with ruxolitinib for the treatment of myelofibrosis |
| title_sort | phase i trial of pevonedistat in combination with ruxolitinib for the treatment of myelofibrosis |
| url | https://doi.org/10.1177/20406207241237607 |
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