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Mannitol

Patients will receive PXS-5505 dose level 1, twice daily for a period of 4 weeks.

Patients will receive PXS-5505 dose level 2, twice daily for a period of 4 weeks.

Patients will receive PXS-5505 dose level 3, twice daily for a period of 4 weeks.

All patients will receive PXS-5505 at the selected twice daily dose for a period of 24 weeks, or until progressive disease, unacceptable toxicity, dose-limiting toxicity or withdrawal of consent.

Patients already receiving a stable dose of ruxolitinib for at least 12 weeks, will receive PXS-5505 (the dose used in the cohort expansion phase) on top of their ruxolitinib dose for up to 52 weeks or until progressive disease, unacceptable toxicity, dose-limiting toxicity, or withdrawal of consent.

PXS-5505 is a hard capsule (size 0) with the additional excipients mannitol and magnesium stearate.

PXS-5505

Jana Baskar, MBBS MMedSc MBA

Vachhani Pankit

Chen Franklin

Masarova Lucia

Pinky Patel

Stanley Cheung

Tan Shuhying

Peter Tan

Shona Garlick

Won Sik Lee

Do 도 Young Rok 영록

Sung-Eun Lee

Chih-Cheng 志丞 Chen 陳

Hui-Hua 惠樺 Hsiao 蕭

Su-Peng 士芃 Yeh 葉

Chen 陳 Tsai-Yun 彩雲

Shang-Ju 尚儒 Wu 吳

This study will be an open-label phase 1/2a study to evaluate the safety and tolerability of PXS-5505 in patients with primary, postpolycythemia vera (PV) or post-essential thrombocythemia (ET) myelofibrosis.

The study consists of three phases: a dose escalation phase, a cohort expansion phase, and an add-on phase.

The dose escalation phase will follow a 3+3 design with a starting dose of 100 mg twice daily, and a treatment duration of 4 weeks. Patients will be able to participate in more than one dose level.

During the cohort expansion phase, up to 24 patients will be treated at the dose determined appropriate based on safety, pharmacokinetic and pharmacodynamic results from the dose escalation phase, for a period of up to 6 months. Patients from the dose escalation phase will be able to participate in the cohort expansion phase.

In the add-on phase PXS-5505 will be given to patients, already receiving a stable dose of ruxolitinib, for a period of 12 months. Up to 15 patients will enrol in the add-on phase in order to obtain 12 patients with at least 1 month's exposure to PXS-5505 on top of ruxolitinib.

Note: The decision to include an add-on phase, where PXS-5505 is to be given on top of a stable ruxolitinib dose, was taken following a review of the data (safety, PK and PD) from the cohort expansion phase.

There will be no washout period between dose escalation and dose expansion cohorts.

Study to Evaluate Safety, Pharmacokinetic and Pharmacodynamic Dose Escalation and Expansion Study of PXS-5505 in Patients With Primary, Post-polycythemia Vera or Post-essential Thrombocythemia Myelofibrosis

A Phase 1/2a Study to Evaluate Safety, Pharmacokinetic and Pharmacodynamic Dose Escalation and Expansion Study of PXS-5505 in Patients With Primary, Postpolycythemia Vera or Post-essential Thrombocythemia Myelofibrosis

Safety and tolerability of PXS-5505 in patients with myelofibrosis will be assessed

Pharmacokinetic parameters of PXS-5505 in patients with myelofibrosis will be assessed.

Pharmacodynamic parameters of PXS-5505 in patients with myelofibrosis will be assessed.

Change in bone marrow fibrosis will be assessed according to European Consensus on grading of bone marrow fibrosis

Response rates as defined by International Working Group (IWG)-Myeloproliferative Neoplasms Research and Treatment criteria in patients with myelofibrosis administered PXS-5505 will be determined.

Changes in spleen volume, as measured by computed tomography (CT) or magnetic resonance imaging (MRI) scan, in patients with myelofibrosis administered PXS-5505 will be determined.

Changes in myelofibrosis related symptoms based on Myelofibrosis-Symptom Assessment Form (MFSAF) v4.0 scores, in patients with myelofibrosis administered PXS-5505 will be determined. A higher score indicates worse symptoms.

Syntara

Participants will receive parsaclisib and ruxolitinib starting from Day 1 for the duration of study, ruxolitinib dose will be determined by baseline platelet count.

Participants will receive placebo and ruxolitinib starting from Day 1 for the duration of study, ruxolitinib dose will be determined by baseline platelet count.

parsaclisib will be administered QD orally

parsaclisib

ruxolitinib will be administered BID orally

ruxolitinib

placebo

Albert Assad, M.D

The purpose of the study is to compare the efficacy of parsaclisib when combined with ruxolitinb versus placebo combined with ruxolitinib in participants with myelofibrosis.

This is a Phase 3, randomized, double-blind study of the combination of the PI3Kδ inhibitor parsaclisib or matching placebo and the JAK1/2 inhibitor ruxolitinib in participants with PMF or secondary MF (PPV-MF or PET-MF) with DIPSS risk category of intermediate or high. Prospective participants must have not received prior MF therapy with a JAK inhibitor or a PI3K inhibitor. After participants have been determined to be eligible for the study and completed the baseline symptom diary assessment for 7 days, they will be randomized to 1 of 2 treatment groups, with stratification for platelet count (≥ 100 × 10\^9/L vs 50 to \< 100 × 10\^9/L inclusive) and DIPSS risk category (high vs intermediate-2 vs intermediate-1).

Once all enrolled participants completed the week 24 assessments the study will be unblinded and and participants randomized to placebo will have the opportunity to cross over to begin receiving parsaclisib, together with continued ruxolitinib, as long as hematology parameters are adequate.

To Evaluate the Efficacy and Safety of Parsaclisib and Ruxolitinib in Participants With Myelofibrosis (LIMBER-313)

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of the Combination of PI3Kδ Inhibitor Parsaclisib and Ruxolitinib in Participants With Myelofibrosis

Incyte shares data with qualified external researchers after a research proposal is submitted. These requests are reviewed and approved by a review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

The trial data availability is according to the criteria and process described on https://www.incyte.com/our-company/compliance-and-transparency

Reduction in spleen volume is measured by Magnetic Resonance Imaging (MRI) or Computed Tomography (CT).

Reduction in TSS is measured by Myelofibrosis Symptom Assessment Form (MFSAF) v4.0.

Change in TSS is measured by Myelofibrosis Symptom Assessment Form (MFSAF) v4.0.

OS is defined as randomization date to death due to any cause.

Defined as any adverse event either reported for the first time or worsening of a pre-existing event after first dose of study drug up to 35 days after last dose of study drug.

Incyte Corporation

Participants will receive parsaclisib starting from Day 1 for the duration of study, while continuing to receive the stable dose of ruxolitinib they were taking for the 8 weeks prior to Day 1.

Participants will receive placebo starting from Day 1 for the duration of study, while continuing to receive the stable dose of ruxolitinib they were taking for the 8 weeks prior to Day 1.

Albert Assad, M.D.

The purpose of the study is to compare the efficacy and safety of parsaclisib when combined with ruxolitinb versus placebo combined with ruxolitinib in participants with myelofibrosis who have suboptimal response while receiving ruxolitinib monotherapy.

Prospective participants must be on stable doses of ruxolitinib ranging from 5 mg BID to 25 mg BID and will have been on that dose for at least the last 8 weeks prior to Day 1. At least 3 months duration of prior ruxolitinib is required. Participants must meet Protocol-defined criteria for suboptimal response to ruxolitinib monotherapy. After participants have been determined to be eligible for the study and completed the baseline symptom diary assessment for 7 days, they will be randomized to 1 of 2 treatment groups, with stratification for platelet count (≥ 100 × 10\^9/L vs 50 to \< 100 × 10\^9/L inclusive) and DIPSS risk category (high vs intermediate-2 vs intermediate-1).

Once a participant has completed the week 24 assessments, the participant's treatment assignment will then be unblinded and if found to be placebo, the participant will have the opportunity to crossover to begin receiving parsaclisib, together with continued ruxolitinib, as long as hematology parameters are adequate.

To Evaluate Efficacy and Safety of Parsaclisib and Ruxolitinib in Participants With Myelofibrosis Who Have Suboptimal Response to Ruxolitinib (LIMBER-304)

A Randomized, Double-Blind, Placebo-Controlled Study of the PI3Kδ Inhibitor Parsaclisib Plus Ruxolitinib in Participants With Myelofibrosis Who Have Suboptimal Response to Ruxolitinib

OS is defined as randomization date to death due to any cause

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study to Evaluate Safety, Pharmacokinetic and Pharmacodynamic Dose Escalation and Expansion Study of PXS-5505 in Patients With Primary, Post-polycythemia Vera or Post-essential Thrombocythemia Myelofibrosis	NCT04676529	Myelofibrosis	PXS-5505	18 Years -	Syntara
Study to Evaluate Safety, Pharmacokinetic and Pharmacodynamic Dose Escalation and Expansion Study of PXS-5505 in Patients With Primary, Post-polycythemia Vera or Post-essential Thrombocythemia Myelofibrosis	NCT04676529	Myelofibrosis	PXS-5505	18 Years -	Syntara
To Evaluate the Efficacy and Safety of Parsaclisib and Ruxolitinib in Participants With Myelofibrosis (LIMBER-313)	NCT04551066	Myelofibrosis Primary Myelofi... Post Essential ... Post Polycythem...	parsaclisib ruxolitinib placebo	18 Years -	Incyte Corporation
Study to Evaluate Safety, Pharmacokinetic and Pharmacodynamic Dose Escalation and Expansion Study of PXS-5505 in Patients With Primary, Post-polycythemia Vera or Post-essential Thrombocythemia Myelofibrosis	NCT04676529	Myelofibrosis	PXS-5505	18 Years -	Syntara
To Evaluate Efficacy and Safety of Parsaclisib and Ruxolitinib in Participants With Myelofibrosis Who Have Suboptimal Response to Ruxolitinib (LIMBER-304)	NCT04551053	Myelofibrosis Primary Myelofi... Post Essential ... Post Polycythem...	parsaclisib ruxolitinib placebo	18 Years -	Incyte Corporation

Spots Global Cancer Trial Database for post polycythemia vera myelofibrosis