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

Inclusion Criteria:

• Be ≥ 18 years of age at time of signing the ICF

• Able to voluntarily sign the ICF

• Have a pathologically confirmed diagnosis of PMF, post-ET-MF, or post-PV-MF as perthe WHO diagnostic criteria with intermediate-2 or higher risk disease by DIPSS

• Have an ECOG performance status ≤ 2

• Willing to undergo a bone marrow biopsy at screening; however, a bone marrow biopsyobtained within 90 days of screening without intervening treatments and approved bythe 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 2units/month for 2 months)

• NCI CTCAE grade ≥ 3 AEs of thrombocytopenia, anemia, hematoma, and/orhemorrhage while being treated with a dosage of < 20 mg BID

• 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 (including investigational therapies and excluding hydroxyurea) and studyenrollment

• Have adequate organ function as demonstrated by the following:

• ALT (SGPT) and/or AST (SGOT) ≤ 3x ULN, or ≤ 4 x ULN (if upon judgment of thetreating physician, it is believed to be due to MF-related EMH);

• 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.

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

Exclusion Criteria:

• Use of an investigational agent or an investigational device within 4 weeks of thefirst dose of study therapy

• 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 ECG abnormalities (not responding to medical treatments)

• Presence of active serious infection

• Any serious, unstable medical or psychiatric condition that would prevent (as judgedby the Investigator) the subject from signing the informed consent form or anycondition, including the presence of laboratory abnormalities, which places thesubject at unacceptable risk if he/she were to participate in the study or confoundsthe ability 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)

• Note: The use of topical steroids or < 10mg oral prednisone for ongoing skinGVHD is 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 IRB approval (by chair or designee) is given allowingexception to this criterion for a specific subject

• Organ transplant recipients other than bone marrow transplant

• Women who are pregnant or lactating