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

NCT03112174 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: PCYC-1143-CA2017-000129-12
• Study Type: interventional
• Target: 366
• Locations: 17 countries
• Sites: 120

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.

Conditions

Mantle-Cell Lymphoma

Keywords

PCYC; MCL; Non-Hodgkin's Lymphoma; NHL; ibrutinib; venetoclax; Pharmacyclics

Outcome Measures

Primary Outcomes (5)

• 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 Outcomes (27)

• Overall Survival (OS) (Safety Run-in)

  For an overall median time on study of 74.78 months

• Progression-free Survival (PFS) (Safety Run-in)

  For an overall median time on study of 74.78 months

• Duration of Response (DOR) (Safety Run-in)

  For an overall median time on study of 74.78 months

• Overall Response Rate (ORR) (Safety Run-in)

  For an overall median time on study of 74.78 months

• Percentage of Participants With a Complete Response (CR) (Randomization Phase)

  For an overall median time on study of 61.34 months

Study Arms (4)

Safety Run-in

EXPERIMENTAL

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; Drug: Venetoclax

Randomization Phase: Ibrutinb + Venetoclax

EXPERIMENTAL

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; Drug: Venetoclax

Randomization Phase: Ibrutinib + Placebo

PLACEBO COMPARATOR

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; Drug: Placebo Oral tablet to match Venetoclax

Treatment-naive Open-label Arm

EXPERIMENTAL

Participants are treated with ibrutinib 560 mg and venetoclax 400 mg, administered using the 5-week ramp-up schedule.

Drug: Ibrutinib; Drug: Venetoclax

Interventions

Ibrutinib DRUG

Administered orally once daily

Randomization Phase: Ibrutinb + Venetoclax; Randomization Phase: Ibrutinib + Placebo; Safety Run-in; Treatment-naive Open-label Arm

Venetoclax DRUG

Administered orally once daily

Randomization Phase: Ibrutinb + Venetoclax; Safety Run-in; Treatment-naive Open-label Arm

Placebo Oral tablet to match Venetoclax DRUG

Administered orally once daily

Randomization Phase: Ibrutinib + Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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
• 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.
• 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.

Sponsors & Collaborators

• Pharmacyclics LLC.: lead
• Janssen Research & Development, LLC: collaborator

Study Sites (120)

The University of Arizona Cancer Centre-North Campus

Tucson, Arizona, 85719, United States

Location

City of Hope

Duarte, California, 91010, United States

Location

UCLA Department of Medicine-Hematology/Oncology

Los Angeles, California, 90095, United States

Location

Orlando Health Inc.

Orlando, Florida, 32806, United States

Location

The University of Kansas Cancer Center and Medical Pavilion

Westwood, Kansas, 66205, United States

Location

Norton Cancer Institute

Louisville, Kentucky, 40207, United States

Location

Barbara Ann Karmanos Cancer institute

Detroit, Michigan, 48201, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Stony Brook University

New York, New York, 11794, United States

Location

Levine Cancer Institute

Charlotte, North Carolina, 28204, United States

Location

Tennessee Oncology

Chattanooga, Tennessee, 37404, United States

Location

University of Tennessee medical Center

Knoxville, Tennessee, 37920, United States

Location

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Swedish Cancer Institute

Seattle, Washington, 98194, United States

Location

The Canberra Hospital

Canberra, Australian Capital Territory, 2605, Australia

Location

Border Medical Oncology Research Unit

Albury, New South Wales, 2640, Australia

Location

Icon Cancer Care

Auchenflower, Queensland, 4101, Australia

Location

Austin Health

Heidelberg, Victoria, 3084, Australia

Location

Peter MacCallum Cancer

Melbourne, Victoria, 3000, Australia

Location

St.Vincent's Hospital

Melbourne, Victoria, 3065, Australia

Location

Sir Charles Gairdner Hospital

Nedlands, Western Australia, 6009, Australia

Location

ZiekenhuisNetwerk Antwerpen (ZNA) Stuivenberg

Antwerp, 2060, Belgium

Location

AZ Sint-Jan Brugge-Oostende AV

Bruges, 8000, Belgium

Location

Institut Jules Bordet

Brussels, 1000, Belgium

Location

CHU UCL Namur asbl- Mont Godinne

Yvoir, 5530, Belgium

Location

Tom Baker Cancer Centre

Calgary, Alberta, T2N 4N2, Canada

Location

Cross Cancer Institute

Edmonton, Alberta, T6G 1 Z2, Canada

Location

BC Cancer-Vancouver Centre

Vancouver, British Columbia, V5Z 4E6, Canada

Location

Queen Elizabeth II Health Science Centre

Halifax, Nova Scotia, B3H 2Y9, Canada

Location

The Ottawa Hospital

Ottawa, Ontario, K1H 8L6, Canada

Location

Jewish General Hospital

Montreal, Quebec, H3T 1E2, Canada

Location

FN Brno, Interni hematologicka a onkologicka klinika

Brno, 625 00, Czechia

Location

Fakultni Nemocnice (FN) Hradec Kravlove, a.s. IV. Interni hematologicka klinika

Hradec Králové, 500 05, Czechia

Location

FN Olomouc

Olomouc, 77900, Czechia

Location

FN Ostrava

Ostrava-Poruba, 708 52, Czechia

Location

Fakultni nemocnice Kralovske Vinohrady

Prague, 100 34, Czechia

Location

Vseobecna fakultni nemocnice v Praze, l. interni klinika-klinika hematologie

Prague, 128 08, Czechia

Location

CHU CAEN-Hôpital de la Côte de Nacre

Caen, Calvados, 14033, France

Location

Institut Bergonié

Bordeaux, 33076, France

Location

CHU Clermont Ferrand - Hôpital d'Estaing

Clermont-Ferrand, 63003, France

Location

Institut Paoli Calmettes, Service Hematologie

Marseille, 13009, France

Location

Centre Antoine Lacassagne

Nice, 06189, France

Location

Hôpital Saint-Louis

Paris, 75010, France

Location

Centre Hospitalier Lyon Sud

Pierre-Bénite, 69495, France

Location

CHU de Tours

Tours, 37044, France

Location

Kliniken Ostalb Stauferklinikum Schwab. Gmund

Mutlangen, Baden-Wuttemberg, 73557, Germany

Location

Universitaetsklinikum Ulm

Ulm, Baden-Wuttemberg, 89081, Germany

Location

Klinikum der Universitaet Muenchen Campus Grosshadern

Munich, Bavaria, 81377, Germany

Location

Universitatsklinikum Koln

Kerpen, Koln, 50937, Germany

Location

Universitaetsmedizin der Johannes Gutenberg, Langenbeckstrasse 1

Langen, Mainz, 55131, Germany

Location

Gemeinschaftpraxis Haematologie und Onkologie

Dresden, Saxony, 01307, Germany

Location

Vivantes Klinikum Am Urban

Berlin, 10967, Germany

Location

Charite- Universitatsmedizin Berlin, Campus Benjamin Franklin

Berlin, 12200, Germany

Location

Universitatsklinikum Essen, Klinik fur Hamatologie

Essen, 45147, Germany

Location

Universitatsklinikum des Saarlandes, Klinik fur Innere Medizin I

Homburg/Saar, 66421, Germany

Location

University Hospital of Alexandroupolis

Alexandroupoli, 68100, Greece

Location

251 Air Force General Hospital

Athens, 11525, Greece

Location

General Hospital of Athens Laiko

Athens, 11527, Greece

Location

General Hospital of Athens "Alexandra"

Athens, 11528, Greece

Location

University General Hospital of Ioannina

Ioannina, 45500, Greece

Location

University General Hospital of Larissa

Larissa, 41110, Greece

Location

University Hospital of Patras

Pátrai, 26504, Greece

Location

Orszagos Onkologiai Intezet

Budapest, 1122, Hungary

Location

Semmelweis Egyetem

Budapest, 1125, Hungary

Location

Debreceni Egyetem Klinikai Kozpont, Belgyogyaszati Klinika

Debrecen, 4032, Hungary

Location

Petz Aladar Megyei Oktato Korhaz, II. Belgyogyaszat-Hematologia

Győr, 9024, Hungary

Location

Somogy Megyei Kaposi Mor Oktato Korhaz

Kaposvár, 7400, Hungary

Location

Szegedi Tudományegyetem Szent-Györgyi Albert Klinikai Központ

Szeged, 6725, Hungary

Location

Markusovszky Egyetemi Oktatokorhaz, Haematologiai es Haemoszatazeologiai Osztaly

Szombathely, 9700, Hungary

Location

Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo di Alessandria

Alessandria, Alessandria/Piemonte, 15121, Italy

Location

Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII (Presidio Papa Giovanni XXIII)

Bergamo, Bergamo/Lombardia, 21427, Italy

Location

Azienda Ospedaliera Universitaria di Bologna Policlinico Saint Orsola Malpighi

Bologna, Bologna/Emilia-Romagna, 40138, Italy

Location

ASST degli Spedali Civili di Brescia

Brescia, Brescia/Lombardia, 25123, Italy

Location

Azienda Ospedaliera S. Croce e Carle Cuneo

Cuneo, Cuneo/Piemonte, 12100, Italy

Location

Istituto Scientifico Romagnolo Per Lo Studio e La Cura Dei Tumori

Meldola, Forli-Cesena/Emilia-Rom, 47014, Italy

Location

IRCCS Ospedale S. Raffaele di Milano

Milan, Milano/Lombardia, 20132, Italy

Location

Asst Grande Ospedale Metropolitano Niguarda

Milan, Milano/Lombardia, 20162, Italy

Location

Fondazione IRCCS Policlinico San Matteo

Pavia, Pavia/Lombardia, 27100, Italy

Location

Azienda Ospedaliero Universitaria Molinette San Giovanni Battista di Torino

Torino, Torino/Piemonte, 10126, Italy

Location

Azienda Ospedaliero-Universitaria Santa Maria della Misericordia

Udine, Udine/Friuli-Venezia Giulia, 33010, Italy

Location

Universitair Medisch Centrum Groningen

Groningen, 9713 GZ, Netherlands

Location

Spaarne Gasthuis

Hoofddorp, 2134 TM, Netherlands

Location

Leiden University Medical Center

Leiden, 2333 ZA, Netherlands

Location

Erasmus MC

Rotterdam, 3015 CE, Netherlands

Location

Franciscus Vlietland

Schiedam, 3118 JH, Netherlands

Location

Szpital Uniwersytecki nr 2 im. dr J. Biziela w Bydgoszcz

Bydgoszcz, 85-168, Poland

Location

Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespol Szpitali Miejskich, Oddzial Hematologiczny

Chorzów, 41-500, Poland

Location

Malopolskie Centrum Medyczne s c

Krakow, 30-510Komisja Bioctyczn, Poland

Location

Wojewodzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii im. Kopernika w Lodzi

Lodz, 93-513, Poland

Location

Instytut Hematologii i Transfuzjologii

Warsaw, 02-776, Poland

Location

Uniwersytecki Szpital Kliniczny im. J. Mikulicza-Radeckiego we Wroclawiu, PZOZ

Wroclaw, 50-367, Poland

Location

Gachon University Gil Medical Center

Incheon, 21565, South Korea

Location

Seoul National University Hospital

Seoul, 03080, South Korea

Location

Severance Hospital, Yonsei University Health System

Seoul, 03722, South Korea

Location

Samsung Medical Center

Seoul, 06351, South Korea

Location

The Catholic University of Korea, Seoul St. Mary's Hospital

Seoul, 06591, South Korea

Location

Hospital Universitari Germans Trias I Pujol

Badalona, Barcelona, 08916, Spain

Location

ICO l'Hospitalet- Hospital Duran i Reynals

L'Hospitalet de Llobregat, Barcelona, 08907, Spain

Location

Clinica Universidad de Navarra

Pamplona, Navarre, 31008, Spain

Location

Hospital Universitario de Cabuenes

Gijón, Principality of Asturias, 33203, Spain

Location

Hospital de la Santa Creu i Sant Pau

Barcelona, 08041, Spain

Location

Hospital Universitario Ramon y Cajal

Madrid, 28034, Spain

Location

Fundacion Jimenez Diaz

Madrid, 28040, Spain

Location

Ondokuz Mayiz universitesi Tip Fakultesi

Kurupelit, Samsun, 55139, Turkey (Türkiye)

Location

Gazi Universitesi Tip Fakultesi, Besevler

Ankara, 06500, Turkey (Türkiye)

Location

Dokuz Eylul Universitesi Tip Fakultesi

Izmir, Turkey (Türkiye)

Location

Namik Kemal Universitesi Saglik Uyg. ve.Ars. Hastanesi

Tekirdağ, 59030, Turkey (Türkiye)

Location

Communal Nonprofit enterprise Cherkasy Regional Oncology Dispensary ofCherkasy Oblast Council,Regional Treatment and Diagnostic Hematological Center

Cherkasy, 18009, Ukraine

Location

Communal Non-profit Enterprise Regional Center of Oncology, Department of Hematology

Kharkiv, 61070, Ukraine

Location

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, 03022, Ukraine

Location

SI national Scientific Center of Radiation Medicine of NAMS of Ukraine, Dep. of Radiation Oncohematology and Stem Cell Transplantation Unit

Kyiv, 03115, Ukraine

Location

Andrii Novak Transcarpathian Regional Clinical Hospital, Department of Hematology

Uzhhorod, 88018, Ukraine

Location

Communal Institution O.F. Herbachevskyi Regional Clinical Hospital of Zhytomyr Regional Council Dept of Hematology with beds of Intensive Therapy

Zhytomyr, 10002, Ukraine

Location

Barts Health NHS Trust

London, Greater London, EC1A 7BE, United Kingdom

Location

The Christie NHS Foundation Trust

Manchester, Greater Manchester, M20 4BX, United Kingdom

Location

Nottingham University Hospitals NHS Trust

Nottingham, Nottinghamshire, NG5 1PB, United Kingdom

Location

The Churchill Hospital

Oxford, Oxfordshire, OX3 7LE, United Kingdom

Location

The Royal Marsden NHS Foundation Trust

Sutton, Surrey, SM2 5PT, United Kingdom

Location

St James University Hospital

Leeds, West Yorkshire, LS9 7TF, United Kingdom

Location

University College London Hospitals NHS Foundation Trust

London, NW1 2PG, United Kingdom

Location

Related Publications (2)

• Wang M, Jurczak W, Trneny M, Belada D, Wrobel T, Ghosh N, Keating MM, van Meerten T, Alvarez RF, von Keudell G, Thieblemont C, Peyrade F, Andre M, Hoffmann M, Szafer-Glusman E, Lin J, Dean JP, Neuenburg JK, Tam CS. Ibrutinib plus venetoclax in relapsed or refractory mantle cell lymphoma (SYMPATICO): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2025 Feb;26(2):200-213. doi: 10.1016/S1470-2045(24)00682-X.

  PMID: 39914418 DERIVED

• 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.

  PMID: 34717692 DERIVED

MeSH Terms

Conditions

Lymphoma, Mantle-Cell; Lymphoma, Non-Hodgkin

Interventions

ibrutinib; venetoclax

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Results Point of Contact

• Title: Global Medical Services
• Organization: AbbVie

abbvieclinicaltrials@abbvie.com

800-633-9110

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 4, 2017
• First Posted: April 13, 2017
• Study Start: June 19, 2017
• Primary Completion: June 26, 2024
• Study Completion: June 27, 2024
• Last Updated: July 22, 2025
• Results First Posted: July 22, 2025

Record last verified: 2025-07

Locations

IT (11); ES (7); DE (10); GR (7); HU (7); CA (6); BE (4); CZ (6); UA (6); KR (5); US (14); TU (4); AU (7); FR (8); GB (7); NL (5); PL (6)