MethoTRExATE in MyelOpRolifErative Neoplasms (TREATMORE) Trial

Inclusion Criteria * Be ≥18 years of age at time of signing the informed consent form (ICF) * Must voluntarily sign ICF and be willing and able to adhere to the study visit schedule and all protocol requirements * Have a pathologically confirmed diagnosis of PV, ET, PMF, post-ET-MF, or post-PV-MF as per WHO diagnostic criteria * Participants with MF may have low, intermediate 1, intermediate 2, or high-risk disease by Dynamic International Prognostic Scoring System (DIPSS). Participants with PV and ET with both low- and high-risk disease may be included. * Must have received at least 12 weeks of current MPN therapy at stable doses and have persistent clinical burden and/or cytologic abnormalities as defined by the following: * Clinical burden is defined as MPN-SAF TSS \>12 points and/or palpable spleen of ≥5cm * Cytologic abnormalities include the following for each disease state: * MF: * Persistent leukocytosis as defined by WBC \>12 x 109/L * PV: * Persistent therapeutic phlebotomy dependence (\>2 phlebotomies within 24 weeks of screening, and \>1 phlebotomy within 16 weeks of screening, as defined in the PROUD-PV studies) for a goal HCT \<45% and/or * Leukocytosis as defined by WBC \>12 x 109/L and/or * Thrombocytosis defined as platelet count \>500 x 109/L * ET: * Persistent leukocytosis as defined by WBC \>12 x 109/L and/or * Thrombocytosis defined as platelet count \>500 x 109/L * Permitted concurrent MPN therapies include: aspirin, hydroxyurea, anagrelide, ropeginterferon alfa-2b, peginterferon alfa-2a, erythropoiesis-stimulating agents, phlebotomy, and/or ruxolitinib. * A stable dose is defined as 12 weeks of treatment without a change in dosing * Patients with myelofibrosis must be on stable dose of ruxolitinib * Must have adequate organ function as demonstrated by the following: * AST, ALT \<3x upper limit of normal (ULN) and no known history of cirrhosis * Total bilirubin \<3mg/dL * Creatinine clearance (CrCl) \>40 mL/min as estimated with the Cockcroft-Gault equation * Baseline platelet count \>50 x 109/L for MF and \>150 x 109/L for ET/PV * Baseline absolute neutrophil count (ANC) \>1000 * Peripheral blood blast count \<10% * ECOG performance status ≤2 * Life expectancy of at least six months * Female participants of childbearing potential must have a negative serum pregnancy test at screening and Cycle 1 Day 1 and must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 6 months following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately * Recommended methods of birth control are: * The consistent use of an approved hormonal contraception (birth control pill/patches, rings), an intrauterine device (IUD), contraceptive injection (Depo-Provera), double barrier methods (diaphragm with spermicidal gel or condoms with contraceptive foam), sexual abstinence (no sexual intercourse), or sterilization * A woman of childbearing potential is any woman (regardless of sexual orientation, having undergone a tubal litigation, or remaining celibate by choice) who meets the following criteria: * Has not undergone a hysterectomy or bilateral oophorectomy; or * Has not been naturally postmenopausal for at least 12 consecutive months * Male participants must agree to use an adequate method of contraception and must not father a child or donate sperm starting with the first dose of study therapy through 120 days after the last dose of study therapy Exclusion Criteria * Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment * Prescribed MTX for another indication * History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control within the last 6 months * Have other invasive malignancies within the last 3 years, except non-melanoma skin cancer and localized, cured prostate and cervical cancer * Have moderate or severe cardiovascular disease as defined by the following: * Have cardiac disease, including a myocardial infarction within 6 months prior to study entry, unstable angina pectoris, New York Heart Association Class III/IV congestive heart failure, or uncontrolled hypertension * Have documented major ECG abnormalities (not responding to medical treatments) * Be an organ transplant recipient other than bone marrow transplant * Presence of active serious infection * Have a known history B, or untreated hepatitis C infection * Have a known history of pulmonary fibrosis, interstitial pneumonitis * Have a known history of chronic pericardial effusions, pleural effusions, or ascites * Have a known history of cirrhosis, or current heavy alcohol consumption * Have impairment of gastrointestinal function or gastrointestinal disease that could significantly alter the absorption of MTX, including any unresolved nausea, vomiting, or diarrhea \> CTCAE v5.0 grade 1 * Have known history of tuberculosis or severe fungal infection * Is receiving specific concomitant medications that are contraindicated with MTX. * Women who are pregnant or lactating, or plan to become pregnant during trial period * Have any serious, unstable medical or psychiatric condition that would prevent (as judged by the Investigator) the participant from signing the informed consent form or any condition, including the presence of laboratory abnormalities, which places the participant at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study * 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 this trial, unless prospective IRB approval (by chair or designee) is given allowing exception to this criterion for a specific participant