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

NCT ID: NCT03222609

Last Updated: 2026-01-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 191 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-10-31
• Study Completion Date: 2025-01-29

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.

Conditions

Myelofibrosis (MF)

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Navitoclax + ruxolitinib (Cohort 1a)

Participants must have received ruxolitinib for at least 12 weeks and on stable dose of ≥10 mg tablets orally twice daily (BID) for ≥8 weeks prior to the 1st dose of navitoclax. Navitoclax tablets are administered once daily (QD) at a starting dose of 50 mg. This was increased after approximately ≥7 days to next dose level if platelet count is ≥75 × 10\^9/L up to a maximum dose of navitoclax 300 mg QD. Participants continued their treatment until the end of clinical benefit, unacceptable toxicity, or they met other protocol criteria for discontinuation (whichever occurred first).

Group Type: EXPERIMENTAL

Ruxolitinib

Intervention Type: DRUG

Tablet; Oral

Navitoclax

Intervention Type: DRUG

Film-coated tablet; Oral

Navitoclax + ruxolitinib (Cohort 1b)

Those receiving ruxolitinib at Screening must be on a stable dose ≥10 mg tablets orally twice daily (BID) for ≥ 4 weeks prior to 1st dose of navitoclax. Those not receiving ruxolitinib at Screening received 10 mg ruxolitinib BID starting on Day 1. Navitoclax tablets were administered orally once daily (QD) per Baseline platelet count (\>150 × 10\^9/L starting dose of 200 mg; ≤150 × 10\^9/L starting dose of 100 mg, which could be increased to 200 mg QD after 7 days provided platelet count is ≥75 × 10\^9/L). Navitoclax didn't exceed 200 mg QD for first 24 weeks of treatment. After Week 24 disease assessment, navitoclax dose was increased to 300 mg QD at discretion of the Investigator for those with suboptimal spleen response defined as failure to achieve spleen volume reduction of at least 10% per imaging. Participants continued their treatment until the end of clinical benefit, unacceptable toxicity, or they met other protocol criteria for discontinuation (whichever occurred first).

Group Type: EXPERIMENTAL

Ruxolitinib

Intervention Type: DRUG

Tablet; Oral

Navitoclax

Intervention Type: DRUG

Film-coated tablet; Oral

Navitoclax (Cohort 2)

Participants must have received prior treatment with a Janus Kinase 2 (JAK-2) inhibitor. Those with Baseline platelet count \>150 × 10\^9/L initiated navitoclax film-coated tablets orally once daily (QD) at the starting dose of 200 mg. Those with a Baseline platelet count ≤150 × 10\^9/L initiated navitoclax film-coated tablets orally once daily (QD) at the starting dose of 100 mg, which could be increased to 200 mg once daily after 7 days provided the platelet count is ≥75 × 10\^9/L. Navitoclax didn't exceed 200 mg QD for the first 24 weeks of treatment. After Week 24 disease assessment, navitoclax dose may be increased to 300 mg QD at discretion of the Investigator for those with suboptimal spleen response defined as failure to achieve spleen volume reduction of at least 10% per imaging. Participants continued their treatment until the end of clinical benefit, unacceptable toxicity, or they met other protocol criteria for discontinuation (whichever occurred first).

Group Type: EXPERIMENTAL

Navitoclax

Intervention Type: DRUG

Film-coated tablet; Oral

Navitoclax + ruxolitinib (Cohort 3)

Prior treatment with a Janus Kinase 2 (JAK-2) or Bromodomain and Extra-Terminal motif (BET) proteins inhibitor was prohibited. Ruxolitinib tablets administered orally twice daily (BID) based on Baseline platelet count as per the local approved label. Navitoclax tablets were administered orally once daily (QD) per Baseline platelet count (\>150 × 10\^9/L starting dose of 200 mg; ≤150 × 10\^9/L starting dose of 100 mg, which could be increased to 200 mg QD after 7 days provided platelet count is ≥75 × 10\^9/L). Navitoclax didn't exceed 200 mg QD for first 24 weeks of treatment. After Week 24 disease assessment, navitoclax dose may be increased to 300 mg QD at discretion of Investigator for those with suboptimal spleen response defined as failure to achieve spleen volume reduction of at least 10% per imaging. Participants continued their treatment until the end of clinical benefit, unacceptable toxicity, or they met other protocol criteria for discontinuation (whichever occurred first).

Group Type: EXPERIMENTAL

Ruxolitinib

Intervention Type: DRUG

Tablet; Oral

Navitoclax

Intervention Type: DRUG

Film-coated tablet; Oral

Interventions

Ruxolitinib

Tablet; Oral

Intervention Type: DRUG

Navitoclax

Film-coated tablet; Oral

Intervention Type: DRUG

Other Intervention Names

Jakafi; ABT-263

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AbbVie

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

ABBVIE INC.

Role: STUDY_DIRECTOR

AbbVie

Locations

UAB Comprehensive Cancer Cente /ID# 165464

Birmingham, Alabama, United States

TOI Clinical Research /ID# 222546

Cerritos, California, United States

City of Hope /ID# 221395

Duarte, California, United States

Moores Cancer Center at UC San Diego /ID# 164084

La Jolla, California, United States

Long Beach Memorial Medical Ct /ID# 230148

Long Beach, California, United States

University of Southern California /ID# 164095

Los Angeles, California, United States

Colorado Blood Cancer Institute /ID# 224250

Denver, Colorado, United States

Baptist MD Anderson Cancer Center - Jacksonville /ID# 222548

Jacksonville, Florida, United States

Mayo Clinic /ID# 164201

Jacksonville, Florida, United States

Moffitt Cancer Center /ID# 164082

Tampa, Florida, United States

University of Chicago Medicine /ID# 164115

Chicago, Illinois, United States

Mid Illinois Hematology & Oncology Associates, Ltd /ID# 230536

Normal, Illinois, United States

Indiana Blood & Marrow Transpl /ID# 165075

Indianapolis, Indiana, United States

Duplicate_American Oncology Partners of Maryland, PA /ID# 231299

Bethesda, Maryland, United States

Dana-Farber Cancer Institute /ID# 162675

Boston, Massachusetts, United States

University of Massachusetts - Worcester /ID# 222547

Worcester, Massachusetts, United States

Henry Ford Hospital /ID# 162682

Detroit, Michigan, United States

Ascension Providence Southfield Cancer Center /ID# 223876

Southfield, Michigan, United States

MidAmerica Division, Inc. /ID# 222058

Kansas City, Missouri, United States

Weill Cornell Medical College /ID# 162679

New York, New York, United States

The Ohio State University /ID# 217402

Columbus, Ohio, United States

Bend Memorial Clinic /ID# 224184

Bend, Oregon, United States

West Penn Hospital /ID# 222618

Pittsburgh, Pennsylvania, United States

Duplicate_Medical University of South Carolina /ID# 222597

Charleston, South Carolina, United States

Prairie Lakes Healthcare System /ID# 224358

Watertown, South Dakota, United States

Tennessee Oncology-Nashville Centennial /ID# 221410

Nashville, Tennessee, United States

Texas Oncology - West Texas /ID# 224784

Abilene, Texas, United States

Texas Oncology- Baylor Charles A. Sammons Cancer Center /ID# 225159

Dallas, Texas, United States

Oncology Consultants /ID# 230930

Houston, Texas, United States

MD Anderson Cancer Center at Texas Medical Center /ID# 162683

Houston, Texas, United States

University of Texas Health San Antonio MD Anderson Cancer Center /ID# 164094

San Antonio, Texas, United States

Utah Cancer Specialists Salt Lake Clinic /ID# 222806

Salt Lake City, Utah, United States

University of Utah /ID# 164116

Salt Lake City, Utah, United States

The Kinghorn Cancer Centre /ID# 214657

Darlinghurst, New South Wales, Australia

Barwon Health /ID# 222430

Geelong, Victoria, Australia

Peter MacCallum Cancer Ctr /ID# 218352

Melbourne, Victoria, Australia

The Alfred Hospital /ID# 215545

Melbourne, Victoria, Australia

Fiona Stanley Hospital /ID# 216809

Murdoch, Western Australia, Australia

Duplicate_University of Alberta Hospital - Division of Hematology /ID# 217698

Edmonton, Alberta, Canada

University Health Network_Princess Margaret Cancer Centre /ID# 214483

Toronto, Ontario, Canada

McGill University Health Center Research Institute /ID# 223976

Montreal, Quebec, Canada

Clinical Hospital Dubrava /ID# 230504

Zagreb, City of Zagreb, Croatia

Klinicka bolnica Merkur /ID# 230599

Zagreb, City of Zagreb, Croatia

Klinicki bolnicki centar Zagreb /ID# 230602

Zagreb, City of Zagreb, Croatia

Klinicki Bolnicki Centar (KBC) Split /ID# 230601

Split, Split-Dalmatia County, Croatia

General Hospital of Athens Laiko /ID# 230394

Athens, Attica, Greece

Duplicate_University General Hospital Attikon /ID# 230395

Athens, Attica, Greece

Szabolcs-Szatmar-Bereg Varmegyei Oktatokorhaz /ID# 230585

Nyíregyháza, Szabolcs-Szatmár-Bereg, Hungary

Semmelweis Egyetem /ID# 230518

Budapest, , Hungary

Duplicate_Del-pesti Centrumkorhaz Orszagos Hematologiai es Infektologiai Intezet /ID# 230306

Budapest, , Hungary

Hadassah Medical Center-Hebrew University /ID# 230310

Jerusalem, Jerusalem, Israel

Galilee Medical Center /ID# 230397

Nahariya, Northern District, Israel

Assuta Ashdod Medical Center /ID# 230396

Ashdod, Southern District, Israel

Tel Aviv Sourasky Medical Center /ID# 230311

Tel Aviv, Tel Aviv, Israel

IRCCS AOU di Bologna - Policlinico Sant'Orsola-Malpighi /ID# 230012

Bologna, Emilia-Romagna, Italy

Azienda Ospedaliero Universitaria Careggi /ID# 214555

Florence, Firenze, Italy

Fondazione Policlinico Universitario Agostino Gemelli IRCCS-Università Cattolica /ID# 214553

Rome, Roma, Italy

ASST Papa Giovanni XXIII /ID# 214900

Bergamo, , Italy

ASST degli Spedali Civili di Brescia /ID# 230420

Brescia, , Italy

AOU Policlinico G. Rodolico - San Marco /ID# 214549

Catania, , Italy

Grande Ospedale Metropolitano Bianchi - Melacrino - Morelli P.O. Riuniti /ID# 230011

Reggio Calabria, , Italy

ASST Sette Laghi - Ospedale Di Circolo E Fondazione Macchi Varese /ID# 214551

Varese, , Italy

Fujita Health University Hospital /ID# 221539

Toyoake, Aichi-ken, Japan

Aomori Prefectural Central Hospital /ID# 221773

Aomori, Aomori, Japan

Kyushu University Hospital /ID# 222691

Fukuoka, Fukuoka, Japan

Sapporo Hokuyu Hospital /ID# 222693

Sapporo, Hokkaido, Japan

Kansai Medical University Hospital /ID# 222690

Hirakata-shi, Osaka, Japan

Kindai University Hospital /ID# 222689

Osakasayama-shi, Osaka, Japan

Duplicate_Dokkyo Medical University Saitama Medical Center /ID# 222332

Koshigaya-shi, Saitama, 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

VA Caribbean Healthcare System /ID# 222416

San Juan, , Puerto Rico

Hospital del Centro Comprensivo de Cancer de la UPR /ID# 222544

San Juan, , Puerto Rico

Seoul National University Hospital /ID# 230380

Seoul, Seoul Teugbyeolsi, South Korea

Samsung Medical Center /ID# 230381

Seoul, Seoul Teugbyeolsi, South Korea

Hospital Universitario Germans Trias i Pujol /ID# 214704

Badalona, Barcelona, Spain

Duplicate_CLINICA UNIVERSIDAD DE NAVARRA-Pamplona /ID# 230718

Pamplona, Navarre, Spain

Hospital Universitario Vall d'Hebron /ID# 222415

Barcelona, , Spain

Hospital General Universitario Gregorio Maranon /ID# 214676

Madrid, , Spain

CLINICA UNIVERSIDAD DE NAVARRA-Madrid /ID# 230719

Madrid, , Spain

Hospital Universitario 12 de Octubre /ID# 214710

Madrid, , Spain

Hospital Universitario Virgen de la Victoria /ID# 214709

Málaga, , Spain

Hospital Regional Universitario de Malaga /ID# 230858

Málaga, , Spain

Kaohsiung Chang Gung Memorial Hospital /ID# 230371

Kaohsiung City, Kaohsiung, Taiwan

National Cheng Kung University Hospital /ID# 230372

Tainan, , Taiwan

Guys and St Thomas NHS Foundation Trust /ID# 164110

London, Greater London, United Kingdom

Oxford University Hospitals NHS Foundation Trust /ID# 214503

Oxford, Oxfordshire, United Kingdom

Belfast Health and Social Care Trust /ID# 216991

Belfast, , United Kingdom

The Christie Hospital /ID# 164111

Manchester, , United Kingdom

Aneurin Bevan University Health Board /ID# 230332

Newport, , United Kingdom

Countries

United States; Australia; Canada; Croatia; Greece; Hungary; Israel; Italy; Japan; Puerto Rico; South Korea; Spain; Taiwan; United Kingdom

References

Pemmaraju N, Somervaille TCP, Palandri F, Harrison C, Komrokji RS, Perkins A, Ayala Diaz RM, Lavie D, Tomita A, Feng Y, Qin Q, Harb J, Polepally AR, Potluri J, Garcia JS. Addition of navitoclax to ruxolitinib for patients with myelofibrosis with progression or suboptimal response. Blood Neoplasia. 2024 Nov 2;2(1):100056. doi: 10.1016/j.bneo.2024.100056. eCollection 2025 Feb.

Reference Type: DERIVED

PMID: 40454409 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 35576960 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 35180010 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2017-001398-17

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

M16-109

Identifier Type: -

Identifier Source: org_study_id