A Study Evaluating Tolerability and Efficacy of Navitoclax Alone or in Combination With Ruxolitinib in Participants With Myelofibrosis
- Registration Number
- NCT03222609
- Lead Sponsor
- AbbVie
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 191
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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.
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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:
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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.
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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.
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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
-
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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
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No prior treatment with a JAK-2 or BET inhibitor.
-
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Participant has splenomegaly as defined in the protocol.
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Participant must meet the laboratory parameters (adequate bone marrow, renal and hepatic function) as defined in the protocol.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Navitoclax + ruxolitinib (Cohort 1a) Ruxolitinib 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 will continue their treatment until end of clinical benefit, unacceptable toxicity, or they meet other protocol criteria for discontinuation (whichever occurs first). Navitoclax + ruxolitinib (Cohort 1a) Navitoclax 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 will continue their treatment until end of clinical benefit, unacceptable toxicity, or they meet other protocol criteria for discontinuation (whichever occurs first). Navitoclax + ruxolitinib (Cohort 1b) Ruxolitinib 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 will continue their treatment until end of clinical benefit, unacceptable toxicity, or they meet other protocol criteria for discontinuation (whichever occurs first). Navitoclax + ruxolitinib (Cohort 1b) Navitoclax 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 will continue their treatment until end of clinical benefit, unacceptable toxicity, or they meet other protocol criteria for discontinuation (whichever occurs first). Navitoclax (Cohort 2) Navitoclax 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 will continue their treatment until end of clinical benefit, unacceptable toxicity, or they meet other protocol criteria for discontinuation (whichever occurs first). Navitoclax + ruxolitinib (Cohort 3) Ruxolitinib 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 will continue their treatment until end of clinical benefit, unacceptable toxicity, or they meet other protocol criteria for discontinuation (whichever occurs first). Navitoclax + ruxolitinib (Cohort 3) Navitoclax 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 will continue their treatment until end of clinical benefit, unacceptable toxicity, or they meet other protocol criteria for discontinuation (whichever occurs first).
- Primary Outcome Measures
Name Time Method Percentage of Participants With ≥ 35% Reduction From Baseline in Spleen Volume at Week 24 Baseline, Week 24 Reduction in spleen volume is measured by magnetic resonance imaging/computerized tomography (MRI/CT).
- Secondary Outcome Measures
Name Time Method Percentage of Participants Achieving ≥ 50% Reduction From Baseline in Total System Score (TSS) at Week 24 Baseline, Week 24 TSS is assessed by the Myelofibrosis Symptom Assessment Form (MFSAF) version 4.0. Participants complete a symptom diary and rate the following seven MF symptoms: fatigue, night sweats, abdominal discomfort, pruritus, pain under the ribs on the left side, early satiety, and bone pain daily using a scale from 0 (absent) to 10 (worst imaginable), and the scores are averaged over 7 days, with a minimum of 4 days required to calculate the average score. Participants for whom a valid average score cannot be calculated either at baseline or post-baseline are considered non-responders. The TSS reflects the sum of the scores of these symptoms, for a maximum possible score of 70 (i.e., most severe symptom experience).
Percentage of Participants Achieving Anemia Response Up to 254 weeks For a participant who is transfusion independent (TI) at Baseline with hemoglobin value \< 10 g/dL, anemia response is achieved if the post-Baseline hemoglobin level increases by ≥2 g/dL without receiving packed red blood cells (PRBC) transfusion (for any reason) within 2 weeks and without any erythropoietin or mimetics within the last 4 weeks prior to the increase in hemoglobin level by ≥2g/dL was observed. Hemoglobin values more than 30 days after the last dose of study treatment or after the start of post-study treatment or disease progression, whichever is earlier, will not be considered in the analysis of anemia response.
For a participant who is transfusion dependent (TD) at Baseline, anemia response is defined as a period of at least 12 consecutive weeks without PRBC transfusion at any time after the first dose of study drug and on or prior to 30 days post last dose of study drug, the start of post-study treatment, disease progression or death, whichever occurs earlier.Percentage of Participants With ≥ 1 Grade Reduction From Baseline in Fibrosis Grade At Any Time Up to 254 weeks Bone marrow grading is assessed according to the European Consensus Grading System. The 4-point grading scale ranges from MF-0, which corresponds to normal bone marrow, to MF-3, diffuse and dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with significant osteosclerosis.
Time to First Reduction in Fibrosis Grade Up to 254 weeks Grade of bone marrow fibrosis was assessed by investigators according to the European Consensus Grading System. The 4-point grading scale ranges from MF-0, which corresponds to normal bone marrow, to MF-3, diffuse and dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with significant osteosclerosis. The time to first achieving a reduction of at least 1 grade in bone marrow fibrosis from Baseline was summarized.
Trial Locations
- Locations (91)
Barwon Health /ID# 222430
🇦🇺Geelong, Victoria, Australia
Klinicki Bolnicki Centar (KBC) Split /ID# 230601
🇭🇷Split, Splitsko-dalmatinska Zupanija, Croatia
General Hospital of Athens Laiko /ID# 230394
🇬🇷Athens, Attiki, Greece
Duplicate_University General Hospital Attikon /ID# 230395
🇬🇷Athens, Attiki, Greece
Szabolcs-Szatmar-Bereg Varmegyei Oktatokorhaz /ID# 230585
🇭🇺Nyiregyhaza, Szabolcs-Szatmar-Bereg, Hungary
Semmelweis Egyetem /ID# 230518
🇭🇺Budapest, Hungary
Duplicate_Del-pesti Centrumkorhaz Orszagos Hematologiai es Infektologiai Intezet /ID# 230306
🇭🇺Budapest, Hungary
Assuta Ashdod Medical Center /ID# 230396
🇮🇱Ashdod, HaDarom, Israel
Galilee Medical Center /ID# 230397
🇮🇱Nahariya, HaTsafon, Israel
Tel Aviv Sourasky Medical Center /ID# 230311
🇮🇱Tel Aviv, Tel-Aviv, Israel
Long Beach Memorial Medical Ct /ID# 230148
🇺🇸Long Beach, California, United States
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
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
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, Grad Zagreb, Croatia
Klinicka bolnica Merkur /ID# 230599
🇭🇷Zagreb, Grad Zagreb, Croatia
Klinicki bolnicki centar Zagreb /ID# 230602
🇭🇷Zagreb, Grad Zagreb, Croatia
Hadassah Medical Center-Hebrew University /ID# 230310
🇮🇱Jerusalem, Yerushalayim, 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, Japan
Aomori Prefectural Central Hospital /ID# 221773
🇯🇵Aomori-shi, Aomori, Japan
Kyushu University Hospital /ID# 222691
🇯🇵Fukuoka-shi, Fukuoka, Japan
Sapporo Hokuyu Hospital /ID# 222693
🇯🇵Sapporo-shi, 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
Seoul National University Hospital /ID# 230380
🇰🇷Seoul, Seoul Teugbyeolsi, Korea, Republic of
Samsung Medical Center /ID# 230381
🇰🇷Seoul, Seoul Teugbyeolsi, Korea, Republic of
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
Hospital Universitario Germans Trias i Pujol /ID# 214704
🇪🇸Badalona, Barcelona, Spain
Duplicate_CLINICA UNIVERSIDAD DE NAVARRA-Pamplona /ID# 230718
🇪🇸Pamplona, Navarra, 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
🇪🇸Malaga, Spain
Hospital Regional Universitario de Malaga /ID# 230858
🇪🇸Malaga, 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