A Study to Evaluate the Efficacy and Safety of Vismodegib in Combination With Ruxolitinib for the Treatment of Intermediate- or High-Risk Myelofibrosis (MF)

Study Overview
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Brief Summary
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This multicenter, randomized, double-blind, placebo-controlled study will evaluate the efficacy and safety of vismodegib plus (+) ruxolitinib versus placebo + ruxolitinib in participants with intermediate- or high-risk MF. The study will be divided into 2 components. The Phase Ib portion of the study consists of participants receiving open-label vismodegib (150 milligrams [mg] orally [PO] once daily [QD]) + ruxolitinib (PO twice daily [BID]). A safety assessment will be performed after the first 10 participants have been treated for 6 weeks. An analysis for efficacy and safety is planned in the first 10 participants at Week 24. There will be a hold on participant screening and enrollment during this assessment. Another 10 participants may be enrolled, thereafter, to further assess efficacy and safety (at Week 24) before the initiation of the Phase III randomization portion of the study. Similarly, there will be another hold on participant screening and enrollment during this assessment. The participants enrolled in the Phase Ib portion of the study will continue to receive vismodegib (150 mg PO QD) + ruxolitinib (PO BID) for up to 48 weeks, if clinical benefit is observed after 24 weeks. The Phase III randomized, double-blind portion of the study will enroll approximately 84 participants. Participants will be randomly assigned in a 1:1 ratio (double blind) to receive either vismodegib (150 mg PO QD) + ruxolitinib (PO BID) or placebo (PO QD) + ruxolitinib (PO BID) for up to 48 weeks.

Official Title
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A Phase IB/III, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Vismodegib in Combination With Ruxolitinib Versus Placebo and Ruxolitinib in Patients With Intermediate- or High-Risk Myelofibrosis

Conditions
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Myelofibrosis

Intervention / Treatment
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* Other: Placebo
* Drug: Ruxolitinib
* Drug: Vismodegib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically confirmed diagnosis of primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF, according to the 2008 revised World Health Organization criteria Intermediate-1, intermediate-2, or high-risk according to the IWG-MRT Dynamic International Prognostic Scoring System Life expectancy >= 6 months Peripheral blood blast count of less than (<) 10% Palpable splenomegaly of greater than (>) 5 centimeters (cm) below the left costal margin Eastern Cooperative Oncology Group performance status of 0 to 2 Adequate hepatic and renal function Exclusion Criteria: Prior treatment with a Hedgehog or Janus kinase pathway inhibitor Treatment with strong cytochrome P450 3A4 inhibitors/inducers within 28 days prior to Day 1 Prior therapy for the treatment of intermediate- or high-risk MF including chemotherapy, interferon, thalidomide, busulfan, lenalidomide, anagrelide, or androgens within 28 days prior to Day 1 Prior splenectomy or splenic irradiation Inadequate bone marrow reserve Participants with any history of platelet counts of < 50,000/mccL or ANC of < 500/mL, except during treatment for myeloproliferative neoplasm or treatment with cytotoxic therapy for any other reason Planned allogeneic bone marrow transplant during the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Placebo + Ruxolitinib<br>Participants will receive placebo (PO QD) in combination with ruxolitinib (dose will depend on the participant's baseline platelet count) for up to 48 weeks. | Other: Placebo<br>* Placebo will be administered PO QD for up to 48 weeks.<br>Drug: Ruxolitinib<br>* Ruxolitinib will be administered PO BID at a starting dose depending on the participants's baseline platelet count for up to 48 weeks.<br>|
| Experimental: Vismodegib + Ruxolitinib<br>Participants will receive vismodegib (150 mg PO QD) in combination with ruxolitinib (dose will depend on the participant's baseline platelet count) for up to 48 weeks. | Drug: Ruxolitinib<br>* Ruxolitinib will be administered PO BID at a starting dose depending on the participants's baseline platelet count for up to 48 weeks.<br>Drug: Vismodegib<br>* Vismodegib will be administered at a dose of 150 mg PO QD for up to 48 weeks.<br>* Other names: Erivedge;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants who Achieve a Greater Than or Equal to (>=) 35% Reduction in Spleen Volume from Baseline at Week 24 | Determined by an Independent Review Committee (IRC) Using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Revised Response Criteria | Week 24 | 
| Percentage of Participants with Complete Remission (CR) and Partial Remission (PR) at Week 24, as Determined by an IRC Using IWG-MRT Revised Response Criteria |  | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Vismodegib Concentration at Steady State |  | Predose (0 hour) on Weeks 6, 12, 24, 36, and 48 | 
| Unbound Vismodegib Concentration at Steady State |  | Predose (0 hour) on Weeks 6, 12, 24, 36, and 48 | 
| Alpha 1-Acid Glycoprotein Concentration at Steady State |  | Predose (0 hour) on Weeks 6, 12, 24, 36, and 48 | 
| Percentage of Participants who Achieve a >= 35% Reduction in Spleen Volume from Baseline, as Determined by an IRC Using IWG-MRT Revised Response Criteria at Week 48 |  | Baseline, Week 48 | 
| Percentage of Participants who Achieve a >= 35% Reduction in Spleen Volume from Baseline, as Determined by an Investigator at Weeks 24 and 48 |  | Baseline, Weeks 24 and 48 | 
| Percentage of Participants with CR and PR, as Determined by an IRC Using IWG-MRT Revised Response Criteria at Week 48 |  | Week 48 | 
| Percentage of Participants with CR and PR, as Determined by an Investigator at Weeks 24 and 48 |  | Weeks 24 and 48 | 
| Percentage of Participants with Overall Response Rate (CR, PR, and Clinical Improvement) at Weeks 24 and 48, as Determined by an IRC Using IWG-MRT Revised Response Criteria |  | Weeks 24 and 48 | 
| Percentage of Participants with Overall Response Rate (CR, PR, and Clinical Improvement) at Weeks 24 and 48, as Determined by the Investigator Using IWG-MRT Revised Response Criteria |  | Weeks 24 and 48 | 
| Percentage of Participants who Achieve Anemia Response at Weeks 24 and 48, as Determined by the Investigator Using IWG-MRT Revised Response Criteria |  | Weeks 24 and 48 | 
| Percentage of Participants with Symptom Response (Participants who Achieve a >= 50% Reduction from Baseline in the Myeloproliferative Neoplasm Symptom Assessment Form [MPN-SAF] Total Symptom Score [TSS]) |  | Baseline, Weeks 24 and 48 | 
| Duration of Response, as Determined by the Investigator and an IRC Using IWG-MRT Revised Response Criteria or Death from Any Cause During the Study |  | Baseline up to 28 days after the last dose of study drug (52 weeks) | 
| Percentage of Participants with Improvement from Baseline in Bone Marrow Fibrosis at Weeks 24 and 48, as Determined by the Investigator Using the European Consensus Grading System |  | Baseline, Weeks 24 and 48 | 
| Percentage of Participants with Improvement from Baseline in Bone Marrow Fibrosis at Weeks 24 and 48, as Determined by Independent Pathology Review Using the European Consensus Grading System |  | Baseline, Weeks 24 and 48 | 
| Progression-Free Survival |  | Baseline up to the end of the study (up to 1 year after completing 48 weeks of treatment by the last participant) | 
| Percentage of Participants who Achieve a >= 50% Reduction in Fatigue from Baseline to Weeks 24 and 48 as Measured by MPN-SAF TSS |  | Baseline, Weeks 24 and 48 | 
| Percentage of Participants who Achieve a >= 50% Reduction in Other Symptom and Impact Item Scores from Baseline to Weeks 24 and 48, as Measured by the MPN-SAF |  | Baseline, Weeks 24 and 48 | 
| Percentage of Participants who Achieve a Meaningful Improvement on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Scale Scores from Baseline to Weeks 24 and 48 | Meaningful improvement is defined as a 10-point change. | Baseline, Weeks 24 and 48 | 
| Overall Survival |  | Baseline up to the end of the study (up to 1 year after completing 48 weeks treatment by the last participant) | 
| Percentage of Participants with Adverse Events (AEs) |  | Baseline up to Month 48 |