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

Myelofibrosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02593760
• Other study ID #: WO29806
• Secondary ID: 2015-001620-33
• Status: Completed
• Phase: Phase 1
• Start date: January 25, 2016
• Est. completion date: July 12, 2017

Study information

• Verified date: May 2018
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: July 12, 2017
• Est. primary completion date: March 29, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Myelofibrosis
• Primary Myelofibrosis

Intervention

Other:
• Placebo
Placebo will be administered PO QD for up to 48 weeks.

Drug:
• Ruxolitinib
Ruxolitinib will be administered PO BID at a starting dose depending on the participants's baseline platelet count for up to 48 weeks.
• Vismodegib
Vismodegib will be administered at a dose of 150 mg PO QD for up to 48 weeks.

Locations

Country	Name	City	State
Canada	Tom Baker Cancer Centre-Calgary; Clinical Research Unit	Calgary	Alberta
Canada	Queen Elizabeth II Health Sciences Centre; Oncology	Halifax	Nova Scotia
Canada	Centre Hospitalier De L'Universite De Montreal, Hopital Notre-Dame	Montreal	Quebec
Germany	Uniklinik RWTH Aachen; Med. Klinik IV; Klinik für Hämatologie, Onkologie, Hämostaseologie und Stammz	Aachen
Germany	Campus Virchow-Klinikum Charité Centrum 14; Medizinische Klinik m.S. Hämatologie u. Onkologie	Berlin
Italy	Az. Osp. Di Careggi; Divisione Di Ematologia	Firenze	Toscana
Italy	A.O.U. Citta' Della Salute E Della Scienza-P.O. Molinette;S.C. Ematologia	Torino	Piemonte
United States	Oncology Hematology Care Inc	Cincinnati	Ohio
United States	Florida Cancer Specialists-Broadway, Fort Myers	Fort Myers	Florida
United States	Uni of Texas - Md Anderson Cancer Center; Dept of Leukemia	Houston	Texas
United States	Sarah Cannon Research Institute	Nashville	Tennessee
United States	Florida Cancer Specialist, North Region	Saint Petersburg	Florida
United States	Florida Cancer Specialists	West Palm Beach	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Canada,  Germany,  Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	Plasma Vismodegib Concentration at Steady State		Predose (0 hour) on Weeks 6, 12, 24, 36, and 48
Secondary	Unbound Vismodegib Concentration at Steady State		Predose (0 hour) on Weeks 6, 12, 24, 36, and 48
Secondary	Alpha 1-Acid Glycoprotein Concentration at Steady State		Predose (0 hour) on Weeks 6, 12, 24, 36, and 48
Secondary	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
Secondary	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
Secondary	Percentage of Participants with CR and PR, as Determined by an IRC Using IWG-MRT Revised Response Criteria at Week 48		Week 48
Secondary	Percentage of Participants with CR and PR, as Determined by an Investigator at Weeks 24 and 48		Weeks 24 and 48
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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
Secondary	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
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	Overall Survival		Baseline up to the end of the study (up to 1 year after completing 48 weeks treatment by the last participant)
Secondary	Percentage of Participants with Adverse Events (AEs)		Baseline up to Month 48