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

Sponsor

Incyte Corporation (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04551053

Collaborator

(none)

212

Enrollment

176

Locations

Arms

48.2

Anticipated Duration (Months)

1.2

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Myelofibrosis Primary Myelofibrosis Post Essential Thrombocythemia Myelofibrosis Post Polycythemia Vera Myelofibrosis	Drug: parsaclisib Drug: ruxolitinib Drug: placebo	Phase 3

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

212 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Investigator, Outcomes Assessor)

Masking Description:

Triple blind

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

May 26, 2021

Anticipated Primary Completion Date :

Nov 28, 2023

Anticipated Study Completion Date :

May 31, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group A : ruxolitinib +parsaclisib 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.	Drug: parsaclisib parsaclisib will be administered QD orally Other Names: INCB050465 Drug: ruxolitinib ruxolitinib will be administered BID orally Other Names: Jakafi Jakavi
Placebo Comparator: Group B : ruxolitinib + placebo 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.	Drug: ruxolitinib ruxolitinib will be administered BID orally Other Names: Jakafi Jakavi Drug: placebo placebo will be administered QD orally

Arm

Intervention/Treatment

Experimental: Group A : ruxolitinib +parsaclisib

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.

Drug: parsaclisib

parsaclisib will be administered QD orally

Other Names:

INCB050465

Drug: ruxolitinib

ruxolitinib will be administered BID orally

Other Names:

Jakafi

Jakavi

Placebo Comparator: Group B : ruxolitinib + placebo

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.

Drug: ruxolitinib

ruxolitinib will be administered BID orally

Other Names:

Jakafi

Jakavi

Drug: placebo

placebo will be administered QD orally

Outcome Measures

Primary Outcome Measures

Proportion of participants achieving targeted reduction in spleen volume [Baseline to Week 24]
Reduction in spleen volume is measured by Magnetic Resonance Imaging (MRI) or Computed Tomography (CT).

Secondary Outcome Measures

Proportion of participants who have a targeted reduction in Total Symptom Score (TSS) [Baseline to Week 24]
Reduction in TSS is measured by Myelofibrosis Symptom Assessment Form (MFSAF) v4.0.
Change in TSS [Baseline to Week 24]
Change in TSS is measured by Myelofibrosis Symptom Assessment Form (MFSAF) v4.0.
Time to the first ≥ 50% reduction in TSS [Baseline to Week 24]
Reduction in TSS is measured by Myelofibrosis Symptom Assessment Form (MFSAF) v4.0.
Overall Survival (OS) [Up to approximately 36 months]
OS is defined as randomization date to death due to any cause
Number of Treatment Emergent Adverse Events (TEAE) [Up to approximately 36 months]
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.
Time of onset of targeted reduction in spleen volume [Baseline to Week 108]
Reduction in spleen volume is measured by Magnetic Resonance Imaging (MRI) or Computed Tomography (CT).
Duration of maintenance of targeted reduction in spleen volume [Baseline to Week 108]
Reduction in spleen volume is measured by Magnetic Resonance Imaging (MRI) or Computed Tomography (CT).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Diagnosis of PMF, PPV-MF, or PET-MF.
DIPSS risk category of intermediate-1, intermediate-2, or high.
Treated with ruxolitinib for ≥ 3 months with a stable dose for at least the last 8 weeks prior to Day 1
Palpable spleen of ≥ 5 cm below the left costal margin on physical examination at the screening visit.
Active symptoms of MF at the screening visit, as demonstrated by the presence of a TSS of ≥ 10 using the Screening Symptom Form.
Participants with an ECOG performance status score of 0, 1, or 2.
Screening bone marrow biopsy specimen and pathology report(s) available that was obtained within the prior 2 months or willingness to undergo a bone marrow biopsy at screening/baseline; willingness to undergo bone marrow biopsy at Week 24 and every 24 weeks there after. Screening/baseline biopsy specimen must show diagnosis of MF.
Life expectancy of at least 24 weeks.
Willingness to avoid pregnancy or fathering children.

Exclusion Criteria:

Prior therapy with any drug that inhibits PI3K (examples of drugs targeting this pathway include but are not limited to INCB040093, idelalisib, duvelisib, buparlisib, copanlisib, and umbralisib).
Use of experimental drug therapy for MF or any other standard drug used for MF (whether for treatment of MF or another indication) with the exception of ruxolitinib, within 3 months of starting study drug, and/or lack of recovery from all toxicities from previous therapy (except ruxolitinib) to Grade 1 or better.
Inability to swallow food or any condition of the upper gastrointestinal tract that precludes administration of oral medications.
Recent history of inadequate bone marrow reserve.
Inadequate liver and renal function at screening.
Active bacterial, fungal, parasitic, or viral infection that requires therapy.
Active HBV or HCV infection that requires treatment or at risk for HBV reactivation.
Known HIV infection.
Uncontrolled, severe, or unstable cardiac disease that in the investigator's opinion may jeopardize the safety of the participant or compliance with the Protocol.
Active invasive malignancy over the previous 2 years.
Splenic irradiation within 6 months before receiving the first dose of study drug.
Concurrent use of any prohibited medications.
Active alcohol or drug addiction that would interfere with the ability to comply with the study requirements.
Use of any potent CYP3A4 inhibitors or inducers within 14 days or 5 half lives(whichever is longer) before the first dose of study drug or anticipated during the study.
Inadequate recovery from toxicity and/or complications from a major surgery before starting therapy.
Currently breastfeeding or pregnant.
Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study drug and attending required study visits; pose a significant risk to the participant; or interfere with interpretation of study data.
History of Grade 3 or 4 irAEs from prior immunotherapy.
Receipt of any live vaccine within 30 days of the first dose of study drug
Unwillingness to receive RBC transfusions to treat low hemoglobin levels.
Known hypersensitivity or severe reaction to parsaclisib or ruxolitinib or excipients of parsaclisib/matching placebo or ruxolitinib formulations.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sutter Health Alta Bates Summit Medical Center Absmc Alta Bates Summit Comprehensive Cancer Center	Berkeley	California	United States	94704
2	CCARE	Fresno	California	United States	93720
3	California Research Institute (Cri)	Los Angeles	California	United States	90027-6005
4	Emad Ibrahim Md Inc	Redlands	California	United States	92373
5	Scripps Clinic	San Diego	California	United States	92103
6	Coastal Integrated Cancer Care - Cicc	San Luis Obispo	California	United States	93401
7	Stamford Hospital - Medical Oncology Hematology	Stamford	Connecticut	United States	06904
8	Georgetown University	Washington	District of Columbia	United States	20057
9	Emory University	Atlanta	Georgia	United States	30322
10	Augusta University - Medical College of Georgia	Augusta	Georgia	United States	30912
11	Indiana University Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202
12	University of Kansas Hospital Authority	Westwood	Kansas	United States	66205
13	Tulane University	New Orleans	Louisiana	United States	70112
14	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
15	Beth Israel Deaconess	Boston	Massachusetts	United States	02215
16	Midamerica Cancer Care	Kansas City	Missouri	United States	64114
17	New Jersey Hematology Oncology Associates Llc	Brick	New Jersey	United States	08724
18	Morristown Medical Center - Atlantic Health System	Morristown	New Jersey	United States	07960
19	Montefiore Medical Center	Bronx	New York	United States	10467
20	Westchester Medical Center Advanced Oncology	Hawthorne	New York	United States	10532
21	Mount Sinai School of Medicine	New York	New York	United States	10029
22	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
23	Advent Health Hendersonville Park Ridge Hospital Hendersonville	Clyde	North Carolina	United States	28721
24	Duke Cancer Center	Durham	North Carolina	United States	27710
25	Cleveland Clinic	Cleveland	Ohio	United States	44195
26	Ohio State University	Columbus	Ohio	United States	43210
27	Oregon Health & Science University	Columbus	Ohio	United States	43210
28	Hillman Cancer Center	Pittsburgh	Pennsylvania	United States	15232
29	Baptist Cancer Center	Memphis	Tennessee	United States	38120
30	Texas Oncology - Medical City Dallas	Dallas	Texas	United States	75230
31	Texas Oncology - Baylor Sammons Cancer Center	Dallas	Texas	United States	75246-2092
32	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390-8565
33	Renovatio Clinical	Houston	Texas	United States	77005
34	Kelsey Seybold Clinic	Houston	Texas	United States	77025
35	Providence Regional Medical Center	Everett	Washington	United States	98201
36	Hanusch-Krankenhaus Wiener Gebietskrankenkasse	Wien		Austria	01140
37	A.Z. St.-Jan A.V.	Brugge		Belgium	08000
38	Jessa Ziekenhuis	Hasselt		Belgium	3500
39	AZ Delta	Roeselare		Belgium	8800
40	Chu Ucl Namur University Hospital Mont-Godinne	Yvoir		Belgium	05530
41	Peking University People'S Hospital (Pkuph) - Institute of Hematology	Beijing		China	100044
42	Xuanwu Hospital Capital Medical University	Beijing		China	100053
43	Peking University Third Hospital	Beijing		China	100091
44	Peking University Third Hospital	Beijing		China	100191
45	The First Hospital of Jilin University	Changchun		China	130021
46	The First Peoples Hospital of Changzhou	Changzhou		China	213003
47	Fujian Medical University Union Hospital	Fuzhou		China	350001
48	Nanfang Hospital	Guangzhou		China	510515
49	The First Affiliated Hospital of Zhejiang University	Hangzhou		China	310003
50	Harbin Institute of Hematology and Oncology	Harbin		China	150010
51	University of Science and Technology of China-First Affiliated Hospital (Anhui Provincial Hospital)	Hefei		China	230022
52	The Affiliated Hospital of Inner Mongolia Medical University	Hohhot		China	10050
53	Jinan Central Hospital	Jinan		China	250013
54	The Second Affiliated Hospital of Kunming Medical University	Kunming		China	650101
55	The First Hospital of Lanzhou University	Lanzhou		China	730000
56	Lanzhou University Second Hospital	Lanzhou		China	730030
57	Jiangxi Provincial of People Hospital	Nanchang		China	330000
58	The First Affiliated Hospital of Nanchang University	Nanchang		China	330006
59	Jiangsu Province Hospital	Nanjing		China	210029
60	The Affiliated Hospital of Qingdao University	Shandong		China	266071
61	The First Hospital of China Medical University	Shenyang		China	110001
62	Shenzhen University Hospital	Shenzhen		China	518055
63	Tianjin Medical University General Hospital	Tianjin		China	300052
64	Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Pek	Tianjin		China	510080
65	Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology	Wuhan		China	430022
66	Tongji Hospital Huazhong University of Science and Technology	Wuhan		China	430030
67	The Second Affiliated Hospital of Xi an Jiaotong University	Xi'an		China	710004
68	Yantai Yuhuangding Hospital	Yantai		China	264000
69	Henan Provincial Peoples Hospital	Zhengzhou		China	450003
70	Henan Cancer Hostipal	Zhengzhou		China	450008
71	Helsinki University Central Hospital	Helsinki		Finland	FI-00029
72	Centre Hospitalier Universitaire Grenoble Alpes (Chu Grenoble Alpes) - Hopital Albert Michallon	La Tronche		France	38700
73	Chu de Limoges	Limoges Cedex		France	87042
74	CHU Limoges - Hopital Duputren	Limoges Cedex		France	87042
75	Centre Hospitalier Universitaire de Nantes (Chu de Nantes) - Hotel-Dieu	Nantes		France	44093
76	Chu Nimes	Nimes		France	30900
77	Ap-Hp Groupe Hospitalier Saint-Louis Lariboisiere Fernand-Widal Site Saint Louis (Paris)	Paris		France	75010
78	Hospital Saint Antoine	Paris		France	75012
79	Hospices Civils de Lyon Centre Hospitalier Lyon Sud	Pierre-Benite		France	69495
80	Institut Universitaire Du Cancer de Toulouse Oncopole	Toulouse		France	31059
81	Chu Vandoeuvre-Les-Nancy Hopital Brabois	Vandoeuvre-les-nancy		France	54500
82	Universitatsklinikum Bonn Aoer	Bonn		Germany	53127
83	Universitaetsmedizin Greifswald	Greifswald		Germany	17475
84	Universitatsklinikum Halle (Saale)	Halle (saale)		Germany	06120
85	Universitaetsmedizin Rostock	Rostock		Germany	18057
86	Semmelweis Egyetem	Budapest		Hungary	01083
87	Markhot Ferenc Korhaz	Eger		Hungary	3300
88	Petz Aladar County Teaching Hospital	Gyor		Hungary	09024
89	Samson Assuta Ashdod University Hospital	Ashdod		Israel	7747629
90	Rambam Health Care Campus	Haifa		Israel	31999
91	Hadassah Hebrew University Medical Center Ein Karem Hadassah	Jerusalem		Israel	91120
92	Kaplan Medical Center	Rehovot		Israel	76100
93	Tel Aviv Sourasky Medical Center	Tel Aviv		Israel	64239
94	Assuta Ramat Hahayal	Tel Aviv		Israel	69710
95	Azienda Ospedaliera San Giuseppe Moscati	Avellino		Italy	83100
96	Piazza Giulo Cesare 11	Bari		Italy	70124
97	Lstituto Di Ematologia Lorenzo Ea.Seragnoli Universita Degli Studi Di Bologna - Policlinico S. Or	Bologna		Italy	40138
98	Azienda Ospedaliera Di Rilievo Nazionale E Di Alta Specializzazione Garibaldi	Catania		Italy	11111
99	University of Florence	Florence		Italy	50134
100	Irccs Azienda Ospedaliera Universitaria San Martino	Genova		Italy	16132
101	Fondazione Irccs Ca Granda Ospedale Maggiore	Milano		Italy	20122
102	Universita Di Napoli Federico Ii	Napoli		Italy	80131
103	Azienda Ospedaliero Universitaria Maggiore Della Carita Di Novara	Novara		Italy	28100
104	Azienda Ospedaliera Ospedali Riuniti Villa Sofia - Cervello	Palermo		Italy	90146
105	Ospedale S.Maria Della Misericordia	Perugia		Italy	06156
106	Ospedale S.Maria Della Misericordia	Perugia		Italy	6156
107	Presidio Ospedaliero Pescara	Pescara		Italy	65124
108	Azienda Ospedaliero Universitaria Pisana	Pisa		Italy	56126
109	Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli	Reggio Calabria		Italy	89133
110	Univ. Di Roma Facolta Di Armacia E Medicina	Roma		Italy	00161
111	Policlinico Universitario Agostino Gemelli Universita Cattolica Del Sacro Cuore	Roma		Italy	00168
112	Ospedale Sant. Eugenio	Roma		Italy	144
113	Policlinico Universitario Agostino Gemelli Universita Cattolica Del Sacro Cuore	Rome		Italy	00168
114	Azienda Ospedaliera Universitaria Senese Policlinico Santa Maria Alle Scotte	Siena		Italy	53100
115	Azienda Ospedaliera San Giuseppe Moscati	Taranto		Italy	74123
116	Azienda Sanitaria Universitaria Friuli Centrale Asu Fc	Udine		Italy	33100
117	A.O. Universitaria Ospedale Di Circolo E Fondazione Macchi	Varese		Italy	21100
118	Kyushu University Hospital	Fukuoka		Japan	812-8582
119	Japanese Red Cross Society Himeji Hospital	Himeji-shi		Japan	670-8540
120	Kansai Medical University Hospital	Hirakata		Japan	573-1191
121	Tokai University Hospital	Isehara		Japan	2591193
122	Juntendo University Hospital	Izunokuni		Japan	410-2211
123	Kagoshima University Hospital	Kagoshima		Japan	890-8520
124	Hospital of the University of Occupation and Environmental Health	Kitakyushu-shi		Japan	807-8556
125	Kobe City Medical Center General Hospital	Kobe-shi		Japan	650-0047
126	University of Miyazaki Hospital	Miyazaki		Japan	889-1692
127	Japanese Red Cross Nagoya Daini Hospital	Nagoya-shi		Japan	453-8511
128	Ogaki Municipal Hospital	Ogaki		Japan	5038502
129	Osaka Metropolitan University Hospital	Osaka		Japan	545-8585
130	Dokkyo Medical University Saitama Medical Center	Saitama		Japan	343-8555
131	Hokuyukai Sapporo Hokuyu Hospital	Sapporo		Japan	003-0006
132	Juntendo University Hospital	Tokyo		Japan	113-8431
133	Nippon Medical School Hospital	Tokyo		Japan	113-8603
134	University of Yamanashi Hospital	Yamanashi		Japan	409-3898
135	Pusan National University Yangsan Hospital	Busan		Korea, Republic of	49241
136	Seoul National University Hospital	Seoul		Korea, Republic of	03080
137	Samsung Medical Center	Seoul		Korea, Republic of	06351
138	The Catholic University of Korea Seoul St. Mary?S Hospital	Seoul		Korea, Republic of	06591
139	Haukeland University Hospital	Bergen		Norway	05021
140	Akershus University Hospital	Lorenskog		Norway	01478
141	Pratia Hematologia Katowice	Katowice		Poland	41-081
142	Pratia Hematologia Katowice	Katowice		Poland	41-519
143	Sp Zoz Szpital Uniwersytecki	Krakow		Poland	31-501
144	Samodzielny Publiczny Szpital Kliniczny Nr 1	Lublin		Poland	20-081
145	Institute of Hematology and Transfusion Medicine	Warszawa		Poland	02-776
146	Spitalul Clinic Coltea - Clinica Hematologie	Bucharest		Romania	30171
147	Spitalul Clinic Judetean de Urgenta Targu Mures	Târgu Mureș		Romania	540139
148	Hospital General Unviersitario de Alicante	Alicante		Spain	03010
149	Ico Hospital Germans Trias I Pujol	Badalona		Spain	08916
150	Hospital Del Mar	Barcelona		Spain	08003
151	Hospital General Universitario Vall D Hebron	Barcelona		Spain	08035
152	Institut Catala Doncologia Ico - Hospital Duran I Reynals Location	Barcelona		Spain	08908
153	Hospital Universitario Insular de Gran Canaria	Las Palmas de Gran Canaria		Spain	35010
154	Hospital Universitario 12 de Octubre	Madrid		Spain	24041
155	Fundacion Jimenez Diaz University Hospital	Madrid		Spain	28040
156	Hospital General Universitario Morales Meseguer	Murcia		Spain	30008
157	Hospital Universitario Virgen de La Arrixaca	Murcia		Spain	30120
158	Hospital Clinico Universitario de Salamanca	Salamanca		Spain	37007
159	Hospital Universitario Virgen Del Rocio	Sevilla		Spain	41013
160	Hospital Universitari I Politecnic La Fe	Valencia		Spain	46000
161	Hospital Universitario Doctor Peset	Valencia		Spain	46017
162	Hospital Universitario Miguel Servet	Zaragoza		Spain	50009
163	Kaohsiung Chang Gung Memorial Hospital	Kaohsiung City		Taiwan	83301
164	China Medical University Hospital	Taichung		Taiwan	00404
165	National Cheng Kung University (Ncku) Hospital	Tainan		Taiwan	00704
166	Baskent University Adana Hospital	Adana		Turkey	01250
167	Gazi University Hospital Gazi University Faculty of Medicine	Ankara		Turkey	06500
168	Istanbul Medipol Universitesi Ibagcilar Medipol Mega Universitesi Hastanesi	Istanbul		Turkey	34214
169	Baskent University Istanbul Hospital	Istanbul		Turkey	34662
170	Ege Univ. Hospital	Izmir		Turkey	35040
171	Ondokuz Mayis University Medicine Faculty	Samsun		Turkey	55200
172	Grampian Health Board	Aberdeen		United Kingdom	AB15 6RE
173	United Lincolnshire Hospitals	Boston		United Kingdom	PE21 9QS
174	Gloucestershire Royal Hospital	Gloucester		United Kingdom	GL1 3NN
175	University College London Hospitals Nhs Foundation Trust	London		United Kingdom	NW1 2BU
176	James Cook University Hospital	Middlesborough		United Kingdom	TS4 3BW