A Study of PCI-32765 (Ibrutinib) in Combination With Either Bendamustine and Rituximab or Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Participants With Previously Treated Indolent Non-Hodgkin Lymphoma

Study Description

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Brief Summary:

The purpose of this study is to evaluate the efficacy and safety of PCI-32765 (ibrutinib) administered in combination with either bendamustine and rituximab (BR) or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in adult participants with previously treated indolent Non-Hodgkin lymphoma.

Condition or disease	Intervention/treatment	Phase
Lymphoma	Drug: Bendamustine; Drug: Rituximab; Drug: Cyclophosphamide; Drug: Doxorubicin; Drug: Vincristine; Drug: Prednisone; Drug: PCI-32765 (Ibrutinib); Drug: Placebo	Phase 3

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 in approximately 400 adult participants with follicular lymphoma or marginal zone lymphoma. The study will include the following phases: Screening, Treatment, and a Post-treatment Follow-up. Eligible participants will be randomly assigned in a 1:1 ratio to either treatment Arm A (background immune-chemotherapy + placebo) or treatment Arm B (background immune-chemotherapy + 560 milligram [mg] of ibrutinib). All participants will receive 6 cycles of background immune-chemotherapy with either BR or R-CHOP in combination with either placebo (Arm A) or ibrutinib (Arm B). Selection of background immune-chemotherapy will be based on prior treatment history and cardiac function. After completion of background immune-chemotherapy, study drug (ibrutinib or placebo) will continue until disease progression, unacceptable toxicity, or study end, whichever comes first. Assessment of tumor response and progression will be conducted in accordance with the Revised Response Criteria for Malignant Lymphoma. Serial pharmacokinetic (study of what a drug does to the body) blood samples will be collected. Safety will be assessed throughout the study.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	403 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Double (Participant, Investigator)
Primary Purpose:	Treatment
Official Title:	A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of the Bruton's Tyrosine Kinase Inhibitor, PCI-32765 (Ibrutinib), in Combination With Either Bendamustine and Rituximab (BR) or Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in Subjects With Previously Treated Indolent Non-Hodgkin Lymphoma (iNHL)
Actual Study Start Date :	January 31, 2014
Estimated Primary Completion Date :	July 15, 2020
Estimated Study Completion Date :	August 3, 2021

Arms and Interventions

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Arm	Intervention/treatment
Placebo Comparator: Treatment Arm A; Treatment Arm A = background immune-chemotherapy (bendamustine and rituximab [BR] or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]) for 6 cycles + placebo.	Drug: Bendamustine; 90 milligram per meter square (mg/m^2) administered intravenously on Days 1 to 2 of Cycles 1 to 6.; Drug: Rituximab; 375 mg/m^2 administered intravenously on Day 1 of Cycles 1 to 6.; Drug: Cyclophosphamide; 750 mg/m^2 administered intravenously on Day 1 of Cycles 1 to 6.; Drug: Doxorubicin; 50 mg/m^2 administered intravenously on Day 1 of Cycles 1 to 6.; Drug: Vincristine; 1.4 mg/m^2 (maximum total 2 mg) administered intravenously on Day 1 of Cycles 1 to 6.; Drug: Prednisone; 100 mg administered orally on Days 1 to 5 of Cycles 1 to 6.; Drug: Placebo; Placebo (4 capsules) matched to ibrutinib administered orally once daily, continuously starting on Cycle 1, Day 1.
Experimental: Treatment Arm B; Treatment Arm B = background immune-chemotherapy (BR or R-CHOP) for 6 cycles + PCI-32765 (Ibrutinib).	Drug: Bendamustine; 90 milligram per meter square (mg/m^2) administered intravenously on Days 1 to 2 of Cycles 1 to 6.; Drug: Rituximab; 375 mg/m^2 administered intravenously on Day 1 of Cycles 1 to 6.; Drug: Cyclophosphamide; 750 mg/m^2 administered intravenously on Day 1 of Cycles 1 to 6.; Drug: Doxorubicin; 50 mg/m^2 administered intravenously on Day 1 of Cycles 1 to 6.; Drug: Vincristine; 1.4 mg/m^2 (maximum total 2 mg) administered intravenously on Day 1 of Cycles 1 to 6.; Drug: Prednisone; 100 mg administered orally on Days 1 to 5 of Cycles 1 to 6.; Drug: PCI-32765 (Ibrutinib); 560 mg (4*140 mg) capsules administered orally once daily, continuously starting on Cycle 1, Day 1.

Outcome Measures

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Primary Outcome Measures :

1. Progression-free survival [ Time Frame: Up to approximately 7 years after the first participant is randomized ]

Secondary Outcome Measures :

1. Overall survival [ Time Frame: Up to approximately 7 years after the first participant is randomized ]
2. Complete response rate [ Time Frame: Up to approximately 7 years after the first participant is randomized ]
3. Overall response rate [ Time Frame: Up to approximately 7 years after the first participant is randomized ]
4. Duration of response [ Time Frame: Up to approximately 7 years after the first participant is randomized ]
5. Participants with change in patient-reported lymphoma symptoms and concerns as measured by the Lym subscale of the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) [ Time Frame: Up to approximately 7 years after the first participant is randomized ]
6. Number of participants affected by adverse events by MedDRA system organ class (SOC) and Preferred term (PT) [ Time Frame: Up to 30 days after the last dose of study medication ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Histologically confirmed diagnosis of B-cell indolent Non-Hodgkin lymphoma with histological subtype limited to follicular lymphoma or marginal zone lymphoma, at initial diagnosis and without evidence of pathological transformation or clinical signs suggesting transformation
• At least 1 prior treatment with a CD20 antibody combination chemo-immunotherapy regimen
• Disease that has relapsed or was refractory after prior chemo-immunotherapy
• At least 1 measurable site of disease according to Revised Response Criteria for Malignant Lymphoma 2007
• Eastern Cooperative Oncology Group performance status grade 0 or 1
• Laboratory values within protocol-defined parameters
• Agrees to protocol-defined use of effective contraception
• Men must agree not to donate sperm during and after the study for 6 months after the last dose of bendamustine, 12 months after the last dose of rituximab, or 3 months after the last dose of study medication, whichever is later
• Women of childbearing potential must have a negative serum or urine pregnancy test at Screening

Exclusion Criteria:

• Prior treatment according to protocol-defined criteria
• Unable to receive background chemotherapy based on prior treatment history and cardiac function
• Known central nervous system lymphoma
• Diagnosed or treated for malignancy other than indolent Non-Hodgkin lymphoma
• History of stroke or intracranial hemorrhage within 6 months prior to randomization
• Requires anticoagulation with warfarin or equivalent Vitamin K antagonists
• Requires treatment with strong CYP3A inhibitors
• Clinically significant cardiovascular disease
• Known history of human immunodeficiency virus or active hepatitis C virus (HCV; ribonucleic acid [RNA] polymerase chain reaction [PCR]-positive) or active hepatitis B virus (HBV; DNA PCR-positive) infection or any uncontrolled active systemic infection requiring intravenous antibiotics
• Any life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator's opinion, could compromise the participant's safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk
• Women who are pregnant or breastfeeding

Contacts and Locations

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  Show 134 Study Locations

Sponsors and Collaborators

Janssen Research & Development, LLC

Pharmacyclics LLC.

Investigators

Study Director:	Janssen Research & Development, LLC Clinical Trial	Janssen Research & Development, LLC

More Information

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Responsible Party:	Janssen Research & Development, LLC
ClinicalTrials.gov Identifier:	NCT01974440 History of Changes
Other Study ID Numbers:	CR102786; PCI-32765FLR3001 ( Other Identifier: Janssen Research & Development, LLC ); 2013-003093-27 ( EudraCT Number )
First Posted:	November 1, 2013
Last Update Posted:	November 16, 2018
Last Verified:	November 2018

Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Janssen Research & Development, LLC:

Lymphoma; Follicular lymphoma; Marginal zone lymphoma; Indolent Non-Hodgkin lymphoma; PCI-32765; Ibrutinib; Bendamustine	Rituximab; Cyclophosphamide; Doxorubicin; Vincristine; Prednisone; R-CHOP

Additional relevant MeSH terms:

Lymphoma; Lymphoma, Non-Hodgkin; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Cyclophosphamide; Rituximab; Bendamustine Hydrochloride; 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; Glucocorticoids