Tasquinimod in Patients with Myelofibrosis Refractory to or Intolerant for JAK2 Inhibition

The goal of this clinical trial is to learn if therapy can be improved in patients with myelofibrosis (MF) who have primary resistance or who have progressed after treatment with a Janus kinase (JAK) inhibitor or are intolerant for this category of drugs.

The main questions it aims to answer are:

* To evaluate the feasibility and safety of once daily dose of tasquinimod for 24 weeks (6 cycles)
* To determine the optimal dose

Patients will be treated once daily with tasquinimod for a maximum period of 24 weeks (6 cycles).

During the study most (diagnostic) procedures are part of the standard of care. Different from standard of care:

* Participation may lead to extra visits to the outpatient clinic
* Additional blood will be drawn when blood is already taken per standard of care
* Bone marrow sampling at entry and at the end of the trial
* MRI scans (or CT-scans) have to be performed
* Quality-of-life questionnaires have to be filled out


Eligibility Criteria:
Inclusion Criteria:

* Diagnosis of PMF or Post-PV MF or Post-ET MF based on a bone marrow (BM) biopsy not older than 6 months, according to the 2016 World Health Organization.
* Refactory or intolerant to treatment with an approved JAK inhibitor or ineligible for JAK inhibitor treatment.
* MF classified as Intermediate-1 with disease-related symptoms (e.g. symptomatic splenomegaly), Intermediate-2 or high-risk by Dynamic International Prognostic Scoring System Plus
* Spleen ≥5 cm below costal margin as measured by palpation.
* Age ≥18 years.
* Peripheral blood blast count of \<10%.
* WHO/ECOG performance status of 0, 1, or 2.
* Able to swallow and retain oral medication.
* Willing and able to comply with scheduled visits, treatment plan and laboratory tests.
* Negative pregnancy test at study entry for women of childbearing potential. Women of child-bearing potential and sexually active males must be willing and able to use highly effective methods of contraception, during treatment, and for 4 months and 6 months respectively, after study treatment.
* Patient is capable of giving informed consent.
* Written informed consent.

Exclusion Criteria:

* Patients eligible for hematopoietic stem cell transplantation (suitable candidate and a suitable donor is available).
* Splenectomy.
* Splenic irradiation within the last 6 months.
* Prior allogeneic stem cell transplantation.
* Following laboratory values within 14 days prior to registration:

  * Absolute Neutrophil Count (ANC) \<0.5 x 109/L without G-CSF support
  * Platelet count \<25 x 109/L without platelet transfusion
  * Serum creatinine \>1.5 x Upper limit of normal (ULN) or GFR \<30 ml/min
  * Serum amylase and lipase \>1.5 x ULN
  * Alanine aminotransferase (ALT) ≥2.5 x ULN
  * Total bilirubin \>1.5 times the upper limit of the normal range (ULN), unless elevated bilirubin is due to unconjugated hyperbilirubinemia from Gilbert's syndrome or related to MF
* Known active (acute or chronic) Hepatitis A, B, or C; and Hepatitis B and C carriers, HIV.
* Prior history of chronic liver disease (eg, chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemachromatosis).
* Patients with any other prior malignancies are not eligible, except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which subject has been disease-free for at least 5 years.
* Failure to have fully recovered (i.e. to CTCAE Grade 1 or previous baseline) from clinically significant adverse effects of prior chemotherapy (examples of adverse effects that are not clinically significant include alopecia and lymphopenia).
* Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of tasquinimod (e.g., ulcerative diseases, pancreatitis uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection).
* Evidence of severe or currently uncontrolled cardiovascular condition (e.g. cardiac amyloidosis, pulmonary embolism, angina, hypertension, peripheral vascular disease, congestive heart failure class III or IV of the NYHA classification (appendix F), cardiac arrhythmia, acute coronary syndrome, myocardial infarction, cerebrovascular accident, major hemorrhage, intracranial hemorrhage, transient ischemic attack, or limb claudication) within 6 months prior to registration.
* Patients with clinically significant bacterial, fungal, parasitic or viral infection which require therapy. Patients with acute bacterial infections requiring antibiotic use should delay screening/ enrollment until the course of antibiotic therapy has been completed.
* Any chemotherapy, immunomodulatory drug therapy (eg, thalidomide, interferon-alpha), anagrelide, immunosuppressive therapy, corticosteroids \>10 mg/day prednisone or equivalent, or growth factor treatment (eg, erythropoietin), or hormones (eg, androgens, danazol) within 2 weeks prior to initiation of tasquinimod; erythropoetin use within 28 days prior to initiation of tasquinimod. The only chemotherapy allowed will be hydroxyurea which has to be stopped within 1 day prior to initiation of tasquinimod.
* Treatment with fedratinib within 7 days, or momelotinib within 2 days prior to initiation of tasquinimod. For ruxolitinib no wash-out period is required before start of tasquinimod.
* Any investigational treatment for MF within 2 weeks or 5 half-lives whichever is shorter.
* History of severe hypersensitivity reaction to any component of tasquinimod.
* Systemic treatment within 14 days prior to the initiation of tasquinimod with any of the moderate or strong inhibitor, or moderate or strong inducer of cytochrome P-3A4 (CYP3A4)
* Need for ongoing therapy with drug substances of narrow therapeutic range that are metabolized mainly by CYP3A4
* Need for ongoing therapy with drug substances of narrow therapeutic range metabolized mainly by CYP1A2
* Ongoing treatment with vitamin K antagonist, unless the INR is ≤ 3.0
* Prior treatment with tasquinimod.
* Major surgery within 3 months.
* Pregnant or breast feeding (lactating) women.
* Any other condition that would, in the Investigator's judgment, contraindicate subject's participation in the clinical study due to safety concerns or compliance with clinical study procedures e.g. any uncontrolled disease such as pulmonary disease, infection or seizure disorder; intestinal obstruction, inability to swallow medication, any altered mental status or psychiatric condition that would interfere with the understanding of the informed consent
* Current participation (during interventional treatment) in another clinical trial.
* Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.