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

Mantle-Cell Lymphoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03112174
• Other study ID #: PCYC-1143-CA
• Secondary ID: 2017-000129-12
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: June 29, 2017
• Est. completion date: November 15, 2024

Study information

• Verified date: September 2023
• Source: Pharmacyclics LLC.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 352
• Est. completion date: November 15, 2024
• Est. primary completion date: November 15, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, Mantle-Cell
• Mantle-Cell Lymphoma

Intervention

Drug:
• Ibrutinib
Administered orally once daily
• Venetoclax
Administered orally once daily
• Placebo Oral tablet to match Venetoclax
Administered orally once daily

Locations

Country	Name	City	State
Australia	Border Medical Oncology Research Unit	Albury	New South Wales
Australia	Icon Cancer Care	Auchenflower	Queensland
Australia	The Canberra Hospital	Canberra	Australian Capital Territory
Australia	Austin Health	Heidelberg	Victoria
Australia	Peter MacCallum Cancer	Melbourne	Victoria
Australia	St.Vincent's Hospital	Melbourne	Victoria
Australia	Sir Charles Gairdner Hospital	Nedlands	Western Australia
Belgium	ZiekenhuisNetwerk Antwerpen (ZNA) Stuivenberg	Antwerpen
Belgium	AZ Sint-Jan Brugge-Oostende AV	Brugge
Belgium	Institut Jules Bordet	Bruxelles
Belgium	CHU UCL Namur asbl- Mont Godinne	Yvoir
Canada	Tom Baker Cancer Centre	Calgary	Alberta
Canada	Cross Cancer Institute	Edmonton	Alberta
Canada	Queen Elizabeth II Health Science Centre	Halifax	Nova Scotia
Canada	Jewish General Hospital	Montréal	Quebec
Canada	The Ottawa Hospital	Ottawa	Ontario
Canada	BC Cancer-Vancouver Centre	Vancouver	British Columbia
Czechia	FN Brno, Interni hematologicka a onkologicka klinika	Brno
Czechia	Fakultni Nemocnice (FN) Hradec Kravlove, a.s. IV. Interni hematologicka klinika	Hradec Králové
Czechia	FN Olomouc	Olomouc
Czechia	FN Ostrava	Ostrava-Poruba
Czechia	Fakultni nemocnice Kralovske Vinohrady	Praha 10
Czechia	Vseobecna fakultni nemocnice v Praze, l. interni klinika-klinika hematologie	Praha 2
France	Institut Bergonié	Bordeaux
France	CHU CAEN-Hôpital de la Côte de Nacre	CAEN Cedex	Calvados
France	CHU Clermont Ferrand - Hôpital d'Estaing	Clermont Ferrand cedex
France	Institut Paoli Calmettes, Service Hematologie	Marseille
France	Centre Antoine Lacassagne	Nice Cedex 2
France	Hôpital Saint-Louis	Paris
France	Centre Hospitalier Lyon Sud	Pierre Benite cedex
France	CHU de Tours	Tours Cedex 01
Germany	Charite- Universitatsmedizin Berlin, Campus Benjamin Franklin	Berlin
Germany	Vivantes Klinikum Am Urban	Berlin
Germany	Gemeinschaftpraxis Haematologie und Onkologie	Dresden	Sachsen
Germany	Universitatsklinikum Essen, Klinik fur Hamatologie	Essen
Germany	Universitatsklinikum des Saarlandes, Klinik fur Innere Medizin I	Homburg/Saar
Germany	Universitatsklinikum Koln	Kerpen	Koln
Germany	Universitaetsmedizin der Johannes Gutenberg, Langenbeckstrasse 1	Langen	Mainz
Germany	Klinikum der Universitaet Muenchen Campus Grosshadern	Muenchen	Bayern
Germany	Kliniken Ostalb Stauferklinikum Schwab. Gmund	Mutlangen	Baden-Wuttemberg
Germany	Universitaetsklinikum Ulm	Ulm	Baden-Wuttemberg
Greece	University Hospital of Alexandroupolis	Alexandroupolis
Greece	251 Air Force General Hospital	Athens
Greece	General Hospital of Athens "Alexandra"	Athens
Greece	General Hospital of Athens Laiko	Athens
Greece	University General Hospital of Ioannina	Ioánnina
Greece	University General Hospital of Larissa	Larissa
Greece	University Hospital of Patras	Patra
Hungary	Orszagos Onkologiai Intezet	Budapest
Hungary	Semmelweis Egyetem	Budapest
Hungary	Debreceni Egyetem Klinikai Kozpont, Belgyogyaszati Klinika	Debrecen
Hungary	Petz Aladar Megyei Oktato Korhaz, II. Belgyogyaszat-Hematologia	Gyor
Hungary	Somogy Megyei Kaposi Mor Oktato Korhaz	Kaposvár
Hungary	Szegedi Tudományegyetem Szent-Györgyi Albert Klinikai Központ	Szeged
Hungary	Markusovszky Egyetemi Oktatokorhaz, Haematologiai es Haemoszatazeologiai Osztaly	Szombathely
Italy	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	Istituto Scientifico Romagnolo Per Lo Studio e La Cura Dei Tumori	Meldola	Forli-Cesena/Emilia-Rom
Italy	Asst Grande Ospedale Metropolitano Niguarda	Milano	Milano/Lombardia
Italy	IRCCS Ospedale S. Raffaele di Milano	Milano	Milano/Lombardia
Italy	Fondazione IRCCS Policlinico San Matteo	Pavia	Pavia/Lombardia
Italy	Azienda Ospedaliero Universitaria Molinette San Giovanni Battista di Torino	Torino	Torino/Piemonte
Italy	Azienda Ospedaliero-Universitaria Santa Maria della Misericordia	Udine	Udine/Friuli-Venezia Giulia
Korea, Republic of	Gachon University Gil Medical Center	Incheon
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Korea, Republic of	The Catholic University of Korea, Seoul St. Mary's Hospital	Seoul
Netherlands	Universitair Medisch Centrum Groningen	Groningen
Netherlands	Spaarne Gasthuis	Hoofddorp
Netherlands	Leiden University Medical Center	Leiden
Netherlands	Erasmus MC	Rotterdam
Netherlands	Franciscus Vlietland	Schiedam
Poland	Szpital Uniwersytecki nr 2 im. dr J. Biziela w Bydgoszcz	Bydgoszcz
Poland	Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespol Szpitali Miejskich, Oddzial Hematologiczny	Chorzów
Poland	Malopolskie Centrum Medyczne s c	Kraków
Poland	Wojewodzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii im. Kopernika w Lodzi	Lódz
Poland	Instytut Hematologii i Transfuzjologii	Warszawa
Poland	Uniwersytecki Szpital Kliniczny im. J. Mikulicza-Radeckiego we Wroclawiu, PZOZ	Wroclaw
Spain	Hospital Universitari Germans Trias I Pujol	Badalona	Barcelona
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hospital Universitario de Cabuenes	Gijón	Asturias
Spain	ICO l'Hospitalet- Hospital Duran i Reynals	L'Hospitalet De Llobregat	Barcelona
Spain	Fundacion Jimenez Diaz	Madrid
Spain	Hospital Universitario Ramon y Cajal	Madrid
Spain	Clinica Universidad de Navarra	Pamplona	Navarra
Turkey	Gazi Universitesi Tip Fakultesi, Besevler	Ankara
Turkey	Dokuz Eylul Universitesi Tip Fakultesi	Izmir
Turkey	Ondokuz Mayiz universitesi Tip Fakultesi	Kurupelit	Samsun
Turkey	Namik Kemal Universitesi Saglik Uyg. ve.Ars. Hastanesi	Tekirdag
Ukraine	Communal Nonprofit enterprise Cherkasy Regional Oncology Dispensary ofCherkasy Oblast Council,Regional Treatment and Diagnostic Hematological Center	Cherkasy
Ukraine	Communal Non-profit Enterprise Regional Center of Oncology, Department of Hematology	Kharkiv
Ukraine	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	Andrii Novak Transcarpathian Regional Clinical Hospital, Department of Hematology	Uzhgorod
Ukraine	Communal Institution O.F. Herbachevskyi Regional Clinical Hospital of Zhytomyr Regional Council Dept of Hematology with beds of Intensive Therapy	Zhytomyr
United Kingdom	St James University Hospital	Leeds	West Yorkshire
United Kingdom	Barts Health NHS Trust	London	Greater London
United Kingdom	University College London Hospitals NHS Foundation Trust	London
United Kingdom	The Christie NHS Foundation Trust	Manchester	Greater Manchester
United Kingdom	Nottingham University Hospitals NHS Trust	Nottingham	Nottinghamshire
United Kingdom	The Churchill Hospital	Oxford	Oxfordshire
United Kingdom	The Royal Marsden NHS Foundation Trust	Sutton	Surrey
United States	Levine Cancer Institute	Charlotte	North Carolina
United States	Tennessee Oncology	Chattanooga	Tennessee
United States	Barbara Ann Karmanos Cancer institute	Detroit	Michigan
United States	City of Hope	Duarte	California
United States	University of Texas MD Anderson Cancer Center	Houston	Texas
United States	University of Tennessee medical Center	Knoxville	Tennessee
United States	UCLA Department of Medicine-Hematology/Oncology	Los Angeles	California
United States	Norton Cancer Institute	Louisville	Kentucky
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Stony Brook University	New York	New York
United States	Orlando Health Inc.	Orlando	Florida
United States	Swedish Cancer Institute	Seattle	Washington
United States	The University of Arizona Cancer Centre-North Campus	Tucson	Arizona
United States	The University of Kansas Cancer Center and Medical Pavilion	Westwood	Kansas

Sponsors (2)

Lead Sponsor	Collaborator
Pharmacyclics LLC.	Janssen Research & Development, LLC

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  Czechia,  France,  Germany,  Greece,  Hungary,  Italy,  Korea, Republic of,  Netherlands,  Poland,  Spain,  Turkey,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Occurrence of Tumor Lysis Syndrome (TLS) (Safety Run-in Period)	To evaluate the occurrence of tumor lysis syndrome (TLS) with the concurrent administration of ibrutinib and venetoclax.	Approximately 3 months after last subject enrolled into safety run-in portion
Primary	Occurrence of Dose Limiting Toxicities (DLT) (Safety Run-in Period)	To evaluate the occurrence of DLTs with the concurrent administration of ibrutinib and venetoclax.	Approximately 3 months after last subject enrolled into safety run-in portion
Primary	Number of Participants With Adverse Events (AEs) (Safety Run-in Period)	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.	Up to approximately 5 years
Primary	Overall response rate (ORR) (Safety Run-in Period)	ORR is defined as CR or PR per investigator assessment according to the Revised Response Criteria for Malignant Lymphoma.	approximately 1 year after last subject has stopped treatment with study drug(s)
Primary	Duration of Response (DOR) (Safety Run-in Period)	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.	Up to approximately 5 years
Primary	Progression-free Survival (PFS) (Safety Run-in Period)	To evaluate PFS of ibrutinib and venetoclax compared to ibrutinib and placebo.	approximately 1 year after last subject has stopped treatment with study drug(s)
Primary	Overall Survival (OS) (Safety Run-in Period)	OS is defined as the time from the date of the first dose of study treatment to death from any cause.	Up to approximately 5 years
Primary	Progression-free Survival (PFS) (Randomization Period)	To evaluate PFS of ibrutinib and venetoclax compared to ibrutinib and placebo.	approximately 1 year after last subject has stopped treatment with study drug(s)
Primary	Complete Response (CR) (Treatment-Naive Arm)	To evaluate the complete response (CR) rate with the combination of ibrutinib and venetoclax in subjects with treatment-naive MCL	approximately 1 year after last subject has stopped treatment with study drug(s)
Secondary	Complete Response (CR) (Randomization Period)	Complete response rate (CR) based on the best overall response per investigator assessment according to the Revised Response Criteria for Malignant Lymphoma.	approximately 1 year after last subject has stopped treatment with study drug(s)
Secondary	Overall response rate (ORR) (Randomization Period and Treatment-Naive Arm)	ORR is defined as CR or PR per investigator assessment according to the Revised Response Criteria for Malignant Lymphoma.	approximately 1 year after last subject has stopped treatment with study drug(s)
Secondary	MRD-negative remission rate in participants who achieve CR per investigator assessment (Randomization Period and Treatment-Naive Arm)	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.	approximately 1 year after last subject has stopped treatment with study drug(s)
Secondary	Overall Survival (OS) (Randomization Period and Treatment-Naive Arm)	OS is defined as the time from the date of the first dose of study treatment to death from any cause.	Up to approximately 5 years
Secondary	Duration of Response (DOR) (Randomization Period and Treatment-Naive Arm)	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.	Up to approximately 5 years
Secondary	Time to Next Treatment (TTNT) (Randomization Period and Treatment-Naive Arm)	TTNT is defined as the duration from the date of randomization to the start date of any anti-lymphoma treatment subsequent to study treatment.	Up to approximately 5 years
Secondary	Percentage of participants experiencing Adverse Events (Randomization Period)	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.	Up to approximately 5 years
Secondary	Occurrence of Tumor Lysis Syndrome (TLS) (Randomization Period)	To evaluate the occurrence of tumor lysis syndrome (TLS) with the concurrent administration of ibrutinib and venetoclax.	Approximately 3 months after last subject enrolled into safety run-in portion
Secondary	Cmax if Ibrutinib (Randomization Period)	Cmax if Ibrutinib.	Week 6
Secondary	Tmax if Ibrutinib (Randomization Period)	Tmax if Ibrutinib.	Week 6
Secondary	AUClast if Ibrutinib (Randomization Period)	AUClast if Ibrutinib.	Week 6
Secondary	Half-Life (T1/2) if Ibrutinib (Randomization Period)	Half-Life (T1/2) if Ibrutinib.	Week 6
Secondary	Cmax of Venetoclax (Randomization Period)	Cmax of Venetoclax.	Week 6
Secondary	Tmax of Venetoclax (Randomization Period)	Tmax of Venetoclax.	Week 6
Secondary	AUC of Venetoclax (Randomization Period)	AUC of Venetoclax.	Week 6
Secondary	Time to worsening in FACT-Lym subscale of the health-related quality of life (Randomization Period) questionnaire (FACT-Lym)	Time to worsening in FACT-Lym subscale of the health-related quality of life questionnaire (FACT-Lym) will be compared between treatment arms.	Week 6
Secondary	Duration of CR (Treatment-Naive Arm Period)	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.	Up to approximately 5 years
Secondary	Progression-free Survival (PFS) (Treatment-Naive Arm Period)	To evaluate PFS of ibrutinib and venetoclax compared to ibrutinib and placebo.	approximately 1 year after last subject has stopped treatment with study drug(s)