CLL11: A Study of Rituximab With Chlorambucil or Chlorambucil Alone in Patients With Previously Untreated Chronic Lymphocytic Leukemia (Stage 1b)

Lymphocytic Leukemia, Chronic Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01998880
• Other study ID #: BO21004 (Stage 1b)
• Secondary ID: 2009-012476-28
• Status: Completed
• Phase: Phase 3
• Start date: December 22, 2009
• Est. completion date: August 23, 2017

Study information

• Verified date: August 2018
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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 (1000mg 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.

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 separately.

• BO21004 (Stage 1b) [NCT01998880] includes the analysis of 2 of the 3 arms rituximab plus chlorambucil (RClb) compared to chlorambucil (Clb) reported here.

• 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 787
• Est. completion date: August 23, 2017
• Est. primary completion date: August 1, 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Lymphocytic Leukemia, Chronic

Intervention

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).
• 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.
• chlorambucil
Chlorambucil 0.5 mg/kg orally on Day 1 and 15 of each 28-day cycle.

Locations

Country	Name	City	State
n/a

Sponsors (3)

Lead Sponsor	Collaborator
Hoffmann-La Roche	Genentech, Inc., German CLL Study Group

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Brazil,  Bulgaria,  Canada,  Croatia,  Czechia,  Denmark,  Egypt,  Estonia,  France,  Germany,  Hong Kong,  Italy,  Mexico,  Netherlands,  New Zealand,  Romania,  Russian Federation,  Slovakia,  Spain,  Switzerland,  Thailand,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free Survival (PFS)	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 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).	Randomization to clinical cutoff (median observation 57.7 months)
Primary	Percentage of Participants With Progression Free Survival Events	Percentage of Participants with Progression Free Survival Events: progression, relapse, or death.	Randomization to clinical cutoff (median observation 57.7 months)
Secondary	Event Free Survival	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 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).	Randomization to clinical cutoff (median observation 57.7 months)
Secondary	Overall Survival	Overall Survival (OS) was defined as the time between the date of randomization and the date of death due to any cause.	Randomization to clinical cutoff (median observation 57.7 months)
Secondary	Percentage of Participants With End of Treatment Response (EOTR)	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.	Randomization to clinical cutoff (median observation 57.7 months)
Secondary	Percentage of Participants With Molecular Remission at the End of Treatment	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 CLL cell in 10000 leukocytes (MRD value < 0.0001) based on the method of allele specific polymerase chain reaction (ASO-PCR).	Randomization to clinical cutoff (median observation 57.7 months)
Secondary	Progression Free Survival Based on Independent Review Committee (IRC) Data	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).	Randomization to clinical cutoff date of 9 May 2013 (median observation 22.7 months)
Secondary	Percentage of Participants With Progression Free Survival Events Based on Independent Review Committee (IRC) Data	Percentage of Participants with Progression Free Survival Events: progression, relapse, or death from any cause as assessed by an Independent Review Committee.	Randomization to clinical cutoff date of 9 May 2013 (median observation 22.7 months)
Secondary	European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire Score	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.	Baseline and Cycle 4 Day 1 (Cy4D1)
Secondary	European Organization for Research and Treatment of Cancer (EORTC) QLQ-CLL16 Questionnaire Score	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.	Baseline and Cycle 4 Day 1 (Cy4D1)
Secondary	Time to Re-Treatment/New-antileukemic Therapy	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.	Randomization to clinical cutoff (median observation 57.7 months)
Secondary	Duration of Response	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.	Randomization to clinical cutoff (median observation 57.7 months)
Secondary	Percentage of Participants With Best Overall Response	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.	Randomization to clinical cutoff (median observation 57.7 months)