TY - JOUR
T1 - A phase Ib study to assess the efficacy and safety of vismodegib in combination with ruxolitinib in patients with intermediate- or high-risk myelofibrosis 11 Medical and Health Sciences 1103 Clinical Sciences 11 Medical and Health Sciences 1102 Cardiorespiratory Medicine and Haematology
AU - Couban, Stephen
AU - Benevolo, Giulia
AU - Donnellan, William
AU - Cultrera, Jennifer
AU - Koschmieder, Steffen
AU - Verstovsek, Srdan
AU - Hooper, Gregory
AU - Hertig, Christian
AU - Tandon, Maneesh
AU - Dimier, Natalie
AU - Malhi, Vikram
AU - Passamonti, Francesco
N1 - Funding Information:
This study was funded by F. Hoffmann-La Roche Ltd. The trial was designed by the sponsor (F. Hoffmann-La Roche Ltd). Data were collected by the site investigators and were retained and analyzed by the sponsor (F. Hoffmann-La Roche Ltd). All authors had full access to the data. FP was supported by grants of the Fondazione Regionale Ricerca Biomedica, Milan, Italy [FRRB project no. 2015-0042: genomic profiling of rare hematologic malignancies, development of personalized medicine strategies, and their implementation into the Rete Ematologica Lombarda (REL) clinical network].
Funding Information:
Third-party medical writing support was provided by Lucy Smithers, PhD (ApotheCom, London, UK) and was funded by F. Hoffmann-La Roche Ltd. The authors thank the participating investigators and patients.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/9/24
Y1 - 2018/9/24
N2 - Background: The JAK inhibitor (JAKi) ruxolitinib is standard treatment for myelofibrosis (MF), but some patients are unresponsive. Pre-clinical and clinical data suggest that addition of a Hedgehog pathway inhibitor (HPI) to ruxolitinib might improve response. Vismodegib is an HPI approved for treatment of locally advanced and metastatic basal cell carcinoma. The MYLIE study assessed the safety and efficacy of combining ruxolitinib with vismodegib in ruxolitinib-naive patients with MF and characterized the pharmacokinetics (PK) of vismodegib in this setting. Methods: In this phase Ib study, ten patients with intermediate- or high-risk primary or secondary MF received open-label vismodegib (150 mg/day orally) and ruxolitinib (15 or 20 mg orally twice daily, depending on baseline platelet count) for up to 48 weeks, or until withdrawal or discontinuation. PK samples were collected throughout the study for comparison with other patient populations. Efficacy outcomes at week 24 included spleen response (≥ 35% reduction in volume by imaging) and improvement in bone marrow fibrosis by central and investigator assessment, symptom response (≥ 50% reduction in Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom score), and anemia response (per International Working Group for Myeloproliferative Neoplasms Research and Treatment revised response criteria). Results: As of November 17, 2017, eight patients had completed 48 weeks of treatment with vismodegib and ruxolitinib; two discontinued treatment early. At week 24 (± 1 week), three patients experienced a spleen response by central review and no patients showed a 1-grade improvement in bone marrow fibrosis by central review. Five patients experienced symptom response at week 24, and no patients experienced an anemia response. The most common adverse events were muscle spasm (100% of patients), alopecia (70%), dysgeusia (50%), thrombocytopenia (50%), and nausea (40%); these events were predominantly grade 1/2. Three patients experienced a total of six serious adverse events. Conclusions: The combination of vismodegib and ruxolitinib was tolerable and no new safety signals were seen, but there was no evidence that the addition of vismodegib to ruxolitinib improved any of the efficacy outcome measures assessed. Further evaluation of this combination will not be pursued. Trial registration: ClinicalTrials.gov, NCT02593760. Registered November 2, 2015.
AB - Background: The JAK inhibitor (JAKi) ruxolitinib is standard treatment for myelofibrosis (MF), but some patients are unresponsive. Pre-clinical and clinical data suggest that addition of a Hedgehog pathway inhibitor (HPI) to ruxolitinib might improve response. Vismodegib is an HPI approved for treatment of locally advanced and metastatic basal cell carcinoma. The MYLIE study assessed the safety and efficacy of combining ruxolitinib with vismodegib in ruxolitinib-naive patients with MF and characterized the pharmacokinetics (PK) of vismodegib in this setting. Methods: In this phase Ib study, ten patients with intermediate- or high-risk primary or secondary MF received open-label vismodegib (150 mg/day orally) and ruxolitinib (15 or 20 mg orally twice daily, depending on baseline platelet count) for up to 48 weeks, or until withdrawal or discontinuation. PK samples were collected throughout the study for comparison with other patient populations. Efficacy outcomes at week 24 included spleen response (≥ 35% reduction in volume by imaging) and improvement in bone marrow fibrosis by central and investigator assessment, symptom response (≥ 50% reduction in Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom score), and anemia response (per International Working Group for Myeloproliferative Neoplasms Research and Treatment revised response criteria). Results: As of November 17, 2017, eight patients had completed 48 weeks of treatment with vismodegib and ruxolitinib; two discontinued treatment early. At week 24 (± 1 week), three patients experienced a spleen response by central review and no patients showed a 1-grade improvement in bone marrow fibrosis by central review. Five patients experienced symptom response at week 24, and no patients experienced an anemia response. The most common adverse events were muscle spasm (100% of patients), alopecia (70%), dysgeusia (50%), thrombocytopenia (50%), and nausea (40%); these events were predominantly grade 1/2. Three patients experienced a total of six serious adverse events. Conclusions: The combination of vismodegib and ruxolitinib was tolerable and no new safety signals were seen, but there was no evidence that the addition of vismodegib to ruxolitinib improved any of the efficacy outcome measures assessed. Further evaluation of this combination will not be pursued. Trial registration: ClinicalTrials.gov, NCT02593760. Registered November 2, 2015.
KW - Hedgehog pathway inhibitor
KW - Hematologic malignances
KW - Hematopoiesis
KW - Myelofibrosis
KW - Ruxolitinib
KW - Vismodegib
UR - http://www.scopus.com/inward/record.url?scp=85053820642&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85053820642&partnerID=8YFLogxK
U2 - 10.1186/s13045-018-0661-x
DO - 10.1186/s13045-018-0661-x
M3 - Article
C2 - 30249277
AN - SCOPUS:85053820642
SN - 1756-8722
VL - 11
JO - Journal of Hematology and Oncology
JF - Journal of Hematology and Oncology
IS - 1
M1 - 122
ER -