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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Pharmacyclics
Information provided by (Responsible Party):
Janssen Research & Development, LLC
ClinicalTrials.gov Identifier:
NCT01855750
First received: May 14, 2013
Last updated: July 1, 2016
Last verified: July 2016
  Purpose
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).

Condition Intervention Phase
Lymphoma
Drug: Ibrutinib
Drug: Placebo
Drug: Rituximab
Drug: Cyclophosphamide
Drug: Doxorubicin
Drug: Vincristine
Drug: Prednisone (or equivalent)
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Janssen Research & Development, LLC:

Primary Outcome Measures:
  • Event-free survival [ Time Frame: Up to disease progression, relapse from complete response, initiation of subsequent systemic antilymphoma therapy after completion of at least 6 cycles of R-CHOP therapy, or death, whichever occurs first, up to Year 7 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Progression-free survival [ Time Frame: Up to disease progression, relapse from complete response, or death, whichever occurs first, up to Year 7 ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: Up to the date of the participants death, up to Year 7 ] [ Designated as safety issue: No ]
  • Complete response rate [ Time Frame: Up to completion of chemotherapy treatment, up to Year 7 ] [ Designated as safety issue: No ]
  • Time to worsening symptoms in the Lym subscale of the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) [ Time Frame: Up to the start date of the worsening of patient symptoms, up to Year 7 ] [ Designated as safety issue: No ]
  • Oral plasma clearance of ibrutinib [ Time Frame: Predose Day 1 of Cycles 1, 2, and 3, and postdose 1 h, 2 h, and 4 h of Cycles 1 and 2 ] [ Designated as safety issue: No ]
  • Oral volume of distribution at steady state of ibrutinib [ Time Frame: Predose Day 1 of Cycles 1, 2, and 3, and postdose 1 h, 2 h, and 4 h of Cycles 1 and 2 ] [ Designated as safety issue: No ]
  • Area under the plasma concentration-time curve of ibrutinib [ Time Frame: Predose Day 1 of Cycles 1, 2, and 3, and postdose 1 h, 2 h, and 4 h of Cycles 1 and 2 ] [ Designated as safety issue: No ]
  • Minimum observed plasma concentration of ibrutinib [ Time Frame: Predose Day 1 of Cycles 1, 2, and 3, and postdose 1 h, 2 h, and 4 h of Cycles 1 and 2 ] [ Designated as safety issue: No ]
  • Number of participants affected by an adverse event [ Time Frame: Up to 30 days after the last dose of study medication ] [ Designated as safety issue: Yes ]

Enrollment: 838
Study Start Date: September 2013
Estimated Study Completion Date: June 2020
Estimated Primary Completion Date: June 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Treatment Arm A: placebo + R-CHOP
Treatment Arm A = placebo + R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone)
Drug: Placebo
4 matched capsules administered by mouth once daily (21-day cycles)
Drug: Rituximab
375 mg/m2 administered intravenously once on Day 1 of each cycle (21-day cycles)
Drug: Cyclophosphamide
750 mg/m2 administered intravenously once on Day 1 of each cycle (21-day cycles)
Drug: Doxorubicin
50 mg/m2 administered intravenously once on Day 1 of each cycle (21-day cycles)
Drug: Vincristine
1.4 mg/m2 administered intravenously once on Day 1 of each cycle (21-day cycles)
Drug: Prednisone (or equivalent)
100 mg capsules administered by mouth once daily on Day 1 to Day 5 of each cycle
Experimental: Treatment Arm B: ibrutinib + R-CHOP
Treatment Arm B = ibrutinib + R-CHOP
Drug: Ibrutinib
560 mg capsules administered by mouth once daily (21-day cycles)
Drug: Rituximab
375 mg/m2 administered intravenously once on Day 1 of each cycle (21-day cycles)
Drug: Cyclophosphamide
750 mg/m2 administered intravenously once on Day 1 of each cycle (21-day cycles)
Drug: Doxorubicin
50 mg/m2 administered intravenously once on Day 1 of each cycle (21-day cycles)
Drug: Vincristine
1.4 mg/m2 administered intravenously once on Day 1 of each cycle (21-day cycles)
Drug: Prednisone (or equivalent)
100 mg capsules administered by mouth once daily on Day 1 to Day 5 of each cycle

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. The study will include screening, active treatment, and posttreatment follow-up phases. The study will end when 50% of participants have died or the sponsor terminates the study, whichever occurs first (up to approximately 7 years). 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

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01855750

  Hide Study Locations
Locations
United States, Arizona
Tucson, Arizona, United States
United States, California
Greenbrae, California, United States
La Jolla, California, United States
Los Angeles, California, United States
Salinas, California, United States
Stanford, California, United States
United States, Connecticut
Danbury, Connecticut, United States
Hartford, Connecticut, United States
United States, District of Columbia
Washington, District of Columbia, United States
United States, Georgia
Atlanta, Georgia, United States
Marietta, Georgia, United States
United States, Illinois
Peoria, Illinois, United States
United States, Indiana
Fort Wayne, Indiana, United States
Goshen, Indiana, United States
Indianapolis, Indiana, United States
United States, Kansas
Topeka, Kansas, United States
United States, Kentucky
Louisville, Kentucky, United States
United States, Louisiana
Baton Rouge, Louisiana, United States
New Orleans, Louisiana, United States
United States, Maryland
Baltimore, Maryland, United States
Bethesda, Maryland, United States
United States, Massachusetts
Boston, Massachusetts, United States
United States, Michigan
Ann Arbor, Michigan, United States
United States, Missouri
St. Louis, Missouri, United States
United States, Nebraska
Omaha, Nebraska, United States
United States, New Jersey
Hackensack, New Jersey, United States
New Brunswick, New Jersey, United States
United States, New York
Bronx, New York, United States
Johnson City, New York, United States
Mineola, New York, United States
New York, New York, United States
Rochester, New York, United States
United States, North Carolina
Charlotte, North Carolina, United States
Greenville, North Carolina, United States
Hickory, North Carolina, United States
United States, Ohio
Columbus, Ohio, United States
United States, Oregon
Portland, Oregon, United States
United States, South Carolina
N Charleston, South Carolina, United States
United States, Tennessee
Nashville, Tennessee, United States
United States, Texas
Houston, Texas, United States
Temple, Texas, United States
United States, Vermont
Burlington, Vermont, United States
United States, Washington
Seattle, Washington, United States
Argentina
Ciudad Autonoma Buenos Aires, Argentina
Ciudad Autonoma De Buenos Aires, Argentina
Ciudad De Buenos Aires, Argentina
La Capital, Argentina
Australia
Adelaide, Australia
Concord, Australia
Darlinghurst, Australia
Hobart, Australia
Melbourne, Australia
Nedlands, Australia
Perth, Australia
South Brisbane, Australia
Woolloongabba, Australia
Belgium
Antwerpen, Belgium
Brugge, Belgium
Brussel, Belgium
Gent, Belgium
Haine-Saint-Paul, La Louviere, Belgium
Kortrijk, Belgium
Leuven, Belgium
Brazil
Porto Alegre, Brazil
Rio De Janeiro, Brazil
Sao Paulo, Brazil
São Paulo, Brazil
Canada, Alberta
Edmonton, Alberta, Canada
Canada, British Columbia
Vancouver, British Columbia, Canada
Canada, Nova Scotia
Halifax, Nova Scotia, Canada
Canada, Ontario
Toronto, Ontario, Canada
Canada, Quebec
Levis, Quebec, Canada
Montreal, Quebec, Canada
China
Beijing, China
Changchun, China
Chengdu, China
Guangzhou, China
Hangzhou, China
Harbin, China
Jinan, China
Nanjing, China
Shanghai, China
Tianjin, China
Czech Republic
Brno, Czech Republic
Hradec Kralove, Czech Republic
Ostrava, Czech Republic
Praha 10, Czech Republic
Praha 2, Czech Republic
Denmark
Aarhus C, Denmark
Copenhagen, Denmark
Roskilde, Denmark
Vejle, Denmark
Finland
Helsinki, Finland
Jyväskylä, Finland
Oulu, Finland
Turku, Finland
France
Grenoble Cedex 9, France
Limoges, France
Paris, France
Pessac, France
Pierre Benite, France
Rouen, France
Tours, France
Villejuif, France
Germany
Augsburg, Germany
Bamberg, Germany
Berlin, Germany
Dresden, Germany
Essen, Germany
Frankfurt, Germany
Jena, Germany
Muenchen, Germany
Münster, Germany
Villingen-Schwenningen, Germany
Hungary
Budapest N/A, Hungary
Debrecen, Hungary
Gyula, Hungary
Szombathely, Hungary
Veszprem, Hungary
Israel
Beer-Sheva, Israel
Hadera, Israel
Haifa, Israel
Nahariya, Israel
Petah Tikva, Israel
Ramat-Gan, Israel
Tel Aviv, Israel
Japan
Fukuoka, Japan
Hiroshima, Japan
Isehara, Japan
Kobe, Japan
Kumamoto, Japan
Kyoto, Japan
Nagano, Japan
Nagoya, Japan
Narita, Japan
Osaka, Japan
Osaka-Sayama, Japan
Sapporo, Japan
Sendai, Japan
Suita, Japan
Tachikawa, Japan
Tokyo, Japan
Tsukuba, Japan
Korea, Republic of
Busan, Korea, Republic of
Goyang, Korea, Republic of
Seoul, Korea, Republic of
Mexico
Mexico, Mexico
Monterrey, Mexico
San Luis Potosi, Mexico
Netherlands
Amsterdam Zuidoost, Netherlands
Arnhem, Netherlands
Dordrecht, Netherlands
Groningen, Netherlands
Leiden, Netherlands
Nieuwegein, Netherlands
Rotterdam, Netherlands
Norway
Oslo, Norway
Tromsø, Norway
Poland
Brzozow, Poland
Chorzów, Poland
Krakow, Poland
Lodz, Poland
Olsztyn, Poland
Poznan, Poland
Warszawa, Poland
Wroclaw, Poland
Russian Federation
Ekaterinburg, Russian Federation
Moscow, Russian Federation
Nizhny Novgorod, Russian Federation
Rostov-Na-Donu, Russian Federation
Saint-Petersburg,, Russian Federation
Sochi, Russian Federation
St. Petersburg, Russian Federation
Volgograd, Russian Federation
Spain
Barcelona, Spain
Madrid, Spain
Salamanca, Spain
Sevilla, Spain
Sweden
Linköping, Sweden
Luleå, Sweden
Lund, Sweden
Uppsala, Sweden
Taiwan
Taichung, Taiwan
Tainan, Taiwan
Taoyuan County, Taiwan
Turkey
Adana, Turkey
Ankara, Turkey
Istanbul, Turkey
Izmir, Turkey
Kayseri, Turkey
Samsun, Turkey
Ukraine
Cherkassy, Ukraine
Khmelnitskiy, Ukraine
Kiev, Ukraine
Lviv, Ukraine
Makiivka, Ukraine
United Kingdom
Glasgow, United Kingdom
Liverpool, United Kingdom
London, United Kingdom
Maidstone, United Kingdom
Manchester, United Kingdom
Nottingham, United Kingdom
Oxford, United Kingdom
Romford, United Kingdom
Southampton, United Kingdom
Sponsors and Collaborators
Janssen Research & Development, LLC
Pharmacyclics
Investigators
Study Director: Janssen Research & Development, LLC Clinical Trial Janssen Research & Development, LLC
  More Information

Responsible Party: Janssen Research & Development, LLC
ClinicalTrials.gov Identifier: NCT01855750     History of Changes
Other Study ID Numbers: CR102118  PCI-32765DBL3001  U1111-1139-6222  2013-000959-40 
Study First Received: May 14, 2013
Last Updated: July 1, 2016
Health Authority: Australia: Department of Health and Ageing Therapeutic Goods Administration
Czech Republic: State Institute for Drug Control
Germany: Ethics Commission
Great Britain: Research Ethics Committee
Hungary: National Institute for Quality and Organizational Development in Healthcare and Medicines
Japan: Pharmaceuticals and Medical Devices Agency
Spain: Spanish Agency of Medicines
Turkey: Ministry of Health
United States: Food and Drug Administration
Germany: Federal Institute for Drugs and Medical Devices
Great Britain: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Janssen Research & Development, LLC:
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

Additional relevant MeSH terms:
Lymphoma
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Cyclophosphamide
Rituximab
Liposomal doxorubicin
Doxorubicin
Prednisone
Vincristine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Anti-Inflammatory Agents

ClinicalTrials.gov processed this record on July 28, 2016