A Phase 1 Study of LY5830966 in Participants With Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (PPV-MF), or Post-Essential Thrombocythemia Myelofibrosis (PET-MF) Who Have Been Failed by a Type I JAK2 Inhibitor (JAK2i)
Study Phase: Phase 1
Recruitment Status: Recruiting
Start Date: October 23, 2024
End Date: February 15, 2027
Inclusion Criteria:
- Diagnosis of PMF, post-PV MF, or post-ET MF.
- Dynamic International Prognostic Scoring System (DIPSS) Intermediate-1, Intermediate-2 or High-risk MF with less than or equal to (≤)10% blasts, regardless of JAK2 mutation status.
- Estimated spleen volume greater than or equal to (≥)450 cubic centimeter (cm ³)
- Myelofibrosis Symptom Assessment Form, version 4.0 (MFSAF v.4.0) TSS ≥10, or at least 2 of 7 MFSAF-assessed symptoms with scores ≥3.
- Eastern Cooperative Oncology Group performance score (ECOG PS) of 0, 1, 2, or 3.
- Prior therapy with at least 1 type I JAK2 inhibitor, and either failed to achieve a response or relapsed after achieving a response.
- Absolute neutrophil count greater than or equal to 1,000 per microliter of blood (ANC ≥1.0×10^9/L).
- Platelet count ≥75×10^9/L.
- Estimated glomerular filtration rate greater than or equal to 45 milliliters per minute per 1.73 square meters (eGFR ≥45 mL/min/1.73m²).
- Serum total bilirubin ≤2.0 × upper limit of normal (ULN).
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0 × upper limit normal (ULN).
- QTcF ≤470 msec. Polycythemia vera (PV) Only
- Confirmed diagnosis of PV
- Participants must have high-risk disease as defined by 60 years of age or older and/or have prior history of thrombotic event
- R/R or intolerant to at least one line of prior therapy including but not limited to interferon-based therapies, ruxolitinib, or hydroxyurea (HU) as defined by European LeukemiaNet (ELN) criteria
Exclusion Criteria:
- Prior splenectomy or splenic irradiation within 3 months.
- Ongoing use of systemic corticosteroids at dose equivalent to greater than (>) 20 milligrams per day (mg/day) of prednisone.
- Active, uncontrolled systemic infection or active Hepatitis B or C
- Chemotherapy in the previous 4 weeks or prior JAK2 inhibitor not discontinued per required washout prior to first dose
- Peripheral neuropathy ≥ Grade 2 (NCI CTCAE v 5.0).
- Pregnant or breastfeeding: males planning to father a child during treatment and for 3 months after last dose.
- Requirement for therapy with a medication that is a strong Cytochrome P450 3A4 CYP3A4 inhibitor as a concomitant medication.
- Currently on an interventional therapeutic trial in the treatment phase.
- Significant cardiovascular disease
- Active second primary malignancy (or diagnosed within 2 years) at high risk of progression, with standard exceptions (treated skin cancer, in situ cervical cancer, curatively treated localized breast/prostate cancer)
- Prolongation of the corrected QTcF ≥470 millisecond during screening
- Individual with a history of (noninfectious) pneumonitis/interstitial lung disease. First line (1L) MF only:
- Prior treatment with JAK2 inhibitors High-risk R/R PV only:
- Prior PV-directed therapy without required washout
- Active or chronic bleeding within 2 months prior to enrollment
- Clinically significant thrombosis (e.g., pulmonary embolism, deep vein thrombosis, or splenic vein thrombosis) within 2 months prior to enrollment
- Requires phlebotomy at hematocrit levels <45%.
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Conditions:
- Primary Myelofibrosis