Clinical trial NCT02593760: A Study to Evaluate the Efficacy and Safety of Vismodegib in Combination With Ruxolitinib for the Treatment of Intermediate- or High-Risk Myelofibrosis (MF)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Myelofibrosis
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2015-11-01
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Percentage of Participants who Achieve a Greater Than or Equal to (>=) 35% Reduction in Spleen Volume from Baseline at Week 24
timeFrame: Week 24
measure: 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
timeFrame: Week 24
Secondary outcomes:
measure: Plasma Vismodegib Concentration at Steady State
timeFrame: Predose (0 hour) on Weeks 6, 12, 24, 36, and 48
measure: Unbound Vismodegib Concentration at Steady State
timeFrame: Predose (0 hour) on Weeks 6, 12, 24, 36, and 48
measure: Alpha 1-Acid Glycoprotein Concentration at Steady State
timeFrame: Predose (0 hour) on Weeks 6, 12, 24, 36, and 48
measure: 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
timeFrame: Baseline, Week 48
measure: Percentage of Participants who Achieve a >= 35% Reduction in Spleen Volume from Baseline, as Determined by an Investigator at Weeks 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: Percentage of Participants with CR and PR, as Determined by an IRC Using IWG-MRT Revised Response Criteria at Week 48
timeFrame: Week 48
measure: Percentage of Participants with CR and PR, as Determined by an Investigator at Weeks 24 and 48
timeFrame: Weeks 24 and 48
measure: 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
timeFrame: Weeks 24 and 48
measure: 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
timeFrame: Weeks 24 and 48
measure: Percentage of Participants who Achieve Anemia Response at Weeks 24 and 48, as Determined by the Investigator Using IWG-MRT Revised Response Criteria
timeFrame: Weeks 24 and 48
measure: 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])
timeFrame: Baseline, Weeks 24 and 48
measure: 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
timeFrame: Baseline up to 28 days after the last dose of study drug (52 weeks)
measure: 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
timeFrame: Baseline, Weeks 24 and 48
measure: 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
timeFrame: Baseline, Weeks 24 and 48
measure: Progression-Free Survival
timeFrame: Baseline up to the end of the study (up to 1 year after completing 48 weeks of treatment by the last participant)
measure: Percentage of Participants who Achieve a >= 50% Reduction in Fatigue from Baseline to Weeks 24 and 48 as Measured by MPN-SAF TSS
timeFrame: Baseline, Weeks 24 and 48
measure: 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
timeFrame: Baseline, Weeks 24 and 48
measure: 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
timeFrame: Baseline, Weeks 24 and 48
measure: Overall Survival
timeFrame: Baseline up to the end of the study (up to 1 year after completing 48 weeks treatment by the last participant)
measure: Percentage of Participants with Adverse Events (AEs)
timeFrame: Baseline up to Month 48
Other outcomes:
Locations:
city: Fort Myers
country: United States
facility: Florida Cancer Specialists-Broadway, Fort Myers
state: Florida
city: Saint Petersburg
country: United States
facility: Florida Cancer Specialist, North Region
state: Florida
city: West Palm Beach
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Cincinnati
country: United States
facility: Oncology Hematology Care Inc
state: Ohio
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Houston
country: United States
facility: Uni of Texas - Md Anderson Cancer Center; Dept of Leukemia
state: Texas
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre-Calgary; Clinical Research Unit
state: Alberta
city: Halifax
country: Canada
facility: Queen Elizabeth II Health Sciences Centre; Oncology
state: Nova Scotia
city: Montreal
country: Canada
facility: Centre Hospitalier De L'Universite De Montreal, Hopital Notre-Dame
state: Quebec
city: Aachen
country: Germany
facility: Uniklinik RWTH Aachen; Med. Klinik IV; Klinik für Hämatologie, Onkologie, Hämostaseologie und Stammz
city: Berlin
country: Germany
facility: Campus Virchow-Klinikum Charité Centrum 14; Medizinische Klinik m.S. Hämatologie u. Onkologie
city: Torino
country: Italy
facility: A.O.U. Citta' Della Salute E Della Scienza-P.O. Molinette;S.C. Ematologia
state: Piemonte
city: Firenze
country: Italy
facility: Az. Osp. Di Careggi; Divisione Di Ematologia
state: Toscana
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.