Therapeutic RSK1 Targeting in Myelofibrosis
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.
• 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.