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

NCT01671904 | Completed Phase 1

• 2 other identifiers: GO284402012-002351-42
• Study Type: interventional
• Target: 84
• Locations: 3 countries
• Sites: 12

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.

Conditions

Chronic Lymphocytic Leukemia

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Dose Limiting Toxicities (DLTs)

  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.

  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.

Secondary Outcomes (10)

• Plasma Concentrations of Venetoclax

  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.

• Serum Concentrations of Rituximab

  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.

• Serum Concentrations of Obinutuzumab

  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.

• Plasma Concentrations of Bendamustine

  Sch A: Cy1D2: predose, end of infusion. Sch B: Cy1D2, Cy3D2: predose, end of infusion.

• 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

  Baseline up to approximately 5.75 years

Study Arms (3)

1L CLL BR+V

EXPERIMENTAL

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; Drug: Rituximab; Drug: Venetoclax

1L CLL BG+V

EXPERIMENTAL

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; Drug: Obinutuzumab; Drug: Venetoclax

R/R CLL BR+V

EXPERIMENTAL

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; Drug: Rituximab; Drug: Venetoclax

Interventions

Bendamustine DRUG

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.

1L CLL BG+V; 1L CLL BR+V; R/R CLL BR+V

Obinutuzumab DRUG

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.

Also known as: GA101; RO5072759

1L CLL BG+V

Rituximab DRUG

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.

Also known as: MabThera; Rituxan

1L CLL BR+V; R/R CLL BR+V

Venetoclax DRUG

Participants will receive multiple doses of venetoclax orally once daily.

Also known as: ABT-199; GDC-0199

1L CLL BG+V; 1L CLL BR+V; R/R CLL BR+V

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Genentech, Inc.: lead
• AbbVie (prior sponsor, Abbott): collaborator

Study Sites (12)

University of California San Diego Medical Center

La Jolla, California, 92093-5354, United States

Location

Ingalls Hospital; Cancer Clinical Trials

Harvey, Illinois, 60426, United States

Location

Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

North Star Lodge

Yakima, Washington, 98902, United States

Location

Hopital Claude Huriez

Lille, 59037, France

Location

Hopital Saint Eloi

Montpellier, 34295, France

Location

Centre Hospitalier Lyon Sud

Pierre-Bénite, 69495, France

Location

Centre Henri Becquerel

Rouen, 76038, France

Location

Universitatsklinik Koln

Cologne, 50924, Germany

Location

Apotheke des Universitätsklinikums Freiburg

Freiburg im Breisgau, 79106, Germany

Location

Klinikum Schwabing

München, 80804, Germany

Location

Universtitätsklinikum Ulm; Klinik für Innere Medizin III

Ulm, 89081, Germany

Location

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

Bendamustine Hydrochloride; obinutuzumab; Rituximab; venetoclax

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Butyrates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Clinical Trials

  Genentech, Inc.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 10, 2012
• First Posted: August 24, 2012
• Study Start: January 13, 2014
• Primary Completion: August 17, 2018
• Study Completion: August 11, 2020
• Last Updated: October 14, 2020

Record last verified: 2020-10

Locations

US (4); FR (4); DE (4)