Blood and Lymph Conditions

All Conditions

Neoplasms

Rare Diseases

Myeloproliferative Disorders

Polycythemia Vera

Polycythemia

Primary Myelofibrosis

Thrombocytosis

Thrombocythemia, Essential

Bone Marrow Diseases

Hematologic Diseases

Chronic Myeloproliferative Disorders

Essential Thrombocythemia

Initial cohort dose of parsaclisib added to existing stable regimen of ruxolitinib, with subsequent cohort escalations based on protocol-specific criteria.

Part 2 will compare 2 doses of parsaclisib .

Part 3 will compare 2 different long term dosing strategies.

Part 4 will compare 2 different daily dosing strategies.

Up to 3 oral once a day (QD) doses of parsaclisib. Doses will be taken once daily for 8 weeks, followed by once weekly dosing at the same dose level.

Parsaclisib

Two recommended oral QD doses of parsaclisib. Once daily doses of parsaclisib will be taken for 8 weeks, followed by once weekly dosing at the same dose level.

The dose of ruxolitinib will be that which the subjects had been taking for at least 8 weeks before the first dose of parsaclisib.

Ruxolitinib

20 mg oral QD dose of parsaclisib for 8 weeks. After 8 weeks patients will take either 20 mg once weekly or 5 mg once daily.

2 dose strategies will be compared:

1. 5 mg parsaclisib beginning on Day 1 until end of treatment.
2. 20 mg oral QD dose of parsaclisib for 8 weeks; after 8 weeks patients will take 5 mg once daily.

Albert Assad, MD

The purpose of this study is to evaluate the safety, tolerability, and efficacy of the combination of parsaclisib and ruxolitinib in subjects with myelofibrosis.

A Study of INCB050465 in Combination With Ruxolitinib in Subjects With Myelofibrosis

A Phase 2 Study of the Safety, Tolerability, and Efficacy of INCB050465 in Combination With Ruxolitinib in Subjects With Myelofibrosis

DLTs were defined as the occurrence of any protocol-defined toxicities occurring up to and including Day 28, except those with a clear alternative explanation (e.g., disease progression, other medications) or transient (≤ 72 hours) abnormal laboratory values without associated clinically significant signs or symptoms based on investigator determination. All DLTs were assessed by the investigator using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 criteria.

Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] / Baseline value) x 100.

The MFSAF v3.0 is comprised of 19 individual symptom scores, each collected daily using an 11-point scale. The daily TSS is composed of 6 of these individual symptom scores (nights sweats, itchiness, abdominal discomfort, pain under left ribs, early satiety, bone/muscle pain) collected on the same day. Participants scored each symptom using a scale from 0 (absent) to 10 (worst imaginable). The TSS was calculated as a sum of all 6 symptom scores; scores ranged from 0 to 60, with higher scores corresponding to more severe symptoms. The Baseline TSS was defined as the average of daily total scores from the last 7 days before the first dose of INCB050465. The Week 12 TSS was the average of the daily total scores from the last 7 consecutive days before the Week 12 visit. Change from Baseline was calculated as the post-Baseline score minus the Baseline score.

The MFSAF v3.0 is comprised of 19 individual symptom scores, each collected daily using an 11-point scale. The daily TSS is composed of 6 of these individual symptom scores (nights sweats, itchiness, abdominal discomfort, pain under left ribs, early satiety, bone/muscle pain) collected on the same day. Participants scored each symptom using a scale from 0 (absent) to 10 (worst imaginable). The TSS was calculated as a sum of all 6 symptom scores; scores ranged from 0 to 60, with higher scores corresponding to more severe symptoms. The Baseline TSS was defined as the average of daily total scores from the last 7 days before the first dose of INCB050465. The Week 12 TSS was the average of the daily total scores from the last 7 consecutive days before the Week 12 visit. Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] / Baseline value) x 100.

The MFSAF v3.0 is comprised of 19 individual symptom scores, each collected daily using an 11-point scale. The daily TSS is composed of 6 of these individual symptom scores (nights sweats, itchiness, abdominal discomfort, pain under left ribs, early satiety, bone/muscle pain) collected on the same day. Participants scored each symptom using a scale from 0 (absent) to 10 (worst imaginable). The TSS was calculated as a sum of all 6 symptom scores; scores ranged from 0 to 60, with higher scores corresponding to more severe symptoms. The Baseline TSS was defined as the average of daily total scores from the last 7 days before the first dose of INCB050465. The Week 24 TSS was the average of the daily total scores from the last 7 consecutive days before the Week 24 visit. Change from Baseline was calculated as the post-Baseline score minus the Baseline score.

The MFSAF v3.0 is comprised of 19 individual symptom scores, each collected daily using an 11-point scale. The daily TSS is composed of 6 of these individual symptom scores (nights sweats, itchiness, abdominal discomfort, pain under left ribs, early satiety, bone/muscle pain) collected on the same day. Participants scored each symptom using a scale from 0 (absent) to 10 (worst imaginable). The TSS was calculated as a sum of all 6 symptom scores; scores ranged from 0 to 60, with higher scores corresponding to more severe symptoms. The Baseline TSS was defined as the average of daily total scores from the last 7 days before the first dose of INCB050465. The Week 24 TSS was the average of the daily total scores from the last 7 consecutive days before the Week 24 visit. Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] / Baseline value) x 100.

The MPN-SAF weekly total score is defined as the sum of 10 individual symptom scores (fatigue, nights sweats, itchiness, bone pain, fever, unintentional weight loss last 6 months, early satiety, abdominal discomfort, inactivity, problems with concentration) collected at the same visit using an 11-point scale. Participants scored each symptom using a scale from 0 (absent) to 10 (worst imaginable). The TSS was calculated as a sum of all 10 symptom scores; scores ranged from 0 to 100, with higher scores corresponding to more severe symptoms. Change from Baseline was calculated as the post-Baseline score minus the Baseline score.

The MPN-SAF weekly total score is defined as the sum of 10 individual symptom scores (fatigue, nights sweats, itchiness, bone pain, fever, unintentional weight loss last 6 months, early satiety, abdominal discomfort, inactivity, problems with concentration) collected at the same visit using an 11-point scale. Participants scored each symptom using a scale from 0 (absent) to 10 (worst imaginable). The TSS was calculated as a sum of all 10 symptom scores; scores ranged from 0 to 100, with higher scores corresponding to more severe symptoms. Percent change from Baseline was calculated as the (\[post-Baseline value minus the Baseline value\] / Baseline value) x 100.

The PGIC questionnaire consists of a single question with 7 possible answers: "Since the start of treatment you've received in this study, your myelofibrosis symptoms are: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; 7, very much worse."

A participant was considered as a responder if the participant had a best overall response of CR or PR. CR: (a) bone marrow (BM): age-adjusted normocellularity (AAN); \< 5% blasts; ≤ grade 1 myelofibrosis (MF); (b) peripheral blood (PD): hemoglobin (Hg) ≥ 100 grams per Liter (g/L) and \< upper normal limit (UNL); neutrophils ≥ 1 × 10\^9/L and \< UNL; (c) platelets ≥ 100 × 10\^9/L and \< UNL; \< 2% immature myeloid cells (IMCs); (d) clinical: resolution of disease symptoms; spleen/liver not palpable; no extramedullary hematopoiesis (EMH). PR: (a) PB: Hg ≥ 100 g/L and \< UNL; neutrophils ≥ 1 × 10\^9/L and \< UNL; platelets ≥ 100 × 10\^9/L and \< UNL; \< 2% IMCs; (b) clinical: resolution of disease symptoms; spleen/liver not palpable; no EMH; (c) BM: AAN; \< 5% blasts; ≤ Grade 1 MF; and PB: Hg ≥ 85 g/L but \< 100 g/L and \< UNL; neutrophils ≥ 1 × 10\^9/L and \< UNL; platelets ≥ 50 × 10\^9/L but \< 100 × 10\^9/L and \< UNL; \< 2% IMCs.

An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related, that occurred after a participant provided informed consent. Abnormal laboratory values or test results occurring after informed consent constituted AEs only if they induced clinical signs or symptoms, were considered clinically meaningful, required therapy (e.g., hematologic abnormality that required transfusion), or requird changes in the study drug(s). TEAEs were defined as AEs that began or worsened from Baseline after the first administration of study drug.

An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related, that occurred after a participant provided informed consent. Abnormal laboratory values or test results occurring after informed consent constituted AEs only if they induced clinical signs or symptoms, were considered clinically meaningful, required therapy (e.g., hematologic abnormality that required transfusion), or requird changes in the study drug(s). TEAEs were defined as AEs that began or worsened from Baseline after the first administration of study drug. Participants who had been assigned to dosing arms with weekly dosing beyond Week 8 had the opportunity to transition to all daily dosing at 5 mg if agreed upon by the participant and the Investigator.

Cmax was defined as the maximum observed plasma concentration.

tmax was defined as the time to the maximum concentration.

Cmin was defined as the minimum observed plasma concentration.

AUC0-4h was defined as the area under the plasma concentration-time curve from time = 0 to 4 hours post-dose.

AUC0-t was defined as the area under the plasma concentration-time curve from time =0 to the last measurable concentration at time = t.

Clast was defined as the last quantifiable concentration.

tlast was defined as the time of the last quantifiable concentration.

Incyte Corporation

An AE was reported in the initial randomization group (TG10, TG20) if it started before transition to TG5D. An AE was reported in the TG5D Transition arm if it started after transition to TG5D. Due to early termination of the study, per the Statistical Analysis Plan, the 4 dosage groups (TG10: Daily/Weekly Dosing; TG20: Daily/Weekly Dosing; TG5I/M; TG5D), as well as the participants who transitioned from daily/weekly to all-daily dosing (TG5D Transition), were compared separately for safety.

Participants received at least 6 months of prior ruxolitinib therapy, including ruxolitinib administration at a stable dose of 5 mg BID to 25 mg BID for at least 8 weeks before randomization. From Day 1 to the end of Week 8, participants received oral parsaclisib 10 milligrams (mg) once daily (QD), followed by the same dose weekly until discontinuation criteria were met, in combination with the pre-Day 1 stable dose of ruxolitinib (5 to 25 mg BID).

TG10: Daily/Weekly Dosing

Participants received at least 6 months of prior ruxolitinib therapy, including ruxolitinib administration at a stable dose of 5 mg BID to 25 mg BID for at least 8 weeks before randomization. From Day 1 to the end of Week 8, participants received oral parsaclisib 20 mg QD, followed by the same dose weekly until discontinuation criteria were met, in combination with the pre-Day 1 stable dose of ruxolitinib (5 to 25 mg BID).

TG20: Daily/Weekly Dosing

Participants received at least 6 months of prior ruxolitinib therapy, including ruxolitinib administration at a stable dose of 5 milligrams (mg) twice a day (BID) to 25 mg BID for at least 8 weeks before randomization. From Day 1 to the end of Week 8, participants received oral parsaclisib 20 mg once daily (QD), followed by 5 mg QD until discontinuation criteria were met, in combination with the pre-Day 1 stable dose of ruxolitinib (5 to 25 mg BID).

TG5I/M

Participants received at least 6 months of prior ruxolitinib therapy, including ruxolitinib administration at a stable dose of 5 mg BID to 25 mg BID for at least 8 weeks before randomization. From Day 1, participants received oral parsaclisib 5 mg QD until discontinuation criteria were met, in combination with the pre-Day 1 stable dose of ruxolitinib (5 to 25 mg BID).

TG5D

Total: Initially Randomized Participants

Participants received at least 6 months of prior ruxolitinib therapy, including ruxolitinib administration at a stable dose of 5 mg BID to 25 mg BID for at least 8 weeks before randomization. Participants randomized to receive oral parsaclisib 10 mg or 20 mg QD from Day 1 to the end of Week 8 transitioned to oral parsaclisib 5 mg QD after Week 8. Transition participants received oral parsaclisib 5 mg QD until discontinuation criteria were met, in combination with the pre-Day 1 stable dose of ruxolitinib (5 to 25 mg BID).

TG5D Transition

Participants received at least 6 months of prior ruxolitinib therapy, including ruxolitinib administration at a stable dose of 5 mg BID to 25 mg BID for at least 8 weeks before randomization. From Day 1 to the end of Week 8, participants in TG10 and TG20 received oral parsaclisib 10 mg or 20 mg QD, respectively, followed by the same dose weekly until discontinuation criteria were met, in combination with the pre-Day 1 stable dose of ruxolitinib (5 to 25 mg BID).

TG10 + TG20: Daily/Weekly Dosing

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

White

Black or African American

Asian

Captured as "Other" in Database

Race/Ethnicity, Customized

Due to early termination of the study, per the Statistical Analysis Plan, participants were combined into arms based on the dosage received regardless of what phase of the study they participated in.

Study Director

Initial Safety Population: all participants who received at least 1 dose of study drug. Treatment groups were determined according to the actual treatment the participant received regardless of assigned study drug treatment. Analysis was conducted on the Safety Population during the initial safety period. Due to early termination of the study, per the Statistical Analysis Plan, daily and weekly dosing arms were combined for analysis.

Number of Participants With Dose-limiting Toxicities (DLTs)

Baseline

Change from Baseline at Week 12

Initial Safety Population: all enrolled participants who received at least 1 dose of study drug. Analysis was conducted on the Safety Population during the initial safety period. Only participants with available data were analyzed. Due to early termination of the study, per the Statistical Analysis Plan, daily and weekly dosing arms were combined for efficacy analysis.

Change From Baseline in Spleen Volume Through Week 12 of the Initial Study Period as Measured by Magnetic Resonance Imaging (MRI) (or Computed Tomography [CT] Scan in Applicable Participants)

Initial Safety Population. Analysis was conducted on the Safety Population during the initial safety period. Only participants with available data were analyzed. Due to early termination of the study, per the Statistical Analysis Plan, daily and weekly dosing arms were combined for efficacy analysis.

Percent Change From Baseline in Spleen Volume Through Week 12 as Measured by MRI (or CT Scan in Applicable Participants)

Change from Baseline at Week 24

Change From Baseline in Spleen Volume Through Week 24 of the Initial Study Period as Measured by MRI (or CT Scan in Applicable Participants)

Percent Change From Baseline in Spleen Volume Through Week 24 as Measured by MRI (or CT Scan in Applicable Participants )

Change From Baseline in the Total Symptom Score (TSS) Through Week 12 as Measured by Myelofibrosis Symptom Assessment Form (MFSAF) Version 3.0 (v3.0) Symptom Diary

Percent Change From Baseline in the TSS Through Week 12 as Measured by MFSAF v3.0 Symptom Diary

Change From Baseline in the TSS Through Week 24 as Measured by MFSAF v3.0 Symptom Diary

Percent Change From Baseline in the TSS Through Week 24 as Measured by MFSAF v3.0 Symptom Diary

Change From Baseline in the TSS Through Week 12 as Measured by Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF)

Percent Change From Baseline in the TSS Through Week 12 as Measured by MPN-SAF

Change From Baseline in the TSS Through Week 24 as Measured by MPN-SAF

Percent Change From Baseline in the TSS Through Week 24 as Measured by MPN-SAF

Week 12, very much improved

Week 12, much improved

Week 12, minimally improved

Week 12, no change

Week 12, minimally worse

Week 12, much worse

Week 12, very much worse

Week 12, not reported

Week 24, very much improved

Week 24, much improved

Week 24, minimally improved

Week 24, no change

Week 24, minimally worse

Week 24, much worse

Week 24, very much worse

Week 24, not reported

EOT, very much improved

EOT, much improved

EOT, minimally improved

EOT, no change

EOT, minimally worse

EOT, much worse

EOT, very much worse

EOT, not reported

Initial Safety Population. Analysis was conducted on the Safety Population during the initial safety period. Due to early termination of the study, per the Statistical Analysis Plan, daily and weekly dosing arms were combined for efficacy analysis.

Number of Participants With the Indicated Patient Global Impression of Change (PGIC) Score at Week 12, Week 24, and the End of Treatment (EOT)

Week 12

Week 24

Mean PGIC Score at Week 12, Week 24, and the EOT

Best Overall Response (Percentage of Participants With Complete Response [CR] or Partial Response [PR]) for Investigator-Reported International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Response Assessment

Initial Safety Population. Analysis was conducted on the Safety Population during the initial safety period. Due to early termination of the study, per the Statistical Analysis Plan, daily and weekly dosing arms were combined for analysis.

Number of Participants With Any Treatment-emergent Adverse Event (TEAE)

Transition Safety Population. AEs were reported in the initial randomization group (TG10, TG20) if the start of the AEs occurred before transitioning to TG5D. If the start of the AEs occurred after transitioning to TG5D, they were reported in the TG5D Transition arm.

Number of Participants With Any TEAE During the Transition Period

Week 2

Week 4

Participants in TG5I/M received oral parsaclisib 5 mg QD from Week 8 until discontinuation criteria were met. Participants in TG5D received oral parsaclisib 5 mg QD until discontinuation criteria were met. Participants in TG10 and TG20 who were randomized to receive oral parsaclisib 10 mg or 20 mg QD transitioned to oral parsaclisib 5 mg QD after Week 8.

Parsaclisib 5 mg

Participants in TG10 received oral parsaclisib 10 mg QD for 8 weeks, followed by the same dose weekly until discontinuation criteria were met. Other participants were randomized to receive oral parsaclisib 10 mg QD for 8 weeks but transitioned to oral parsaclisib 5 mg QD after Week 8.

Parsaclisib 10 mg

Participants in TG5I/M recevied oral parsaclisib 20 mg QD for 8 weeks. Participants in TG20 received oral parsaclisib 20 mg QD for 8 weeks, followed by the same dose weekly until discontinuation criteria were met. Other participants were randomized to receive oral parsaclisib 20 mg QD for 8 weeks, then received 5 mg QD from Week 8 until discontinuation criteria were met.

Parsaclisib 20 mg

Pharmacokinetic (PK) Population: all treated participants who contributed plasma PK samples. Only participants with available data were analyzed. To be able to form a meaningful statistical test with enough participants, participants across all treatment groups were combined according to the dose of parsaclisib received for analysis.

Cmax of Parsaclisib

PK Population. Only participants with available data were analyzed. To be able to form a meaningful statistical test with enough participants, participants across all treatment groups were combined according to the dose of parsaclisib received for analysis.

Tmax of Parsaclisib

Cmin of Parsaclisib

AUC0-4h of Parsaclisib

AUC0-t of Parsaclisib

Clast of Parsaclisib

Tlast of Parsaclisib

Day 1

Throughout the study, participants received a stable dose of ruxolitinib 5 mg BID.

Ruxolitinib 5 mg

Throughout the study, participants received a stable dose of ruxolitinib 10 mg BID.

Ruxolitinib 10 mg

Throughout the study, participants received a stable dose of ruxolitinib 15 mg BID.

Ruxolitinib 15 mg

Throughout the study, participants received a stable dose of ruxolitinib 20 mg BID.

Ruxolitinib 20 mg

Throughout the study, participants received a stable dose of ruxolitinib 25 mg BID.

Ruxolitinib 25 mg

PK Population. Only participants with available data were analyzed. To be able to form a meaningful statistical test with enough participants, participants across all treatment groups were combined according to the pre-Day 1 stable dose of ruxolitinib received for analysis.

Cmax of Ruxolitinib

Tmax of Ruxolitinib

Cmin of Ruxolitinib

AUC0-4h of Ruxolitinib

AUC0-t of Ruxolitinib

Clast of Ruxolitinib

Tlast of Ruxolitinib

Overall Study

The myeloproliferative neoplasms Cases will be tested for expression of heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) and K (HNRNPK) genes

Healthy controls will be tested for expression of heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) and K (HNRNPK) genes

Blood samples from the myeloproliferative neoplasms cases and the controls will be tested with Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) for expression of heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) and K (HNRNPK) genes.

Reverse transcription-quantitative polymerase chain reaction (RT-qPCR)

Alaa Elminshawy, MD, MSc

Alaa A. El-Minshawy, MsC

Alaa Elminshawy, MD, Mac

The aim of the study is to evaluate the expression pattern of heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) and K (HNRNPK) genes in Myeloproliferative neoplasms as a possible indicator of disease progression and as a potential therapeutic target

Self-renewing Hematopoietic pluripotent stem cells can develop into either myeloid or lymphoid lineages. A diverse range of diseases known as myeloproliferative neoplasms (MPNs) develop due to the aberrant proliferation of one or more terminal myeloid cell lines in the peripheral circulation. MPNs come in four traditional forms: chronic myeloid leukaemia (CML), polycythaemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Chronic neutrophilic leukaemia (CNL), chronic eosinophilic leukaemia (CEL), and MPN unclassifiable, were also included in the WHO classification. While PV, ET, and PMF are BCR-ABL1 negative, CML is BCR-ABL1 positive.

In eukaryotic cell's nucleus, many ribonucleoproteins (RNPs) assemble on to recently produced transcripts. The heterogeneous nuclear ribonucleoproteins (hnRNPs) are one type of RNPs. Some hnRNPs are now known to play a role in the development of human hematologic malignancies. Disease research is becoming more interested in how hnRNPs control gene expression. Numerous cancers exhibit changed hnRNPs expression levels, which raises the possibility that they play a part in carcinogenesis.

For instance, leukaemia cells showed downregulation of Heterogeneous nuclear ribonucleoprotein K (HNRNPK). In vivo myeloproliferative neoplasm tumour growth was accelerated by HNRNPK knockdown. On the other hand, A study suggests that HNRNPK overexpression could accelerate CML development and thus a possible indicator of CML progression and a potential therapeutic target might be HNRNPK.

Moreover, one of the earliest RNA-binding proteins (RBPs) to be identified, Heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) contributes to RNA stabilization, RNA editing, and RNA modification. Previous research has demonstrated that high levels of HNRNPH1 expression leads to carcinogenesis by both upregulating the expression of oncogenes and downregulating the expression of tumour suppressor genes such P53, Ron, and BCL-X.

The investigators performed the study with the aim to study the expression level of heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) and K (HNRNPK) genes and their proteins in MPNs and to investigate the association of HNRNPH1 and HNRNPK with molecular diagnostic tests of MPNs.

Expression Pattern of HNRNPH1 and HNRNPK Genes in MPNs

Expression Pattern of Heterogeneous Nuclear Ribonucleoprotein H1 (HNRNPH1) and K (HNRNPK) Genes in Myeloproliferative Neoplasms

There is not a plan to make IPD available

Expression levels of Heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) and Heterogeneous nuclear ribonucleoprotein K (HNRNPK) genes for diagnosis of myeloproliferative neoplasms.

Correlation between expression levels of HNRNPH1 and HNRNPK genes and molecular diagnostic tests for myeloproliferative neoplasms as Philadelphia chromosome or JAK2 V617F or JAK2 exon 12 mutation or CALR or MPL mutation according to the case

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Study of INCB050465 in Combination With Ruxolitinib in Subjects With Myelofibrosis	NCT02718300	MPN (Myeloproli...	Parsaclisib Parsaclisib Ruxolitinib Parsaclisib Parsaclisib	18 Years -	Incyte Corporation
Expression Pattern of HNRNPH1 and HNRNPK Genes in MPNs	NCT05782985	Myeloproliferat...	Reverse transcr...	-	Assiut University

Spots Global Cancer Trial Database for myeloproliferative neoplasms (mpns)