Study of Ibrutinib Combined With Venetoclax in Subjects With Mantle Cell Lymphoma (MCL) (SYMPATICO)

Phase 3 Study of Ibrutinib in Combination With Venetoclax in Subjects With Mantle Cell Lymphoma

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.

Study Overview

• Status: Completed
• Conditions: Mantle-Cell Lymphoma
• Intervention / Treatment: Drug: Ibrutinib; Drug: Venetoclax; Drug: Placebo Oral tablet to match Venetoclax

• Study Type: Interventional
• Enrollment (Actual): 366
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Australian Capital Territory
    • Canberra, Australian Capital Territory, Australia, 2605
      • The Canberra Hospital
  • New South Wales
    • Albury, New South Wales, Australia, 2640
      • Border Medical Oncology Research Unit
  • Queensland
    • Auchenflower, Queensland, Australia, 4101
      • ICON Cancer Care
  • Victoria
    • Heidelberg, Victoria, Australia, 3084
      • Austin Health
    • Melbourne, Victoria, Australia, 3000
      • Peter MacCallum Cancer
    • Melbourne, Victoria, Australia, 3065
      • St.Vincent's hospital
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Sir Charles Gairdner Hospital
• Belgium
  • Antwerpen, Belgium, 2060
    • ZiekenhuisNetwerk Antwerpen (ZNA) Stuivenberg
  • Brugge, Belgium, 8000
    • AZ Sint-Jan Brugge-Oostende AV
  • Bruxelles, Belgium, 1000
    • Institut Jules Bordet
  • Yvoir, Belgium, 5530
    • CHU UCL Namur asbl- Mont Godinne
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Tom Baker Cancer Centre
    • Edmonton, Alberta, Canada, T6G 1 Z2
      • Cross Cancer Institute
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • BC Cancer-Vancouver Centre
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 2Y9
      • Queen Elizabeth II Health Science Centre
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • The Ottawa Hospital
  • Quebec
    • Montréal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital
• Czechia
  • Brno, Czechia, 625 00
    • FN Brno, Interni hematologicka a onkologicka klinika
  • Hradec Králové, Czechia, 500 05
    • Fakultni Nemocnice (FN) Hradec Kravlove, a.s. IV. Interni hematologicka klinika
  • Olomouc, Czechia, 77900
    • FN Olomouc
  • Ostrava-Poruba, Czechia, 708 52
    • FN Ostrava
  • Praha 10, Czechia, 100 34
    • Fakultni nemocnice Kralovske Vinohrady
  • Praha 2, Czechia, 128 08
    • Vseobecna fakultni nemocnice v Praze, l. interni klinika-klinika hematologie
• France
  • Bordeaux, France, 33076
    • Institut Bergonie
  • Clermont Ferrand cedex, France, 63003
    • CHU Clermont Ferrand - Hôpital d'Estaing
  • Marseille, France, 13009
    • Institut Paoli Calmettes, Service Hematologie
  • Nice Cedex 2, France, 06189
    • Centre Antoine Lacassagne
  • Paris, France, 75010
    • Hôpital Saint-Louis
  • Pierre Benite cedex, France, 69495
    • Centre Hospitalier Lyon Sud
  • Tours Cedex 01, France, 37044
    • Chu De Tours
  • Calvados
    • CAEN Cedex, Calvados, France, 14033
      • CHU CAEN-Hôpital de la Côte de Nacre
• Germany
  • Berlin, Germany, 10967
    • Vivantes Klinikum Am Urban
  • Berlin, Germany, 12200
    • Charite- Universitatsmedizin Berlin, Campus Benjamin Franklin
  • Essen, Germany, 45147
    • Universitätsklinikum Essen, Klinik für Hämatologie
  • Homburg/Saar, Germany, 66421
    • Universitatsklinikum des Saarlandes, Klinik fur Innere Medizin I
  • Baden-Wuttemberg
    • Mutlangen, Baden-Wuttemberg, Germany, 73557
      • Kliniken Ostalb Stauferklinikum Schwab. Gmund
    • Ulm, Baden-Wuttemberg, Germany, 89081
      • Universitaetsklinikum Ulm
  • Bayern
    • Muenchen, Bayern, Germany, 81377
      • Klinikum der Universitaet Muenchen Campus Grosshadern
  • Koln
    • Kerpen, Koln, Germany, 50937
      • Universitätsklinikum Köln
  • Mainz
    • Langen, Mainz, Germany, 55131
      • Universitaetsmedizin der Johannes Gutenberg, Langenbeckstrasse 1
  • Sachsen
    • Dresden, Sachsen, Germany, 01307
      • Gemeinschaftpraxis Haematologie und Onkologie
• Greece
  • Alexandroupolis, Greece, 68100
    • University Hospital of Alexandroupolis
  • Athens, Greece, 11527
    • General Hospital of Athens Laiko
  • Athens, Greece, 11528
    • General Hospital of Athens "Alexandra"
  • Athens, Greece, 11525
    • 251 Air Force General Hospital
  • Ioánnina, Greece, 45500
    • University General Hospital of Ioannina
  • Larissa, Greece, 41110
    • University General Hospital of Larissa
  • Patra, Greece, 26504
    • University Hospital of Patras
• Hungary
  • Budapest, Hungary, 1122
    • Orszagos Onkologiai Intezet
  • Budapest, Hungary, 1125
    • Semmelweis Egyetem
  • Debrecen, Hungary, 4032
    • Debreceni Egyetem Klinikai Kozpont, Belgyogyaszati Klinika
  • Győr, Hungary, 9024
    • Petz Aladar Megyei Oktato Korhaz, II. Belgyogyaszat-Hematologia
  • Kaposvár, Hungary, 7400
    • Somogy Megyei Kaposi Mor Oktato Korhaz
  • Szeged, Hungary, 6725
    • Szegedi Tudományegyetem Szent-Györgyi Albert Klinikai Központ
  • Szombathely, Hungary, 9700
    • Markusovszky Egyetemi Oktatokorhaz, Haematologiai es Haemoszatazeologiai Osztaly
• Italy
  • Alessandria/Piemonte
    • Alessandria, Alessandria/Piemonte, Italy, 15121
      • Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo di Alessandria
  • Bergamo/Lombardia
    • Bergamo, Bergamo/Lombardia, Italy, 21427
      • Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII (Presidio Papa Giovanni XXIII)
  • Bologna/Emilia-Romagna
    • Bologna, Bologna/Emilia-Romagna, Italy, 40138
      • Azienda Ospedaliera Universitaria di Bologna Policlinico Saint Orsola Malpighi
  • Brescia/Lombardia
    • Brescia, Brescia/Lombardia, Italy, 25123
      • ASST degli Spedali Civili di Brescia
  • Cuneo/Piemonte
    • Cuneo, Cuneo/Piemonte, Italy, 12100
      • Azienda Ospedaliera S. Croce e Carle Cuneo
  • Forli-Cesena/Emilia-Rom
    • Meldola, Forli-Cesena/Emilia-Rom, Italy, 47014
      • Istituto Scientifico Romagnolo Per Lo Studio e La Cura Dei Tumori
  • Milano/Lombardia
    • Milano, Milano/Lombardia, Italy, 20132
      • IRCCS Ospedale S. Raffaele di Milano
    • Milano, Milano/Lombardia, Italy, 20162
      • ASST Grande Ospedale Metropolitano Niguarda
  • Pavia/Lombardia
    • Pavia, Pavia/Lombardia, Italy, 27100
      • Fondazione IRCCS Policlinico San Matteo
  • Torino/Piemonte
    • Torino, Torino/Piemonte, Italy, 10126
      • Azienda Ospedaliero Universitaria Molinette San Giovanni Battista di Torino
  • Udine/Friuli-Venezia Giulia
    • Udine, Udine/Friuli-Venezia Giulia, Italy, 33010
      • Azienda Ospedaliero-Universitaria Santa Maria della Misericordia
• Korea, Republic of
  • Incheon, Korea, Republic of, 21565
    • Gachon University Gil Medical Center
  • Seoul, Korea, Republic of, 03080
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 03722
    • Severance Hospital, Yonsei University Health System
  • Seoul, Korea, Republic of, 06591
    • The Catholic University of Korea, Seoul St. Mary's Hospital
  • Seoul, Korea, Republic of, 06351
    • Samsung Medical Center
• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • Universitair Medisch Centrum Groningen
  • Hoofddorp, Netherlands, 2134 TM
    • Spaarne Gasthuis
  • Leiden, Netherlands, 2333 ZA
    • Leiden University Medical Center
  • Rotterdam, Netherlands, 3015 CE
    • Erasmus MC
  • Schiedam, Netherlands, 3118 JH
    • Franciscus Vlietland
• Poland
  • Bydgoszcz, Poland, 85-168
    • Szpital Uniwersytecki nr 2 im. dr J. Biziela w Bydgoszcz
  • Chorzów, Poland, 41-500
    • Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespol Szpitali Miejskich, Oddzial Hematologiczny
  • Kraków, Poland, 30-510Komisja Bioctyczn
    • Malopolskie Centrum Medyczne s c
  • Warszawa, Poland, 02-776
    • Instytut Hematologii i Transfuzjologii
  • Wrocław, Poland, 50-367
    • Uniwersytecki Szpital Kliniczny im. J. Mikulicza-Radeckiego we Wroclawiu, PZOZ
  • Łódź, Poland, 93-513
    • Wojewodzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii im. Kopernika w Lodzi
• Spain
  • Barcelona, Spain, 08041
    • Hospital De La Santa Creu I Sant Pau
  • Madrid, Spain, 28040
    • Fundación Jiménez Díaz
  • Madrid, Spain, 28034
    • Hospital Universitario Ramon y Cajal
  • Asturias
    • Gijón, Asturias, Spain, 33203
      • Hospital Universitario de Cabueñes
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Hospital Universitari Germans Trias i Pujol
    • L'Hospitalet De Llobregat, Barcelona, Spain, 08907
      • ICO l'Hospitalet- Hospital Duran i Reynals
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Clinica Universidad de Navarra
• Turkey
  • Ankara, Turkey, 06500
    • Gazi Universitesi Tip Fakultesi, Besevler
  • Tekirdağ, Turkey, 59030
    • Namik Kemal Universitesi Saglik Uyg. ve.Ars. Hastanesi
  • İzmir, Turkey
    • Dokuz Eylul Universitesi Tip Fakultesi
  • Samsun
    • Kurupelit, Samsun, Turkey, 55139
      • Ondokuz Mayiz universitesi Tip Fakultesi
• Ukraine
  • Cherkasy, Ukraine, 18009
    • Communal Nonprofit enterprise Cherkasy Regional Oncology Dispensary ofCherkasy Oblast Council,Regional Treatment and Diagnostic Hematological Center
  • Kharkiv, Ukraine, 61070
    • Communal Non-profit Enterprise Regional Center of Oncology, Department of Hematology
  • Kyiv, Ukraine, 03022
    • 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, 03115
    • SI national Scientific Center of Radiation Medicine of NAMS of Ukraine, Dep. of Radiation Oncohematology and Stem Cell Transplantation Unit
  • Uzhgorod, Ukraine, 88018
    • Andrii Novak Transcarpathian Regional Clinical Hospital, Department of Hematology
  • Zhytomyr, Ukraine, 10002
    • Communal Institution O.F. Herbachevskyi Regional Clinical Hospital of Zhytomyr Regional Council Dept of Hematology with beds of Intensive Therapy
• United Kingdom
  • London, United Kingdom, NW1 2PG
    • University College London Hospitals NHS Foundation Trust
  • Greater London
    • London, Greater London, United Kingdom, EC1A 7BE
      • Barts Health NHS Trust
  • Greater Manchester
    • Manchester, Greater Manchester, United Kingdom, M20 4BX
      • The Christie NHS Foundation Trust
  • Nottinghamshire
    • Nottingham, Nottinghamshire, United Kingdom, NG5 1PB
      • Nottingham University Hospitals NHS Trust
  • Oxfordshire
    • Oxford, Oxfordshire, United Kingdom, OX3 7LE
      • The Churchill Hospital
  • Surrey
    • Sutton, Surrey, United Kingdom, SM2 5PT
      • The Royal Marsden NHS Foundation Trust
  • West Yorkshire
    • Leeds, West Yorkshire, United Kingdom, LS9 7TF
      • St James University Hospital
• United States
  • Arizona
    • Tucson, Arizona, United States, 85719
      • The University of Arizona Cancer Centre-North Campus
  • California
    • Duarte, California, United States, 91010
      • City of Hope
    • Los Angeles, California, United States, 90095
      • UCLA Department of Medicine-Hematology/Oncology
  • Florida
    • Orlando, Florida, United States, 32806
      • Orlando Health Inc.
  • Kansas
    • Westwood, Kansas, United States, 66205
      • The University of Kansas Cancer Center and Medical Pavilion
  • Kentucky
    • Louisville, Kentucky, United States, 40207
      • Norton Cancer Institute
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Barbara Ann Karmanos Cancer Institute
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 11794
      • Stony Brook University
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Levine Cancer Institute
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Tennessee Oncology
    • Knoxville, Tennessee, United States, 37920
      • University of Tennessee Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center
  • Washington
    • Seattle, Washington, United States, 98194
      • Swedish Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Relapsed/Refractory Arm

Inclusion Criteria:

• 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).
• 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.

Exclusion Criteria:

• 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 to 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 by CT.
• Must have adequate fresh or paraffin-embedded tissue.
• Eastern Cooperative Oncology Group (ECOG) performance status score 0 to <= 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Safety Run-in; Participants with a low or high risk of TLS enroll into the open-label Safety Run-in Period to receive concurrent ibrutinib at 560 mg once daily and venetoclax starting at 20 mg, and gradually ramp up to a target dose of 400 mg once daily over a 5-week period.	Drug: Ibrutinib; Administered orally once daily; Drug: Venetoclax; Administered orally once daily
Experimental: Randomization Phase: Ibrutinb + Venetoclax; Participants randomized to ibrutinib and venetoclax for approximately 104 weeks, followed by ibrutinib monotherapy until disease progression (PD), unacceptable toxicity or withdrawal of consent. Venetoclax is discontinued after 104 weeks of treatment, regardless of response assessment.	Drug: Ibrutinib; Administered orally once daily; Drug: Venetoclax; Administered orally once daily
Placebo Comparator: Randomization Phase: Ibrutinib + Placebo; Participants randomized to ibrutinib and placebo for approximately 104 weeks, followed by ibrutinib monotherapy until PD, unacceptable toxicity or withdrawal of consent. Placebo is discontinued after 104 weeks of treatment, regardless of response assessment.	Drug: Ibrutinib; Administered orally once daily; Drug: Placebo Oral tablet to match Venetoclax; Administered orally once daily
Experimental: Treatment-naive Open-label Arm; Participants are treated with ibrutinib 560 mg and venetoclax 400 mg, administered using the 5-week ramp-up schedule.	Drug: Ibrutinib; Administered orally once daily; Drug: Venetoclax; Administered orally once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Tumor Lysis Syndrome (TLS) Events (Safety Run-in)	TLS events are defined as follows: Clinical TLS: any event that meets Howard criteria (N Engl J Med 2011;364:1844-1854) with the following exceptions:For the purpose of TLS assessment during the Safety Run-in Period, only those increases in serum creatinine > 1.0 mg/dL from pre-treatment baseline will be considered clinical TLS.In participants with renal dysfunction at baseline (CrCl < 60 mL/min), clinical TLS is defined as the presence of laboratory TLS plus either seizures, cardiac dysrhythmia, or death.; Laboratory TLS: any event that meets Howard criteria (N Engl J Med 2011;364:1844-1854) for laboratory TLS, that does not resolve within 72 hours despite protocol required management.	After at least 3 months of treatment, with an overall median treatment duration of 20.0 months
Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in)	DLT: any Grade (Gr) 3 or higher non-TLS adverse event (AE) at least possibly related to study drug occurring during the DLT assessment period with the following clarifications: Non-Hematologic DLTs: Gr ≥3 nausea, vomiting or diarrhea uncontrolled despite maximum medical supportive care and persisting >5 days; Gr 3 fatigue persisting >7 days; Gr 3 infection is not a DLT, however an infection with lifethreatening consequences or requiring urgent intervention (Gr 4) was considered a DLT; Treatment delay of any study drug >7 days for toxicity. Hematologic DLTs: Gr 3 neutropenia is not a DLT, however, Gr 4 neutropenia (ANC <500/mm^3) lasting for > 7 days is a DLT; Gr 3 or 4 neutropenia complicated by fever ≥38.5°C or infection; Gr 4 thrombocytopenia (<25,000/mm^3) that persists for > 7 days; Gr 3 or 4 thrombocytopenia associated with Gr 2 or greater bleeding; Gr 3 anemia is not a DLT, however, Gr 4 anemia is a DLT; Treatment delay of any study drug >7 days for hematologic toxicity.	After at least 3 months of treatment, with an overall median treatment duration of 20.0 months
Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	AE: any untoward medical occurrence in a participant that does not necessarily have a causal relationship with treatment. The investigator assesses the relationship of each event to the use of study. Serious adverse event (SAE): 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): any event that began or worsened in severity on or after the first dose of study drug. Event severity is graded as mild (1), moderate (2), severe (3), life threatening (4), death (5).	From first dose of study drug until the end of treatment + 30 days, with an overall median treatment duration of 20.0 months
Progression-free Survival (PFS) (Randomization Phase)	PFS is defined as the time from the date of randomization to the date of disease progression using the Revised Response Criteria for Malignant Lymphoma (Cheson 2014), or death from any cause, whichever occurs first.	For an overall median time on study of 61.34 months
Complete Response (CR) Rate (Treatment-Naive Arm)	CR rate is defined as the percentage of participants with a CR according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2014).	For an overall median time on study of 40.51 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS) (Safety Run-in)	OS is defined as the time from the date of the first dose of study treatment to death from any cause.	For an overall median time on study of 74.78 months
Progression-free Survival (PFS) (Safety Run-in)	PFS is defined as the time from the date of the first dose of study treatment to the date of disease progression using the Revised Response Criteria for Malignant Lymphoma (Cheson 2014), or death from any cause, whichever occurs first.	For an overall median time on study of 74.78 months
Duration of Response (DOR) (Safety Run-in)	DOR is defined for participants who achieve an overall response as the time from the first occurrence of response (CR or PR according to the Revised Response Criteria for Malignant Lymphoma [Cheson 2014]) to disease progression or death, whichever occurs first.	For an overall median time on study of 74.78 months
Overall Response Rate (ORR) (Safety Run-in)	ORR is defined as the percentage of participants with CR or PR per investigator assessment according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2014).	For an overall median time on study of 74.78 months
Percentage of Participants With a Complete Response (CR) (Randomization Phase)	Complete response rate (CR) based on the best overall response per investigator assessment according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2014).	For an overall median time on study of 61.34 months
Overall Response Rate (ORR) (Randomization Phase and Treatment-Naive Arm)	ORR is defined as the percentage of participants with CR or PR per investigator assessment according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2014).	For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm)
MRD-negative Remission Rate in Participants Who Achieve CR Per Investigator Assessment (Randomization Phase and Treatment-Naive Arm)	MRD-negative remission rate is defined as the percentage of participants with undetectable MRD at documented CR in participants 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.	For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm)
Overall Survival (OS) (Randomization Phase and Treatment-Naive Arm)	OS is defined as the time from the date of randomization (Randomization Phase) or the first dose of study treatment (Treatment-Naïve arm) to death from any cause.	For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm)
Duration of Response (DOR) (Randomization Phase and Treatment-Naive Arm)	DOR is defined as the time frame for participants who achieve an overall response as the time from the first occurrence of response (CR or PR according to the Revised Response Criteria for Malignant Lymphoma [Cheson 2014]) to disease progression or death, whichever occurs first.	For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm)
Time to Next Treatment (TTNT) (Randomization Phase and Treatment-Naive Arm)	TTNT is defined as the duration from the date of randomization (Randomization Phase) or date of first dose of study treatment (Treatment-Naive Arm) to the start date of any anti-lymphoma treatment subsequent to study treatment. Post-treatment stem cell transplantation, chimeric antigen receptor (CAR) T-cell therapy, or other cellular therapies were not considered subsequent anti-cancer treatments for participants responding to the study treatment (CR or PR).	For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm)
Number of Participants With TEAEs (Randomization Phase)	AE: any untoward medical occurrence in a participant that does not necessarily have a causal relationship with treatment. The investigator assesses the relationship of each event to the use of study. Serious adverse event (SAE): 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): any event that began or worsened in severity on or after the first dose of study drug. Event severity is graded as mild (1), moderate (2), severe (3), life threatening (4), death (5).	From first dose of study drug until the end of treatment + 30 days, with an overall median treatment duration of 19.5 months
Number of Participants With TLS TEAEs (Randomization Phase)	Treatment-emergent adverse events/treatment-emergent serious adverse events (TEAEs/TESAEs): any event that began or worsened in severity on or after the first dose of study drug (SD). Event severity is graded as mild (1), moderate (2), severe (3), life threatening (4), death (5).	From first dose of study drug until the end of treatment + 7 days, with an overall median treatment duration 19.5 months
Steady-State Pharmacokinetics (PK) of Ibrutinib: Maximum Observed Plasma Concentration (Cmax) (Randomization Phase)	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose
Steady-State PK of Ibrutinib: Time to Cmax (Tmax) (Randomization Phase)	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose
Steady-State PK of Ibrutinib: Area Under the Concentration-Time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast) (Randomization Phase)	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose
Steady-State PK of Ibrutinib: Terminal Elimination Half-Life (t1/2,Term) (Randomization Phase)	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose
Steady-State PK of Ibrutinib: Time of Last Measurable Concentration (Tlast) (Randomization Phase)	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose
Steady-State PK of Ibrutinib: Area Under the Concentration-Time Curve From 0-24 Hours (AUC0-24) (Randomization Phase)	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose
Steady-State PK of Ibrutinib: Terminal Elimination Rate Constant (λz) (Randomization Phase)	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose
Steady-State PK of Ibrutinib: Apparent Total Clearance at Steady State (CLss/F) (Randomization Phase)	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose
Steady-State PK of Venetoclax: Cmax (Randomization Phase)	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose
Steady-State PK of Venetoclax: AUC0-24 (Randomization Phase)	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose
Steady-State PK of Venetoclax: Time to Cmax (Tmax) (Randomization Phase)	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose
Steady-State PK of Venetoclax: CLss/F (Randomization Phase)	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose
Time to Worsening in Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Subscale of the Health-related Quality of Life (Randomization Phase)	The FACT-Lym lymphoma-specific additional concerns subscale responses to all items are rated on a 5-point scale ranging from 0 "not at all" to 4 "very much". The lymphoma subscale includes 15 items and scores range from 0 to 60, with higher scores representing better functional status and well-being. A 5-point change in the Lym subscale was selected as a conservative estimate of clinically meaningful deterioration in lymphoma symptoms.	For an overall median time on study of 61.34 months (Randomization Phase)
Duration of CR (Treatment-Naive Arm)	Duration of CR, defined for subjects who achieve CR according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2014) as the time from the first occurrence of CR to disease progression or death, whichever occurs first.	For an overall median time on study of 40.51 months
Progression-free Survival (PFS) (Treatment-Naive Arm)	PFS is defined as the time from the date of the first dose of study treatment to the date of disease progression using the Revised Response Criteria for Malignant Lymphoma (Cheson 2014), or death from any cause, whichever occurs first.	For an overall median time on study of 40.51 months

Collaborators and Investigators

• Sponsor: Pharmacyclics LLC.
• Collaborators: Janssen Research & Development, LLC

Publications and helpful links

General Publications

• Wang M, Ramchandren R, Chen R, Karlin L, Chong G, Jurczak W, Wu KL, Bishton M, Collins GP, Eliadis P, Peyrade F, Lee Y, Eckert K, Neuenburg JK, Tam CS. Concurrent ibrutinib plus venetoclax in relapsed/refractory mantle cell lymphoma: the safety run-in of the phase 3 SYMPATICO study. J Hematol Oncol. 2021 Oct 30;14(1):179. doi: 10.1186/s13045-021-01188-x.

Study record dates

Study Major Dates

• Study Start (Actual): June 19, 2017
• Primary Completion (Actual): June 26, 2024
• Study Completion (Actual): June 27, 2024

Study Registration Dates

• First Submitted: April 4, 2017
• First Submitted That Met QC Criteria: April 7, 2017
• First Posted (Actual): April 13, 2017

Study Record Updates

• Last Update Posted (Actual): July 22, 2025
• Last Update Submitted That Met QC Criteria: July 2, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: NHL; Pharmacyclics; PCYC; MCL; venetoclax; Non-Hodgkin's Lymphoma; ibrutinib
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, Mantle-Cell; Tyrosine Kinase Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Venetoclax; Ibrutinib
• Other Study ID Numbers: PCYC-1143-CA; 2017-000129-12 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No