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

Inclusion Criteria:

• Diagnosis of PMF or Post-PV MF or Post-ET MF based on a bone marrow (BM) biopsy notolder than 6 months, according to the 2016 World Health Organization.

• Refactory or intolerant to treatment with an approved JAK inhibitor or ineligiblefor JAK inhibitor treatment.

• MF classified as Intermediate-1 with disease-related symptoms (e.g. symptomaticsplenomegaly), Intermediate-2 or high-risk by Dynamic International PrognosticScoring 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 laboratorytests.

• Negative pregnancy test at study entry for women of childbearing potential. Women ofchild-bearing potential and sexually active males must be willing and able to usehighly effective methods of contraception, during treatment, and for 4 months and 6months respectively, after study treatment.

• Patient is capable of giving informed consent.

• Written informed consent.

Exclusion Criteria:

• Patients eligible for hematopoietic stem cell transplantation (suitable candidateand 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), unlesselevated bilirubin is due to unconjugated hyperbilirubinemia from Gilbert'ssyndrome or related to MF

• Known active (acute or chronic) Hepatitis A, B, or C; and Hepatitis B and Ccarriers, 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 thefollowing: adequately treated basal cell or squamous cell skin cancer, in situcervical cancer, or other cancer from which subject has been disease-free for atleast 5 years.

• Failure to have fully recovered (i.e. to CTCAE Grade 1 or previous baseline) fromclinically significant adverse effects of prior chemotherapy (examples of adverseeffects that are not clinically significant include alopecia and lymphopenia).

• Impairment of gastrointestinal (GI) function or GI disease that may significantlyalter the absorption of tasquinimod (e.g., ulcerative diseases, pancreatitisuncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowelresection).

• Evidence of severe or currently uncontrolled cardiovascular condition (e.g. cardiacamyloidosis, 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, cerebrovascularaccident, major hemorrhage, intracranial hemorrhage, transient ischemic attack, orlimb claudication) within 6 months prior to registration.

• Patients with clinically significant bacterial, fungal, parasitic or viral infectionwhich require therapy. Patients with acute bacterial infections requiring antibioticuse should delay screening/ enrollment until the course of antibiotic therapy hasbeen completed.

• Any chemotherapy, immunomodulatory drug therapy (eg, thalidomide, interferon-alpha),anagrelide, immunosuppressive therapy, corticosteroids >10 mg/day prednisone orequivalent, or growth factor treatment (eg, erythropoietin), or hormones (eg,androgens, danazol) within 2 weeks prior to initiation of tasquinimod; erythropoetinuse within 28 days prior to initiation of tasquinimod. The only chemotherapy allowedwill be hydroxyurea which has to be stopped within 1 day prior to initiation oftasquinimod.

• Treatment with fedratinib within 7 days, or momelotinib within 2 days prior toinitiation of tasquinimod. For ruxolitinib no wash-out period is required beforestart of tasquinimod.

• Any investigational treatment for MF within 2 weeks or 5 half-lives whichever isshorter.

• History of severe hypersensitivity reaction to any component of tasquinimod.

• Systemic treatment within 14 days prior to the initiation of tasquinimod with any ofthe 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 aremetabolized mainly by CYP3A4

• Need for ongoing therapy with drug substances of narrow therapeutic rangemetabolized 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, contraindicatesubject's participation in the clinical study due to safety concerns or compliancewith clinical study procedures e.g. any uncontrolled disease such as pulmonarydisease, infection or seizure disorder; intestinal obstruction, inability to swallowmedication, any altered mental status or psychiatric condition that would interferewith the understanding of the informed consent

• Current participation (during interventional treatment) in another clinical trial.

• Any psychological, familial, sociological and geographical condition potentiallyhampering compliance with the study protocol and follow-up schedule.