Fedratinib in Combination with Nivolumab

Inclusion Criteria:

1. Signed Informed Consent Form available and patient willing and able to adhere to thestudy visit schedule and other protocol requirements.

2. Patients* ≥18 years of age

3. diagnosed with myelofibrosis (MF) according to the WHO 2008 or 2016 criteria,including primary (pre-fibrotic or overt) and secondary myelofibrosis.

4. Patients with an indication for therapy (either symptomatic patients withsplenomegaly >11cm diameter and/or symptoms restricting their daily activity orpatients with DIPSS int-2, or high risk or MIPSS70 int or high)

5. Patients with no response or suboptimal response to any JAK-inhibitor therapy (regarding persistence of symptoms, splenomegaly, cytopenia or hyperproliferation)defined either by

• Persisting Splenomegaly >11cm total diameter

• OR Persisting leukoerythroblastosis

• OR Anemia <6.2 mmol/l (<10g/dl)

• OR Elevated WBC (>11 Gpt/l)

• OR Persisting general or constitutional symptoms (persistence is defined asless than 50% reduction to baseline when using the MPN10 TSS Score)

• OR failure [secondary resistance] to JAK-inhibitor treatment as defined byIWG-MRT criteria.

6. ECOG performance status <3 at screening and adequate organ function

7. Reliable contraception should be maintained throughout the study and for 1 monthafter discontinuation of Fedratinib or 5 months after discontinuation of Nivolumab**

8. Subject must be willing to receive transfusion of blood products

9. Thiamine levels not below lower limit of normal (prior substitution is possible)

10. Normal nutritional status, as judged by the physician

11. Females of childbearing potential (FCBP) must undergo repetitive pregnancy testing (serum or urine) and pregnancy results must be negative.

12. Unless practicing complete abstinence from heterosexual intercourse, sexually activeFCBP must agree to use adequate contraceptive methods (i.e. failure rate of < 1% peryear).

13. Males (including those who have had a vasectomy) must use barrier contraception (condoms) when engaging in sexual activity with FCBP. Males must agree not to donatesemen or sperm.

Exclusion Criteria:

1. Planned hematopoietic stem cell transplantation within 3 months and suitable donoravailable

2. >10% blasts in bone marrow smear (cytology) or >2x in blood smear within thescreening phase or >20% blasts at any time in bone marrow or peripheral blood smears

3. Creatinine >2xULN and Creatinine-Clearance <45ml/min; ALAT, ASAT & bilirubin >3xULN (if MF impact on liver >5xULN)

4. Baseline platelets count below 50 x 10^9/L and ANC < 1.0 x 10^9/L

5. Diagnosis of PV, ET (according to WHO 2016) or positive molecular test for BCR-ABL

6. Patients on ongoing medication for myelofibrosis including systemic corticosteroids (detailed list of permitted medications is provided in paragraph 9.1.10.4 andAppendix V). Use of steroids within 14 days prior to the first dose of study drugand until end of treatment is prohibited by patients.

7. Uncontrolled infection

8. Evidence of acute or chronic infection with hepatitis B, hepatitis C, humanimmunodeficiency virus (HIV) or tuberculosis

9. Current participation in any other interventional clinical study within 30 daysbefore the first administration of the investigational product or at any time duringthe study, unless it is an observational (non-interventional) study, or during thefollow-up period of an interventional study with last dose of investigationalproduct ≥30 days prior first administration of investigational product within thisstudy.

10. No consent for registration, storage and processing of the individual diseasecharacteristics and course as well as information of the family physician aboutstudy participation

11. No consent for biobanking of patient's biological specimens

12. Prior therapy with checkpoint-inhibitors

13. Vaccination within 4 weeks prior to treatment start

14. Hypersensitivity to the IMPs or to any of the excipients

15. History of or uncontrolled autoimmune disease such as autoimmune-hepatitis, -pneumonitis, -thyroiditis, chronic inflammatory bowel disease, multiple sclerosis,or rheumatologic diseases (including but not limited to systemic lupus andvasculitis)

16. History of malignancy except for i) adequately treated local basal cell or squamouscell carcinoma of the skin, ii) asymptomatic prostate cancer without knownmetastatic disease and with no requirement for therapy or requiring only hormonaltherapy and with normal prostate-specific antigen for ≥ 1 year prior torandomization, or iii) any other cancer that has been in complete remission for ≥ 5years

17. Secondary malignancy that limits survival to less than 6 months.

18. Drug or alcohol abuse within the last 6 months

19. Patients who cannot adhere to the Pregnancy Prevention Plan

20. Pregnant or breast-feeding females

21. Thiamine levels below normal limit despite supplementation

22. Patients who are unable to consent because they do not understand the nature,significance and implications of the clinical trial and therefore cannot form arational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG]