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A Study of Venetoclax in Combination With Bendamustine + Rituximab or Bendamustine + Obinutuzumab in Participants With Relapsed/Refractory or Previously Untreated Chronic Lymphocytic Leukemia (CLL)

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ClinicalTrials.gov Identifier: NCT01671904
Recruitment Status : Active, not recruiting
First Posted : August 24, 2012
Last Update Posted : September 6, 2019
Sponsor:
Collaborator:
AbbVie (prior sponsor, Abbott)
Information provided by (Responsible Party):
Genentech, Inc.

Brief Summary:
This multi-center, open-label, dose-finding study will evaluate the safety and pharmacokinetics of venetoclax (GDC-0199, ABT-199) administered in combination with bendamustine and rituximab (BR) (MabThera/Rituxan) or bendamustine and obinutuzumab (BG) to participants with first-line (1L)/previously untreated or relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). The study will explore two venetoclax combination regimens in participants with 1L CLL: BR+venetolax (V) and BG+V. Participants with R/R CLL will be administered BR+V.

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukemia Drug: Bendamustine Drug: Obinutuzumab Drug: Rituximab Drug: Venetoclax Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 83 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase IB, Open-Label Study Evaluating the Safety and Pharmacokinetics of Venetoclax (GDC-0199, ABT-199) in Combination With Bendamustine+Rituximab (BR) or Bendamustine+Obinutuzumab (BG) in Patients With Relapsed/Refractory or Previously Untreated Chronic Lymphocytic Leukemia
Actual Study Start Date : January 13, 2014
Actual Primary Completion Date : August 17, 2018
Estimated Study Completion Date : December 31, 2019


Arm Intervention/treatment
Experimental: 1L CLL BR+V
Participants with first-line (1L)/previously untreated CLL were administered escalating doses of venetoclax (V) in combination with fixed dose bendamustine and rituximab (BR). Participants received six 28-day cycles of BR+V. Participants with 1L CLL received 6 months of single-agent venetoclax for a total of 1-year treatment duration. Single-agent venetoclax could be extended if there was detectable minimal residual disease (MRD) in the bone marrow and/or partial response (PR) after 1 year of treatment and upon the request of the treating physician.
Drug: Bendamustine
Participants will receive intravenous (IV) infusion of bendamustine (90 or 70 milligrams per square meter [mg/m^2]) on Days 2-3 of Cycle 1 and Days 1-2 of Cycles 2-6.

Drug: Rituximab
Participants will receive IV infusion of rituximab (375 mg/m^2) on Day 1 of Cycle 1 and 500 mg/m^2 administered on Day 1 of Cycles 2-6.
Other Name: MabThera; Rituxan

Drug: Venetoclax
Participants will receive multiple doses of venetoclax orally once daily.
Other Name: ABT-199; GDC-0199

Experimental: 1L CLL BG+V
Participants with first-line (1L)/previously untreated CLL were administered escalating doses of venetoclax (V) in combination with fixed dose bendamustine and obinutuzumab (BG). Participants received six 28-day cycles of BG+V. Participants with 1L CLL received 6 months of single-agent venetoclax for a total of 1-year treatment duration. Single-agent venetoclax could be extended if there was detectable minimal residual disease (MRD) in the bone marrow and/or partial response (PR) after 1 year of treatment and upon the request of the treating physician.
Drug: Bendamustine
Participants will receive intravenous (IV) infusion of bendamustine (90 or 70 milligrams per square meter [mg/m^2]) on Days 2-3 of Cycle 1 and Days 1-2 of Cycles 2-6.

Drug: Obinutuzumab
Participants will receive IV infusion of obinutuzumab (100 milligrams [mg]) on Day 1 of Cycle 1; 900 mg administered on Day 2 of Cycle 1; and 1000 mg administered on Days 8 and 15 of Cycle 1 and on Day 1 of Cycles 2-6.
Other Name: GA101; RO5072759

Drug: Venetoclax
Participants will receive multiple doses of venetoclax orally once daily.
Other Name: ABT-199; GDC-0199

Experimental: R/R CLL BR+V
Participants with relapsed/refractory (R/R) CLL were administered escalating doses of venetoclax (V) in combination with fixed dose bendamustine and rituximab (BR). Participants received six 28-day cycles of BR+V. Participants with R/R CLL continued single-agent venetoclax until disease progression, death, or unacceptable toxicity.
Drug: Bendamustine
Participants will receive intravenous (IV) infusion of bendamustine (90 or 70 milligrams per square meter [mg/m^2]) on Days 2-3 of Cycle 1 and Days 1-2 of Cycles 2-6.

Drug: Rituximab
Participants will receive IV infusion of rituximab (375 mg/m^2) on Day 1 of Cycle 1 and 500 mg/m^2 administered on Day 1 of Cycles 2-6.
Other Name: MabThera; Rituxan

Drug: Venetoclax
Participants will receive multiple doses of venetoclax orally once daily.
Other Name: ABT-199; GDC-0199




Primary Outcome Measures :
  1. Number of Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: Schedule (Sch) A (venetoclax [V] introduced before other agents): Cycle 1 Day 1 (Cy1D1) to Cy1D21; Sch B (V introduced after other agents): Cy1D21 to Cy2D28; Cycle length = 28 days. ]
    DLTs in this study were defined as specific adverse events (AEs) occurring during the DLT observation window: 1) Grade 4 neutropenia not responsive to granulocyte colony stimulating factors (G-CSF) lasting more than 14 days; 2) Grade 3 or 4 febrile neutropenia with fever lasting longer than 4 days; 3) Grade 4 thrombocytopenia resulting in bleeding, or that did not improve to Grade </=2 within 3 weeks; 4) Clinical tumor lysis syndrome (TLS) defined by the presence of laboratory TLS and one or more clinical manifestations related to the electrolyte abnormalities; 5) Grade 4 infusion-related reactions (IRRs) secondary to rituximab or obinutuzumab despite appropriate premedication and administration rate; 6) All other Grades 3, 4, or 5 AEs persisting for more than 2 weeks with or without treatment with some exceptions.


Secondary Outcome Measures :
  1. Plasma Concentrations of Venetoclax [ Time Frame: Sch A: Ramp-up D1, 8, 15, 22, 29: predose (pd), 8 h; Cy1D1: pd; Cy1D3: pd, 2, 4, 6, 8, 10 h; Cy2D1, Cy4D1, Cy6D1: pd. Sch B: Cy1D1: pd; Cy1D22, Cy2D1, Cy2D8, Cy2D15, Cy2D22 (ramp-up): pd, 8 h; Cy3D1: pd, 2, 4, 6, 8 h; Cy4D1, Cy6D1: pd. ]
  2. Serum Concentrations of Rituximab [ Time Frame: Sch A: Cy1D1, Cy2D1, Cy4D1, Cy6D1: predose, end of infusion. Sch B: Cy1D1: predose, end of infusion; Cy2D1, (ramp-up): predose, end of infusion; Cy3D1, Cy4D1, Cy6D1: predose. ]
  3. Serum Concentrations of Obinutuzumab [ Time Frame: Sch A: Cy1D1, Cy1D2: pd, end of infusion (EoI); Cy1D3: pd; Cy1D8, Cy1D15, Cy2D1: pd, EoI; Cy3D1, Cy4D1, Cy5D1, Cy6D1: pd; Sch B: Cy1D1, Cy1D2, Cy1D8, Cy1D15: pd, EoI; Cy1D22 (ramp-up): pd; Cy2D1, Cy3D1, Cy4D1, Cy5D1, Cy6D1: pd, EoI. ]
  4. Plasma Concentrations of Bendamustine [ Time Frame: Sch A: Cy1D2: predose, end of infusion. Sch B: Cy1D2, Cy3D2: predose, end of infusion. ]
  5. Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR) According to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 Guidelines [ Time Frame: Baseline up to approximately 5.75 years ]
    CR or CR with incomplete bone marrow recovery (CRi) or PR or nodular PR (nPR) was determined by the investigator according to IWCLL 2008 criteria. CR requires all of the following: Peripheral blood lymphocytes below 4x10^9/L, absence of lymphadenopathy by physical examination and computed tomography (CT) scan, No hepatomegaly or splenomegaly, Absence of disease or constitutional symptoms, Blood counts of neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L, Bone marrow at least normocellular for age without clonal infiltrate (except for Cri). PR: two of the following features for at least 2 months: >/= 50% decrease in peripheral blood lymphocyte count from the pretreatment value, >/=50% reduction in lymphadenopathy, >/=50% reduction of liver and/or spleen enlargement, and at least one of the following blood counts: neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L.

  6. Duration of Response According to IWCLL 2008 Guidelines [ Time Frame: Baseline up to approximately 5.75 years ]
    CR or CR with incomplete bone marrow recovery (CRi) or PR or nodular PR (nPR) was determined by the investigator according to IWCLL 2008 criteria. CR requires all of the following: Peripheral blood lymphocytes below 4x10^9/L, absence of lymphadenopathy by physical examination and computed tomography (CT) scan, No hepatomegaly or splenomegaly, Absence of disease or constitutional symptoms, Blood counts of neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L, Bone marrow at least normocellular for age without clonal infiltrate (except for Cri). PR: two of the following features for at least 2 months: >/= 50% decrease in peripheral blood lymphocyte count from the pretreatment value, >/=50% reduction in lymphadenopathy, >/=50% reduction of liver and/or spleen enlargement, and at least one of the following blood counts: neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L.

  7. Percentage of Participants with CR [ Time Frame: Baseline up to approximately 5.75 years ]
    CR or CR with incomplete bone marrow recovery (CRi) was determined by the investigator according to IWCLL 2008 criteria. CR requires all of the following: Peripheral blood lymphocytes below 4x10^9/L, absence of lymphadenopathy by physical examination and computed tomography (CT) scan, No hepatomegaly or splenomegaly, Absence of disease or constitutional symptoms, Blood counts of neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L, Bone marrow at least normocellular for age without clonal infiltrate (except for Cri).

  8. Progression-Free Survival (PFS) According to IWCLL 2008 Guidelines [ Time Frame: Baseline up to approximately 5.75 years ]
    PFS was determined according to IWCLL 2008 criteria and defined as the time from randomization to the first occurrence of progressive disease (PD) or death. Disease progression was characterized by at least one of the following: 1) >/= 50% increase in the absolute number of circulating lymphocytes to at least 5*10^9/L, 2) Appearance of new palpable lymph nodes (> 15 mm in longest diameter) or any new extra-nodal lesion; 3) >/= 50% increase in the longest diameter of any previous site of lymphadenopathy; 4) >/= 50% increase in the enlargement of the liver and/or spleen; 5) Transformation to a more aggressive histology.

  9. Overall Survival (OS) [ Time Frame: Baseline up to approximately 5.75 years ]
    OS was defined as the time from randomization to death from any cause.

  10. Number of Participants With Adverse Events [ Time Frame: Up to approximately 5.75 years ]
    An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.



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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:

  • Diagnosis of relapsing/refractory or previously untreated CLL
  • Eastern Cooperative Oncology Group (ECOG) performance score of less than equal to (</=) 1
  • Adequate bone marrow function
  • Adequate coagulation, renal and hepatic function
  • Hematological values within the limits independent of growth factor support or transfusion unless cytopenia is caused by the underlying disease, i.e., no evidence of additional bone marrow dysfunction (e.g., myelodysplastic syndrome, hypoplastic bone marrow)

Exclusion Criteria:

  • Participants received an allogeneic stem cell transplant
  • Known human immunodeficiency virus (HIV) positivity
  • Uncontrolled autoimmune hemolytic anemia or thrombocytopenia
  • Positive test results for chronic hepatitis B infection and hepatitis C virus (HCV)
  • Received any anti-cancer therapy including chemotherapy or radiotherapy, steroid therapy for anti-neoplastic intent, and investigational therapy, including targeted small molecule agents within 28 days prior to the first dose of study drug or has not recovered to less than Grade 2 clinically significant adverse effect(s)/toxicity(s) of the previous therapy
  • Significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, cardiovascular, or hepatic disease

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01671904


Locations
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United States, California
University of California San Diego Medical Center
La Jolla, California, United States, 92093-5354
United States, Illinois
Ingalls Hospital; Cancer Clinical Trials
Harvey, Illinois, United States, 60426
United States, Michigan
Karmanos Cancer Institute
Detroit, Michigan, United States, 48201
United States, Washington
Evergreen Hematology and Oncology
Spokane, Washington, United States, 99218
North Star Lodge
Yakima, Washington, United States, 98902
Yakima Valley Memorial Hospital/North Star Lodge
Yakima, Washington, United States, 98902
France
Hopital Claude Huriez
Lille, France, 59037
Hopital Saint Eloi
Montpellier, France, 34295
Centre Hospitalier Lyon Sud
Pierre Benite, France, 69495
Centre Henri Becquerel
Rouen, France, 76038
Germany
Apotheke des Universitätsklinikums Freiburg
Freiburg, Germany, 79106
UKSH Klinik für Innere Medizin II, Hämatologie und Internistische Onkologie
Kiel, Germany, 24105
Universitatsklinik Koln
Köln, Germany, 50924
Klinikum Schwabing
München, Germany, 80804
Universtitätsklinikum Ulm; Klinik für Innere Medizin III
Ulm, Germany, 89081
Sponsors and Collaborators
Genentech, Inc.
AbbVie (prior sponsor, Abbott)
Investigators
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Study Director: Clinical Trials Genentech, Inc.

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Responsible Party: Genentech, Inc.
ClinicalTrials.gov Identifier: NCT01671904     History of Changes
Other Study ID Numbers: GO28440
2012-002351-42 ( EudraCT Number )
First Posted: August 24, 2012    Key Record Dates
Last Update Posted: September 6, 2019
Last Verified: September 2019
Additional relevant MeSH terms:
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Venetoclax
Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Rituximab
Obinutuzumab
Bendamustine Hydrochloride
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action