Heart and Blood Diseases

Blood and Lymph Conditions

All Conditions

Neoplasms

Rare Diseases

Hemostatic Disorders

Blood Coagulation Disorders

Myeloproliferative Disorders

Polycythemia Vera

Polycythemia

Blood Platelet Disorders

Bone Marrow Diseases

Thrombocytosis

Thrombocythemia, Essential

Hematologic Diseases

Hemorrhagic Disorders

Bone Marrow Neoplasms

Hematologic Neoplasms

Chronic Myeloproliferative Disorders

Essential Thrombocythemia

All Drugs and Chemicals

N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide

Protein Kinase Inhibitors

Enzyme Inhibitors

Participants with polycythemia vera will receive 100 mg of momelotinib.

Participants with polycythemia vera will receive 200 mg of momelotinib.

Participants with essential thrombocythemia will receive 100 mg of momelotinib.

Participants with essential thrombocythemia will receive 200 mg of momelotinib.

Momelotinib tablet administered orally once daily

Momelotinib

Peter Lee, MD, PhD

This open-label study is to determine the safety and efficacy of momelotinib in participants with either polycythemia vera (PV) or essential thrombocythemia (ET) who have not yet received treatment with a Janus kinase (JAK) inhibitor.

Safety and Efficacy of Momelotinib in Subjects With Polycythemia Vera or Essential Thrombocythemia

A Phase 2, Open-label, Randomized Study to Evaluate the Safety and Efficacy of Momelotinib in Subjects With Polycythemia Vera or Essential Thrombocythemia

For the PV Cohort, overall response rate (ORR) is defined as the proportion of participants with all of the following at some point during the treatment period:

* Hematocrit \< 45% in the absence of phlebotomy that lasts at least 4 weeks
* White blood cell (WBC) count \< 10 x 10\^9/L that lasts at least 4 weeks
* Platelet count ≤ 400 x 10\^9/L that lasts at least 4 weeks
* Resolution of palpable splenomegaly that lasts at least 4 weeks

For the ET Cohort, overall response rate is defined as the proportion of participants with all of the following at some point during the treatment period:

* WBC count \< 10 x 10\^9/L that lasts at least 4 weeks
* Platelet count ≤ 400 x 10\^9/L that lasts at least 4 weeks
* Resolution of palpable splenomegaly that lasts at least 4 weeks

Confirmed overall response rate is defined as the proportion of participants who meet all the criteria listed for the primary endpoints of PV or ET, sustained for at least 12 weeks.

Sierra Oncology LLC - a GSK company

Symptoms and General Pathology

Anemia

Thrombocytopenia

Primary Myelofibrosis

Splenomegaly

Anticoagulants

Antineoplastic Agents

Antisickling Agents

Other Dietary Supplements

Citric Acid

Sodium Citrate

Hydroxyurea

Danazol

Citrate

To receive pacritinib 200 mg twice daily (BID) orally, at the same time of day, with or without food

The Physician's Choice (P/C) therapy (limited to single drugs from the following list: corticosteroids, hydroxyurea, danazol, or low-dose ruxolitinib). The proposed P/C regimen for a patient must be selected prior to randomization.

Oral administration. Supplied in capsules containing 100 mg (as the free base) in red cap/gray body size 0 opaque hard gelatin capsules. The inactive ingredients are microcrystalline cellulose, magnesium stearate, and polyethylene glycol 8000. Each capsule contains 146 mg of pacritinib citrate, which is equivalent to 100 mg pacritinib free base

Pacritinib

Physician's Choice medications will be selected and administered according to the investigator's judgement. Investigators can select individual P/C agents but cannot combine agents or give them sequentially.

Physician's Choice medications

Simran Bedi Singh

This study (study ID PAC203 North America; PAC303 ex-North America) is evaluating 200 mg BID of pacritinib compared to physician's choice (P/C) therapy in patients with MF and severe thrombocytopenia (platelet count \<50,000/μL). Approximately 399 patients in total will be enrolled, randomized 2:1 to either pacritinib (approximately 266 patients) or to P/C therapy (approximately 133 patients)

Condition or disease: Primary Myelofibrosis/Post-Polycythemia Vera Myelofibrosis/ Post-essential Thrombocythemia Myelofibrosis

Intervention/treatment: Drug-Pacritinib

The study is a randomized, controlled phase 3 study comparing the efficacy of pacritinib with P/C therapy in patients with PMF, PPV-MF, or PET-MF (Dynamic International Prognostic Scoring System \[DIPSS\] risk score of Intermediate-1 to High-Risk), who have had had no or limited exposure to any JAK2 inhibitor or are JAK2 inhibitor-naive, and who have severe thrombocytopenia (platelet count \<50,000/µL). This study was designed to use the pacritinib 200 mg BID dose, which was determined to be the optimal dose based on dose- and exposure-response analyses conducted using all available data, including the dosing data from the previous portion of this study. Patients will be randomized 2:1 to receive pacritinib 200 mg BID or the P/C therapy (limited to single drugs from the following list: corticosteroids, hydroxyurea, danazol, or low-dose ruxolitinib). The proposed P/C regimen for a patient must be selected prior to randomization. Randomization will be stratified by prior JAK2 inhibitor therapy (yes/no) and P/C therapy selected prior to randomization. Prior JAK2 inhibitor therapy will be defined as any duration of treatment with a JAK2 inhibitor, such as ruxolitinib, fedratinib, or momelotinib. To be eligible, patients are not allowed to have been treated with more than one JAK2 inhibitor. Assigned treatment will continue until the patient experiences progressive disease or intolerable AEs, withdraws consent, or initiates new MF-directed therapy. No study treatment crossover will be allowed at any time. All patients should complete all visit procedures through Week 24, including patients who stop treatment or have protocol-defined progressive disease prior to Week 24, unless the patient withdraws consent for study procedures, dies, undergoes splenic irradiation or splenectomy, initiates any non-protocol-directed anti-MF treatment, or the study is terminated. In addition to the above, patients will be considered to have discontinued treatment if pacritinib or P/C therapy is held for \>28 consecutive days due to treatment toxicity, or if treatment is discontinued for lack of efficacy, or at the request of the principal investigator or the patient. Following the Week 24 assessment, patients who are benefiting from therapy will be allowed to continue receiving the assigned treatment (pacritinib or P/C) until the patient experiences progressive disease, intolerable AEs, withdraws consent, or initiates new MF-directed therapy. All randomized patients will be followed for survival for 2.5 years from the date of randomization unless consent for follow-up is withdrawn.

A Phase 3 Study of Pacritinib in Patients With Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis

A Randomized, Controlled Phase 3 Study of Pacritinib Versus Physician's Choice in Patients With Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis With Severe Thrombocytopenia (Platelet Count <50,000/μL)(PACIFICA)

Proportion of patients achieving \>25% SVR

Achievement of red blood cell (RBC) transfusion independence at Weeks 12 and 24

Improvement in hemoglobin level without transfusion at Weeks 12 and 24

Improvement in platelet count at Weeks 12 and 24

Frequency of platelet transfusions at Weeks 12 and 24

Improvement in fatigue as measured by Patient-Reported Outcomes Measurement Information System (PROMIS) v.1.0 - Fatigue from Baseline through Week 24

Leukemia-free survival (LFS) of patients treated with pacritinib versus P/C therapy

The percentage of red blood cell transfusion-independent patients at baseline achieving a 1 g/dL and a 2 g/dL increase in hemoglobin at week 24

The percentage of platelet transfusion-independent patients at baseline with improvement in grade of thrombocytopenia at week 24

The percentage of transfusion-dependent patients at baseline achieving transfusion independence and achieving 50% reduction in transfusion rate at week 24

Changes in mutated allelic burden, gene expression, and pharmacodynamic (PD) biomarkers

MACE is a composite endpoint that is considered to occur if any of the following TEAEs occur:

* cardiovascular death, defined as death due to acute myocardial infarction, sudden cardiac death, death due to heart failure, death due to stroke, death due to cardiovascular procedures, death due to cardiovascular hemorrhage, or death due to peripheral artery disease
* non-fatal myocardial infarction
* non-fatal stroke of any classification, including reversible focal neurological defects with imaging evidence of a new cerebral lesion consistent with ischemia or hemorrhage

To compare the efficacy of pacritinib with that of physician's choice (P/C) therapy, as assessed by the proportion of patients achieving a ≥35% spleen volume reduction (SVR) as measured by magnetic resonance imaging (MRI, preferred) or computed tomography (CT) scans

To compare the efficacy of pacritinib compared to P/C therapy, as assessed by the proportion of patients achieving a ≥50% reduction in Total Symptom Score (TSS). The TSS is the sum of the individual symptom scores for tiredness, early satiety, abdominal discomfort, night sweats, pruritus, bone pain, and pain under ribs on the left side. Symptoms are ranked 0 (absent) to 10 (worst imaginable)

To compare the overall survival (OS) of patients treated with pacritinib versus those treated with P/C

To compare the percentage of patients who self-assess as "very much improved" or "much improved" as measured by the Patient Global Impression of Change (PGIC) in patients treated with pacritinib versus those treated with P/C

Safety will be assessed based on the incidence and severity (according to the Common Terminology Criteria for Adverse Events) of treatment emergent adverse events from the time of randomization until 30 days after completion of treatment with pacritinib and/or physician's choice therapy.

PSI CRO

CTI BioPharma

Vascular Diseases

Janus Kinase Inhibitors

LDE225

INC424

Novartis Pharmaceuticals

The purpose of this phase Ib/II clinical trial was to: a) evaluate the safety of the co-administration of LDE225 and INC424 in myelofibrosis patients and establish a maximum tolerated dose and/or Recommended Phase II dose of the combination and b) to assess the efficacy of the co-administration of LDE225 and INC424 on spleen volume reduction.

The study is considered to have been completed because the participants completed the study as per study design at the time of trial termination. If participants were already in extension phase until discontinuation criteria were met or alternative setting was available, they were considered as completed. The study was terminated due to one of the compounds being divested.

A Phase Ib/II Dose-finding Study to Assess the Safety and Efficacy of LDE225 + INC424 in Patients With MF

A Phase Ib/II, Open-label, Multi-center, Dose-finding Study to Assess the Safety and Efficacy of the Oral Combination of LDE225 and INC424 (Ruxolitinib) in Patients With Myelofibrosis

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert 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.

This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.

A dose-limiting toxicity (DLT) was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease progression, inter-current illness, or concomitant medications that met certain criteria as defined in the protocol.

Reduction in spleen volume as measured by magnetic resonance imaging/Cat Scan (MRI/CT) in Phase Ib expansion and Phase II Stage 1 patients

Plasma Concentration Time Curve: AUC0-24h: Area under the concentration-time curve from time zero to 24 hours extrapolate from AUClast\[mass x time x volume-1\]

AUC0-12h: Area under the concentration-time curve from time zero to 12 hours extrapolate from AUClast\[mass x time x volume-1\]. AUCinf: Area under the concentration-time curve from time zero to infinity with extrapolation of the terminal phase \[mass x time x volume-1\]. AUClast: Area under the concentration-time curve from time zero to the time of last measurable concentration \[mass x time x volume-1\].

Cmax: Maximum observed plasma concentration after drug administration \[mass x volume-

1\].

CL/F: Apparent total plasma clearance of drug after oral administration \[volume x time-1\]

The number of patients experiencing improvement in their bone marrow fibrosis by at least one grade and assessment of cellularity.

Phase Ib and Phase ll: Change in Pharmacodynamic Biomarkers: JAK2V617F allele burden

Summary of cytokine levels in Pharmacodynamic Biomarkers for all 26 collected at Week 25 Day 1 and Week 49 Day 1

The 7-day modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 is a 7-item PRO instrument based on the modified MFSAF v2.0 diary administered at specified visits. The first 6 items assess MF symptom severity at its worst as recalled in the 7 days prior to the clinic visit assessment. The symptoms measured include night sweats, itching, abdominal discomfort, pain under the ribs (left side), early satiety, \& bone/muscle pain. The 7th item captures MF-related inactivity in the past 7 days prior to the clinic visit assessment. All 7 items ask subjects to record their answers on an 11-point numeric rating scale (NRS), (0 = Absent, 10 = Worst Imaginable). The first 6 items of the instrument focus on MF symptoms \& are summed to create a Total Symptom score.

EORTC QLQ-C30 is the European Organization for Research \& Treatment of Cancer, Quality of Life (QoL) Questionnaire \& is one of the most widely used \& validated instruments to measure health-related QoL in subjects with cancer. The scale includes 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning \& social functioning), global health status/QoL \& 9 symptom scale/items (fatigue, nausea \& vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, \& financial difficulties). This instrument asks the subject to respond according to the past week, with the exception of the first 5 questions that represent physical functioning \& capture the subject's current status. The range of scores for all of the scales is from 0 to 100. For functional \& global health status/QoL scales, higher scores indicate better QoL \& level of functioning; for symptom scales, higher scores indicate greater level of symptoms or difficulties.

Racc: Accumulation ratio calculated as AUC0-12h on Week 9 Day 1 divided by AUC0-12h on Week 1 Day 1 \[fold\]

T1/2: Elimination half-life associated with the terminal slope (lambda_z) of a semi logarithmic concentration-time curve \[time\]

Vss/F: Apparent volume of distribution at steady state after oral administration \[volume\]

Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase

LDE225 400 mg + INC424 10 mg

Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase

LDE225 400 mg + INC424 15 mg

Participants who took a combination of LDED225 400mg and INC424 20mg in the dose escalation phase

LDE225 400 mg + INC424 20 mg

Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase

LDE225 400 mg + INC424 20 mg (Dose Expansion)

All Patients

Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.

LDE225 400mg + INC424 10 mg (Dose Escalation Phase)

LDE225 400mg + INC424 15 mg (Dose Escalation Phase)

Participants who took a combination of LDE225 400mg and INC424 20mg in the dose escalation phase.

LDE225 400mg + INC424 20mg (Dose Escalation Phase)

LDED225 400mg + INC424 20mg (Dose Expansion Phase)

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Please refer to detailed description regarding reason for early termination of study.

Study Director

LDE225 400mg + INC424 10mg (Dose Escalation Phase)

LDE225 400mg + INC424 15mg (Dose Escalation Phase)

Safety Analysis Set (SAS) included all participants in Phase Ib \& Phase II who received at least 1 dose of LDE225 and/or INC424 \& had at least 1 valid post-baseline safety assessment. DLT was measured in the Phase Ib dose escalation \& expansion phase, as part of the primary outcome. All participants in the safety set were considered for toxicities.

Number of Participants With Dose Limiting Toxicities (DLTs) (Phase 1b)

Week 24

Week 48

The Full Analysis Set (FAS) comprised all subjects in Phase Ib and Phase II who received at least one dose of LDE225 and/or INC424. The data disclosed includes only participants from Phase Ib dose expansion phase and Ph II Stage 1. This data does not include dose escalation Phase Ib participants.

Percentage of Patients Achieving >= 35% Reduction in Spleen Volume in Phase Ib Expansion and Phase II Stage 1

LDE225 (Week 1, Day 1) (n=6,10,4,24)

LDE225 (Week 9, Day 1) (n=6,6,4,14)

The Pharmacokinetic Analysis set (PAS) consisted of all subjects in Phase Ib and Phase II who received at least one (full or partial) dose of LDE225 and/or INC424 and provided at least one evaluable PK blood sample for LDE225 and/or INC424.

Phase Ib and Phase II: LDE225: Plasma Pharmacokinetics (PK) Parameter: Area Under the Curve(AUC0-24h)

AUC0-12h: Wk1 Day 1 (n=8,10,5,25)

AUC0-12h: Wk 9 Day 1 (n=8,9,4,20)

AUCinf: Wk1 Day 1 (n=7,9,4,16)

AUCinf: Wk 9 Day 1 (n=8,9,3,15)

AUClast: Wk1 Day 1 (n=8,10,5,26)

AUClast: Wk 9 Day 1 (n=8,9,4,20)

Phase Ib and Phase II: INC424: PK Parameters: Area Under the Curve for AUC0-12h, AUCinf & AUClast

LDE225 (Week 1, Day 1) (n=6,10,5,26)

LDE225 (Week 9, Day 1) (n=8,8,5,20)

INC424 (Week 1, Day 1) (n=8,10,5,27)

INC424 (Week 9, Day 1) (n=8,9,4,20)

The pharmacokinetic analysis set (PAS) consisted of all subjects in Phase Ib and Phase II who received at least one (full or partial) dose of LDE225 and/or INC424 and provided at least one evaluable PK blood sample for LDE225 and/or INC424.

Phase Ib and Phase II: LDE225 & INC424: PK Parameter: Maximum Plasma Concentration (Cmax)

Phase Ib and Phase II: LDE225 & INC424: Plasma PK Parameter: Time to Maximum Plasma Concentration (Tmax)

LDE225 (Week 1, Day 1) (n=5,5,1,12)

INC424 (Week 1, Day 1) (n=7,9,4,16)

INC424 (Week 9, Day 1) (n=0,0,0,0)

Phase Ib and Phase II: LDE225 & INC424:: Plasma Pharmacokinetics (PK) Parameters: Area Under the Curve(CL/F)

Baseline, grade 0 (n=0,0,0,1)

Baseline, grade 1 (n=0,1,0,4)

Baseline, grade 2 (n=4,6,3,8)

Baseline, grade 3 (n=3,3,0,8)

Baseline, missing grade (n=1,0,2,6)

Week 25 Day 1, grade 1 (n=1,1,0,1)

Week 25 Day 1, grade 2 (n=0,3,2,7)

Week 25 Day 1, grade 3 (n=5,4,1,5)

Week 25 Day 1, missing grade (n=2,2,2,14)

Week 49 Day 1, grade 0 (n=0,0,0,1)

Week 49, Day 1 grade 1 (n=0,0,0,1)

Week 49 Day 1, grade 2 (n=0,1,1,2)

Week 49 Day 1, grade 3 (n=2,2,2,3)

Week 49 Day 1, missing grade (n=6,7,2,20)

The Full Analysis Set (FAS) comprised all subjects in Phase Ib and Phase II who received at least one dose of LDE225 and/or INC424.

Phase Ib and Phase II: Percentage of Participants With Fibrosis Grade Assessed by Bone Marrow Histomorphology, by Time and Treatment in Phase Ib and Phase II Stage 1

Baseline

Week 25 Day 1 (n=7,6,5,21)

Week 49 Day 1 (n=4,3,4,13)

The Biomarker Analysis Set (BAS) consisted of all subjects in Phase Ib and Phase II who received at least one (full or partial) dose of LDE225 and/or INC424 and provided at least one evaluable biomarker sample.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Safety and Efficacy of Momelotinib in Subjects With Polycythemia Vera or Essential Thrombocythemia	NCT01998828	Polycythemia Ve... Essential Throm...	Momelotinib	18 Years -	Sierra Oncology LLC - a GSK company
A Phase 3 Study of Pacritinib in Patients With Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis	NCT03165734	Primary Myelofi... Post-polycythem... Post-essential ...	Pacritinib Physician's Cho...	18 Years -	CTI BioPharma
A Phase Ib/II Dose-finding Study to Assess the Safety and Efficacy of LDE225 + INC424 in Patients With MF	NCT01787552	Primary Myelofi... Thrombocytosis Essential Throm... Polycythemia Ve... Myeloproliferat... Bone Marrow Dis... Hematologic Dis... Blood Coagulati... Blood Platelet ... Hemorrhagic Dis...	LDE225 INC424	18 Years -	Novartis
A Phase 3 Study of Pacritinib in Patients With Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis	NCT03165734	Primary Myelofi... Post-polycythem... Post-essential ...	Pacritinib Physician's Cho...	18 Years -	CTI BioPharma

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