Clinical trial NCT03222609: A Study Evaluating Tolerability and Efficacy of Navitoclax Alone or in Combination With Ruxolitinib in Participants With Myelofibrosis
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Myelofibrosis (MF)
Keywords: 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
Lead sponsor: AbbVie
Sponsor class: INDUSTRY
First posted: 2017-07-19
Enrollment: 191
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Safety and efficacy data through 16 January 2023 are included in the interim analysis.


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 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.

Primary outcomes:
measure: Percentage of Participants With ≥ 35% Reduction From Baseline in Spleen Volume at Week 24
timeFrame: Baseline, Week 24
Secondary outcomes:
measure: Percentage of Participants Achieving ≥ 50% Reduction From Baseline in Total System Score (TSS) at Week 24
timeFrame: Baseline, Week 24
measure: Percentage of Participants Achieving Anemia Response
timeFrame: Up to 254 weeks
measure: Percentage of Participants With ≥ 1 Grade Reduction From Baseline in Fibrosis Grade At Any Time
timeFrame: Up to 254 weeks
measure: Time to First Reduction in Fibrosis Grade
timeFrame: Up to 254 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: UAB Comprehensive Cancer Cente /ID# 165464
state: Alabama
city: Cerritos
country: United States
facility: TOI Clinical Research /ID# 222546
state: California
city: Duarte
country: United States
facility: City of Hope /ID# 221395
state: California
city: La Jolla
country: United States
facility: Moores Cancer Center at UC San Diego /ID# 164084
state: California
city: Long Beach
country: United States
facility: Long Beach Memorial Medical Ct /ID# 230148
state: California
city: Los Angeles
country: United States
facility: University of Southern California /ID# 164095
state: California
city: Denver
country: United States
facility: Colorado Blood Cancer Institute /ID# 224250
state: Colorado
city: Jacksonville
country: United States
facility: Baptist MD Anderson Cancer Center - Jacksonville /ID# 222548
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic /ID# 164201
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center /ID# 164082
state: Florida
city: Chicago
country: United States
facility: University of Chicago Medicine /ID# 164115
state: Illinois
city: Normal
country: United States
facility: Mid Illinois Hematology & Oncology Associates, Ltd /ID# 230536
state: Illinois
city: Indianapolis
country: United States
facility: Indiana Blood & Marrow Transpl /ID# 165075
state: Indiana
city: Bethesda
country: United States
facility: Duplicate_American Oncology Partners of Maryland, PA /ID# 231299
state: Maryland
city: Boston
country: United States
facility: Dana-Farber Cancer Institute /ID# 162675
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts - Worcester /ID# 222547
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital /ID# 162682
state: Michigan
city: Southfield
country: United States
facility: Ascension Providence Southfield Cancer Center /ID# 223876
state: Michigan
city: Kansas City
country: United States
facility: MidAmerica Division, Inc. /ID# 222058
state: Missouri
city: New York
country: United States
facility: Weill Cornell Medical College /ID# 162679
state: New York
city: Columbus
country: United States
facility: The Ohio State University /ID# 217402
state: Ohio
city: Bend
country: United States
facility: Bend Memorial Clinic /ID# 224184
state: Oregon
city: Pittsburgh
country: United States
facility: West Penn Hospital /ID# 222618
state: Pennsylvania
city: Charleston
country: United States
facility: Duplicate_Medical University of South Carolina /ID# 222597
state: South Carolina
city: Watertown
country: United States
facility: Prairie Lakes Healthcare System /ID# 224358
state: South Dakota
city: Nashville
country: United States
facility: Tennessee Oncology-Nashville Centennial /ID# 221410
state: Tennessee
city: Abilene
country: United States
facility: Texas Oncology - West Texas /ID# 224784
state: Texas
city: Dallas
country: United States
facility: Texas Oncology- Baylor Charles A. Sammons Cancer Center /ID# 225159
state: Texas
city: Houston
country: United States
facility: Oncology Consultants /ID# 230930
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center at Texas Medical Center /ID# 162683
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health San Antonio MD Anderson Cancer Center /ID# 164094
state: Texas
city: Salt Lake City
country: United States
facility: Utah Cancer Specialists Salt Lake Clinic /ID# 222806
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah /ID# 164116
state: Utah
city: Darlinghurst
country: Australia
facility: The Kinghorn Cancer Centre /ID# 214657
state: New South Wales
city: Geelong
country: Australia
facility: Barwon Health /ID# 222430
state: Victoria
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Ctr /ID# 218352
state: Victoria
city: Melbourne
country: Australia
facility: The Alfred Hospital /ID# 215545
state: Victoria
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital /ID# 216809
state: Western Australia
city: Edmonton
country: Canada
facility: Duplicate_University of Alberta Hospital - Division of Hematology /ID# 217698
state: Alberta
city: Toronto
country: Canada
facility: University Health Network_Princess Margaret Cancer Centre /ID# 214483
state: Ontario
city: Montreal
country: Canada
facility: McGill University Health Center Research Institute /ID# 223976
state: Quebec
city: Zagreb
country: Croatia
facility: Clinical Hospital Dubrava /ID# 230504
state: Grad Zagreb
city: Zagreb
country: Croatia
facility: Klinicka bolnica Merkur /ID# 230599
state: Grad Zagreb
city: Zagreb
country: Croatia
facility: Klinicki bolnicki centar Zagreb /ID# 230602
state: Grad Zagreb
city: Split
country: Croatia
facility: Klinicki Bolnicki Centar (KBC) Split /ID# 230601
state: Splitsko-dalmatinska Zupanija
city: Athens
country: Greece
facility: General Hospital of Athens Laiko /ID# 230394
state: Attiki
city: Athens
country: Greece
facility: Duplicate_University General Hospital Attikon /ID# 230395
state: Attiki
city: Nyiregyhaza
country: Hungary
facility: Szabolcs-Szatmar-Bereg Varmegyei Oktatokorhaz /ID# 230585
state: Szabolcs-Szatmar-Bereg
city: Budapest
country: Hungary
facility: Semmelweis Egyetem /ID# 230518
city: Budapest
country: Hungary
facility: Duplicate_Del-pesti Centrumkorhaz Orszagos Hematologiai es Infektologiai Intezet /ID# 230306
city: Ashdod
country: Israel
facility: Assuta Ashdod Medical Center /ID# 230396
state: HaDarom
city: Nahariya
country: Israel
facility: Galilee Medical Center /ID# 230397
state: HaTsafon
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center /ID# 230311
state: Tel-Aviv
city: Jerusalem
country: Israel
facility: Hadassah Medical Center-Hebrew University /ID# 230310
state: Yerushalayim
city: Bologna
country: Italy
facility: IRCCS AOU di Bologna - Policlinico Sant'Orsola-Malpighi /ID# 230012
state: Emilia-Romagna
city: Florence
country: Italy
facility: Azienda Ospedaliero Universitaria Careggi /ID# 214555
state: Firenze
city: Rome
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli IRCCS-Università Cattolica /ID# 214553
state: Roma
city: Bergamo
country: Italy
facility: ASST Papa Giovanni XXIII /ID# 214900
city: Brescia
country: Italy
facility: ASST degli Spedali Civili di Brescia /ID# 230420
city: Catania
country: Italy
facility: AOU Policlinico G. Rodolico - San Marco /ID# 214549
city: Reggio Calabria
country: Italy
facility: Grande Ospedale Metropolitano Bianchi - Melacrino - Morelli P.O. Riuniti /ID# 230011
city: Varese
country: Italy
facility: ASST Sette Laghi - Ospedale Di Circolo E Fondazione Macchi Varese /ID# 214551
city: Toyoake
country: Japan
facility: Fujita Health University Hospital /ID# 221539
state: Aichi
city: Aomori-shi
country: Japan
facility: Aomori Prefectural Central Hospital /ID# 221773
state: Aomori
city: Fukuoka-shi
country: Japan
facility: Kyushu University Hospital /ID# 222691
state: Fukuoka
city: Sapporo-shi
country: Japan
facility: Sapporo Hokuyu Hospital /ID# 222693
state: Hokkaido
city: Hirakata-shi
country: Japan
facility: Kansai Medical University Hospital /ID# 222690
state: Osaka
city: Osakasayama-shi
country: Japan
facility: Kindai University Hospital /ID# 222689
state: Osaka
city: Koshigaya-shi
country: Japan
facility: Duplicate_Dokkyo Medical University Saitama Medical Center /ID# 222332
state: Saitama
city: Bunkyo-ku
country: Japan
facility: Juntendo University Hospital /ID# 221484
state: Tokyo
city: Bunkyo-ku
country: Japan
facility: Nippon Medical School Hospital /ID# 222692
state: Tokyo
city: Chuo-shi
country: Japan
facility: University of Yamanashi Hospital /ID# 221700
state: Yamanashi
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital /ID# 230380
state: Seoul Teugbyeolsi
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center /ID# 230381
state: Seoul Teugbyeolsi
city: San Juan
country: Puerto Rico
facility: VA Caribbean Healthcare System /ID# 222416
city: San Juan
country: Puerto Rico
facility: Hospital del Centro Comprensivo de Cancer de la UPR /ID# 222544
city: Badalona
country: Spain
facility: Hospital Universitario Germans Trias i Pujol /ID# 214704
state: Barcelona
city: Pamplona
country: Spain
facility: Duplicate_CLINICA UNIVERSIDAD DE NAVARRA-Pamplona /ID# 230718
state: Navarra
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron /ID# 222415
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Maranon /ID# 214676
city: Madrid
country: Spain
facility: CLINICA UNIVERSIDAD DE NAVARRA-Madrid /ID# 230719
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre /ID# 214710
city: Malaga
country: Spain
facility: Hospital Universitario Virgen de la Victoria /ID# 214709
city: Malaga
country: Spain
facility: Hospital Regional Universitario de Malaga /ID# 230858
city: Kaohsiung City
country: Taiwan
facility: Kaohsiung Chang Gung Memorial Hospital /ID# 230371
state: Kaohsiung
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital /ID# 230372
city: London
country: United Kingdom
facility: Guys and St Thomas NHS Foundation Trust /ID# 164110
state: Greater London
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals NHS Foundation Trust /ID# 214503
state: Oxfordshire
city: Belfast
country: United Kingdom
facility: Belfast Health and Social Care Trust /ID# 216991
city: Manchester
country: United Kingdom
facility: The Christie Hospital /ID# 164111
city: Newport
country: United Kingdom
facility: Aneurin Bevan University Health Board /ID# 230332
Study officials:
affiliation: AbbVie
name: ABBVIE INC.
role: STUDY_DIRECTOR
References:
citation: Pemmaraju N, Garcia JS, Potluri J, Harb JG, Sun Y, Jung P, Qin QQ, Tantravahi SK, Verstovsek S, Harrison C. Addition of navitoclax to ongoing ruxolitinib treatment in patients with myelofibrosis (REFINE): a post-hoc analysis of molecular biomarkers in a phase 2 study. Lancet Haematol. 2022 Jun;9(6):e434-e444. doi: 10.1016/S2352-3026(22)00116-8. Epub 2022 May 13.
citation: Harrison CN, Garcia JS, Somervaille TCP, Foran JM, Verstovsek S, Jamieson C, Mesa R, Ritchie EK, Tantravahi SK, Vachhani P, O'Connell CL, Komrokji RS, Harb J, Hutti JE, Holes L, Masud AA, Nuthalapati S, Potluri J, Pemmaraju N. Addition of Navitoclax to Ongoing Ruxolitinib Therapy for Patients With Myelofibrosis With Progression or Suboptimal Response: Phase II Safety and Efficacy. J Clin Oncol. 2022 May 20;40(15):1671-1680. doi: 10.1200/JCO.21.02188. Epub 2022 Feb 18.