CLL11: A Study of Obinutuzumab (RO5072759 [GA101]) With Chlorambucil in Patients With Previously Untreated Chronic Lymphocytic Leukemia (Stage 1a)
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| ClinicalTrials.gov Identifier: NCT01010061 |
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Recruitment Status :
Completed
First Posted : November 9, 2009
Results First Posted : April 1, 2014
Last Update Posted : September 14, 2018
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Sponsor:
Hoffmann-La Roche
Collaborators:
German CLL Study Group
Genentech, Inc.
Information provided by (Responsible Party):
Hoffmann-La Roche
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Brief Summary:
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 or disease | Intervention/treatment | Phase |
|---|---|---|
| Lymphocytic Leukemia, Chronic | Drug: obinutuzumab Drug: rituximab Drug: chlorambucil | Phase 3 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 787 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (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. |
| Actual Study Start Date : | December 21, 2009 |
| Actual Primary Completion Date : | July 1, 2012 |
| Actual Study Completion Date : | August 23, 2017 |
Resource links provided by the National Library of Medicine
| Arm | Intervention/treatment |
|---|---|
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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).
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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:
Drug: chlorambucil Chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle. |
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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).
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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:
Drug: chlorambucil Chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle. |
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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.
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Drug: chlorambucil
Chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle. |
Primary Outcome Measures :
- Progression-free Survival (PFS) [ Time Frame: Randomization to clinical cutoff date of 10 Oct 2017 (median observation 62.5 months from randomization) ]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 date of 10 Oct 2017 (median observation 62.5 months from randomization) ]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 date of 9 May 2013 (median observation 22.8 months) ]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 date of 9 May 2013 (median observation 22.8 months) ]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 date of 10 Oct 2017 (median observation 62.5 months from randomization) ]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 date of 10 Oct 2017 (median observation 62.5 months from randomization) ]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 date of 10 Oct 2017 (median observation 62.5 months from randomization) ]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 date of 10 Oct 2017 (median observation 62.5 months from randomization) ]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 date of 10 Oct 2017 (median observation 62.5 months from randomization) ]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 date of 10 Oct 2017 (median observation 62.5 months from randomization) ]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 date of 10 Oct 2017 (median observation 62.5 months from randomization) ]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) ]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 Score [ Time Frame: Baseline and Cycle 4 Day 1 (Cy4D1) ]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 participants. A positive change from Baseline indicated improvement.
- European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire Score [ Time Frame: Baseline and Cycle 4 Day 1 (Cy4D1) ]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 participants. A positive change from Baseline indicated improvement.
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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:
- 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
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): NCT01010061
Locations
Show 262 study locations
Sponsors and Collaborators
Hoffmann-La Roche
German CLL Study Group
Genentech, Inc.
Investigators
| Study Director: | Clinical Trials | Hoffmann-La Roche |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Hoffmann-La Roche |
| ClinicalTrials.gov Identifier: | NCT01010061 |
| Obsolete Identifiers: | NCT02035462 |
| Other Study ID Numbers: |
BO21004 (Stage 1a) 2009-012476-28; CLL11 |
| First Posted: | November 9, 2009 Key Record Dates |
| Results First Posted: | April 1, 2014 |
| Last Update Posted: | September 14, 2018 |
| Last Verified: | August 2018 |
Additional relevant MeSH terms:
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Leukemia Leukemia, Lymphoid Leukemia, Lymphocytic, Chronic, B-Cell Neoplasms by Histologic Type Neoplasms Hematologic Diseases Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Leukemia, B-Cell Chronic Disease Disease Attributes |
Pathologic Processes Rituximab Obinutuzumab Chlorambucil Antineoplastic Agents, Immunological Antineoplastic Agents Immunologic Factors Physiological Effects of Drugs Antirheumatic Agents Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action |