Clinical trial NCT01855750: A Study of the Bruton's Tyrosine Kinase Inhibitor, PCI-32765 (Ibrutinib), in Combination With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With Newly Diagnosed Non-Germinal Center B-Cell Subtype of Diffuse Large B-Cell Lymphoma
Official title: A Randomized, Double-blind, Placebo-controlled Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, PCI-32765 (Ibrutinib), in Combination With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in Subjects With Newly Diagnosed Non-Germinal Center B-Cell Subtype of Diffuse Large B-Cell Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Lymphoma
Keywords: Lymphoma
B-cell lymphoma
Non-germinal center B-cell subtype
Diffuse large B-cell lymphoma
Bruton's tyrosine kinase inhibitor
PCI-32765
JNJ-54179060
Ibrutinib
Rituximab
Cyclophosphamide
Doxorubicin
Vincristine
Prednisone
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
Collaborators: name: Pharmacyclics LLC.
First posted: 2013-05-16
Enrollment: 838
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: The purpose of this study is to evaluate if ibrutinib administered in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) improves the clinical outcome in newly diagnosed patients with non-germinal center B-cell subtype (GCB) of diffuse large B-cell lymphoma (DLBCL) selected by immunohistochemistry (IHC) or newly diagnosed patients with activated B cell-like (ABC) subtype of DLBCL identified by gene expression profiling (GEP) or both populations.

Detailed description: This is a randomized (individuals assigned to study treatment by chance), double-blind (individuals and study personnel will not know the identity of study treatments), placebo (an inactive substance that is compared with a drug to test whether the drug has a real effect in a clinical trial)-controlled study to compare the efficacy and safety of ibrutinib in combination with R-CHOP versus R-CHOP alone in adult patients newly diagnosed non-GCB DLBCL selected by IHC or newly diagnosed patients with ABC subtype of DLBCL identified by GEP or both populations. The study will include screening, active treatment, and posttreatment follow-up phases. The study will end when 50% of participants have died or 5 years after the last participant is randomized or the sponsor terminates the study, whichever occurs first. Approximately 800 participants will be randomly assigned in a 1:1 ratio to receive either placebo+R-CHOP (treatment arm A) or ibrutinib+R-CHOP (treatment arm B). All participants will receive R-CHOP as background therapy for 6 or 8 cycles (21 days per cycle) prespecified according to local practice. After 4 treatment cycles, an interim response assessment will be performed to evaluate disease progression for each participant. Participants with progressive disease or relapsed disease after complete response will be discontinued from treatment. Participants who discontinue R-CHOP without disease progression will continue study drug (placebo or ibrutinib) until 6 or 8 cycles are completed, disease progression, or unacceptable toxicity, whichever occurs first. After completion of study drug, participants will undergo assessment of tumor response based on the Revised Response Criteria for Malignant Lymphoma. Participants with documented residual disease upon completion of at least 6 cycles of R-CHOP therapy are considered eligible to initiate subsequent antilymphoma therapy. Serial pharmacokinetic samples will be collected before and after dosing, and safety will be monitored throughout the study.

Eligibility criteria: Inclusion Criteria:

* No prior treatment for diffuse B-cell lymphoma (DLBCL)
* Histologically-confirmed non-germinal center B-cell subtype DLBCL
* Stage II (not candidates for local x-ray therapy), III, or IV disease by the Ann Arbor Classification
* At least 1 measurable site of disease according to Revised Response Criteria for Malignant Lymphoma
* Revised International Prognostic Index score of \>=1
* Eastern Cooperative Oncology Group performance status grade of 0, 1, or 2
* Hematology and biochemical laboratory values within protocol-defined parameters prior to random assignment and at baseline
* Left ventricular ejection fraction within institutional normal limits, as determined by echocardiography or multiple uptake gated acquisition (MUGA) scan
* Agrees to protocol-defined use of effective contraception (for women, these restrictions apply for 12 months after the last dose of rituximab or 1 month after the last dose of study drug, whichever is later; for men, these restrictions apply for 12 months after the last dose of rituximab or 3 months after the last dose of study drug, whichever is later)
* Men must agree to not donate sperm during and after the study for 12 months after the last dose of rituximab or 3 months after the last dose of study drug, whichever is later
* Women of childbearing potential must have a negative serum or urine pregnancy test at screening

Exclusion Criteria:

* Major surgery within 4 weeks of random assignment
* Known central nervous system or primary mediastinal lymphoma
* Prior history of indolent lymphoma
* Diagnosed or treated for malignancy other than DLBCL, except: malignancy treated with curative intent and with no known active disease present for \>=3 years before random assignment; adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; adequately treated carcinoma in situ without evidence of disease
* History of stroke or intracranial hemorrhage within 6 months prior to random assignment
* Requires anticoagulation with warfarin or equivalent vitamin K antagonists
* Requires treatment with strong CYP3A inhibitors
* Prior anthracycline use \>=150 mg/m2
* Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification
* Known history of human immunodeficiency virus or active hepatitis C virus or active hepatitis B virus infection or any uncontrolled active systemic infection requiring intravenous antibiotics
* Women who are pregnant or breastfeeding
* Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the patient's safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk

Primary outcomes:
measure: Event-Free Survival (EFS) - Intent-to-Treat (ITT) Population
timeFrame: Up to 5.5 years
measure: Event-Free Survival (EFS) - Activated B-Cell (ABC) Population
timeFrame: Up to approximately 4.5 years
Secondary outcomes:
measure: Progression-Free Survival (PFS)
timeFrame: Up to approximately 4.5 years
measure: Percentage of Participants Who Achieved Complete Response (CR)
timeFrame: Up to approximately 4.5 years
measure: Overall Survival
timeFrame: Up to 5.5 years
measure: Time to Worsening in the Lymphoma Subscale of Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym)
timeFrame: Up to approximately 4.5 years
Other outcomes:
Locations:
city: Tucson
country: United States
state: Arizona
city: Greenbrae
country: United States
state: California
city: La Jolla
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state: California
city: Los Angeles
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state: California
city: Salinas
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state: California
city: Stanford
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state: California
city: Danbury
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state: Connecticut
city: Hartford
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state: Connecticut
city: Washington
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state: District of Columbia
city: Atlanta
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state: Georgia
city: Marietta
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city: Peoria
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state: Illinois
city: Fort Wayne
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state: Indiana
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state: Louisiana
city: New Orleans
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state: Louisiana
city: Baltimore
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state: Maryland
city: Bethesda
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state: Maryland
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state: Massachusetts
city: Ann Arbor
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state: Michigan
city: Saint Louis
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state: Missouri
city: Omaha
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state: Nebraska
city: Hackensack
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state: New Jersey
city: New Brunswick
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state: New Jersey
city: Bronx
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state: New York
city: Fresh Meadows
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state: New York
city: Johnson City
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state: New York
city: Mineola
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state: New York
city: New York
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state: New York
city: Rochester
country: United States
state: New York
city: Charlotte
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state: North Carolina
city: Greenville
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state: North Carolina
city: Hickory
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state: North Carolina
city: Columbus
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state: Ohio
city: Portland
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state: Oregon
city: North Charleston
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state: South Carolina
city: Nashville
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state: Tennessee
city: Houston
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state: Texas
city: Temple
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state: Texas
city: Burlington
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state: Vermont
city: Seattle
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state: Washington
city: Buenos Aires
country: Argentina
city: Ciudad Autonoma de Buenos Aires
country: Argentina
city: Ciudad de Buenos Aires
country: Argentina
city: Adelaide
country: Australia
city: Concord
country: Australia
city: Darlinghurst
country: Australia
city: Hobart
country: Australia
city: Melbourne
country: Australia
city: Nedlands
country: Australia
city: Perth
country: Australia
city: Randwick
country: Australia
city: South Brisbane
country: Australia
city: Woolloongabba
country: Australia
city: Antwerpen
country: Belgium
city: Brugge
country: Belgium
city: Brussel
country: Belgium
city: Gent
country: Belgium
city: Haine Saint Paul La Louviere
country: Belgium
city: Kortrijk
country: Belgium
city: Leuven
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city: Porto Alegre
country: Brazil
city: Rio De Janeiro
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city: Sao Paulo
country: Brazil
city: Edmonton
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state: Alberta
city: Vancouver
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state: British Columbia
city: Halifax
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state: Nova Scotia
city: Toronto
country: Canada
state: Ontario
city: Levis
country: Canada
state: Quebec
city: Montreal
country: Canada
state: Quebec
city: Montréal
country: Canada
state: Quebec
city: Beijing
country: China
city: Changchun
country: China
city: Chengdu
country: China
city: Guangzhou
country: China
city: Hangzhou
country: China
city: Harbin
country: China
city: Jinan
country: China
city: Nanjing
country: China
city: Shanghai
country: China
city: Tianjin
country: China
city: Brno
country: Czechia
city: Hradec Kralove
country: Czechia
city: Ostrava
country: Czechia
city: Praha 10
country: Czechia
city: Praha 2
country: Czechia
city: Aarhus N.
country: Denmark
city: Copenhagen
country: Denmark
city: Roskilde
country: Denmark
city: Vejle
country: Denmark
city: Helsinki
country: Finland
city: Jyväskylä
country: Finland
city: Oulu
country: Finland
city: Turku
country: Finland
city: Grenoble Cedex 9
country: France
city: Limoges
country: France
city: Paris
country: France
city: Pessac
country: France
city: Pierre Benite
country: France
city: Rouen
country: France
city: Tours
country: France
city: Villejuif
country: France
city: Augsburg
country: Germany
city: Bamberg
country: Germany
city: Berlin
country: Germany
city: Dresden
country: Germany
city: Essen
country: Germany
city: Frankfurt
country: Germany
city: Jena
country: Germany
city: Muenchen
country: Germany
city: Münster
country: Germany
city: Villingen-Schwenningen
country: Germany
city: Budapest N/a
country: Hungary
city: Debrecen
country: Hungary
city: Gyula
country: Hungary
city: Szombathely
country: Hungary
city: Veszprém
country: Hungary
city: Beer-Sheva
country: Israel
city: Hadera
country: Israel
city: Haifa
country: Israel
city: Petah Tikva
country: Israel
city: Ramat-Gan
country: Israel
city: Tel Aviv
country: Israel
city: Fukuoka
country: Japan
city: Hiroshima
country: Japan
city: Isehara
country: Japan
city: Kobe
country: Japan
city: Kumamoto
country: Japan
city: Kyoto
country: Japan
city: Nagano
country: Japan
city: Nagoya
country: Japan
city: Narita
country: Japan
city: Osaka-Sayama
country: Japan
city: Osaka
country: Japan
city: Sapporo
country: Japan
city: Sendai-shi
country: Japan
city: Suita
country: Japan
city: Tachikawa
country: Japan
city: Tokyo
country: Japan
city: Tsukuba
country: Japan
city: Busan
country: Korea, Republic of
city: Goyang-Si
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Mexico
country: Mexico
city: Monterrey
country: Mexico
city: San Luis Potosi
country: Mexico
city: Amsterdam Zuidoost
country: Netherlands
city: Arnhem
country: Netherlands
city: Dordrecht
country: Netherlands
city: Groningen
country: Netherlands
city: Leiden
country: Netherlands
city: Nieuwegein
country: Netherlands
city: Rotterdam
country: Netherlands
city: Oslo
country: Norway
city: Tromso
country: Norway
city: Brzozow
country: Poland
city: Chorzow
country: Poland
city: Krakow
country: Poland
city: Lodz
country: Poland
city: Olsztyn
country: Poland
city: Poznan
country: Poland
city: Warszawa
country: Poland
city: Wroclaw
country: Poland
city: Ekaterinburg
country: Russian Federation
city: Moscow
country: Russian Federation
city: Nizhny Novgorod
country: Russian Federation
city: Rostov-Na-Donu
country: Russian Federation
city: Saint-Petersburg
country: Russian Federation
city: Sochi
country: Russian Federation
city: St. Petersburg
country: Russian Federation
city: Volgograd
country: Russian Federation
city: Barcelona
country: Spain
city: Madrid
country: Spain
city: Salamanca
country: Spain
city: Sevilla
country: Spain
city: Linköping
country: Sweden
city: Luleå
country: Sweden
city: Lund
country: Sweden
city: Uppsala
country: Sweden
city: Taichung
country: Taiwan
city: Tainan
country: Taiwan
city: Taoyuan County
country: Taiwan
city: Adana
country: Turkey
city: Ankara
country: Turkey
city: Istanbul
country: Turkey
city: Izmir
country: Turkey
city: Kayseri
country: Turkey
city: Samsun
country: Turkey
city: Cherkassy
country: Ukraine
city: Khmelnitskiy
country: Ukraine
city: Kiev
country: Ukraine
city: Lviv
country: Ukraine
city: Makiivka
country: Ukraine
city: Glasgow
country: United Kingdom
city: Liverpool
country: United Kingdom
city: London
country: United Kingdom
city: Maidstone
country: United Kingdom
city: Manchester
country: United Kingdom
city: Nottingham
country: United Kingdom
city: Oxford
country: United Kingdom
city: Romford
country: United Kingdom
city: Southampton
country: United Kingdom
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References:
citation: Wilson WH, Wright GW, Huang DW, Hodkinson B, Balasubramanian S, Fan Y, Vermeulen J, Shreeve M, Staudt LM. Effect of ibrutinib with R-CHOP chemotherapy in genetic subtypes of DLBCL. Cancer Cell. 2021 Dec 13;39(12):1643-1653.e3. doi: 10.1016/j.ccell.2021.10.006. Epub 2021 Nov 4.
citation: Younes A, Sehn LH, Johnson P, Zinzani PL, Hong X, Zhu J, Patti C, Belada D, Samoilova O, Suh C, Leppa S, Rai S, Turgut M, Jurczak W, Cheung MC, Gurion R, Yeh SP, Lopez-Hernandez A, Duhrsen U, Thieblemont C, Chiattone CS, Balasubramanian S, Carey J, Liu G, Shreeve SM, Sun S, Zhuang SH, Vermeulen J, Staudt LM, Wilson W; PHOENIX investigators. Randomized Phase III Trial of Ibrutinib and Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Non-Germinal Center B-Cell Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2019 May 20;37(15):1285-1295. doi: 10.1200/JCO.18.02403. Epub 2019 Mar 22.