Sympathicomimetic Agonist in Patients With Myeloproliferative Neoplasms With JAK2-mutation

NCT02311569 | Completed Phase 2

• 1 other identifier: SAKK 33/14
• Study Type: interventional
• Target: 39
• Locations: 1 country
• Sites: 11

Brief Summary

The aim of this phase II study is to test a novel concept in the treatment of patients with myeloproliferative neoplasms (MPN), a disease of the bone marrow. With no current cure available, MPN are a group of chronic leukemias (blood cancers) in which patients produce too many blood cells. These increased blood cell numbers cause problems to the patient such as bleedings or thrombosis and some patients may progress to acute leukemia, a life threatening condition. Most MPN patients have a gene mutation called JAK2-V617F. The disease is maintained by mutant MPN stem cells that reside in the bone marrow in specialized locations called "niches". These niches need connections to the nervous system. New findings show that these connections are destroyed by the presence of the mutated MPN stem cells. Research teams found that some drugs (beta3-sympathicomimetics) can restore these damaged niches and at the same time reduce the MPN disease manifestation in a mouse model of MPN. Such sympathicomimetic drugs are already being used to treat patients with asthma or hyperactive bladder. These drugs have shown to have only few side effects. The study tests the effects of the beta-3-sympathicomimetic drug Mirabegron (Betmiga®) on MPN disease in 39 patients that carry a JAK2-V617F mutation. The hypothesis is that Mirabegron will have a beneficial effect on bone marrow niche cells and will thereby improve the disease manifestation in MPN patients. This study should provide a rapid answer whether targeting the nervous system of the niche cells could be useful for patients with MPN and warrants to be tested in larger and more long-term studies.

Conditions

Myeloproliferative Neoplasm; Primary Myelofibrosis; Essential Thrombocythemia; Polycythemia Vera

Keywords

JAK2; Mirabegron; Primary myelofibrosis; beta-3-mimetic drugs; Myeloproliferative neoplasm; Essential thrombocythemia; Polycythemia vera; Betmiga; JAK2-V617F

Outcome Measures

Primary Outcomes (1)

• Reduction in the burden of mutated alleles of ≥50% at 24 weeks.

  Primary endpoint of the trial is reduction in the burden of mutated alleles of ≥50% at 24 weeks (Red-50@24). Patients are defined as success for this endpoint, if they show a reduction of the JAK2-V617F allelic burden of 50% or more 24 weeks ± 4 weeks after registration when compared to baseline, and if they did not start a new MPN treatment before. All other evaluable patients will be considered as failures for this endpoint.

  at 24 weeks

Secondary Outcomes (3)

• Reduction in the burden of mutated alleles of ≥50%

  at 12 weeks

• Reduction in the burden of mutated alleles of ≥25%

  at 24 weeks

• Reduction in the burden of mutated alleles of ≥25%

  at 12 weeks

Study Arms (1)

Arm Mirabegron

EXPERIMENTAL

Mirabegron treatment of at least 24 weeks with an initial dose of 25 mg daily during the first week followed by 50 mg Mirabegron daily during the remaining treatment period.

Drug: Mirabegron

Interventions

Mirabegron DRUG

25 mg daily during the first week followed by 50 mg Mirabegron daily during the remaining treatment period.

Also known as: Betmiga®

Arm Mirabegron

Eligibility Criteria

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

You may qualify if:

• Histologically or cytologically confirmed diagnosis of JAK2-V617F positive ET, PV or PMF at primary diagnosis or pretreated
• JAK2-V617F mutant allele burden \> 20% in the peripheral blood at study entry
• Patient must give written informed consent before registration
• WHO performance status 0-2
• Age ≥ 18 years
• Adequate hematological values: neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/ L
• Adequate hepatic function: bilirubin ≤ 1.5 x ULN, AST/ALT/AP ≤ 2.5 x ULN
• Adequate renal function (calculated creatinine clearance \> 50 mL/min, according to the formula of Cockcroft-Gault)
• Patient compliance and geographic proximity allow proper staging and follow-up.

You may not qualify if:

• Leukemic transformation (\>20% blasts in blood, marrow or extramedullary site)
• Diabetic neuropathy
• Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV, unstable angina pectoris, history of myocardial infarction within the last twelve months, known cardiac rhythm disturbance including atrial fibrillation or QT prolongation
• Uncontrolled hypertension
• Treatment of ET, PV or PMF with IFNα or treatment of PMF with JAK inhibitors such as ruxolitinib within 3 months prior to trial entry.
• Previous malignancy within 5 years with the exception of adequately treated cervical carcinoma in situ or localized non-melanoma skin cancer.
• Psychiatric disorder precluding understanding of information on trial related topics, giving informed consent or interfering with compliance for oral drug intake.
• Treatment with hematopoietic stem cell transplantation
• Concurrent treatment with cytoreductive drugs, other experimental drugs or other anti-cancer therapy as well as treatment in a clinical trial within 2 months prior to trial entry.
• Any serious underlying medical condition (at the judgment of the investigator), which could impair the ability of the patient to participate in the trial (e.g. active autoimmune disease, uncontrolled diabetes, uncontrolled infection (HIV, Hepatitis B and C).
• Known hypersensitivity to trial drug or hypersensitivity to any other component of the trial drug.
• Any concomitant drugs contraindicated for use with the trial drug according to the approved product information.

Sponsors & Collaborators

• Swiss Cancer Institute: lead

Study Sites (11)

Kantonsspital Aarau

Aarau, CH-5001, Switzerland

Location

Universitaetsspital-Basel

Basel, CH-4031, Switzerland

Location

Istituto Oncologico della Svizzera Italiana - Ospedale San Giovanni

Bellinzona, CH-6500, Switzerland

Location

Inselspital Bern

Bern, CH-3010, Switzerland

Location

Hopitaux Universitaires de Geneve

Geneva, 1211, Switzerland

Location

Centre Hospitalier Universitaire Vaudois CHUV

Lausanne, 1011, Switzerland

Location

Kantonsspital Liestal

Liestal, CH-4410, Switzerland

Location

Kantonsspital Luzern

Lucerne, CH-6000, Switzerland

Location

Kantonsspital Münsterlingen

Münsterlingen, 8596, Switzerland

Location

Stadtspital Triemli

Zurich, 8063, Switzerland

Location

Universitätsspital Zürich

Zurich, CH-8091, Switzerland

Location

Related Publications (1)

• Drexler B, Passweg JR, Tzankov A, Bigler M, Theocharides AP, Cantoni N, Keller P, Stussi G, Ruefer A, Benz R, Favre G, Lundberg P, Nienhold R, Fuhrer A, Biaggi C, Manz MG, Bargetzi M, Mendez-Ferrer S, Skoda RC; Swiss Group for Clinical Cancer Research (SAKK). The sympathomimetic agonist mirabegron did not lower JAK2-V617F allele burden, but restored nestin-positive cells and reduced reticulin fibrosis in patients with myeloproliferative neoplasms: results of phase II study SAKK 33/14. Haematologica. 2019 Apr;104(4):710-716. doi: 10.3324/haematol.2018.200014. Epub 2018 Nov 8.

  PMID: 30409796 RESULT

MeSH Terms

Conditions

Myeloproliferative Disorders; Primary Myelofibrosis; Thrombocythemia, Essential; Polycythemia Vera

Interventions

mirabegron

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Blood Coagulation Disorders; Thrombocytosis; Blood Platelet Disorders; Hemorrhagic Disorders; Bone Marrow Neoplasms; Hematologic Neoplasms; Neoplasms by Site; Neoplasms

Study Officials

• Jakob R. Passweg, Prof

  University Hospital, Basel, Switzerland

  STUDY CHAIR

• Radek Skoda, Prof

  University Hospital, Basel, Switzerland

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 4, 2014
• First Posted: December 8, 2014
• Study Start: April 1, 2015
• Primary Completion: December 1, 2016
• Study Completion: December 1, 2016
• Last Updated: May 15, 2019

Record last verified: 2019-05

Data Sharing

• IPD Sharing: Will not share

Locations

CH (11)