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

The researchers are doing this study to find out whether the combination of ruxolitinib and ulixertinib is a safe and effective treatment for people with myelofibrosis. The researchers will test different doses of ulixertinib to find the highest dose that causes few or mild side effects in participants when given in combination with ruxolitinib.

Inclusion Criteria: * Patients with a diagnosis of primary myelofibrosis, post-ET myelofibrosis, post-PV myelofibrosis, 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 BID to 20mg BID) for at least 4 weeks before first dose of study drug. Note: stable ruxolitinib dosing should be achieved according to strict adherence to dose modification/reduction guidelines detailed in the ruxolitinib package insert, for patients with renal impairment, and/or hepatic impairment. * Must have DIPSS+ intermediate 2 or greater risk disease, or MIPSS70+ intermediate or greater 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 or two scores \>3) * ECOG performance status ≤2 * Participants must have adequate organ and marrow function as defined below unless the elevated laboratory values are attributable to Gilbert's Syndrome with Sponsor review 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 \30 days prior to study initiation are eligible. * QTc \> 480 msec using Fredericia formula. * History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to study entry; * Class II congestive heart failure or greater or ejection fraction ≤50% on baseline echocardiogram. * History of uncontrolled hypertension. * A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR). * Psychiatric illness/social situations, active drug, alcohol or substance use that would interfere with study compliance. * Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study drug and attending study visits; pose a significant risk to the participant; or interfere with interpreting study data. * Participants eligible for allogeneic stem cell transplantation in the opinion of the treating 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.