This is a phase Ib study evaluating PMD-026, an oral inhibitor of ribosomal protein S6 kinase A1 (RSK1), in participants with myelofibrosis (MF).The dose escalation portion utilizes a standard 3+3 design to evaluate two dose levels with an additional dose de-escalation portion to identify the recommended phase II dose (RP2D); subsequently, an additional 6 patients will be enrolled in the dose expansion portion evaluating the efficacy of PMD-026.

Inclusion Criteria:

• Histologically confirmed diagnosis of primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis in chronic phase, according to the 2016 WHO criteria

  • Patients must have had at least 1 prior JAK inhibitor treatment for a minimum of 12 weeks and their disease was determined resistant or refractory, and/or their response was lost or intolerant to treatment.

• Intermediate-2 or High-risk MF, as defined by the Dynamic International Prognostic Scoring System (DIPSS).

• Presence of measurable disease as defined by:

  • Splenomegaly defined as estimated spleen volume of ≥450 cm3 by imaging with either MRI, CT or ultrasound, or a palpable spleen >=5 cm from the costal margin.
  • Baseline MFSAF v4.0 Total Symptom Score ≥ 10

• At least 18 years of age.

• ECOG performance status ≤ 2.

• Adequate organ function as defined below:

  • Total bilirubin ≤ 1.5 x IULN (unless the participant has a history of Gilbert's syndrome)
  • AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN
  • Creatinine clearance ≥ 30 mL/min by Cockcroft-Gault

• Adequate laboratory parameters:

  • Absolute Neutrophil Count (ANC) ≥ 100/mm^3
  • Platelets ≥50,000/mm^3
  • Blasts ≤ 10% on manual differential

• The effects of PMD-026 on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 30 days after completion of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study or should a man suspect he has fathered a child, s/he must inform her treating physician immediately.

• Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.

Exclusion Criteria:

• Prior allogeneic or autologous stem cell transplantation within the previous 12 months
• Prior splenectomy
• Prior splenic irradiation if < 3 months between last radiation and screening visit.
• Prior or concurrent malignancy whose natural history has the potential to interfere with the safety or efficacy assessment of the investigational regimen. Patients with prior or concurrent malignancy that does NOT meet that definition are eligible for this trial.
• Currently receiving any other investigational agents or planning to receive any investigational agents within 28 days before the planned first dose of PMD-026.
• Currently receiving a JAK inhibitor or planning to receive a JAK inhibitor within 7 days before the planned first dose of PMD-026. In patients with ongoing JAK inhibitor therapy (i.e. ruxolitinib) at screening, it must be tapered over a period of at least 7 days. Patients on a low dose of ruxolitinib (e.g. 5 mg QD) may have a reduced taper period or no taper.
• Known active disease involving the CNS.
• QTcF >450 msec for males, >470 msec for females (calculated using Fridericia's formula).
• A history of hypersensitivity or allergic reactions attributed to compounds of similar chemical or biologic composition to PMD-026 or other agents used in the study.
• Any major surgery within 28 days prior to the first dose of PMD-026.
• Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection, autoimmune disease, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.
• Unable to swallow or retain oral medications.
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 35 days of study entry (repeated on C1D1).