Inclusion Criteria:

1. Signed Informed Consent Form available and patient willing and able to adhere to the study 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 with splenomegaly >11cm diameter and/or symptoms restricting their daily activity or patients 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.

• - Persisting leukoerythroblastosis.

• - Anemia <6.2 mmol/l (<10g/dl) - Elevated WBC (>11 Gpt/l) - Persisting general or constitutional symptoms (persistence is defined as less than 50% reduction to baseline when using the MPN10 TSS Score) OR failure [secondary resistance] to JAK-inhibitor treatment as defined by IWG-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 month after discontinuation of Fedratinib or 5 months after discontinuation of Nivolumab** 8. Subject must be willing to receive transfusion of blood products. 9. Thiamine levels within the normal range (prior substitution is possible) 10. Normal nutritional status. 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 active FCBP must agree to use adequate contraceptive methods (i.e. failure rate of < 1% per year). 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 donate semen or sperm.

Exclusion Criteria:

1. Planned hematopoietic stem cell transplantation within 3 months and suitable donor available. 2. >10% blasts in bone marrow smear (cytology) or >2x in blood smear within the screening 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 and Appendix V) 7. Uncontrolled infection. 8. Evidence of acute or chronic infection with hepatitis B, hepatitis C, human immunodeficiency virus (HIV) or tuberculosis. 9. Current participation in any other interventional clinical study within 30 days before the first administration of the investigational product or at any time during the study, unless it is an observational (non-interventional) study, or during the follow-up period of an interventional study with last dose of investigational product ≥30 days prior first administration of investigational product within this study. 10. No consent for registration, storage and processing of the individual disease characteristics and course as well as information of the family physician about study 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 and vasculitis) 16. History of malignancy except for i) adequately treated local basal cell or squamous cell carcinoma of the skin, ii) asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for ≥ 1 year prior to randomization, or iii) any other cancer that has been in complete remission for ≥ 5 years. 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 a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG]

The FRACTION trial will evaluate the clinical efficacy of Fedratinib and Nivolumab combination therapy in patients with primary and secondary myelofibrosis based on the consensus criteria of the International Working Group for Myelofibrosis Research and treatment (IWG-MRT), extended by the criterion RBC-transfusion independence (RBC-TI).

Arms

Experimental: Experimental

Fedratinib (Cycle 1: Run-in-Phase with 400 mg QD for 4 weeks, Cycle 2-12: 400 mg QD, Dose modifications will be allowed based on observed toxicity to a 300 mg or a 200 mg daily dose) + Nivolumab (Cycle 2-12: 240 mg, i.v., q2w) Patients will receive study treatment until loss of response, death or study discontinuation for other reasons.

Interventions

Drug: - Fedratinib Oral Capsule [Inrebic]

400 mg once daily p.o. from cycle 1-n, dose adjustment will be made according to the protocol

Drug: - Nivolumab

240 mg every 2 weeks i.v. from cycle 2-n