A phase Ib study to assess the efficacy and safety of vismodegib in combination with ruxolitinib in patients with intermediate- or high-risk myelofibrosis

Stephen Couban, Giulia Benevolo, William Donnellan, Jennifer Cultrera, Steffen Koschmieder, Srdan Verstovsek, Gregory Hooper, Christian Hertig, Maneesh Tandon, Natalie Dimier, Vikram Malhi, Francesco Passamonti, Stephen Couban, Giulia Benevolo, William Donnellan, Jennifer Cultrera, Steffen Koschmieder, Srdan Verstovsek, Gregory Hooper, Christian Hertig, Maneesh Tandon, Natalie Dimier, Vikram Malhi, Francesco Passamonti

Abstract

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.

Keywords: Hedgehog pathway inhibitor; Hematologic malignances; Hematopoiesis; Myelofibrosis; Ruxolitinib; Vismodegib.

Conflict of interest statement

Ethics approval and consent to participate

This study was conducted in full conformance with the ICH E6 Guideline for Good Clinical Practice and the principles of the Declaration of Helsinki. It was approved by the institutional review boards or ethics committees of the study sites.

Consent for publication

Not applicable.

Competing interests

GH, CH, MT, and ND are employees of F. Hoffman-La Roche Ltd., and ND holds stock in F. Hoffman-La Roche Ltd. VM is an employee of Roche-Genentech, Ltd. SK reports receiving honoraria for advisory board participation, travel expenses, and research funding by Novartis, in addition to the funding of this study by F. Hoffmann-LaRoche Ltd. JC, SC, GB, WD, SV, and FP declare that they have no competing interests other than the funding of this study by F. Hoffmann-LaRoche Ltd.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Spleen volume change from baseline per central and investigator review (a) and symptom response change (b) at week 24, by patient. Threshold for clinical efficacy at 35% reduction in spleen volume and 50% reduction in the MPN-SAF TSS is indicated by the dotted line. Spleen volume was assessed by CT or MRI, both by a local radiologist and a central independent review committee. Symptom score data were not available for three patients, including the patient who discontinued early. CT computed tomography; MPN-SAF TSS Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score; MRI magnetic resonance imaging

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