Phase 1b Results of a Study to Assess the Efficacy and Safety of Vismodegib in Combination with Ruxolitinib in Patients with Intermediate- or High-Risk Myelofibrosis

Background: The JAK inhibitor (JAKi) ruxolitinib is approved for treatment of myelofibrosis (MF). Treatment for 5 years or more may be necessary to improve or stabilize bone marrow fibrosis, and a fraction of patients do not respond to ruxolitinib. The Hedgehog signaling pathway is involved in primitive and definitive bone marrow hematopoiesis, and maintenance of hematopoietic precursors, suggesting that addition of a Hedgehog pathway inhibitor (HPI) to ruxolitinib might improve responses. In a murine model of MF, a combination of a JAKi and HPI reduced fibrosis in the bone marrow and spleen and decreased splenomegaly. Vismodegib is a HPI approved for treatment of locally advanced and metastatic basal cell carcinoma. The MYLIE study aimed to assess the safety and efficacy of combined ruxolitinib and vismodegib for the treatment of MF. The pharmacokinetics (PK) of vismodegib were characterized in patients with intermediate or high-risk MF.

Methods: In this phase 1b study, 10 patients with intermediate- or high-risk MF (per Dynamic International Prognostic Scoring System) 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. PK sampling was designed to characterize the PK of total and unbound vismodegib in this study for comparison with PK data collected in other patient populations. Efficacy outcomes assessed for phase 1b included spleen response (≥35% reduction in volume by computed tomography or magnetic resonance imaging) per central and investigator assessment, improvement in bone marrow fibrosis per central and investigator assessment (using European consensus grading system), symptom response (≥50% reduction in Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score [MPN-SAF TSS]) and anemia response (per International Working Group for Myeloproliferative Neoplasms Research and Treatment [IWG-MRT] revised response criteria). We report results from the planned analysis of the phase 1b study for efficacy and safety at week 24.

Results: Six patients with primary MF, 1 with post-polycythemia vera MF and 3 with post-essential thrombocythemia MF were treated with vismodegib and ruxolitinib for a median of 294.0 days. As of the interim analysis data cutoff (March 29, 2017), 4 patients had completed 48 weeks of study treatment with ruxolitinib and vismodegib, 5 patients were still receiving treatment, and 1 had discontinued treatment because of a vismodegib-related adverse event (AE) (dysgeusia). The most common AEs were muscle spasm (100% of patients), dysgeusia (50%), alopecia (50%), thrombocytopenia (50%), and nausea (40%). All were grade 1/2, except for 2 instances of grade 3 thrombocytopenia in 2 patients. Three patients experienced serious AEs: infection (3 patients), lung infiltration (1 patient), and vomiting (1 patient); none were considered by the investigators to be related to vismodegib. Because of AEs, 7 patients modified or interrupted their ruxolitinib dose, and 4 patients interrupted their vismodegib dose. At week 24, three patients achieved a ≥35% reduction in spleen volume (including the patient who discontinued early because the assessment occurred within the week 24 visit window) by central review (a spleen response occurred in 1 patient per the investigator assessment). According to the central reviews, no patients had improvement in bone marrow fibrosis (1 patient had improvement in bone marrow fibrosis per investigator assessment). Five patients experienced symptom response, and no patients experienced an anemia response. A further central review of bone marrow biopsy specimens from 5 patients at week 48 continued to show no improvement in fibrosis.

Conclusions: There was no clear benefit of the addition of vismodegib to ruxolitinib in any of the phase 1b efficacy outcome measures assessed. Given the lack of evidence of a disease-modifying effect with addition of vismodegib to ruxolitinib, further evaluation of this combination will not be pursued.

Source of funding: F. Hoffmann-La Roche