Study of Ibrutinib Combined With Venetoclax in Subjects With Mantle Cell Lymphoma (SYMPATICO)
- Conditions
- Mantle-Cell Lymphoma
- Interventions
- Registration Number
- NCT03112174
- Lead Sponsor
- Pharmacyclics LLC.
- Brief Summary
This Phase 3 multinational, randomized, double-blind study is designed to compare the efficacy and safety of the combination of ibrutinib and venetoclax vs. ibrutinib and placebo in subjects with MCL.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 352
- Pathologically confirmed MCL (in tumor tissue), with documentation of either overexpression of cyclin D1 in association with other relevant markers (eg, CD19, CD20, PAX5, CD5) or evidence of t(11;14) as assessed by cytogenetics, fluorescent in situ hybridization (FISH), or polymerase chain reaction (PCR).
- At least 1 measurable site of disease on cross-sectional imaging (CT/PET).
- At least 1, but no more than 5, prior treatment regimens for MCL.
- Failure to achieve at least partial response (PR) with, or documented disease progression after, the most recent treatment regimen.
- Subjects must have adequate fresh or paraffin embedded tissue.
- Adequate hematologic, hepatic and renal function.
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) of <= 2.
- History or current evidence of central nervous system lymphoma.
- Concurrent enrollment in another therapeutic investigational study or prior therapy with ibrutinib or other BTK inhibitors.
- Prior treatment with venetoclax or other BCL2 inhibitors.
- Anticancer therapy including chemotherapy, radiotherapy, small molecule and investigational agents 21 days prior to receiving the first dose of study drug.
- Treatment with any of the following within 7 days prior to the first dose of study drug: moderate or strong cytochrome P450 3A (CYP3A) inhibitors or strong CYP3A inducers.
Treatment Naïve Arm
Inclusion Criteria:
- Pathologically confirmed treatment-naive MCL (tumor tissue), with documentation of either overexpression of cyclin D1 in association with other relevant markers (eg, CD19, CD20, PAX5, CD5) or evidence of t(11;14), as assessed by cytogenetics, fluorescent in situ hybridization (FISH), or polymerase chain reaction (PCR).
- Men and women ≥18 years of age with a TP53 mutation.
- At least 1 measurable site of disease.
- Must have adequate fresh or paraffin-embedded tissue.
- Eastern Cooperative Oncology Group (ECOG) performance status score 0-2.
- Adequate hematologic, hepatic, and renal function.
Exclusion Criteria:
- Blastoid variant of MCL
- History or current evidence of CNS lymphoma.
- Concurrent enrollment in another therapeutic investigational study or prior therapy including ibrutinib or other BTK inhibitors.
- Prior treatment with venetoclax or other BCL2 inhibitors.
- Vaccinated with live, attenuated vaccines within 4 weeks of the first dose of study drug.
- Clinically significant infection requiring IV systemic treatment that was completed <=14 days before the first dose of study drug.
- Any uncontrolled active systemic infection.
- Known bleeding disorders (eg, von Willebrand's disease or hemophilia).
- History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
- History of HIV or active HCV or HBV.
- Major surgery within 4 weeks of the first dose of study drug.
- Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the participant's safety or put the study outcomes at undue risk.
- Currently active, clinically significant cardiovascular disease; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization.
- Unable to swallow capsules or tablets, or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.
- Treatment with any of the following within 7 days prior to the first dose of study drug: Moderate or strong cytochrome P450 3A (CYP3A) inhibitors or moderate or strong CYP3A inducers.
- Known allergy to xanthine oxidase inhibitors and/or rasburicase for subjects with known risk factors (as defined by high tumor burden and/or diminished renal function, as detailed in "Study Design" section above) for TLS.
- Chronic liver disease with hepatic impairment Child-Pugh class B or C.
- Unwilling or unable to participate in all required study evaluations and procedures.
- Known hypersensitivity to the active ingredient or other components of one or more study drugs.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Phase 3: Ibrutinib + Placebo Placebo Oral tablet to match Venetoclax Subjects will be randomized to receive ibrutinib and venetoclax/placebo until clinical disease progression or unacceptable toxicity Safety Run-in Period Venetoclax Subjects are enrolled into the open-label Safety Run-in Period to evaluate the occurrence of tumor lysis syndrome (TLS) and DLTs with the concurrent administration of ibrutinib and venetoclax. Safety run-in phase for the study is closed to further enrollment as of 07-Nov-2018. Phase 3: Ibrutinb + Venetoclax Ibrutinib Subjects will be randomized to receive ibrutinib and venetoclax/placebo until clinical disease progression or unacceptable toxicity Safety Run-in Period Ibrutinib Subjects are enrolled into the open-label Safety Run-in Period to evaluate the occurrence of tumor lysis syndrome (TLS) and DLTs with the concurrent administration of ibrutinib and venetoclax. Safety run-in phase for the study is closed to further enrollment as of 07-Nov-2018. Phase 3: Ibrutinb + Venetoclax Venetoclax Subjects will be randomized to receive ibrutinib and venetoclax/placebo until clinical disease progression or unacceptable toxicity Treatment-naive Ibrutinib This open-label arm is designed to explore the efficacy and safety of the combination of ibrutinib and venetoclax in subjects with treatment-naive MCL. Approximately 75 subjects (of which \~25 subjects with TP53 mutation) will be enrolled and treated with ibrutinib and venetoclax. Phase 3: Ibrutinib + Placebo Ibrutinib Subjects will be randomized to receive ibrutinib and venetoclax/placebo until clinical disease progression or unacceptable toxicity Treatment-naive Venetoclax This open-label arm is designed to explore the efficacy and safety of the combination of ibrutinib and venetoclax in subjects with treatment-naive MCL. Approximately 75 subjects (of which \~25 subjects with TP53 mutation) will be enrolled and treated with ibrutinib and venetoclax.
- Primary Outcome Measures
Name Time Method Progression-free Survival (PFS) (Randomization Period) approximately 1 year after last subject has stopped treatment with study drug(s) To evaluate PFS of ibrutinib and venetoclax compared to ibrutinib and placebo.
Occurrence of Tumor Lysis Syndrome (TLS) (Safety Run-in Period) Approximately 3 months after last subject enrolled into safety run-in portion To evaluate the occurrence of tumor lysis syndrome (TLS) with the concurrent administration of ibrutinib and venetoclax.
Occurrence of Dose Limiting Toxicities (DLT) (Safety Run-in Period) Approximately 3 months after last subject enrolled into safety run-in portion To evaluate the occurrence of DLTs with the concurrent administration of ibrutinib and venetoclax.
Number of Participants With Adverse Events (AEs) (Safety Run-in Period) Up to approximately 5 years An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. The investigator assesses the relationship of each event to the use of study. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent adverse events/treatment-emergent serious adverse events (TEAEs/TESAEs) are defined as any event that began or worsened in severity on or after the first dose of study drug.
Overall response rate (ORR) (Safety Run-in Period) approximately 1 year after last subject has stopped treatment with study drug(s) ORR is defined as CR or PR per investigator assessment according to the Revised Response Criteria for Malignant Lymphoma.
Progression-free Survival (PFS) (Safety Run-in Period) approximately 1 year after last subject has stopped treatment with study drug(s) To evaluate PFS of ibrutinib and venetoclax compared to ibrutinib and placebo.
Overall Survival (OS) (Safety Run-in Period) Up to approximately 5 years OS is defined as the time from the date of the first dose of study treatment to death from any cause.
Duration of Response (DOR) (Safety Run-in Period) Up to approximately 5 years DOR is defined as participants who achieve an overall response as the time from the first occurrence of response (CR or PR) to disease progression or death, whichever occurs first.
Complete Response (CR) (Treatment-Naive Arm) approximately 1 year after last subject has stopped treatment with study drug(s) To evaluate the complete response (CR) rate with the combination of ibrutinib and venetoclax in subjects with treatment-naive MCL
- Secondary Outcome Measures
Name Time Method Overall Survival (OS) (Randomization Period and Treatment-Naive Arm) Up to approximately 5 years OS is defined as the time from the date of the first dose of study treatment to death from any cause.
Cmax if Ibrutinib (Randomization Period) Week 6 Cmax if Ibrutinib.
Complete Response (CR) (Randomization Period) approximately 1 year after last subject has stopped treatment with study drug(s) Complete response rate (CR) based on the best overall response per investigator assessment according to the Revised Response Criteria for Malignant Lymphoma.
Overall response rate (ORR) (Randomization Period and Treatment-Naive Arm) approximately 1 year after last subject has stopped treatment with study drug(s) ORR is defined as CR or PR per investigator assessment according to the Revised Response Criteria for Malignant Lymphoma.
MRD-negative remission rate in participants who achieve CR per investigator assessment (Randomization Period and Treatment-Naive Arm) approximately 1 year after last subject has stopped treatment with study drug(s) MRD-negative remission is defined as undetectable MRD at documented CR in subjects who were MRD positive at screening as assessed by flow cytometry in bone marrow and/or peripheral blood, with requirement of confirmation of MRD negativity in the subsequent peripheral blood 12 weeks later.
Duration of Response (DOR) (Randomization Period and Treatment-Naive Arm) Up to approximately 5 years DOR is defined as participants who achieve an overall response as the time from the first occurrence of response (CR or PR) to disease progression or death, whichever occurs first.
Time to Next Treatment (TTNT) (Randomization Period and Treatment-Naive Arm) Up to approximately 5 years TTNT is defined as the duration from the date of randomization to the start date of any anti-lymphoma treatment subsequent to study treatment.
Percentage of participants experiencing Adverse Events (Randomization Period) Up to approximately 5 years An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.
Tmax if Ibrutinib (Randomization Period) Week 6 Tmax if Ibrutinib.
Half-Life (T1/2) if Ibrutinib (Randomization Period) Week 6 Half-Life (T1/2) if Ibrutinib.
Occurrence of Tumor Lysis Syndrome (TLS) (Randomization Period) Approximately 3 months after last subject enrolled into safety run-in portion To evaluate the occurrence of tumor lysis syndrome (TLS) with the concurrent administration of ibrutinib and venetoclax.
Cmax of Venetoclax (Randomization Period) Week 6 Cmax of Venetoclax.
AUC of Venetoclax (Randomization Period) Week 6 AUC of Venetoclax.
Time to worsening in FACT-Lym subscale of the health-related quality of life (Randomization Period) questionnaire (FACT-Lym) Week 6 Time to worsening in FACT-Lym subscale of the health-related quality of life questionnaire (FACT-Lym) will be compared between treatment arms.
AUClast if Ibrutinib (Randomization Period) Week 6 AUClast if Ibrutinib.
Tmax of Venetoclax (Randomization Period) Week 6 Tmax of Venetoclax.
Duration of CR (Treatment-Naive Arm Period) Up to approximately 5 years Duration of CR, defined for subjects who achieve CR as the time from the first occurrence of CR to disease progression or death, whichever occurs first.
Progression-free Survival (PFS) (Treatment-Naive Arm Period) approximately 1 year after last subject has stopped treatment with study drug(s) To evaluate PFS of ibrutinib and venetoclax compared to ibrutinib and placebo.
Trial Locations
- Locations (120)
UCLA Department of Medicine-Hematology/Oncology
🇺🇸Los Angeles, California, United States
The University of Kansas Cancer Center and Medical Pavilion
🇺🇸Westwood, Kansas, United States
Institut Jules Bordet
🇧🇪Bruxelles, Belgium
Klinikum der Universitaet Muenchen Campus Grosshadern
🇩🇪Muenchen, Bayern, Germany
ZiekenhuisNetwerk Antwerpen (ZNA) Stuivenberg
🇧🇪Antwerpen, Belgium
Universitaetsklinikum Ulm
🇩🇪Ulm, Baden-Wuttemberg, Germany
Hospital Universitario de Cabuenes
🇪🇸Gijón, Asturias, Spain
Universitair Medisch Centrum Groningen
🇳🇱Groningen, Netherlands
ICO l'Hospitalet- Hospital Duran i Reynals
🇪🇸L'Hospitalet De Llobregat, Barcelona, Spain
Szpital Uniwersytecki nr 2 im. dr J. Biziela w Bydgoszcz
🇵🇱Bydgoszcz, Poland
Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespol Szpitali Miejskich, Oddzial Hematologiczny
🇵🇱Chorzów, Poland
Namik Kemal Universitesi Saglik Uyg. ve.Ars. Hastanesi
🇹🇷Tekirdağ, Turkey
The Royal Marsden NHS Foundation Trust
🇬🇧Sutton, Surrey, United Kingdom
University College London Hospitals NHS Foundation Trust
🇬🇧London, United Kingdom
Icon Cancer Care
🇦🇺Auchenflower, Queensland, Australia
Franciscus Vlietland
🇳🇱Schiedam, Netherlands
Barts Health NHS Trust
🇬🇧London, Greater London, United Kingdom
Communal Non-profit Enterprise Regional Center of Oncology, Department of Hematology
🇺🇦Kharkiv, Ukraine
Hospital de la Santa Creu i Sant Pau
🇪🇸Barcelona, Spain
Fundacion Jimenez Diaz
🇪🇸Madrid, Spain
Dokuz Eylul Universitesi Tip Fakultesi
🇹🇷İzmir, Turkey
Nottingham University Hospitals NHS Trust
🇬🇧Nottingham, Nottinghamshire, United Kingdom
St James University Hospital
🇬🇧Leeds, West Yorkshire, United Kingdom
The Christie NHS Foundation Trust
🇬🇧Manchester, Greater Manchester, United Kingdom
Hospital Universitario Ramon y Cajal
🇪🇸Madrid, Spain
City of Hope
🇺🇸Duarte, California, United States
Norton Cancer Institute
🇺🇸Louisville, Kentucky, United States
Orlando Health Inc.
🇺🇸Orlando, Florida, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Levine Cancer Institute
🇺🇸Charlotte, North Carolina, United States
Stony Brook University
🇺🇸New York, New York, United States
University of Texas MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
University of Tennessee medical Center
🇺🇸Knoxville, Tennessee, United States
Swedish Cancer Institute
🇺🇸Seattle, Washington, United States
The Canberra Hospital
🇦🇺Canberra, Australian Capital Territory, Australia
Border Medical Oncology Research Unit
🇦🇺Albury, New South Wales, Australia
St.Vincent's Hospital
🇦🇺Melbourne, Victoria, Australia
Austin Health
🇦🇺Heidelberg, Victoria, Australia
Sir Charles Gairdner Hospital
🇦🇺Nedlands, Western Australia, Australia
Peter MacCallum Cancer
🇦🇺Melbourne, Victoria, Australia
Tom Baker Cancer Centre
🇨🇦Calgary, Alberta, Canada
AZ Sint-Jan Brugge-Oostende AV
🇧🇪Brugge, Belgium
CHU UCL Namur asbl- Mont Godinne
🇧🇪Yvoir, Belgium
Cross Cancer Institute
🇨🇦Edmonton, Alberta, Canada
Queen Elizabeth II Health Science Centre
🇨🇦Halifax, Nova Scotia, Canada
Jewish General Hospital
🇨🇦Montréal, Quebec, Canada
FN Olomouc
🇨🇿Olomouc, Czechia
FN Ostrava
🇨🇿Ostrava-Poruba, Czechia
Fakultni Nemocnice (FN) Hradec Kravlove, a.s. IV. Interni hematologicka klinika
🇨🇿Hradec Králové, Czechia
FN Brno, Interni hematologicka a onkologicka klinika
🇨🇿Brno, Czechia
Fakultni nemocnice Kralovske Vinohrady
🇨🇿Praha 10, Czechia
Vseobecna fakultni nemocnice v Praze, l. interni klinika-klinika hematologie
🇨🇿Praha 2, Czechia
CHU CAEN-Hôpital de la Côte de Nacre
🇫🇷CAEN Cedex, Calvados, France
Hôpital Saint-Louis
🇫🇷Paris, France
Institut Paoli Calmettes, Service Hematologie
🇫🇷Marseille, France
Institut Bergonié
🇫🇷Bordeaux, France
Centre Antoine Lacassagne
🇫🇷Nice Cedex 2, France
CHU Clermont Ferrand - Hôpital d'Estaing
🇫🇷Clermont Ferrand cedex, France
Centre Hospitalier Lyon Sud
🇫🇷Pierre Benite cedex, France
Charite- Universitatsmedizin Berlin, Campus Benjamin Franklin
🇩🇪Berlin, Germany
CHU de Tours
🇫🇷Tours Cedex 01, France
Kliniken Ostalb Stauferklinikum Schwab. Gmund
🇩🇪Mutlangen, Baden-Wuttemberg, Germany
Universitatsklinikum Koln
🇩🇪Kerpen, Koln, Germany
Universitaetsmedizin der Johannes Gutenberg, Langenbeckstrasse 1
🇩🇪Langen, Mainz, Germany
Gemeinschaftpraxis Haematologie und Onkologie
🇩🇪Dresden, Sachsen, Germany
General Hospital of Athens Laiko
🇬🇷Athens, Greece
Vivantes Klinikum Am Urban
🇩🇪Berlin, Germany
Universitatsklinikum Essen, Klinik fur Hamatologie
🇩🇪Essen, Germany
University Hospital of Alexandroupolis
🇬🇷Alexandroupolis, Greece
251 Air Force General Hospital
🇬🇷Athens, Greece
Universitatsklinikum des Saarlandes, Klinik fur Innere Medizin I
🇩🇪Homburg/Saar, Germany
University Hospital of Patras
🇬🇷Patra, Greece
Orszagos Onkologiai Intezet
🇭🇺Budapest, Hungary
Semmelweis Egyetem
🇭🇺Budapest, Hungary
Petz Aladar Megyei Oktato Korhaz, II. Belgyogyaszat-Hematologia
🇭🇺Győr, Hungary
Szegedi Tudományegyetem Szent-Györgyi Albert Klinikai Központ
🇭🇺Szeged, Hungary
Markusovszky Egyetemi Oktatokorhaz, Haematologiai es Haemoszatazeologiai Osztaly
🇭🇺Szombathely, Hungary
Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo di Alessandria
🇮🇹Alessandria, Alessandria/Piemonte, Italy
Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII (Presidio Papa Giovanni XXIII)
🇮🇹Bergamo, Bergamo/Lombardia, Italy
Azienda Ospedaliera Universitaria di Bologna Policlinico Saint Orsola Malpighi
🇮🇹Bologna, Bologna/Emilia-Romagna, Italy
ASST degli Spedali Civili di Brescia
🇮🇹Brescia, Brescia/Lombardia, Italy
Azienda Ospedaliera S. Croce e Carle Cuneo
🇮🇹Cuneo, Cuneo/Piemonte, Italy
IRCCS Ospedale S. Raffaele di Milano
🇮🇹Milano, Milano/Lombardia, Italy
Azienda Ospedaliero-Universitaria Santa Maria della Misericordia
🇮🇹Udine, Udine/Friuli-Venezia Giulia, Italy
Azienda Ospedaliero Universitaria Molinette San Giovanni Battista di Torino
🇮🇹Torino, Torino/Piemonte, Italy
Fondazione IRCCS Policlinico San Matteo
🇮🇹Pavia, Pavia/Lombardia, Italy
Gachon University Gil Medical Center
🇰🇷Incheon, Korea, Republic of
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
Severance Hospital, Yonsei University Health System
🇰🇷Seoul, Korea, Republic of
Spaarne Gasthuis
🇳🇱Hoofddorp, Netherlands
Leiden University Medical Center
🇳🇱Leiden, Netherlands
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
The Catholic University of Korea, Seoul St. Mary's Hospital
🇰🇷Seoul, Korea, Republic of
Erasmus MC
🇳🇱Rotterdam, Netherlands
General Hospital of Athens "Alexandra"
🇬🇷Athens, Greece
University General Hospital of Ioannina
🇬🇷Ioánnina, Greece
Somogy Megyei Kaposi Mor Oktato Korhaz
🇭🇺Kaposvár, Hungary
Istituto Scientifico Romagnolo Per Lo Studio e La Cura Dei Tumori
🇮🇹Meldola, Forli-Cesena/Emilia-Rom, Italy
Malopolskie Centrum Medyczne s c
🇵🇱Kraków, Poland
Ondokuz Mayiz universitesi Tip Fakultesi
🇹🇷Kurupelit, Samsun, Turkey
Gazi Universitesi Tip Fakultesi, Besevler
🇹🇷Ankara, Turkey
Communal Nonprofit enterprise Cherkasy Regional Oncology Dispensary ofCherkasy Oblast Council,Regional Treatment and Diagnostic Hematological Center
🇺🇦Cherkasy, Ukraine
Andrii Novak Transcarpathian Regional Clinical Hospital, Department of Hematology
🇺🇦Uzhgorod, Ukraine
The University of Arizona Cancer Centre-North Campus
🇺🇸Tucson, Arizona, United States
Tennessee Oncology
🇺🇸Chattanooga, Tennessee, United States
Barbara Ann Karmanos Cancer institute
🇺🇸Detroit, Michigan, United States
University General Hospital of Larissa
🇬🇷Larissa, Greece
Debreceni Egyetem Klinikai Kozpont, Belgyogyaszati Klinika
🇭🇺Debrecen, Hungary
Instytut Hematologii i Transfuzjologii
🇵🇱Warszawa, Poland
Wojewodzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii im. Kopernika w Lodzi
🇵🇱Łódź, Poland
Asst Grande Ospedale Metropolitano Niguarda
🇮🇹Milano, Milano/Lombardia, Italy
Uniwersytecki Szpital Kliniczny im. J. Mikulicza-Radeckiego we Wroclawiu, PZOZ
🇵🇱Wrocław, Poland
The Churchill Hospital
🇬🇧Oxford, Oxfordshire, United Kingdom
Hospital Universitari Germans Trias I Pujol
🇪🇸Badalona, Barcelona, Spain
National Inst. of Cancer, Scientific and Research Dept of Chemotherapy of Hemoblastosis and Adjuvant Treatment Methods, Dept of Oncohematology with Sector of Adjuvant treatment methods
🇺🇦Kyiv, Ukraine
SI national Scientific Center of Radiation Medicine of NAMS of Ukraine, Dep. of Radiation Oncohematology and Stem Cell Transplantation Unit
🇺🇦Kyiv, Ukraine
Communal Institution O.F. Herbachevskyi Regional Clinical Hospital of Zhytomyr Regional Council Dept of Hematology with beds of Intensive Therapy
🇺🇦Zhytomyr, Ukraine
Clinica Universidad de Navarra
🇪🇸Pamplona, Navarra, Spain
BC Cancer-Vancouver Centre
🇨🇦Vancouver, British Columbia, Canada
The Ottawa Hospital
🇨🇦Ottawa, Ontario, Canada