Clinical trial NCT03112174: Study of Ibrutinib Combined With Venetoclax in Subjects With Mantle Cell Lymphoma (SYMPATICO)
Official title: Phase 3 Study of Ibrutinib in Combination With Venetoclax in Subjects With Mantle Cell Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Mantle-Cell Lymphoma
Keywords: PCYC
MCL
Non-Hodgkin's Lymphoma
NHL
ibrutinib
venetoclax
Pharmacyclics
Lead sponsor: Pharmacyclics LLC.
Sponsor class: INDUSTRY
Collaborators: name: Janssen Research & Development, LLC
First posted: 2017-04-13
Enrollment: 352
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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/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.

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 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.

Primary outcomes:
measure: Occurrence of Tumor Lysis Syndrome (TLS) (Safety Run-in Period)
timeFrame: Approximately 3 months after last subject enrolled into safety run-in portion
measure: Occurrence of Dose Limiting Toxicities (DLT) (Safety Run-in Period)
timeFrame: Approximately 3 months after last subject enrolled into safety run-in portion
measure: Number of Participants With Adverse Events (AEs) (Safety Run-in Period)
timeFrame: Up to approximately 5 years
measure: Overall response rate (ORR) (Safety Run-in Period)
timeFrame: approximately 1 year after last subject has stopped treatment with study drug(s)
measure: Duration of Response (DOR) (Safety Run-in Period)
timeFrame: Up to approximately 5 years
measure: Progression-free Survival (PFS) (Safety Run-in Period)
timeFrame: approximately 1 year after last subject has stopped treatment with study drug(s)
measure: Overall Survival (OS) (Safety Run-in Period)
timeFrame: Up to approximately 5 years
measure: Progression-free Survival (PFS) (Randomization Period)
timeFrame: approximately 1 year after last subject has stopped treatment with study drug(s)
measure: Complete Response (CR) (Treatment-Naive Arm)
timeFrame: approximately 1 year after last subject has stopped treatment with study drug(s)
Secondary outcomes:
measure: Complete Response (CR) (Randomization Period)
timeFrame: approximately 1 year after last subject has stopped treatment with study drug(s)
measure: Overall response rate (ORR) (Randomization Period and Treatment-Naive Arm)
timeFrame: approximately 1 year after last subject has stopped treatment with study drug(s)
measure: MRD-negative remission rate in participants who achieve CR per investigator assessment (Randomization Period and Treatment-Naive Arm)
timeFrame: approximately 1 year after last subject has stopped treatment with study drug(s)
measure: Overall Survival (OS) (Randomization Period and Treatment-Naive Arm)
timeFrame: Up to approximately 5 years
measure: Duration of Response (DOR) (Randomization Period and Treatment-Naive Arm)
timeFrame: Up to approximately 5 years
measure: Time to Next Treatment (TTNT) (Randomization Period and Treatment-Naive Arm)
timeFrame: Up to approximately 5 years
measure: Percentage of participants experiencing Adverse Events (Randomization Period)
timeFrame: Up to approximately 5 years
measure: Occurrence of Tumor Lysis Syndrome (TLS) (Randomization Period)
timeFrame: Approximately 3 months after last subject enrolled into safety run-in portion
measure: Cmax if Ibrutinib (Randomization Period)
timeFrame: Week 6
measure: Tmax if Ibrutinib (Randomization Period)
timeFrame: Week 6
measure: AUClast if Ibrutinib (Randomization Period)
timeFrame: Week 6
measure: Half-Life (T1/2) if Ibrutinib (Randomization Period)
timeFrame: Week 6
measure: Cmax of Venetoclax (Randomization Period)
timeFrame: Week 6
measure: Tmax of Venetoclax (Randomization Period)
timeFrame: Week 6
measure: AUC of Venetoclax (Randomization Period)
timeFrame: Week 6
measure: Time to worsening in FACT-Lym subscale of the health-related quality of life (Randomization Period) questionnaire (FACT-Lym)
timeFrame: Week 6
measure: Duration of CR (Treatment-Naive Arm Period)
timeFrame: Up to approximately 5 years
measure: Progression-free Survival (PFS) (Treatment-Naive Arm Period)
timeFrame: approximately 1 year after last subject has stopped treatment with study drug(s)
Other outcomes:
Locations:
city: Tucson
country: United States
facility: The University of Arizona Cancer Centre-North Campus
state: Arizona
city: Duarte
country: United States
facility: City of Hope
state: California
city: Los Angeles
country: United States
facility: UCLA Department of Medicine-Hematology/Oncology
state: California
city: Orlando
country: United States
facility: Orlando Health Inc.
state: Florida
city: Westwood
country: United States
facility: The University of Kansas Cancer Center and Medical Pavilion
state: Kansas
city: Louisville
country: United States
facility: Norton Cancer Institute
state: Kentucky
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer institute
state: Michigan
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Stony Brook University
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Chattanooga
country: United States
facility: Tennessee Oncology
state: Tennessee
city: Knoxville
country: United States
facility: University of Tennessee medical Center
state: Tennessee
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: Swedish Cancer Institute
state: Washington
city: Canberra
country: Australia
facility: The Canberra Hospital
state: Australian Capital Territory
city: Albury
country: Australia
facility: Border Medical Oncology Research Unit
state: New South Wales
city: Auchenflower
country: Australia
facility: Icon Cancer Care
state: Queensland
city: Heidelberg
country: Australia
facility: Austin Health
state: Victoria
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer
state: Victoria
city: Melbourne
country: Australia
facility: St.Vincent's Hospital
state: Victoria
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
city: Antwerpen
country: Belgium
facility: ZiekenhuisNetwerk Antwerpen (ZNA) Stuivenberg
city: Brugge
country: Belgium
facility: AZ Sint-Jan Brugge-Oostende AV
city: Bruxelles
country: Belgium
facility: Institut Jules Bordet
city: Yvoir
country: Belgium
facility: CHU UCL Namur asbl- Mont Godinne
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre
state: Alberta
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Vancouver
country: Canada
facility: BC Cancer-Vancouver Centre
state: British Columbia
city: Halifax
country: Canada
facility: Queen Elizabeth II Health Science Centre
state: Nova Scotia
city: Ottawa
country: Canada
facility: The Ottawa Hospital
state: Ontario
city: Montréal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Brno
country: Czechia
facility: FN Brno, Interni hematologicka a onkologicka klinika
city: Hradec Králové
country: Czechia
facility: Fakultni Nemocnice (FN) Hradec Kravlove, a.s. IV. Interni hematologicka klinika
city: Olomouc
country: Czechia
facility: FN Olomouc
city: Ostrava-Poruba
country: Czechia
facility: FN Ostrava
city: Praha 10
country: Czechia
facility: Fakultni nemocnice Kralovske Vinohrady
city: Praha 2
country: Czechia
facility: Vseobecna fakultni nemocnice v Praze, l. interni klinika-klinika hematologie
city: CAEN Cedex
country: France
facility: CHU CAEN-Hôpital de la Côte de Nacre
state: Calvados
city: Bordeaux
country: France
facility: Institut Bergonié
city: Clermont Ferrand cedex
country: France
facility: CHU Clermont Ferrand - Hôpital d'Estaing
city: Marseille
country: France
facility: Institut Paoli Calmettes, Service Hematologie
city: Nice Cedex 2
country: France
facility: Centre Antoine Lacassagne
city: Paris
country: France
facility: Hôpital Saint-Louis
city: Pierre Benite cedex
country: France
facility: Centre Hospitalier Lyon Sud
city: Tours Cedex 01
country: France
facility: CHU de Tours
city: Mutlangen
country: Germany
facility: Kliniken Ostalb Stauferklinikum Schwab. Gmund
state: Baden-Wuttemberg
city: Ulm
country: Germany
facility: Universitaetsklinikum Ulm
state: Baden-Wuttemberg
city: Muenchen
country: Germany
facility: Klinikum der Universitaet Muenchen Campus Grosshadern
state: Bayern
city: Kerpen
country: Germany
facility: Universitatsklinikum Koln
state: Koln
city: Langen
country: Germany
facility: Universitaetsmedizin der Johannes Gutenberg, Langenbeckstrasse 1
state: Mainz
city: Dresden
country: Germany
facility: Gemeinschaftpraxis Haematologie und Onkologie
state: Sachsen
city: Berlin
country: Germany
facility: Vivantes Klinikum Am Urban
city: Berlin
country: Germany
facility: Charite- Universitatsmedizin Berlin, Campus Benjamin Franklin
city: Essen
country: Germany
facility: Universitatsklinikum Essen, Klinik fur Hamatologie
city: Homburg/Saar
country: Germany
facility: Universitatsklinikum des Saarlandes, Klinik fur Innere Medizin I
city: Alexandroupolis
country: Greece
facility: University Hospital of Alexandroupolis
city: Athens
country: Greece
facility: 251 Air Force General Hospital
city: Athens
country: Greece
facility: General Hospital of Athens Laiko
city: Athens
country: Greece
facility: General Hospital of Athens "Alexandra"
city: Ioánnina
country: Greece
facility: University General Hospital of Ioannina
city: Larissa
country: Greece
facility: University General Hospital of Larissa
city: Patra
country: Greece
facility: University Hospital of Patras
city: Budapest
country: Hungary
facility: Orszagos Onkologiai Intezet
city: Budapest
country: Hungary
facility: Semmelweis Egyetem
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Klinikai Kozpont, Belgyogyaszati Klinika
city: Győr
country: Hungary
facility: Petz Aladar Megyei Oktato Korhaz, II. Belgyogyaszat-Hematologia
city: Kaposvár
country: Hungary
facility: Somogy Megyei Kaposi Mor Oktato Korhaz
city: Szeged
country: Hungary
facility: Szegedi Tudományegyetem Szent-Györgyi Albert Klinikai Központ
city: Szombathely
country: Hungary
facility: Markusovszky Egyetemi Oktatokorhaz, Haematologiai es Haemoszatazeologiai Osztaly
city: Alessandria
country: Italy
facility: Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo di Alessandria
state: Alessandria/Piemonte
city: Bergamo
country: Italy
facility: Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII (Presidio Papa Giovanni XXIII)
state: Bergamo/Lombardia
city: Bologna
country: Italy
facility: Azienda Ospedaliera Universitaria di Bologna Policlinico Saint Orsola Malpighi
state: Bologna/Emilia-Romagna
city: Brescia
country: Italy
facility: ASST degli Spedali Civili di Brescia
state: Brescia/Lombardia
city: Cuneo
country: Italy
facility: Azienda Ospedaliera S. Croce e Carle Cuneo
state: Cuneo/Piemonte
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo Per Lo Studio e La Cura Dei Tumori
state: Forli-Cesena/Emilia-Rom
city: Milano
country: Italy
facility: IRCCS Ospedale S. Raffaele di Milano
state: Milano/Lombardia
city: Milano
country: Italy
facility: Asst Grande Ospedale Metropolitano Niguarda
state: Milano/Lombardia
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo
state: Pavia/Lombardia
city: Torino
country: Italy
facility: Azienda Ospedaliero Universitaria Molinette San Giovanni Battista di Torino
state: Torino/Piemonte
city: Udine
country: Italy
facility: Azienda Ospedaliero-Universitaria Santa Maria della Misericordia
state: Udine/Friuli-Venezia Giulia
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Seoul St. Mary's Hospital
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen
city: Hoofddorp
country: Netherlands
facility: Spaarne Gasthuis
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Schiedam
country: Netherlands
facility: Franciscus Vlietland
city: Bydgoszcz
country: Poland
facility: Szpital Uniwersytecki nr 2 im. dr J. Biziela w Bydgoszcz
city: Chorzów
country: Poland
facility: Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespol Szpitali Miejskich, Oddzial Hematologiczny
city: Kraków
country: Poland
facility: Malopolskie Centrum Medyczne s c
city: Warszawa
country: Poland
facility: Instytut Hematologii i Transfuzjologii
city: Wrocław
country: Poland
facility: Uniwersytecki Szpital Kliniczny im. J. Mikulicza-Radeckiego we Wroclawiu, PZOZ
city: Łódź
country: Poland
facility: Wojewodzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii im. Kopernika w Lodzi
city: Gijón
country: Spain
facility: Hospital Universitario de Cabuenes
state: Asturias
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias I Pujol
state: Barcelona
city: L'Hospitalet De Llobregat
country: Spain
facility: ICO l'Hospitalet- Hospital Duran i Reynals
state: Barcelona
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra
state: Navarra
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Madrid
country: Spain
facility: Fundacion Jimenez Diaz
city: Kurupelit
country: Turkey
facility: Ondokuz Mayiz universitesi Tip Fakultesi
state: Samsun
city: Ankara
country: Turkey
facility: Gazi Universitesi Tip Fakultesi, Besevler
city: İzmir
country: Turkey
facility: Dokuz Eylul Universitesi Tip Fakultesi
city: Tekirdağ
country: Turkey
facility: Namik Kemal Universitesi Saglik Uyg. ve.Ars. Hastanesi
city: Cherkasy
country: Ukraine
facility: Communal Nonprofit enterprise Cherkasy Regional Oncology Dispensary ofCherkasy Oblast Council,Regional Treatment and Diagnostic Hematological Center
city: Kharkiv
country: Ukraine
facility: Communal Non-profit Enterprise Regional Center of Oncology, Department of Hematology
city: Kyiv
country: Ukraine
facility: 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
city: Kyiv
country: Ukraine
facility: SI national Scientific Center of Radiation Medicine of NAMS of Ukraine, Dep. of Radiation Oncohematology and Stem Cell Transplantation Unit
city: Uzhgorod
country: Ukraine
facility: Andrii Novak Transcarpathian Regional Clinical Hospital, Department of Hematology
city: Zhytomyr
country: Ukraine
facility: Communal Institution O.F. Herbachevskyi Regional Clinical Hospital of Zhytomyr Regional Council Dept of Hematology with beds of Intensive Therapy
city: London
country: United Kingdom
facility: Barts Health NHS Trust
state: Greater London
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
state: Greater Manchester
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
state: Nottinghamshire
city: Oxford
country: United Kingdom
facility: The Churchill Hospital
state: Oxfordshire
city: Sutton
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust
state: Surrey
city: Leeds
country: United Kingdom
facility: St James University Hospital
state: West Yorkshire
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
Study officials:
References:
citation: 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.