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

NCT02593760 | Completed Phase 1 DMC FDA Drug

• 2 other identifiers: WO298062015-001620-33
• Study Type: interventional
• Target: 10
• Locations: 4 countries
• Sites: 13

Brief 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.

Conditions

Myelofibrosis

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (20)

• 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

Study Arms (2)

Placebo + Ruxolitinib

ACTIVE COMPARATOR

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; Drug: Ruxolitinib

Vismodegib + Ruxolitinib

EXPERIMENTAL

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; Drug: Vismodegib

Interventions

Placebo OTHER

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

Placebo + Ruxolitinib

Ruxolitinib DRUG

Ruxolitinib will be administered PO BID at a starting dose depending on the participants's baseline platelet count for up to 48 weeks.

Placebo + Ruxolitinib; Vismodegib + Ruxolitinib

Vismodegib DRUG

Vismodegib will be administered at a dose of 150 mg PO QD for up to 48 weeks.

Also known as: Erivedge

Vismodegib + Ruxolitinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (13)

Florida Cancer Specialists-Broadway, Fort Myers

Fort Myers, Florida, 33908, United States

Location

Florida Cancer Specialist, North Region

St. Petersburg, Florida, 33705, United States

Location

Florida Cancer Specialists

West Palm Beach, Florida, 33401, United States

Location

Oncology Hematology Care Inc

Cincinnati, Ohio, 45242, United States

Location

Sarah Cannon Research Institute

Nashville, Tennessee, 37203, United States

Location

Uni of Texas - Md Anderson Cancer Center; Dept of Leukemia

Houston, Texas, 77030, United States

Location

Tom Baker Cancer Centre-Calgary; Clinical Research Unit

Calgary, Alberta, T2N 4N2, Canada

Location

Queen Elizabeth II Health Sciences Centre; Oncology

Halifax, Nova Scotia, B3H 2Y9, Canada

Location

Centre Hospitalier De L'Universite De Montreal, Hopital Notre-Dame

Montreal, Quebec, H2L 4M1, Canada

Location

Uniklinik RWTH Aachen; Med. Klinik IV; Klinik für Hämatologie, Onkologie, Hämostaseologie und Stammz

Aachen, 52074, Germany

Location

Campus Virchow-Klinikum Charité Centrum 14; Medizinische Klinik m.S. Hämatologie u. Onkologie

Berlin, 13353, Germany

Location

A.O.U. Citta' Della Salute E Della Scienza-P.O. Molinette;S.C. Ematologia

Turin, Piedmont, 10126, Italy

Location

Az. Osp. Di Careggi; Divisione Di Ematologia

Florence, Tuscany, 50135, Italy

Location

Related Publications (1)

• Couban S, Benevolo G, Donnellan W, Cultrera J, Koschmieder S, Verstovsek S, Hooper G, Hertig C, Tandon M, Dimier N, Malhi V, Passamonti F. A phase Ib study to assess the efficacy and safety of vismodegib in combination with ruxolitinib in patients with intermediate- or high-risk myelofibrosis. J Hematol Oncol. 2018 Sep 24;11(1):122. doi: 10.1186/s13045-018-0661-x.

  PMID: 30249277 DERIVED

MeSH Terms

Conditions

Primary Myelofibrosis

Interventions

ruxolitinib; HhAntag691

Condition Hierarchy (Ancestors)

Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 29, 2015
• First Posted: November 2, 2015
• Study Start: January 25, 2016
• Primary Completion: March 29, 2017
• Study Completion: July 12, 2017
• Last Updated: May 11, 2018

Record last verified: 2018-05

Locations

US (6); DE (2); CA (3); IT (2)