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Histone Deacetylase Inhibitors

SB939 starting dose 60 mg by mouth every other day, three times weekly for 3 weeks.

Starting dose 60 mg by mouth every other day, three times weekly for 3 weeks.

SB939

Alfonso Quintas-Cardama, MD

The goal of this clinical research study is to learn if SB939 can help to control myelofibrosis. The safety of this drug will also be studied.

The Study Drug:

SB939 is designed to change the DNA (genetic material) of cancer cells. This may keep the cells from growing and cause them to die.

This is the first study in which SB939 is given to patients with myelofibrosis.

Study Drug Administration:

If you are found to be eligible to take part in this study, you will take SB939 by mouth 3 times a week for the first 3 weeks of every 4-week cycle. In some cases, the study doctor may decide your dose can be raised sometime after Cycle 1.

SB939 can be taken at any time of day, 2 hours before or 2 hours after a meal. You should take SB939 at about the same time each day. Do not open, break, or chew the capsules.

If you have any side effects, the doctor may change the amount or how often you take SB939.

You will fill out a study drug diary to keep track of your SB939 doses. You should bring the diary and all used and unused bottles of study drug with you to every study visit.

Study Visits:

At every study visit, you will be asked about any side effects you have had and any drugs you may be taking.

On Day 1 of Cycle 1 (+/- 3 days):

* You will have a physical exam, including measurement of your vital signs.
* You will be asked about any blood transfusions you have had and drugs you have taken since the last visit.
* Your performance status will be recorded.
* Blood (about 4 teaspoons) will be drawn for routine tests.
* You will have an ECG before taking this medication, about 10 minutes after taking medication, and 4-6 hours after taking medication.

On Day 8 of Cycle 1 (+1-3 days), blood (about 2 teaspoons) will be drawn for routine tests.

On Day 15 of Cycle 1 (+/- 3 days):

* You will have a physical exam, including measurement of your vital signs.
* Blood (about 4 teaspoons) will be drawn for routine tests.
* You will have an ECG before taking this medication, about 10 minutes after taking medication, and 4-6 hours after taking medication.

On Day 22 of Cycle 1 (+1-3 days), blood (about 2 teaspoons) will be drawn for routine tests.

On Day 1 of Cycles 2 and 3 (+/- 3 days):

* You will have a physical exam, including measurement of your vital signs.
* You will be asked about any blood transfusions you have had since the last visit.
* Your performance status will be recorded.
* Blood (about 4 teaspoons) will be drawn for routine tests.
* You will have an ECG.

On Day 1 of Cycles 4 and beyond (+/- 3 days), or every 3 cycles starting on Day 1 of Cycle 6 (+/- 3 days) if the doctor decides your schedule can change (if you have not had serious side effects):

* You will have a physical exam, including measurement of your vital signs.
* You will be asked about any blood transfusions you have had and drugs you have taken since the last visit.
* Your performance status will be recorded.
* Blood (about 4 teaspoons) will be drawn for routine tests.
* You will have a bone marrow biopsy and aspiration to check the status of the disease, if the doctor thinks it is needed.
* You will have an ECG at every visit to MD Anderson.

If your study visit schedule is changed to every 3 cycles (Day 1 of Cycles 6, 9, and so on), blood (about 4 teaspoons) will be drawn for routine tests every 28 days (+/- 3 days). These tests will be done at your local doctor's office. Every 28 days (+/- 3 days), the study staff will also call you to ask how you are doing and if you have had any side effects.

You may have additional bone marrow biopsies and aspirations and ECGs any time the doctor thinks it is needed. The study visits may also occur more often than described above, if the doctor thinks it is needed.

Length of Study:

You may continue taking the study drug for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you need radiation therapy, surgery, or other chemotherapy.

Your participation on the study will be over once you have completed the end-of-treatment visit and follow-up.

End-of-Treatment Visit:

After you stop taking the study drug for any reason, the following tests and procedures will be performed:

* You will have a physical exam, including measurement of your vital signs.
* You will be asked about any blood transfusions you have had and drugs you have taken since the last visit.
* Your performance status will be recorded.
* Blood (about 4 teaspoons) will be drawn for routine tests.
* You will have a bone marrow biopsy and aspiration to check the status of the disease, if the doctor thinks it is needed.

Follow-up:

The study staff will call you 30 days and 60 days after your last dose of the study drug (+/- 3 days). You will be asked how you are doing and if you have had any side effects.

If you have any side effects within 60 days after you stop taking the study drug, you may have extra tests and procedures. For example, blood (about 2 teaspoons) may be drawn for routine tests. If you are still having side effects, the study staff will continue calling you to ask how you are doing until the side effects get better. The schedule for how often you are called will depend on the side effects.

This is an investigational study. SB939 is not FDA approved or commercially available. It is currently being used for research purposes only.

Up to 41 patients will take part in this study. All will be enrolled at the University of Texas (UT) MD Anderson Cancer Center.

Study of SB939 in Subjects With Myelofibrosis

A Phase 2, Prospective, Open-Label Study to Determine the Safety and Efficacy of SB939, A Histone Deacetylase Inhibitor, in Subjects With Primary, Post-Polycythemia Vera, or Post-Essential Thrombocythemia Myelofibrosis (PMF; Post-Polycythemia Vera (PV) Myelofibrosis (MF), Or Post- Essential Thrombosis (ET) MF

Objective response defined as Complete, Partial response, and Clinical Improvement based on International Working Group (IWG) Criteria: Complete remission (CR): Absence transfusion \& growth factor support AND Complete resolution disease-related symptoms/signs; Peripheral blood count remission; Normal leukocyte differential; Bone marrow histological remission. Partial remission (PR): All CR except bone marrow histological remission. Clinical improvement (CI): No CR/PR, disease progression with one: ≥2 g/dL increase hemoglobin level or transfusion independent; Either ≥50% reduction in palpable splenomegaly of spleen ≥10 cm baseline or spleen palpable at \>5 cm baseline becomes not palpable; ≥100% increase in platelet count \& absolute platelet count ≥50,000 x 10\^9/L; or ≥100% increase in absolute neutrophil count (ANC) \& ANC ≥0.5 x 10\^9/L. Progressive disease: Progressive splenomegaly or Leukemic transformation confirmed by bone marrow blast of ≥20%; or Increase peripheral blood blast

S*BIO

M.D. Anderson Cancer Center

SB939 starting dose 60 mg by mouth every other day, 3 times weekly for 3 weeks.

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

Alfonso Quintas-Cardama, MD/Assistant Professor

Complete Response (CR)

Partial Response (PR)

Clinical Improvement (CI)

Participants With an Objective Response

Overall Study

Symptoms and General Pathology

Fibrosis

itacitinib

Albert Assad, MD

This is a study of itacitinib (INCB039110) in patients with myelofibrosis. This study will evaluate safety and efficacy parameters of itacitinib (INCB039110).

An Open Label Study of Itacitinib Administered Orally in Patients With Myelofibrosis

An Open-Label, Multiple Simon 2-Stage Study of Itacitinib Administered Orally to Subjects With Primary Myelofibrosis (PMF), Post Polycythemia Vera Myelofibrosis (PPV-MF) or Post Essential Thrombocythemia Myelofibrosis (PET-MF)

Incyte Corporation

Blood Platelet Disorders

Hemostatic Disorders

Blood Coagulation Disorders

Hemorrhagic Disorders

Antineoplastic Agents

Panobinostat

Enzyme Inhibitors

Subjects will be treated with ruxolitinib 5 mg twice daily (BID) and panobinostat 10 mg three times per week (TIW) every other week (QOW) on a 28 day cycle

Subjects will be treated with ruxolitinib 10 mg twice daily (BID) and panobinostat 10 mg three times per week (TIW) every other week (QOW) on a 28 day cycle

Subjects will be treated with ruxolitinib 15 mg twice daily (BID) and panobinostat 10 mg three times per week (TIW) every other week (QOW) on a 28 day cycle

Subjects will be treated with ruxolitinib 15 mg twice daily (BID) and panobinostat 15 mg three times per week (TIW) every other week (QOW) on a 28 day cycle

Subjects will be treated with ruxolitinib 15 mg twice daily (BID) and panobinostat 20 mg three times per week (TIW) every other week (QOW) on a 28 day cycle

Subjects will be treated with ruxolitinib 15 mg twice daily (BID) and panobinostat 25 mg three times per week (TIW) every other week (QOW) on a 28 day cycle

Given 3 times a week, every other week in 28-day cycles.

panobinostat

ruxolitinib

Novartis Pharmaceuticals

This study will assess safety as well as establish a Recommended Phase II dose of the combination of panobinostat and ruxolitinib in patients with or without the JAK2V617F mutation who have been diagnosed with primary myelofibrosis (PMF), Post Essential Thrombocythemia Myelofibrosis (PET MF), or Post-Polycythemia Vera Myelofibrosis (PPV MF).

In 2011 the treatment goals for MF focused on symptom-orientated palliation and quality of life. Both ruxolitinib and panobinostat, as single agents, had shown significant improvement in both of those treatment goals and ruxolitinib had also shown greater reductions in splenomegaly compared to the standard of care at that time. To further the benefit seen with ruxolitinib in MF patients, panobinostat was added to the treatment regimen to act synergistically in the blockade of the dysregulated pathway driving this disease.

The study was conducted in 2 phases - an escalation phase and an expansion phase.

Escalation phase: the study utilised the Bayesian Logistic Regression Model (BLRM), incorporating escalation with overdose control (EWOC), which is a well established method for dose escalation in oncology trials. Following this process, successive cohorts of 3 newly enrolled patients received increasing doses of ruxolitinib and panobinostat until the maximum tolerated dose (MTD) or recommended phase II dose (RPIID) was determined. Once the MTD and/or RPIID were suspected in a minimum of 3 patients, additional patients were enrolled to the same cohort level to reach a minimum of 9 evaluable patients. The process also included safety, PK/PD assessments and estimates of efficacy based on measures of splenic reduction at each dose level.

Expansion: following the determination of the MTD and/or RPIID, a dose expansion phase was conducted at that dose to further define the safety and tolerability of the combination. At least 13, and no more than 23, additional patients were to be enrolled into the expansion phase.

Panobinostat and Ruxolitinib in Primary Myelofibrosis, Post-polycythemia Vera-myelofibrosis or Post-essential Thrombocythemia-myelofibrosis

A Phase 1b, Open-label, Multi-center, Single Arm, Dose Finding Study to Assess Safety and Pharmacokinetics of the Oral Combination of Panobinostat and Ruxolitinib in Patients With Primary Myelofibrosis (PMF), Post-polycythemia Vera-myelofibrosis (PPV-MF) or Post-essential Thrombocythemia-myelofibrosis (PET-MF)

Area under the plasma concentration versus time curve

Tmax: The time of maximum observed concentration sampled during a dosing interval.

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

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.

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 of SB939 in Subjects With Myelofibrosis	NCT01200498	Myeloproliferat...	SB939	18 Years -	M.D. Anderson Cancer Center
An Open Label Study of Itacitinib Administered Orally in Patients With Myelofibrosis	NCT01633372	MPN (Myeloproli...	itacitinib	18 Years -	Incyte Corporation
Panobinostat and Ruxolitinib in Primary Myelofibrosis, Post-polycythemia Vera-myelofibrosis or Post-essential Thrombocythemia-myelofibrosis	NCT01433445	Idiopathic Myel... Post Essential ... Post Polycythem...	panobinostat ruxolitinib	18 Years -	Novartis
Study of SB939 in Subjects With Myelofibrosis	NCT01200498	Myeloproliferat...	SB939	18 Years -	M.D. Anderson Cancer Center
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
An Open Label Study of Itacitinib Administered Orally in Patients With Myelofibrosis	NCT01633372	MPN (Myeloproli...	itacitinib	18 Years -	Incyte Corporation
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
An Open Label Study of Itacitinib Administered Orally in Patients With Myelofibrosis	NCT01633372	MPN (Myeloproli...	itacitinib	18 Years -	Incyte Corporation

Spots Global Cancer Trial Database for post essential thrombocythemia myelofibrosis