A Study Evaluating Tolerability and Efficacy of Navitoclax Alone or in Combination With Ruxolitinib in Participants With Myelofibrosis (REFINE)
Myelofibrosis (MF)
About this trial
This is an interventional treatment trial for Myelofibrosis (MF) focused on measuring Post-polycythemia vera MF (PPV-MF), Post-essential thrombocythemia (PET-MF), ruxolitinib, navitoclax, splenic volume, Primary Myelofibrosis, Jakafi, enlarged spleen, splenomegaly, ABT 263, bone marrow fibrosis
Eligibility Criteria
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.
Sites / Locations
- UAB Comprehensive Cancer Cente /ID# 165464
- City of Hope /ID# 221395
- St. Joseph Heritage Healthcare /ID# 230935
- Moore UC San Diego Cancer Center /ID# 164084
- Long Beach Memorial Medical Ct /ID# 230148
- Universtiy of Southern California /ID# 164095
- Ventura Oncology /ID# 230940
- St Joseph Heritage Healthcare /ID# 230936
- Icri /Id# 222546
- Colorado Blood Cancer Institute /ID# 224250
- Eastern Connecticut Hematology and Oncology Associates /ID# 230918
- Holy Cross Hospital /ID# 230922
- Baptist MD Anderson Cancer Center - Jacksonville /ID# 222548
- Mayo Clinic /ID# 164201
- Cancer Specialists of North Florida /ID# 230917
- Ocala Oncology Florida Cancer Affiliates /ID# 230927
- Moffitt Cancer Center /ID# 164082
- University Cancer & Blood Center /ID# 230939
- University of Chicago Medicine /ID# 164115
- Mid Illinois Hematology & Oncology Associates, Ltd /ID# 230536
- Carle Cancer Institute /ID# 230571
- Fort Wayne Medical Oncology /ID# 230919
- Indiana Blood & Marrow Transpl /ID# 165075
- Community Health Network /ID# 230915
- Memorial Hospital of South Bend /ID# 230912
- Pontchartrain Cancer Center /ID# 230932
- The Center for Cancer and Blood Disorders a division of American Oncology Partners of Maryland, PA /ID# 231299
- Frederick Health /ID# 230920
- Dana-Farber Cancer Institute /ID# 162675
- Southcoast Health Cancer Center /ID# 230934
- University of Massachusetts Wo /ID# 222547
- Henry Ford Hospital /ID# 162682
- Ascension Providence Southfield Cancer Center /ID# 223876
- Central Care Cancer Center /ID# 230913
- Capital Region Medical Center /ID# 232627
- MidAmerica Division, Inc. /ID# 222058
- Heartland Regional Medical Center, St.Joseph Mosaic Life Care Cancer Care / ID# 230924
- Comprehensive Cancer Centers of Nevada /ID# 230916
- New Jersey Cancer Care & Blood Disorders /ID# 230925
- Summit Medical Group /ID# 230937
- Weill Cornell Medical College /ID# 162679
- Southeastern Medical Oncology Center /ID# 230954
- Univ Hosp Cleveland: Seidman Cancer Center /ID# 230938
- The Ohio State University /ID# 217402
- OhioHealth /ID# 230928
- Oklahoma Cancer Specialists /ID# 230929
- Bend Memorial Clinic /ID# 224184
- Oregon Oncology Specialists /ID# 230931
- Gettysburg Cancer Center /ID# 230921
- West Penn Hospital /ID# 222618
- Medical University of South Carolina /ID# 222597
- St Francis Cancer Center /ID# 230254
- Sanford Cancer Center /ID# 230933
- Avera Cancer Institute /ID# 222364
- Prairie Lakes Healthcare System /ID# 224358
- Tennessee Oncology-Nashville Centennial /ID# 221410
- Texas Oncology - West Texas /ID# 224784
- Mary Crowley Cancer Research /ID# 230923
- Texas Oncology- Baylor Charles A. Sammons Cancer Center /ID# 225159
- Oncology Consultants /ID# 230930
- MD Anderson Cancer Center at Texas Medical Center /ID# 162683
- University of Texas Health San Antonio MD Anderson Cancer Center /ID# 164094
- Community Cancer Trials of Utah /ID# 230914
- Utah Cancer Specialists Salt Lake Clinic /ID# 222806
- University of Utah /ID# 164116
- Hematology Oncology Associates of Fredericksburg /ID# 231372
- Northwest Medical Specialties /ID# 230926
- The Kinghorn Cancer Centre /ID# 214657
- Barwon Health /ID# 222430
- Peter MacCallum Cancer Ctr /ID# 218352
- Alfred Health /ID# 215545
- Fiona Stanley Hospital /ID# 216809
- AZ Klina /ID# 230592
- UMHAT Sveti Ivan Rilski /ID# 231163
- UMHAT Sveta Marina /ID# 231411
- University of Alberta Hospital - Division of Hematology /ID# 217698
- Princess Margaret Cancer Centre /ID# 214483
- Jewish General Hospital /ID# 217586
- McGill University Health Center Research Institute /ID# 223976
- Klinicka bolnica Dubrava Zagreb /ID# 230504
- Klinicka bolnica Merkur /ID# 230599
- Klinicki bolnicki centar Zagreb /ID# 230602
- Klinicki bolnicki centar Split /ID# 230601
- Centre Hospitalier de CHAMBERY /ID# 230889
- CHU de Nimes /ID# 230888
- AP-HP - Hopital Necker /ID# 230900
- Hopital Saint Louis /ID# 230887
- General Hospital of Athens Laiko /ID# 230394
- University General Hospital Attikon /ID# 230395
- General Hospital of Athens Evaggelismos and Ophthalmiatrio of Athens Polyclinic /ID# 230393
- Del-pesti Centrumkorhaz - Orszagos Hematologiai es Infektologiai Intezet /ID# 230306
- Semmelweis Egyetem /ID# 230518
- Szabolcs - Szatmar - Bereg Megyei Korhazak es Egyetemi Oktatokorhaz, Josa Andras /ID# 230585
- Hadassah Medical Center-Hebrew University /ID# 230310
- Assuta Ashdod Medical Center /ID# 230396
- Galilee Medical Center /ID# 230397
- Tel Aviv Sourasky Medical Center /ID# 230311
- A.O.U. Policlinico S.Orsola-Malpighi /ID# 230012
- Fondazione Policlinico Universitario Agostino Gemelli IRCCS-Università Cattolica /ID# 214553
- ASST Papa Giovanni XXIII /ID# 214900
- A.O.U. di Bologna Policlinico S.Orsola-Malpighi /ID# 230012
- ASST Spedali civili di Brescia /ID# 230420
- A.O.U. Policlinico G. Rodolico S.Marco- Presidio G.Rodolico /ID# 214549
- Azienda Ospedaliero Universitaria Careggi /ID# 214555
- Grande Ospedale Metropolitano-Bianchi-Melacrino /ID# 230011
- ASST Sette Laghi /ID# 214551
- Fujita Health University Hospital /ID# 221539
- Aomori Prefectural Central Hospital /ID# 221773
- Kyushu University Hospital /ID# 222691
- Keiyukai Daini Hospital /ID# 222693
- Kansai Medical University Hospital /ID# 222690
- Kindai University Hospital /ID# 222689
- Dokkyo Medical University Saitama Medical Center /ID# 222332
- Juntendo University Hospital /ID# 221484
- Nippon Medical School Hospital /ID# 222692
- University of Yamanashi Hospital /ID# 221700
- Seoul National University Hospital /ID# 230380
- Samsung Medical Center /ID# 230381
- ARS-MEDICAL Sp. z o.o. /ID# 230809
- VA Caribbean Healthcare System /ID# 222416
- Hospital del Centro Comprensivo de Cancer de la UPR /ID# 222544
- City Clinical Hospital named after S.P. Botkin /ID# 230508
- Leningrad Regional Clinical Hospital /ID# 230507
- Heart Blood and Endocrinology Federal Center n.a. V.A. Almazov /ID# 230506
- University Clinical Center Serbia /ID# 230629
- Clin Hosp Ctr Bezanijska Kosa /ID# 230681
- University Clinical Center Kragujevac /ID# 230550
- Clinical Center Vojvodina /ID# 230525
- Hospital Universitario Central de Asturias /ID# 230884
- Hospital Universitario Germans Trias i Pujol /ID# 214704
- Hospital Regional de Malaga /ID# 230858
- CLINICA UNIVERSIDAD DE NAVARRA-Pamplona /ID# 230718
- Hospital Universitario Vall d'Hebron /ID# 222415
- Hospital Clinic de Barcelona /ID# 231538
- Hospital General Universitario Gregorio Maranon /ID# 214676
- CLINICA UNIVERSIDAD DE NAVARRA-Madrid /ID# 230719
- Hospital Universitario 12 de Octubre /ID# 214710
- Hospital Universitario Virgen de la Victoria /ID# 214709
- Kaohsiung Chang Gung Memorial Hospital /ID# 230371
- National Cheng Kung University Hospital /ID# 230372
- Ankara Universitesi Fakultesi /ID# 230317
- Adnan Menderes University /ID# 230777
- Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty /ID# 230318
- Dokuz Eylul University Medical Faculty /ID# 231321
- Ondokuz mayis University Facul /ID# 230314
- Guy's and St Thomas' NHS Foundation Trust /ID# 164110
- Oxford Univ Hosp NHS Trust /ID# 214503
- Belfast Health and Social Care Trust /ID# 216991
- The Christie Hospital /ID# 164111
- Aneurin Bevan University Health Board /ID# 230332
Arms of the Study
Arm 1
Arm 2
Experimental
Experimental
Navitoclax + ruxolitinib
Navitoclax
Participants will be administered navitoclax once daily (QD) at various doses and a dose greater than or equal to 10 mg of ruxolitinib twice daily (BID).
Participants will be administered various doses of navitoclax once daily (QD)