Study of Ibrutinib Combined With Venetoclax in Subjects With Mantle Cell Lymphoma (SYMPATICO)
Mantle-Cell Lymphoma
About this trial
This is an interventional treatment trial for Mantle-Cell Lymphoma focused on measuring PCYC, MCL, Non-Hodgkin's Lymphoma, NHL, ibrutinib, venetoclax, Pharmacyclics
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.
Sites / Locations
- The University of Arizona Cancer Centre-North Campus
- City of Hope
- UCLA Department of Medicine-Hematology/Oncology
- Orlando Health Inc.
- The University of Kansas Cancer Center and Medical Pavilion
- Norton Cancer Institute
- Barbara Ann Karmanos Cancer institute
- Memorial Sloan Kettering Cancer Center
- Stony Brook University
- Levine Cancer Institute
- Tennessee Oncology
- University of Tennessee medical Center
- University of Texas MD Anderson Cancer Center
- Swedish Cancer Institute
- The Canberra Hospital
- Border Medical Oncology Research Unit
- Icon Cancer Care
- Austin Health
- Peter MacCallum Cancer
- St.Vincent's Hospital
- Sir Charles Gairdner Hospital
- ZiekenhuisNetwerk Antwerpen (ZNA) Stuivenberg
- AZ Sint-Jan Brugge-Oostende AV
- Institut Jules Bordet
- CHU UCL Namur asbl- Mont Godinne
- Tom Baker Cancer Centre
- Cross Cancer Institute
- BC Cancer-Vancouver Centre
- Queen Elizabeth II Health Science Centre
- The Ottawa Hospital
- Jewish General Hospital
- FN Brno, Interni hematologicka a onkologicka klinika
- Fakultni Nemocnice (FN) Hradec Kravlove, a.s. IV. Interni hematologicka klinika
- FN Olomouc
- FN Ostrava
- Fakultni nemocnice Kralovske Vinohrady
- Vseobecna fakultni nemocnice v Praze, l. interni klinika-klinika hematologie
- CHU CAEN-Hôpital de la Côte de Nacre
- Institut Bergonié
- CHU Clermont Ferrand - Hôpital d'Estaing
- Institut Paoli Calmettes, Service Hematologie
- Centre Antoine Lacassagne
- Hôpital Saint-Louis
- Centre Hospitalier Lyon Sud
- CHU de Tours
- Kliniken Ostalb Stauferklinikum Schwab. Gmund
- Universitaetsklinikum Ulm
- Klinikum der Universitaet Muenchen Campus Grosshadern
- Universitatsklinikum Koln
- Universitaetsmedizin der Johannes Gutenberg, Langenbeckstrasse 1
- Gemeinschaftpraxis Haematologie und Onkologie
- Vivantes Klinikum Am Urban
- Charite- Universitatsmedizin Berlin, Campus Benjamin Franklin
- Universitatsklinikum Essen, Klinik fur Hamatologie
- Universitatsklinikum des Saarlandes, Klinik fur Innere Medizin I
- University Hospital of Alexandroupolis
- 251 Air Force General Hospital
- General Hospital of Athens Laiko
- General Hospital of Athens "Alexandra"
- University General Hospital of Ioannina
- University General Hospital of Larissa
- University Hospital of Patras
- Orszagos Onkologiai Intezet
- Semmelweis Egyetem
- Debreceni Egyetem Klinikai Kozpont, Belgyogyaszati Klinika
- Petz Aladar Megyei Oktato Korhaz, II. Belgyogyaszat-Hematologia
- Somogy Megyei Kaposi Mor Oktato Korhaz
- Szegedi Tudományegyetem Szent-Györgyi Albert Klinikai Központ
- Markusovszky Egyetemi Oktatokorhaz, Haematologiai es Haemoszatazeologiai Osztaly
- Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo di Alessandria
- Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII (Presidio Papa Giovanni XXIII)
- Azienda Ospedaliera Universitaria di Bologna Policlinico Saint Orsola Malpighi
- ASST degli Spedali Civili di Brescia
- Azienda Ospedaliera S. Croce e Carle Cuneo
- Istituto Scientifico Romagnolo Per Lo Studio e La Cura Dei Tumori
- IRCCS Ospedale S. Raffaele di Milano
- Asst Grande Ospedale Metropolitano Niguarda
- Fondazione IRCCS Policlinico San Matteo
- Azienda Ospedaliero Universitaria Molinette San Giovanni Battista di Torino
- Azienda Ospedaliero-Universitaria Santa Maria della Misericordia
- Gachon University Gil Medical Center
- Seoul National University Hospital
- Severance Hospital, Yonsei University Health System
- Samsung Medical Center
- The Catholic University of Korea, Seoul St. Mary's Hospital
- Universitair Medisch Centrum Groningen
- Spaarne Gasthuis
- Leiden University Medical Center
- Erasmus MC
- Franciscus Vlietland
- Szpital Uniwersytecki nr 2 im. dr J. Biziela w Bydgoszcz
- Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespol Szpitali Miejskich, Oddzial Hematologiczny
- Malopolskie Centrum Medyczne s c
- Instytut Hematologii i Transfuzjologii
- Uniwersytecki Szpital Kliniczny im. J. Mikulicza-Radeckiego we Wroclawiu, PZOZ
- Wojewodzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii im. Kopernika w Lodzi
- Hospital Universitario de Cabuenes
- Hospital Universitari Germans Trias I Pujol
- ICO l'Hospitalet- Hospital Duran i Reynals
- Clinica Universidad de Navarra
- Hospital de la Santa Creu i Sant Pau
- Hospital Universitario Ramon y Cajal
- Fundacion Jimenez Diaz
- Ondokuz Mayiz universitesi Tip Fakultesi
- Gazi Universitesi Tip Fakultesi, Besevler
- Dokuz Eylul Universitesi Tip Fakultesi
- Namik Kemal Universitesi Saglik Uyg. ve.Ars. Hastanesi
- Communal Nonprofit enterprise Cherkasy Regional Oncology Dispensary ofCherkasy Oblast Council,Regional Treatment and Diagnostic Hematological Center
- Communal Non-profit Enterprise Regional Center of Oncology, Department of Hematology
- 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
- SI national Scientific Center of Radiation Medicine of NAMS of Ukraine, Dep. of Radiation Oncohematology and Stem Cell Transplantation Unit
- Andrii Novak Transcarpathian Regional Clinical Hospital, Department of Hematology
- Communal Institution O.F. Herbachevskyi Regional Clinical Hospital of Zhytomyr Regional Council Dept of Hematology with beds of Intensive Therapy
- Barts Health NHS Trust
- The Christie NHS Foundation Trust
- Nottingham University Hospitals NHS Trust
- The Churchill Hospital
- The Royal Marsden NHS Foundation Trust
- St James University Hospital
- University College London Hospitals NHS Foundation Trust
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Experimental
Experimental
Placebo Comparator
Experimental
Safety Run-in Period
Phase 3: Ibrutinb + Venetoclax
Phase 3: Ibrutinib + Placebo
Treatment-naive
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.
Subjects will be randomized to receive ibrutinib and venetoclax/placebo until clinical disease progression or unacceptable toxicity
Subjects will be randomized to receive ibrutinib and venetoclax/placebo until clinical disease progression or unacceptable toxicity
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.