A Study Evaluating Tolerability and Efficacy of Navitoclax Alone or in Combination With Ruxolitinib in Participants With Myelofibrosis

Myelofibrosis (MF) Clinical Trial

— REFINE  

Official title:

A Phase 2 Open-Label Study Evaluating Tolerability and Efficacy of Navitoclax Alone or in Combination With Ruxolitinib in Subjects With Myelofibrosis (REFINE)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03222609
• Other study ID #: M16-109
• Secondary ID: 2017-001398-17
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: October 31, 2017
• Est. completion date: February 2, 2029

Study information

• Verified date: March 2023
• Source: AbbVie
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a Phase 2 open-label, multicenter study evaluating tolerability and efficacy of navitoclax alone or when added to ruxolitinib in participants with myelofibrosis.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 191
• Est. completion date: February 2, 2029
• Est. primary completion date: March 28, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Participants with documented diagnosis of intermediate-2 or high-risk primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis or Post-essential Thrombocythemia Myelofibrosis.
• Participant must be ineligible due to age, comorbidities, or unfit for unrelated or unmatched donor transplantation or unwilling to undergo stem cell transplantation at time of study entry.
• Eastern Cooperative Oncology Group (ECOG) of 0, 1, or 2.
• Prior treatment must meet at least one of the following criteria:
• Prior or current treatment with ruxolitinib and no prior treatment with a Bromodomain and Extra-Terminal motif (BET) proteins inhibitor or another Janus

Kinase 2 (JAK-2) inhibitor, and meet all of the following criteria:

• Ruxolitinib treatment must meet at least one of the following criteria:
• Ruxolitinib treatment for >=24 weeks with lack of efficacy defined as a lack of spleen response (refractory) or a loss of spleen or symptom response (relapsed)
• Ruxolitinib treatment for <24 weeks with documented disease progression

on spleen measurements while on ruxolitinib as defined in the protocol:

• Ruxolitinib treatment for >=28 days with intolerance defined as new red blood cell transfusion requirement (at least 2 units/month for 2 months) while receiving a total daily ruxolitinib dose of >=30 mg but unable to reduce dose further due to lack of efficacy.
• If receiving ruxolitinib at the time of screening, must currently be on a stable dose >=10 mg twice daily of ruxolitinib for >=4 weeks prior to the 1st dose of navitoclax.
• Participant has at least 2 symptoms each with a score >=3 or a total score of >=12, as measured by the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 on at least 4 out of 7 days during screening prior to study drug dosing; OR
• Prior treatment with a JAK-2 inhibitor and meet one of the following criteria:
• Prior treatment with a JAK-2 inhibitor for at least 12 weeks
• Prior treatment with a JAK-2 inhibitor for >=28 days complicated by either development of red blood cell transfusion requirement (at least 2 units/month for 2 months) OR Grade >= 3 adverse events of thrombocytopenia, anemia, hematoma and/or hemorrhage while on JAK-2 inhibitor treatment; OR
• No prior treatment with a JAK-2 or BET inhibitor:
• Participant has at least 2 symptoms each with a score >=3 or a total score of >= 12, as measured by the MFSAF v4.0 on at least 4 out of 7 days during screening prior to study drug dosing.
• Participant has splenomegaly as defined in the protocol.
• Participant must meet the laboratory parameters (adequate bone marrow, renal and hepatic function) as defined in the protocol.

Exclusion Criteria:

• Splenic irradiation within 6 months prior to screening, or prior splenectomy.
• Leukemic transformation (> 10% blasts in peripheral blood or bone marrow aspirate/biopsy).
• Participant is currently on medications that interfere with coagulation (including warfarin) or platelet function within 3 days prior to the first dose of study drug or during the study treatment period with the exception of low dose aspirin (up to 100 mg/day) and low-molecular-weight heparin.
• Prior therapy with a BH3 mimetic compound or stem cell transplantation.
• Participant has received strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin) or moderate CYP3A inhibitors (e.g., fluconazole) within 14 days prior to the administration of the first dose of study drug.

Related Conditions & MeSH terms

• Myelofibrosis (MF)
• Primary Myelofibrosis

Intervention

Drug:
• Ruxolitinib
Tablet; Oral
• Navitoclax
Tablet; Oral

Locations

Country	Name	City	State
Australia	The Kinghorn Cancer Centre /ID# 214657	Darlinghurst	New South Wales
Australia	Barwon Health /ID# 222430	Geelong	Victoria
Australia	Alfred Health /ID# 215545	Melbourne	Victoria
Australia	Peter MacCallum Cancer Ctr /ID# 218352	Melbourne	Victoria
Australia	Fiona Stanley Hospital /ID# 216809	Murdoch	Western Australia
Belgium	AZ Klina /ID# 230592	Brasschaat
Bulgaria	UMHAT Sveti Ivan Rilski /ID# 231163	Sofia
Bulgaria	UMHAT Sveta Marina /ID# 231411	Varna
Canada	University of Alberta Hospital - Division of Hematology /ID# 217698	Edmonton	Alberta
Canada	Jewish General Hospital /ID# 217586	Montreal	Quebec
Canada	McGill University Health Center Research Institute /ID# 223976	Montreal	Quebec
Canada	Princess Margaret Cancer Centre /ID# 214483	Toronto	Ontario
Croatia	Klinicki bolnicki centar Split /ID# 230601	Split
Croatia	Klinicka bolnica Dubrava Zagreb /ID# 230504	Zagreb	Grad Zagreb
Croatia	Klinicka bolnica Merkur /ID# 230599	Zagreb	Grad Zagreb
Croatia	Klinicki bolnicki centar Zagreb /ID# 230602	Zagreb	Grad Zagreb
France	Centre Hospitalier de CHAMBERY /ID# 230889	Chambery
France	CHU de Nimes /ID# 230888	Nimes
France	AP-HP - Hopital Necker /ID# 230900	Paris
France	Hopital Saint Louis /ID# 230887	Paris
Greece	General Hospital of Athens Evaggelismos and Ophthalmiatrio of Athens Polyclinic /ID# 230393	Athens
Greece	General Hospital of Athens Laiko /ID# 230394	Athens	Attiki
Greece	University General Hospital Attikon /ID# 230395	Athens	Attiki
Hungary	Semmelweis Egyetem /ID# 230518	Budapest
Hungary	Del-pesti Centrumkorhaz - Orszagos Hematologiai es Infektologiai Intezet /ID# 230306	Budapest IX	Budapest
Hungary	Szabolcs - Szatmar - Bereg Megyei Korhazak es Egyetemi Oktatokorhaz, Josa Andras /ID# 230585	Nyiregyhaza
Israel	Assuta Ashdod Medical Center /ID# 230396	Ashdod
Israel	Hadassah Medical Center-Hebrew University /ID# 230310	Jerusalem	Yerushalayim
Israel	Galilee Medical Center /ID# 230397	Nahariya
Israel	Tel Aviv Sourasky Medical Center /ID# 230311	Tel Aviv
Italy	ASST Papa Giovanni XXIII /ID# 214900	Bergamo
Italy	A.O.U. di Bologna Policlinico S.Orsola-Malpighi /ID# 230012	Bologna
Italy	A.O.U. Policlinico S.Orsola-Malpighi /ID# 230012	Bologna	Emilia-Romagna
Italy	ASST Spedali civili di Brescia /ID# 230420	Brescia
Italy	A.O.U. Policlinico G. Rodolico S.Marco- Presidio G.Rodolico /ID# 214549	Catania
Italy	Azienda Ospedaliero Universitaria Careggi /ID# 214555	Florence
Italy	Grande Ospedale Metropolitano-Bianchi-Melacrino /ID# 230011	Reggio Calabria
Italy	Fondazione Policlinico Universitario Agostino Gemelli IRCCS-Università Cattolica /ID# 214553	Rome	Lazio
Italy	ASST Sette Laghi /ID# 214551	Varese
Japan	Aomori Prefectural Central Hospital /ID# 221773	Aomori-shi	Aomori
Japan	Juntendo University Hospital /ID# 221484	Bunkyo-ku	Tokyo
Japan	Nippon Medical School Hospital /ID# 222692	Bunkyo-ku	Tokyo
Japan	University of Yamanashi Hospital /ID# 221700	Chuo-shi	Yamanashi
Japan	Kyushu University Hospital /ID# 222691	Fukuoka-shi	Fukuoka
Japan	Kansai Medical University Hospital /ID# 222690	Hirakata-shi	Osaka
Japan	Dokkyo Medical University Saitama Medical Center /ID# 222332	Koshigaya-shi	Saitama
Japan	Kindai University Hospital /ID# 222689	Osakasayama-shi	Osaka
Japan	Keiyukai Daini Hospital /ID# 222693	Sapporo-shi	Hokkaido
Japan	Fujita Health University Hospital /ID# 221539	Toyoake-shi	Aichi
Korea, Republic of	Samsung Medical Center /ID# 230381	Seoul
Korea, Republic of	Seoul National University Hospital /ID# 230380	Seoul
Poland	ARS-MEDICAL Sp. z o.o. /ID# 230809	Pila	Wielkopolskie
Puerto Rico	Hospital del Centro Comprensivo de Cancer de la UPR /ID# 222544	San Juan
Puerto Rico	VA Caribbean Healthcare System /ID# 222416	San Juan
Russian Federation	City Clinical Hospital named after S.P. Botkin /ID# 230508	Moscow
Russian Federation	Heart Blood and Endocrinology Federal Center n.a. V.A. Almazov /ID# 230506	Saint Petersburg
Russian Federation	Leningrad Regional Clinical Hospital /ID# 230507	Saint Petersburg
Serbia	Clin Hosp Ctr Bezanijska Kosa /ID# 230681	Belgrade	Beograd
Serbia	University Clinical Center Serbia /ID# 230629	Belgrade	Beograd
Serbia	University Clinical Center Kragujevac /ID# 230550	Kragujevac	Sumadijski Okrug
Serbia	Clinical Center Vojvodina /ID# 230525	Novi Sad	Vojvodina
Spain	Hospital Universitario Germans Trias i Pujol /ID# 214704	Badalona	Barcelona
Spain	Hospital Clinic de Barcelona /ID# 231538	Barcelona
Spain	Hospital Universitario Vall d'Hebron /ID# 222415	Barcelona
Spain	CLINICA UNIVERSIDAD DE NAVARRA-Madrid /ID# 230719	Madrid
Spain	Hospital General Universitario Gregorio Maranon /ID# 214676	Madrid
Spain	Hospital Universitario 12 de Octubre /ID# 214710	Madrid
Spain	Hospital Universitario Virgen de la Victoria /ID# 214709	Malaga
Spain	Hospital Regional de Malaga /ID# 230858	Málaga	Malaga
Spain	Hospital Universitario Central de Asturias /ID# 230884	Oviedo	Asturias
Spain	CLINICA UNIVERSIDAD DE NAVARRA-Pamplona /ID# 230718	Pamplona	Navarra, Comunidad
Taiwan	Kaohsiung Chang Gung Memorial Hospital /ID# 230371	Kaohsiung
Taiwan	National Cheng Kung University Hospital /ID# 230372	Tainan City
Turkey	Ankara Universitesi Fakultesi /ID# 230317	Ankara
Turkey	Adnan Menderes University /ID# 230777	Aydin
Turkey	Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty /ID# 230318	Istanbul
Turkey	Dokuz Eylul University Medical Faculty /ID# 231321	Izmir
Turkey	Ondokuz mayis University Facul /ID# 230314	Samsun
United Kingdom	Belfast Health and Social Care Trust /ID# 216991	Belfast
United Kingdom	Guy's and St Thomas' NHS Foundation Trust /ID# 164110	London	London, City Of
United Kingdom	The Christie Hospital /ID# 164111	Manchester
United Kingdom	Aneurin Bevan University Health Board /ID# 230332	Newport
United Kingdom	Oxford Univ Hosp NHS Trust /ID# 214503	Oxford	Oxfordshire
United States	Texas Oncology - West Texas /ID# 224784	Abilene	Texas
United States	University Cancer & Blood Center /ID# 230939	Athens	Georgia
United States	New Jersey Cancer Care & Blood Disorders /ID# 230925	Belleville	New Jersey
United States	Bend Memorial Clinic /ID# 224184	Bend	Oregon
United States	The Center for Cancer and Blood Disorders a division of American Oncology Partners of Maryland, PA /ID# 231299	Bethesda	Maryland
United States	UAB Comprehensive Cancer Cente /ID# 165464	Birmingham	Alabama
United States	Central Care Cancer Center /ID# 230913	Bolivar	Missouri
United States	Dana-Farber Cancer Institute /ID# 162675	Boston	Massachusetts
United States	Medical University of South Carolina /ID# 222597	Charleston	South Carolina
United States	University of Chicago Medicine /ID# 164115	Chicago	Illinois
United States	Univ Hosp Cleveland: Seidman Cancer Center /ID# 230938	Cleveland	Ohio
United States	OhioHealth /ID# 230928	Columbus	Ohio
United States	The Ohio State University /ID# 217402	Columbus	Ohio
United States	Pontchartrain Cancer Center /ID# 230932	Covington	Louisiana
United States	Mary Crowley Cancer Research /ID# 230923	Dallas	Texas
United States	Texas Oncology- Baylor Charles A. Sammons Cancer Center /ID# 225159	Dallas	Texas
United States	Colorado Blood Cancer Institute /ID# 224250	Denver	Colorado
United States	Henry Ford Hospital /ID# 162682	Detroit	Michigan
United States	City of Hope /ID# 221395	Duarte	California
United States	Southcoast Health Cancer Center /ID# 230934	Fairhaven	Massachusetts
United States	Summit Medical Group /ID# 230937	Florham Park	New Jersey
United States	Holy Cross Hospital /ID# 230922	Fort Lauderdale	Florida
United States	Fort Wayne Medical Oncology /ID# 230919	Fort Wayne	Indiana
United States	Frederick Health /ID# 230920	Frederick	Maryland
United States	Hematology Oncology Associates of Fredericksburg /ID# 231372	Fredericksburg	Virginia
United States	St. Joseph Heritage Healthcare /ID# 230935	Fullerton	California
United States	Gettysburg Cancer Center /ID# 230921	Gettysburg	Pennsylvania
United States	Southeastern Medical Oncology Center /ID# 230954	Goldsboro	North Carolina
United States	St Francis Cancer Center /ID# 230254	Greenville	South Carolina
United States	MD Anderson Cancer Center at Texas Medical Center /ID# 162683	Houston	Texas
United States	Oncology Consultants /ID# 230930	Houston	Texas
United States	Community Health Network /ID# 230915	Indianapolis	Indiana
United States	Indiana Blood & Marrow Transpl /ID# 165075	Indianapolis	Indiana
United States	Baptist MD Anderson Cancer Center - Jacksonville /ID# 222548	Jacksonville	Florida
United States	Cancer Specialists of North Florida /ID# 230917	Jacksonville	Florida
United States	Mayo Clinic /ID# 164201	Jacksonville	Florida
United States	Capital Region Medical Center /ID# 232627	Jefferson City	Missouri
United States	MidAmerica Division, Inc. /ID# 222058	Kansas City	Missouri
United States	Moore UC San Diego Cancer Center /ID# 164084	La Jolla	California
United States	Comprehensive Cancer Centers of Nevada /ID# 230916	Las Vegas	Nevada
United States	Long Beach Memorial Medical Ct /ID# 230148	Long Beach	California
United States	Universtiy of Southern California /ID# 164095	Los Angeles	California
United States	Tennessee Oncology-Nashville Centennial /ID# 221410	Nashville	Tennessee
United States	Weill Cornell Medical College /ID# 162679	New York	New York
United States	Mid Illinois Hematology & Oncology Associates, Ltd /ID# 230536	Normal	Illinois
United States	Eastern Connecticut Hematology and Oncology Associates /ID# 230918	Norwich	Connecticut
United States	Ocala Oncology Florida Cancer Affiliates /ID# 230927	Ocala	Florida
United States	Community Cancer Trials of Utah /ID# 230914	Ogden	Utah
United States	Ventura Oncology /ID# 230940	Oxnard	California
United States	West Penn Hospital /ID# 222618	Pittsburgh	Pennsylvania
United States	Heartland Regional Medical Center, St.Joseph Mosaic Life Care Cancer Care / ID# 230924	Saint Joseph	Missouri
United States	Oregon Oncology Specialists /ID# 230931	Salem	Oregon
United States	University of Utah /ID# 164116	Salt Lake City	Utah
United States	Utah Cancer Specialists Salt Lake Clinic /ID# 222806	Salt Lake City	Utah
United States	University of Texas Health San Antonio MD Anderson Cancer Center /ID# 164094	San Antonio	Texas
United States	St Joseph Heritage Healthcare /ID# 230936	Santa Rosa	California
United States	Avera Cancer Institute /ID# 222364	Sioux Falls	South Dakota
United States	Sanford Cancer Center /ID# 230933	Sioux Falls	South Dakota
United States	Memorial Hospital of South Bend /ID# 230912	South Bend	Indiana
United States	Ascension Providence Southfield Cancer Center /ID# 223876	Southfield	Michigan
United States	Northwest Medical Specialties /ID# 230926	Tacoma	Washington
United States	Moffitt Cancer Center /ID# 164082	Tampa	Florida
United States	Oklahoma Cancer Specialists /ID# 230929	Tulsa	Oklahoma
United States	Carle Cancer Institute /ID# 230571	Urbana	Illinois
United States	Prairie Lakes Healthcare System /ID# 224358	Watertown	South Dakota
United States	Icri /Id# 222546	Whittier	California
United States	University of Massachusetts Wo /ID# 222547	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
AbbVie

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Bulgaria,  Canada,  Croatia,  France,  Greece,  Hungary,  Israel,  Italy,  Japan,  Korea, Republic of,  Poland,  Puerto Rico,  Russian Federation,  Serbia,  Spain,  Taiwan,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants who achieve Spleen Volume Reduction of greater than or equal to 35% (SVR35) from baseline	Reduction in spleen volume is measured by magnetic resonance imaging/computerized tomography (MRI/CT).	From Baseline (Week 0) through Week 24
Secondary	Percentage of participants achieving 50% Reduction in Total System Score (TSS)	TSS is assessed by the Myelofibrosis Symptom Assessment Form (MFSAF) version 4.0.	From Baseline (Week 0) through Week 24
Secondary	Anemia Response	The anemia response will be assessed according to current International Working Group-Myeloproliferative Neoplasms Research and European LeukemiaNet (IWG-MRT/ELN) criteria.	Every 12 weeks up to approximately 96 weeks
Secondary	Change in Grade of Bone Marrow Fibrosis	Bone marrow grading is assessed according to the European Consensus Grading System.	Through Week 96