A Study of Ruxolitinib in Combination With Ulixertinib in People With Myelofibrosis

Inclusion Criteria:

• Patients with a diagnosis of primary myelofibrosis, post-ET myelofibrosis, post-PVmyelofibrosis, or post-pre-fibrotic myelofibrosis by WHO 2016 criteria.

• Age ≥18 years.

• Receiving ruxolitinib monotherapy for at least 3 months with stable dose (10 mg BIDto 20mg BID) for at least 4 weeks before first dose of study drug. Note: stableruxolitinib dosing should be achieved according to strict adherence to dosemodification/reduction guidelines detailed in the ruxolitinib package insert, forpatients with renal impairment, and/or hepatic impairment.

• Must have DIPSS+ intermediate 2 or greater risk disease, or MIPSS70+ intermediate orgreater risk disease

• Persistent disease despite ruxolitinib monotherapy, as demonstrated by: o Grade 2 or 3 reticulin/collagen fibrosis on bone marrow AND

• Splenomegaly (palpable at least 5cm below subcostal margin/or spleen volume > 450cm^3) OR

• Active symptoms (MPN-SAF TSS score >10 with at least one MPNSAF TSS score >5 ortwo scores >3) OR

• ECOG performance status ≤2

• Participants must have adequate organ and marrow function as defined below unlessthe elevated laboratory values are attributable to Gilbert's Syndrome with Sponsorreview and approval:

• Absolute neutrophil count ≥ 0.5 K/mcL

• Platelets ≥ 50 K/mcL

• Direct bilirubin ≤ 1.5 times institutional upper limit of normal (ULN)

• Total bilirubin ≤ 1.5 times institutional upper limit of normal (ULN

• AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN

• Creatinine clearance ≥ 50 mL/min as calculated by institutional standard

• Bone marrow and peripheral blood blast count <10%

• Agreeable to the use of adequate contraception to avoid pregnancy (Appendix D).Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth contro) prior to study entry, for the durationof study participation, and 4 months after completion of drug administration (Appendix D). At least two highly effective methods of contraception, one of whichmust be a barrier method, are required for males and females of childbearing ageduring dosing and for 4 months after completing treatment. Should a woman becomepregnant or suspect she is pregnant while she or her partner is participating inthis study, she should inform her treating physician immediately. Men treated orenrolled on this protocol must also agree to use adequate contraception prior to thestudy, for the duration of study participation, and 4 months after completion ofdrug administration

Exclusion Criteria:

• Use of experimental drug therapy for MF or any other standard drug with theexception of hydroxyurea or ruxolitinib within 2 weeks of starting combinationtherapy and/or lack of recovery from all toxicities from previous therapy (exceptruxolitinib) to Grade 1 or better. Hydroxyurea may be utilized to controlleukocytosis for up to 4 weeks during study

• Participants with a prior or concurrent malignancy whose natural history ortreatment has the potential to interfere with the safety or efficacy assessment ofthe investigational regimen

• Unwilling to receive red blood cell transfusion to treat low hemoglobin.

• Participants who are receiving any other investigational agents.

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to ruxolitinib and ulixertinib.

• Participants requiring any medications or substances that are strong inhibitors orinducers of 3A4, strong inhibitors of CYP1A2 and CYP2D6, and inhibitors ofPglycoprotein (P-gp). Strong inhibitors or inducers of 3A4, strong inhibitors ofCYP1A2 and CYP2D6, and inhibitors of P-gp must be stopped within 14 days (or 5half-lives) of study commencement. Because the lists of these agents are constantlychanging, it is important to regularly consult a frequently-updated medicalreference. As part of the enrollment/informed consent procedures, the participantwill be counseled on the risk of interactions with other agents, and what to do ifnew medications need to be prescribed or if the participant is considering a newover-the-counter medicine or herbal product.

• Participants who are pregnant or breastfeeding.

• Pregnant women are excluded from this study because ruxolitinib and ulixertinib areagents with the potential for teratogenic or abortifacient effects. Because there isan unknown but potential risk for adverse events in nursing infants secondary totreatment of the mother with ruxolitinib and ulixertinib, breastfeeding should bediscontinued if the mother is treated with ruxolitinib and ulixertinib.

• Active bacterial, fungal, or viral infection requiring treatment.

• Participants with chronic Human immunodeficiency virus (HIV) or hepatitis B or Cviral infection.

• HIV-infected participants on effective anti-retroviral therapy withundetectable viral load within 6 months are eligible for this trial. Note:testing does not have to be performed during screening unless participant hasknown or suspected history of HIV.

• For participants with evidence of chronic hepatitis B virus (HBV) infection,the HBV viral load must be undetectable on suppressive therapy, if indicated.

• Presence of active interstitial lung disease or pneumonitis.

• History of cardiovascular risk factors:

• Clinically significant, uncontrolled arrythmias and/or conductionabnormalities. Participants with controlled atrial fibrillation >30 days priorto study initiation are eligible.

• QTc > 480 msec.

• History of acute coronary syndromes (including myocardial infarction andunstable angina), coronary angioplasty, or stenting within 6 months prior tostudy entry;

• Class II congestive heart failure or greater or ejection fraction ≤50% onbaseline echocardiogram.

• History of uncontrolled hypertension.

• A history or current evidence/risk of retinal vein occlusion (RVO) or central serousretinopathy (CSR).

• Psychiatric illness/social situations, active drug, alcohol or substance use thatwould interfere with study compliance.

• Any condition that would, in the investigator's judgment, interfere with fullparticipation in the study, including administration of study drug and attendingstudy visits; pose a significant risk to the participant; or interfere withinterpreting study data.

• Participants eligible for allogeneic stem cell transplantation in the opinion of thetreating physician at the time of enrollment.

• Inability to comprehend or unwilling to sign the informed consent form.

• Transformation to accelerated or blast phase disease, including myeloid sarcoma.