CLL11: A Study of Obinutuzumab (RO5072759 [GA101]) With Chlorambucil in Patients With Previously Untreated Chronic Lymphocytic Leukemia (Stage 1a)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
German CLL Study Group
Genentech
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT01010061
First received: November 6, 2009
Last updated: February 14, 2014
Last verified: February 2014
  Purpose

This open-label, randomized, 3-arm study will evaluate the efficacy and safety of obinutuzumab (RO5072759) in combination with chlorambucil as compared to rituximab plus chlorambucil or chlorambucil alone in patients with previously untreated chronic lymphocytic leukemia (CLL). Patients will be randomized 2:2:1 to receive a maximum of six 28-day cycles of either RO5072759 (1000 mg intravenous (iv) infusion, on days 1, 8 and 15 of cycle 1 and day 1 of cycles 2-6) plus chlorambucil (0.5 mg/kg orally, days 1 and 15 of cycles 1-6), or rituximab (iv infusion day 1, 375 mg/m^2 cycle 1, 500 mg/m^2 cycles 2-6) plus chlorambucil, or chlorambucil alone. Anticipated time on study treatment is >6 months and follow-up for disease-progression and safety will be at least 5 years. In the US, this trial is sponsored/managed by Genentech.


Condition Intervention Phase
Lymphocytic Leukemia, Chronic
Drug: obinutuzumab
Drug: rituximab
Drug: chlorambucil
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open-label, Multi-center, Three Arm Randomized Study to Investigate the Safety and Efficacy on Progression-free Survival of RO5072759 + Chlorambucil (GClb) Compared to Rituximab + Chlorambucil (RClb) or Chlorambucil (Clb) Alone in Previously Untreated CLL Patients With Comorbidities.

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • Progression-free Survival (PFS) [ Time Frame: Randomization to clinical cutoff (median observation 14.2 months) ] [ Designated as safety issue: No ]

    PFS was defined as the time from randomization to the first occurrence of progression, relapse, or death from any cause as assessed by the investigator.

    Progressive disease (PD) required at least one of the following: ≥50% increase in the absolute number of lymphocytes, appearance of new palpable lymph nodes (>15 mm in longest diameter) or any new extra nodal lesion, ≥50% increase in the longest diameter of any previous site of clinically significant lymphadenopathy, ≥50% increase in the enlargement of the liver and/or spleen, Transformation to a more aggressive histology or After treatment, the progression of any cytopenia (a decrease of hemoglobin levels >20 g/L or <10 g/dL or a decrease of platelet counts >50% or <100 x 10^9/L or by a decrease of neutrophil counts >50% or <1.0 x 10^9/L).


  • Percentage of Participants With Progression Free Survival Events [ Time Frame: Randomization to clinical cutoff (median observation 14.2 months) ] [ Designated as safety issue: No ]
    Percentage of Participants with Progression Free Survival Events: disease progression, relapse, or death.


Secondary Outcome Measures:
  • Progression Free Survival Based on Independent Review Committee (IRC) Data [ Time Frame: Randomization to clinical cutoff (median observation 14.2 months) ] [ Designated as safety issue: No ]
    PFS was defined as the time from randomization to the first occurrence of progression, relapse, or death from any cause as assessed by Independent Review Committee. Progressive disease required at least one of the following: ≥50% increase in the absolute number of lymphocytes, appearance of new palpable lymph nodes (>15 mm in longest diameter) or any new extra nodal lesion, ≥50% increase in the longest diameter of any previous site of clinically significant lymphadenopathy, ≥50% increase in the enlargement of the liver and/or spleen, Transformation to a more aggressive histology or After treatment, the progression of any cytopenia (a decrease of hemoglobin levels >20 g/L or <10 g/dL or a decrease of platelet counts >50% or <100 x 10^9/L or by a decrease of neutrophil counts >50% or <1.0 x 10^9/L).

  • Percentage of Participants With Progression Free Survival Events Based on Independent Review Committee (IRC) Data [ Time Frame: Randomization to clinical cutoff (median observation 14.2 months) ] [ Designated as safety issue: No ]
    Percentage of Participants with Progression Free Survival Events: progression, relapse, or death from any cause as assessed by an Independent Review Committee.

  • Percentage of Participants With End of Treatment Response (EOTR) [ Time Frame: Randomization to clinical cutoff (median observation 14.2 months) ] [ Designated as safety issue: No ]
    EOTR was the first response assessment 56 days from the last dose according to the International Workshop on Chronic Lymphocytic Leukaemia (IWCLL) guidelines. CR required: Peripheral blood lymphocytes below 4 x 10^9/L, Absence of significant lymphadenopathy, No hepatomegaly, No splenomegaly, Absence of disease, Blood counts above the following values (Neutrophils >1.5 x 10^9/L, Platelets >100 x 10^9/L, Hemoglobin >11g/dL) and Bone marrow at least normocellular for age. CRi was CR with incomplete bone marrow recovery. PR required the following for at least 2 months from end of treatment: ≥50% decrease in peripheral blood lymphocyte count from the pre-treatment value AND Either a ≥ 50% reduction in lymphadenopathy OR ≥50% reduction of liver enlargement OR ≥50% reduction of spleen enlargement PLUS at least one of the following: Neutrophils >1.5 x 10^9/ or ≥50% increase, Platelets >100 x 10^9/L or ≥50% increase, Hemoglobin 11 g/dL or ≥50% increase.

  • Percentage of Participants With Best Overall Response [ Time Frame: Randomization to clinical cutoff (median observation 14.2 months) ] [ Designated as safety issue: No ]
    Best overall response according to IWCLL guidelines was defined as the percentage of patients with CR, CRi,PR or nPR. CR required all of the following: Peripheral blood lymphocytes below 4 x 10^9/L, Absence of significant lymphadenopathy, No hepatomegaly, No splenomegaly, Absence of disease, Blood counts above the following values (Neutrophils >1.5 x 10^9/L, Platelets >100 x 10^9/L, Hemoglobin >11g/dL) and Bone marrow at least normocellular for age. CRi was CR with incomplete bone marrow recovery. PR required the following for at least 2 months from end of treatment: ≥50% decrease in peripheral blood lymphocyte count from the pre-treatment value AND Either a ≥ 50% reduction in lymphadenopathy OR ≥50% reduction of liver enlargement OR ≥50% reduction of spleen enlargement PLUS at least one of the following: Neutrophils >1.5 x 10^9/ or ≥50% increase, Platelets >100 x 10^9/L or ≥50% increase, Hemoglobin 11 g/dL or ≥50% increase.

  • Event Free Survival [ Time Frame: Randomization to clinical cutoff (median observation 14.2 months) ] [ Designated as safety issue: No ]
    Event-free survival (EFS) was defined as the time between date of randomization and the date of disease progression/relapse, death, or start of a new anti-leukemic therapy. Progressive disease as per IWCLL criteria required at least one of the following: ≥50% increase in the absolute number of lymphocytes, appearance of new palpable lymph nodes (>15 mm in longest diameter) or any new extra nodal lesion, ≥50% increase in the longest diameter of any previous site of clinically significant lymphadenopathy, ≥50% increase in the enlargement of the liver and/or spleen, Transformation to a more aggressive histology or After treatment, the progression of any cytopenia (a decrease of hemoglobin levels >20 g/L or <10 g/dL or a decrease of platelet counts >50% or <100 x 10^9/L or by a decrease of neutrophil counts >50% or <1.0 x 10^9/L).

  • Overall Survival [ Time Frame: Randomization to clinical cutoff (median observation 14.2 months) ] [ Designated as safety issue: No ]
    Overall Survival (OS) was defined as the time between the date of randomization and the date of death due to any cause.

  • Duration of Response [ Time Frame: Randomization to clinical cutoff (median observation 14.2 months) ] [ Designated as safety issue: No ]
    Duration of Response was defined as the date the response [either Complete Response (CR) or Partial Response (PR)] was first recorded until the date of Disease Progression or death due to any cause. Response was assessed according IWCLL guidelines.

  • Percentage of Participants With Molecular Remission at the End of Treatment [ Time Frame: Randomization to clinical cutoff (median observation 14.2 months) ] [ Designated as safety issue: No ]
    Molecular remission was defined as a minimal residual disease (MRD)-negative result at the end of treatment (assessment that occurred between 56 days and 6 months of last treatment). Molecular remission was assessed for all patients using a blood sample. Additionally, a bone marrow sample was obtained from patients whom the investigator assumed to have a complete response, consistent with the IWCLL guidelines. A combined analysis of blood and bone marrow results was conducted. A patient was considered MRD negative if result was less than 1 chronic lymphocytic leukemia (CLL) cell in 10000 leukocytes (MRD value < 0.0001) based on the method of allele specific polymerase chain reaction (ASO-PCR).

  • Time to Re-Treatment/New-antileukemic Therapy [ Time Frame: Randomization to clinical cutoff (median observation 14.2 months) ] [ Designated as safety issue: No ]
    Time to re-treatment/new anti-leukemic therapy was defined as time between the date of randomization and the date of first intake of re-treatment or new anti-leukemic therapy.

  • Pharmacokinetics of Obinutuzumab (RO5072759) in Combination With Chlorambucil (Clb) [ Time Frame: Pre- and post-dose sampling on day 1 of cycles 1-6 (Up to 26.8 months) ] [ Designated as safety issue: No ]
    Blood samples were collected from all patients allocated to the GClb treatment arm pre- and post-dose Day 1 of Cycles 1 to 6 and were sent to a laboratory. The concentration of obinutzumab in serum was determined using a validated enzyme-linked immunosorbent assay (ELISA) and was reported in micrograms/milliliter (μg/mL).

  • European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire [ Time Frame: after 3 cycles, 28 days after last dose and at intervals during follow-up ] [ Designated as safety issue: No ]
    The EORTC Quality of Life Questionnaire QLQ-C30 was used to assess patient-reported outcomes (PRO) and symptom burden. The QLQ-C30 contains 30 items including the functional scales of physical functioning (5 items), role functioning (2 items), emotional functioning (4 items), cognitive functioning (2 items), social functioning (2 items) and symptom scales including fatigue (3 items), nausea and vomiting (2 items), and pain (4 items) and six single item scales on dyspnea, sleep disturbance, appetite loss, constipation, diarrhea and financial impact. final scores are transformed such that they range from 0 − 100, whereby higher scores indicate greater functioning, greater quality of life, or a greater degree of symptoms, with changes of 5 − 10 points considered to be of minimally important difference to patients.

  • European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire [ Time Frame: after 3 cycles, 28 days after last dose and at intervals during follow-up ] [ Designated as safety issue: No ]
    EORTC Quality of Life Questionnaire QLQ-CLL16 module was used to assess patient-reported outcomes and symptom burden. The QLQ-CLL16 module includes three multi-item scales assessing fatigue (2 items), treatment side effects and disease symptoms (8 items), infection (4 items) and two single item scales on social activities and future health worries. final scores are transformed such that they range from 0 − 100, whereby higher scores indicate greater functioning, greater quality of life, or a greater degree of symptoms, with changes of 5 − 10 points considered to be of minimally important difference to patients.


Enrollment: 787
Study Start Date: December 2009
Estimated Study Completion Date: July 2020
Primary Completion Date: July 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: obinutuzumab + chlorambucil (GClb)
Participants received 1000 mg obinutuzumab intravenous (IV) infusion, on Days 1 [first infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 in Cycle 1 and Day 1 in Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 Cycles).
Drug: obinutuzumab
1000 mg obinutuzumab intravenous (IV) infusion, on Days 1 [first infusion split 100 mg on Day 1 and 900 mg on Day 2 as per protocol amendment], 8 and 15 in Cycle 1 and Day 1 in Cycles 2-6 (28-day cycles).
Other Names:
  • RO5072759
  • GA101
  • GAZYVA®
Drug: chlorambucil
Chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle.
Active Comparator: rituximab + chlorambucil (RClb)
Participants received 375 mg/m^2 rituximab IV infusion on Day 1 of Cycle 1 then 500 mg/m^2 IV infusions on Day 1 of Cycles 2-6 (28-day cycles) plus chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 cycles).
Drug: rituximab
375 mg/m^2 rituximab intravenous (IV) infusion on Day 1 of Cycle 1 (Cycle duration is 28 days) then 500 mg/m^2 IV infusions on Day 1 of Cycles 2-6.
Other Names:
  • Rituxan®
  • MabThera®
Drug: chlorambucil
Chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle.
Active Comparator: Chlorambucil (Clb)
Participants received chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle (6 Cycles). Participants with Progressive Disease or within 6 months of follow-up were allowed to cross over to receive obinutuzumab + chlorambucil.
Drug: chlorambucil
Chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle.

Detailed Description:

Protocol BO21004 is divided into 3 separate Unique Protocol IDs for reporting results on clinicaltrials.gov because there are 3 separate primary analyses conducted at different time-points.

  • BO21004 (Stage 1a) [NCT01010061] includes the analysis of 2 of the 3 arms obinutuzumab plus chlorambucil (Glb) compared to chlorambucil (Clb) reported here.
  • BO21004 (Stage 1b) [NCT01998880] includes the analysis of 2 of the 3 arms rituximab plus chlorambucil (RClb) compared to chlorambucil (Clb) reported separately.
  • BO21004 (Stage 2) [NCT02053610] includes the analysis of 2 of the 3 arms obinutuzumab plus chlorambucil (Glb) compared to rituximab plus chlorambucil (RClb) reported separately.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adults >/=18 years
  • Documented Cluster of Differentiation Antigen 20 (CD20) + B-Cell Chronic Lymphocytic Lymphoma (B-CLL)
  • Previously untreated Chronic Lymphocytic Leukemia (CLL) requiring treatment according to the National Cancer Institute (NCI) criteria
  • Total Cumulative Illness Rating Scale (CIRS) > 6 and/or creatinine clearance < 70 ml/min

Exclusion Criteria:

  • Prior CLL therapy
  • Transformation of CLL to aggressive Non-Hodgkin's Lymphoma (NHL) (Richter's transformation)
  • History of other malignancy unless the malignancy has been in remission without treatment for >/=2 years prior to enrolment, and except for carcinoma in situ of the cervix, basal or squamous cell skin cancer, surgically treated low-grade prostate cancer, or ductal carcinoma in situ (DCIS) of the breast treated with lymphectomy alone
  • Positive hepatitis serology (HBV, HCV) or positive HIV or Human T Cell Leukemia Virus (HTLV) testing
  • Patients with active infection requiring systemic treatment
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01010061

  Show 262 Study Locations
Sponsors and Collaborators
Hoffmann-La Roche
German CLL Study Group
Genentech
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

No publications provided by Hoffmann-La Roche

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01010061     History of Changes
Obsolete Identifiers: NCT02035462
Other Study ID Numbers: BO21004 (Stage 1a), 2009-012476-28; CLL11
Study First Received: November 6, 2009
Results First Received: December 2, 2013
Last Updated: February 14, 2014
Health Authority: United States: Food and Drug Administration
Australia: National Health and Medical Research Council
Austria: Austrian Agency for Health and Food Safety
Bulgaria: Bulgarian Drug Agency
Croatia: Agency for medicinal products and medical devices of Croatia
Czech Republic: State Institute for Drug Control
Denmark: Danish Health and Medicines Authority
Estonia: State Agency of Medicines
France: National Agency for the Safety of Medicine and Health Products
Germany: Federal Institute for Drugs and Medical Devices
Italy: Italian Medicines Agency
Netherlands: Medicines Evaluation Board
Romania: National Medicines Agency
Slovakia: State Institute for Drug Control
Spain: Spanish Agency for Medicines and Health Products
Switzerland: Swissmedic
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Argentina: Administración Nacional de Medicamentos, Alimentos y Tecnología Médica , ANMAT (National Administration of Drugs, Food & Medical Technology)
Brazil: Agência Nacional de Vigilância Sanitária, ANVISA (National Health Surveillance Agency)
Canada: Health Canada
Egypt: Egyptian Drug Authority (EDA)
Hong Kong: Department of Health Drug Office
Mexico: Comisión Federal para la Protección contra Riesgos Sanitarios, COFEPRIS (The Federal Commission for the Protection against Sanitary Risk)
New Zealand: Medsafe
Russian Federation: The Federal Service for Surveillance in Healthcare and Social Development
Thailand: Food and Drug Administration, Thailand

Additional relevant MeSH terms:
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Rituximab
Obinutuzumab
Chlorambucil
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 18, 2014