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

• ClinicalTrials.gov Identifier: NCT01594229
• Recruitment Status: Active, not recruiting
• First Posted: May 9, 2012
• Last Update Posted: December 11, 2019
• Sponsor: AbbVie
• Collaborator: Genentech, Inc.
• Information provided by (Responsible Party): AbbVie

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 (Clinical Trial)
• Actual Enrollment: 60 participants
• 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
• Estimated Primary Completion Date: October 26, 2020
• Estimated Study Completion Date: October 26, 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.

Outcome Measures

Primary Outcome Measures :

1. 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 [ Time Frame: 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
2. 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 [ Time Frame: 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
3. Number of participants with adverse events as a measure of safety and tolerability [ Time Frame: 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
4. 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 [ Time Frame: 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 :

1. Evaluate preliminary data regarding progression-free survival when ABT-199 is administered in combination with Bendamustine and Rituximab [ Time Frame: 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
2. Evaluate preliminary data regarding overall survival and duration of overall response when ABT-199 is administered in combination with Bendamustine and Rituximab. [ Time Frame: 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
3. Evaluate preliminary data regarding objective response rate when ABT-199 is administered in combination with Bendamustine and Rituximab [ Time Frame: 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
4. Evaluate preliminary data regarding time to tumor progression when ABT-199 is administered in combination with Bendamustine and Rituximab. [ Time Frame: 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

• Ages Eligible for Study: 18 Years to 99 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

United States, California

Ucsd /Id# 67350

La Jolla, California, United States, 92093

University of California, Los Angeles /ID# 67343

Los Angeles, California, United States, 90095

United States, Georgia

Emory University Hospital /ID# 67349

Atlanta, Georgia, United States, 30322

Georgia Regents University /ID# 67342

Augusta, Georgia, United States, 30912

United States, Illinois

Ingalls Memorial Hosp /ID# 67344

Harvey, Illinois, United States, 60426

United States, Maryland

Johns Hopkins University /ID# 67345

Baltimore, Maryland, United States, 21287

United States, Michigan

Henry Ford Health System /ID# 67346

Detroit, Michigan, United States, 48202

United States, Texas

University of Texas MD Anderson Cancer Center /ID# 69222

Houston, Texas, United States, 77030

Sponsors and Collaborators

AbbVie

Genentech, Inc.

Investigators

• Study Director: AbbVie Inc.; AbbVie

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

de Vos S, Swinnen LJ, Wang D, Reid E, Fowler N, Cordero J, Dunbar M, Enschede SH, Nolan C, Petrich AM, Ross JA, Salem AH, Verdugo M, Agarwal S, Zhou L, Kozloff M, Nastoupil LJ, Flowers CR. Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase Ib dose-finding study. Ann Oncol. 2018 Sep 1;29(9):1932-1938. doi: 10.1093/annonc/mdy256.

• Responsible Party: AbbVie
• ClinicalTrials.gov Identifier: NCT01594229
• Other Study ID Numbers: M12-630
• First Posted: May 9, 2012
• Last Update Posted: December 11, 2019
• Last Verified: December 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by AbbVie:

Pharmacokinetics; Maximum Tolerated Dose; Safety; Bendamustine; Non-Hodgkin's Lymphoma; Rituximab; ABT-199; Cancer; Preliminary Efficacy

Additional relevant MeSH terms:

Lymphoma; Lymphoma, Non-Hodgkin; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Rituximab; Bendamustine Hydrochloride; Venetoclax; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action