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)

This is a phase 1, non-randomized, open-label study utilizing a 3+3 sequential dose escalation design followed by an expansion phase. The primary objective will be to evaluate the safety and tolerability of LY5830966 and establish a Maximally Tolerated Dose (MTD) and/or inform the establishment of a candidate Recommended Phase 3 dose (RP3D). The RP3D may be the maximally tolerated dose (MTD) or may be a dose below the MTD. The candidate RP3D will be based on adverse event (AE) pattern, pharmacokinetics (PK) and biomarker information, in addition to all available safety and efficacy data. Expansion cohorts will be enrolled to gather additional safety and efficacy information and to further refine input for future RP3D discussions. Eligible participants will have PMF, PPV-MF or PET-MF and will have either have relapsed after a response, or be refractory to, at least one prior type I JAK2 inhibitor therapy, either administered as monotherapy or in combination with another drug.

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%.