A Study Evaluating the Safety and Pharmacokinetics of ABT-199 in Combination With Bendamustine/Rituximab (BR) in Subjects With Relapsed or Refractory Non-Hodgkin's Lymphoma

Sponsor

AbbVie (Industry)

Overall Status

Completed

CT.gov ID

NCT01594229

Collaborator

Genentech, Inc. (Industry)

Enrollment

Locations

Arm

97.8

Actual Duration (Months)

7.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a Phase 1, open-label, multicenter study evaluating the safety, pharmacokinetic profile, and preliminary efficacy of ABT-199 in combination with Bendamustine/Rituximab in approximately 60 subjects with relapsed or refractory non-Hodgkin's lymphoma. This study will evaluate the safety and pharmacokinetic profile of ABT-199 in approximately 60 subjects when administered in combination with Bendamustine/Rituximab following a dose escalation scheme, with the objective of defining the dose limiting toxicity and the maximum tolerated dose.

Condition or Disease	Intervention/Treatment	Phase
Non-Hodgkin's Lymphoma	Drug: ABT-199 Drug: Rituximab Drug: Bendamustine	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

60 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1 Study Evaluating the Safety and Pharmacokinetics of ABT-199 in Combination With Bendamustine/Rituximab (BR) in Subjects With Relapsed or Refractory Non-Hodgkin's Lymphoma

Actual Study Start Date :

May 21, 2012

Actual Primary Completion Date :

Jul 14, 2020

Actual Study Completion Date :

Jul 14, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1 Non-Hodgkin's Lymphoma (NHL)	Drug: ABT-199 ABT-199 is taken orally once daily for 3 days out of each 28 day cycle. This is a dose escalation study, therefore the dose of ABT-199 will change throughout the study. Drug: Rituximab Rituximab will be given by intravenous infusion for 1 day out of each 28 day cycle. Drug: Bendamustine Bendamustine will be given by intravenous infusion for 2 days out of each 28 day cycle.

Arm

Intervention/Treatment

Experimental: Arm 1

Non-Hodgkin's Lymphoma (NHL)

Drug: ABT-199

ABT-199 is taken orally once daily for 3 days out of each 28 day cycle. This is a dose escalation study, therefore the dose of ABT-199 will change throughout the study.

Drug: Rituximab

Rituximab will be given by intravenous infusion for 1 day out of each 28 day cycle.

Drug: Bendamustine

Bendamustine will be given by intravenous infusion for 2 days out of each 28 day cycle.

Outcome Measures

Primary Outcome Measures

Determination of the maximum tolerated dose of ABT-199 when administered with Bendamustine and Rituximab in subjects with relapsed or refractory non-Hodgkin's lymphoma [3 days of study drug administration within the 28-day cycle at the designated cohort dose]
Protocol-defined events, which can not be attributed by the investigator to a clearly identifiable cause such as tumor progression, concurrent illness, or concomitant medication, will be considered a dose limiting toxicity
Determination of peak concentration (Cmax), trough concentration (Ctrough) and/or area under the concentration versus time curve (AUC) of ABT-199, Bendamustine and Rituximab in the dose escalation cohort [Up to Cycle 6 for ABT-199 and Bendamustine, Up to Cycle 11 for Rituximab]
Protocol-defined events, which can not be attributed by the investigator to a clearly identifiable cause such as tumor progression, concurrent illness, or concomitant medication, will be considered a dose limiting toxicity
Number of participants with adverse events as a measure of safety and tolerability [First 5 days of study drug administration, weekly through Cycle 2 and then Day 1 of each Cycle for an anticipated maximum duration of 6 months]
Adverse event monitoring, vital signs, physical examination, lymphocyte enumeration, 12-lead ECG, 2D echocardiogram/multiple gated acquisition scan (MUGA), and laboratory assessments
Determination of the recommended Phase 2 dose of ABT-199 when administered with Bendamustine and Rituximab in subjects with relapsed or refractory non-Hodgkin's lymphoma [3 days of study drug administration within the 28-day cycle at the designated cohort dose]
Protocol-defined events, which can not be attributed by the investigator to a clearly identifiable cause such as tumor progression, concurrent illness, or concomitant medication, will be considered a dose limiting toxicity

Secondary Outcome Measures

Evaluate preliminary data regarding progression-free survival when ABT-199 is administered in combination with Bendamustine and Rituximab [Tumor Assessments: Approximately every 2 cycles through Cycle 17 then every 6 cycles thereafter; Clinical Disease Assessment: Weekly through Cycle 2, then every cycle thereafter]
Tumor response or clinical disease progression
Evaluate preliminary data regarding overall survival and duration of overall response when ABT-199 is administered in combination with Bendamustine and Rituximab. [Tumor Assessments: Approximately every 2 cycles through Cycle 17 then every 6 cycles thereafter; Clinical Disease Assessment: Weekly through Cycle 2, then every cycle thereafter]
Tumor response or clinical disease progression
Evaluate preliminary data regarding objective response rate when ABT-199 is administered in combination with Bendamustine and Rituximab [Tumor Assessments: Approximately every 2 cycles through Cycle 17 then every 6 cycles thereafter; Clinical Disease Assessment: Weekly through Cycle 2, then every cycle thereafter]
Tumor response or clinical disease progression
Evaluate preliminary data regarding time to tumor progression when ABT-199 is administered in combination with Bendamustine and Rituximab. [Tumor Assessments: Approximately every 2 cycles through Cycle 17 then every 6 cycles thereafter; Clinical Disease Assessment: Weekly through Cycle 2, then every cycle thereafter]
Tumor response or clinical disease progression

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 99 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Subject must have histologically documented diagnosis of non-Hodgkin's lymphoma as defined by a B-cell neoplasm in the World Health Organization classification scheme except as noted in exclusion criteria.
Subject (non-diffuse large B-cell lymphoma) must have relapsed or refractory non-Hodgkin's lymphoma, and require treatment in the opinion of the investigator.
Subject with diffuse large B-cell lymphoma must have relapsed diffuse large B-cell lymphoma or must have progressed after salvage therapy (with or without standard chemotherapy) for diffuse large B-cell lymphoma. The subject must have received first line therapy with Rituximab-Cyclophosphamide, Hydroxydaunomycin, Vincristine (Oncovin), Prednisone (R-CHOP) [or a similar standard rituximab-containing front-line chemoimmunotherapy regimen including, but not limited to Etoposide, Prednisone, Vincristine (Oncovin), Cyclophosphamide, Doxorubicin (Hydrochloride) + Rituximab (EPOCH + R); Rituximab, Cyclophosphamide, Etoposide, Procarbazine, Prednisone (RCEPP); Rituximab, Cyclophosphamide, Mitoxantrone (Novantrone), Vincristine (Oncovin), Prednisone (RCNOP); Dose-adjusted-Etoposide, Prednisone, Vincristine(Oncovin), Cyclophosphamide, Doxorubicin (Hydrocloride) (DA-EPOCH); and Rituximab, Cyclophosphamide, Etoposide, Vincristine (Oncovin), Prednisone (RCEOP)].
Subject must have adequate coagulation, renal, and hepatic function, per laboratory reference range at Screening.

Exclusion Criteria:

Subject has been diagnosed with Post-Transplant Lymphoproliferative Disease, Burkitt's lymphoma, Burkitt-like lymphoma, lymphoblastic lymphoma/leukemia, chronic lymphocytic leukemia, small lymphocytic lymphoma or mantle cell lymphoma (MCL).
Subject has refractory diffuse large B-cell lymphoma, defined as meeting any of the following criteria:
Subject progressed during or within 3 months of completion of a planned course of first-line therapy with Rituximab-Cyclophosphamide, Hydroxydaunomycin, Vincristine (Oncovin), Prednisone (R-CHOP) or an equivalent regimen;
Subject had no response (i.e., stable disease only) to first-line therapy with R-Cyclophosphamide, Hydroxydaunomycin, Vincristine (Oncovin), Prednisone (R-CHOP) or an equivalent regimen;
Subject progressed during or within 2 months of completion of their last planned course of salvage therapy with chemotherapy (with or without rituximab, may include autologous stem cell transplant).
Subject has tested positive for human immunodeficiency virus (HIV).
Subject has a cardiovascular disability status of New York Heart Association Class greater or equal to 2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity, results in fatigue, palpitations, dyspnea or anginal pain.
Subject has a significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, or hepatic disease that in the opinion of the Investigator would adversely affect his/her participating in this study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ucsd /Id# 67350	La Jolla	California	United States	92093
2	University of California, Los Angeles /ID# 67343	Los Angeles	California	United States	90095
3	Emory University Hospital /ID# 67349	Atlanta	Georgia	United States	30322
4	Georgia Regents University /ID# 67342	Augusta	Georgia	United States	30912
5	Ingalls Memorial Hosp /ID# 67344	Harvey	Illinois	United States	60426
6	Johns Hopkins University /ID# 67345	Baltimore	Maryland	United States	21287
7	Henry Ford Health System /ID# 67346	Detroit	Michigan	United States	48202
8	University of Texas MD Anderson Cancer Center /ID# 69222	Houston	Texas	United States	77030