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

Sponsor

Janssen Research & Development, LLC (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT01974440

Collaborator

Pharmacyclics LLC. (Industry)

403

Enrollment

135

Locations

Arms

111.9

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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

Study Type:

Interventional

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 :

Jan 31, 2014

Actual Primary Completion Date :

May 30, 2022

Anticipated Study Completion Date :

May 29, 2023

Arms and Interventions

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.

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

Primary Outcome Measures

Progression-free survival [Up to approximately 7 years after the first participant is randomized]

Secondary Outcome Measures

Overall survival [Up to approximately 7 years after the first participant is randomized]
Complete response rate [Up to approximately 7 years after the first participant is randomized]
Overall response rate [Up to approximately 7 years after the first participant is randomized]
Duration of response [Up to approximately 7 years after the first participant is randomized]
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) [Up to approximately 7 years after the first participant is randomized]
Number of participants affected by adverse events by MedDRA system organ class (SOC) and Preferred term (PT) [Up to 30 days after the last dose of study medication]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	City	State	Country
1	Gilbert	Arizona	United States
2	Campbell	California	United States
3	Duarte	California	United States
4	La Jolla	California	United States
5	Los Angeles	California	United States
6	Orange	California	United States
7	Ocala	Florida	United States
8	Chicago	Illinois	United States
9	Maywood	Illinois	United States
10	Indianapolis	Indiana	United States
11	Westwood	Kansas	United States
12	Lexington	Kentucky	United States
13	Lafayette	Louisiana	United States
14	Scarborough	Maine	United States
15	Baltimore	Maryland	United States
16	Bethesda	Maryland	United States
17	Boston	Massachusetts	United States
18	Ann Arbor	Michigan	United States
19	Battle Creek	Michigan	United States
20	Detroit	Michigan	United States
21	Saint Louis Park	Minnesota	United States
22	Denville	New Jersey	United States
23	New York	New York	United States
24	Hickory	North Carolina	United States
25	Pinehurst	North Carolina	United States
26	Bend	Oregon	United States
27	Pittsburgh	Pennsylvania	United States
28	Sioux Falls	South Dakota	United States
29	Houston	Texas	United States
30	Lubbock	Texas	United States
31	Spokane	Washington	United States
32	Green Bay	Wisconsin	United States
33	Buenos Aires		Argentina
34	Ciudad Autonoma Buenos Aires		Argentina
35	Cordoba		Argentina
36	La Capital		Argentina
37	Mendoza		Argentina
38	Santa Fe		Argentina
39	Adelaide		Australia
40	Fitzroy		Australia
41	Heidelberg		Australia
42	South Brisbane		Australia
43	Wahroonga		Australia
44	Westmead		Australia
45	Anderlecht		Belgium
46	Edegem		Belgium
47	Gent		Belgium
48	Leuven		Belgium
49	Namur		Belgium
50	Wilrijk		Belgium
51	Porto Alegre		Brazil
52	Rio de Janeiro		Brazil
53	Salvador		Brazil
54	Sao Paulo		Brazil
55	Beijing		China
56	Chengdu		China
57	Guangzhou		China
58	Hangzhou		China
59	Harbin		China
60	Nanjing		China
61	Shanghai		China
62	Tianjin		China
63	Nice Cedex 2		France
64	Paris		France
65	Pessac		France
66	Pierre Benite		France
67	Rennes		France
68	Berlin		Germany
69	Gießen		Germany
70	Göttingen		Germany
71	Ludwigshafen, Rp		Germany
72	Magdeburg		Germany
73	Mainz		Germany
74	Munchen		Germany
75	Wiesbaden		Germany
76	Hadera		Israel
77	Haifa		Israel
78	Jerusalem		Israel
79	Nahariya		Israel
80	Netanya		Israel
81	Petah Tikva		Israel
82	Ramat Gan		Israel
83	Chuo-Ku		Japan
84	Hiroshima-shi		Japan
85	Isehara		Japan
86	Kobe		Japan
87	Nagoya-shi		Japan
88	Osaka-Sayama-shi		Japan
89	Sapporo-shi		Japan
90	Sendai-shi		Japan
91	Suita-shi		Japan
92	Tokyo		Japan
93	Jeollanam-do		Korea, Republic of
94	Seoul		Korea, Republic of
95	Gdynia		Poland
96	Olsztyn		Poland
97	Warszawa		Poland
98	Bayamon		Puerto Rico
99	Ponce		Puerto Rico
100	San Juan		Puerto Rico
101	Krasnodar		Russian Federation
102	Moscow		Russian Federation
103	Nizny Novgorod		Russian Federation
104	Petrozavodsk		Russian Federation
105	Pyatigorsk		Russian Federation
106	Rostov-On-Don		Russian Federation
107	St. Petersburg		Russian Federation
108	Syktyvkar		Russian Federation
109	Volgograd		Russian Federation
110	Barcelona		Spain
111	Madrid		Spain
112	Pozuelo de Alarcon		Spain
113	Salamanca		Spain
114	Göteborg		Sweden
115	Linköping		Sweden
116	Luleå		Sweden
117	Uppsala		Sweden
118	Ankara		Turkey
119	Antalya		Turkey
120	Istanbul		Turkey
121	Izmir		Turkey
122	Kayseri		Turkey
123	Cherkasy		Ukraine
124	Ivano-Frankivsk		Ukraine
125	Khmelnitskiy		Ukraine
126	Kiev		Ukraine
127	Lviv		Ukraine
128	Uzhgorod		Ukraine
129	Glasgow		United Kingdom
130	London		United Kingdom
131	Newcastle upon Tyne		United Kingdom
132	Plymouth		United Kingdom
133	Portsmouth		United Kingdom
134	Sutton		United Kingdom
135	Swansea		United Kingdom