Reparixin in Patients With Myelofibrosis Myeloproliferative Neoplasms Research Consortium (MPN-RC 120)

Inclusion Criteria:

• Be ≥ 18 years of age at time of signing the informed consent form (ICF)

• Willing to voluntarily sign the ICF

• Have a pathologically confirmed diagnosis of PMF, post-ET-MF, or post-PV-MF as perthe World Health Organization (WHO) diagnostic criteria with intermediate-2 orhigher risk disease by DIPSS

• Have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

• Willing to undergo a bone marrow biopsy at screening o A bone marrow biopsy obtained within 90 days of screening without interveningtreatments and approved by the study chair may suffice.

• Be refractory/resistant to or intolerant of/inappropriate for JAKi therapy asdefined by at least one of the following:

• Treatment for ≥ 3 months with inadequate efficacy as demonstrated by persistentpalpable splenomegaly ≥ 5cm or symptoms related to splenomegaly,

• Treatment for ≥ 28 days complicated by either:

• Development of a red blood cell transfusion requirement (at least 2 units/monthfor 2 months)

• CTCAE grade ≥ 3 AEs of thrombocytopenia, anemia, hematoma, or hemorrhage whilebeing treated with a JAKi

• Development of non-hematological toxicity that makes patient intolerant of JAKitherapy

• In the Investigator's judgment, are not candidates for available approved JAKi

• Recovery to ≤ Grade 1 or baseline of any toxicities due to prior systemictreatments, excluding alopecia

• At least two weeks must have elapsed between the last dose of any MF-directed drugtreatments or other investigational therapies and start of reparixin o Participants may continue hydroxyurea until the day prior to C1D1 if needed fordisease control

• Have adequate organ function as demonstrated by the following:

• ALT (SGPT) and/or AST (SGOT) ≤ 3x upper limit of normal (ULN), or ≤ 4 x ULN (ifupon judgment of the treating physician, it is believed to be due to MF-relatedEMH);

• Direct bilirubin ≤ 1.5 x ULN; or ≤ 2x ULN (if upon judgment of the treatingphysician, it is believed to be due to MF-related EMH or documented Gilbert'ssyndrome);

• Creatinine clearance ≥ 40 mL/min;

• Platelet count ≥ 25 x 109/L;

• Bone marrow and peripheral blood blast count < 10%;

• ANC ≥ 1000 mm3.

• Life expectancy of at least six months

• Women of childbearing potential (WCBP) and men must agree to use adequatecontraception prior to study entry, for the duration of study participation, and for 120 days following completion of therapy. WCBP must also have a negative serumpregnancy test at screening and Cycle 1 Day 1. Should a woman become pregnant orsuspect she is pregnant while participating, she should inform her treatingphysician immediately. (Section 5.9.2) o Men must agree to use a condom and not father a child or donate sperm for theduration of the study and for 120 days after the last dose of study therapy

• Ability to adhere to the study visit schedule and all protocol requirements

Exclusion Criteria:

• History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmiarequiring medication or mechanical control within the last 6 months

• Other invasive malignancies within the last 3 years, except non-melanoma skin cancerand localized cured prostate and cervical cancer

• Moderate or severe cardiovascular disease meeting one or both of the below criteria:

• Presence of cardiac disease, including a myocardial infarction within 6 monthsprior to study entry, unstable angina pectoris, New York Heart AssociationClass III/IV congestive heart failure, or uncontrolled hypertension

• Documented major electrocardiogram (ECG) abnormalities (not responding tomedical treatments)

• Presence of active serious infection

• Any serious, unstable medical or psychiatric condition that would prevent (as judgedby the Investigator) the participant from signing the ICF or any condition,including the presence of laboratory abnormalities, which places the participant atunacceptable risk if he/she were to participate in the study or confounds theability to interpret data from the study

• Participants who have undergone a hematopoietic cell transplant (HCT) within 100days of the first dose of study therapy, participants on immunosuppressive therapypost-HCT at screening, use of calcineurin inhibitors within 4 weeks prior to firstdose of study therapy, or participants with clinically significant graft-versus-hostdisease (GVHD) o Note: The use of topical steroids or < 10mg oral prednisone for ongoing skin GVHDis permitted

• Known history of human immunodeficiency virus (HIV), or known active hepatitis A, B,or C infection

• Impairment of gastrointestinal (GI) function or GI disease that could significantlyalter the absorption of reparixin, including any unresolved nausea, vomiting, ordiarrhea > CTCAE grade 1

• Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling,or child) who is investigational site or sponsor staff directly involved with thistrial, unless prospective institutional review board (IRB) approval (by chair ordesignee) is given allowing exception to this criterion for a specific participant

• Organ transplant recipients other than bone marrow transplant

• Women who are pregnant or lactating

• History of splenectomy

• Known hypersensitivity to sulfonamides o Hypersensitivity to sulphanilamide antibiotics alone (e.g. sulfamethoxazole) doesnot qualify for exclusion

• Known hypersensitivity to non-steroidal anti-inflammatory drugs (NSAID), includingibuprofen