Sympathicomimetic Agonist in Patients With Myeloproliferative Neoplasms With JAK2-mutation

• Status: Completed
• Trial end date: 2016-12-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Swiss Group for Clinical Cancer Research
• Treatments: Mirabegron

Criteria

Inclusion Criteria:

• 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)

• Women are not breastfeeding. Women with child-bearing potential are using effective contraception, are not pregnant and agree not to become pregnant during participation in the trial and during 28 days thereafter. A negative pregnancy test before inclusion (within 7 days) into the trial is required for all women with child-bearing potential. Men agree not to father a child during participation in the trial and during 28 days thereafter.

• Patient compliance and geographic proximity allow proper staging and follow-up.

Exclusion Criteria:

• 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.