A Study Evaluating the Efficacy of Obinutuzumab and Bendamustine Treatment in Participants With Refractory or Relapsed Chronic Lymphocytic Leukemia

Study Overview
=================
Brief Summary
-----------------
This phase II trial was designed to evaluate the efficacy of obinutuzumab and bendamustine treatment in participants with refractory or relapsed chronic lymphocytic leukemia (CLL). Participants receive up to six 28-day cycles of treatment. Treatment consists of intravenous (IV) administration of obinutuzumab and bendamustine. Treatment time is expected to last 6 months, and participant follow-up will last 2 years.

Official Title
-----------------
Phase II Trial to Evaluate The Efficacy of Obinutuzumab (RO5072759) + Bendamustine Treatment in Patients With Refractory Or Relapsed Chronic Lymphocytic Leukemia

Conditions
-----------------
Chronic Lymphocytic Leukemia

Intervention / Treatment
-----------------
* Drug: bendamustine
* Drug: obinutuzumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age 18 years or older Diagnosed CD20+ B- chronic lymphocytic leukemia (CLL) according to National Cancer Institute (NCI) criteria Active disease meeting at least 1 of the International Workshop on CLL (IWCLL) 2008 criteria for treatment Refractory CLL (i.e. treatment failure or progression during treatment or within 6 months after the last treatment) or relapse CLL (i.e. participants who met criteria for CR or PR, but progressed beyond 6 months post-treatment) At least 1 prior purine analogue or bendamustine containing therapy Life expectancy greater than (>) 6 months Use of effective contraception as described in the study protocol Exclusion Criteria: Prior Alogenic Bone Marrow Transplant Greater than or equal to (>/=) 3 previous lines of chemotherapy and/or immunotherapy for the CLL Previous obinutuzumab-containing regimen Treatment failure or progression within 6 months of bendamustine-containing regimen Transformation of CLL to aggressive non-Hodgkin lymphoma (NHL; Richter's transformation) Patients with prolymphocytic transformation cannot entry the study either Active haemolytic anaemia Inadequate liver function History of other malignancy which could affect compliance with the protocol or interpretation of results. Patients with a history of malignancy that has been treated but not with curative intent will be excluded, unless the malignancy has been in remission without treatment for >/= 2 years prior to enrolment. Patients with a history of adequately treated carcinoma in situ of the cervix; basal or squamous cell skin cancer; low grade, early stage localized prostate cancer treated surgically with curative intent; good prognosis ductal carcinoma in situ (DCIS) of the breast treated with lumpectomy alone with curative intent are eligible Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease or pulmonary disease Recent major surgery (within 4 weeks prior to the start of Cycle 1), other than for diagnosis Regular treatment with corticosteroids during the 4 weeks prior to study start, unless administered for another condition at a dose equivalent to less than or equal to (</=) 30 milligrams per day (mg/day) prednisone Known active infection or any infection requiring treatment with IV antibiotics or hospitalization within 4 weeks prior to study start Patients with HIV, human T cell leukemia virus 1 (HTLV-1), hepatitis B or hepatitis C Pregnancy or breast-feeding Vaccination with a live vaccine within 4 weeks prior to baseline visit Receipt of any other study drug within 4 weeks prior to study start

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Obinutuzmab + Bendamustine<br>Participants will receive obinutuzumab and bendamustine in 28-days cycles for a maximum of 6 cycles | Drug: bendamustine<br>* 70 milligrams per square meter (mg/m^2) given by intravenous (IV) infusion on Days 2 and 3 of Cycle 1 and on Days 1 and 2 of subsequent cycles.<br>Drug: obinutuzumab<br>* 1000 mg given by IV infusion on Days 1, 8, and 15 of Cycle 1 and on Day 1 of subsequent cycles.<br>* Other names: RO5072759;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) as Assessed by the Investigator Using the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 Criteria | ORR was defined as percentage of participants achieving Complete Response (CR), incomplete CR (CRi) or Partial Response (PR). CR: lymphocytes below 4 x 10^9/L, absence of lymphadenopathy, hepatomegaly and splenomegaly, absence of disease or constitutional symptoms, neutrophils > 1.5 x 10^9/L, platelets > 100 x 10^9/L, hemoglobin > 110 g/L, bone marrow at least normocellular for age. CRi: CR with persistent cytopenia, i.e. anemia, thrombocytopenia and/or neutropenia. PR: reduction ≥ 50% of the lymphocyte count AND reduction ≥ 50% of the lymphadenopathy OR reduction ≥ 50% of the size of the liver if enlarged at baseline OR reduction ≥ 50% of the size of the spleen if enlarged at baseline PLUS one of the following: neutrophils > 1.5 x 10^9/L, platelets > 100 x 10^9/L, hemoglobin > 110 g/L or increase ≥ 50% compared to pre-treatment. | 2-3 months after last dose of the study treatment (up to approximately 9 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Response Rate as Assessed by the Investigator Using the IWCLL 2008 Criteria | Best overall response was defined as percentage of participants achieving a best response of CR, CRi and PR. CR: lymphocytes below 4 x 10^9/L, absence of lymphadenopathy, hepatomegaly and splenomegaly, absence of disease or constitutional symptoms, neutrophils > 1.5 x 10^9/L, platelets > 100 x 10^9/L, hemoglobin > 110 g/L, bone marrow at least normocellular for age. CRi: CR with persistent cytopenia, i.e. anemia, thrombocytopenia and/or neutropenia. PR: reduction ≥ 50% of the lymphocyte count AND reduction ≥ 50% of the lymphadenopathy OR reduction ≥ 50% of the size of the liver if enlarged at baseline OR reduction ≥ 50% of the size of the spleen if enlarged at baseline PLUS one of the following: neutrophils > 1.5 x 10^9/L, platelets > 100 x 10^9/L, hemoglobin > 110 g/L or increase ≥ 50% compared to pre-treatment. | During study treatment and until 6 months after end of study treatment at approximately 12 months | 
| Progression Free Survival (PFS) | PFS is defined as the time from the start of treatment to disease progression (DP), relapse or death from any cause, whichever occurs first, as assessed by the investigator. DP: at least one of the following characteristics: increase ≥ 50% in lymphocytes up to at least 5 x 10^9/L, appearance of new palpable lymph nodes, increase ≥ 50% of the longest diameter of any previous area of clinically significant lymphadenopathy, increase ≥ 50% of the size of the liver and/or spleen, transformation to a more aggressive histology, after treatment progression of any cytopenia: decrease of hemoglobin levels of more than 20 g/L or to below 100 g/L and/or decrease of platelet counts by more than 50% or to below 100 x 10^9/L and/or decrease in the neutrophil counts by more than 50% or to below 1.0 x 10^9/L if the marrow biopsy also shows infiltration of clonal chronic lymphocytic leukemia (CLL) cells. | From start of treatment up to disease progression or relapse or death, whichever occurred first (up to approximately 4.5 years) | 
| Overall Survival (OS) | OS was defined as the time from the start of study treatment to death from any cause. | From start of treatment up to death of any cause (up to approximately 4.5 years) | 
| Event Free Survival (EFS) | EFS was defined as the time from the start of treatment to DP/relapse, death from any cause or start of a new anti-leukemia therapy. DP: at least one of the following characteristics: increase ≥ 50% in lymphocytes up to at least 5 x 10^9/L, appearance of new palpable lymph nodes, increase ≥ 50% of the longest diameter of any previous area of clinically significant lymphadenopathy, increase ≥ 50% of the size of the liver and/or spleen, transformation to a more aggressive histology, after treatment, progression of any cytopenia: decrease of hemoglobin levels of more than 20 g/L or to below 100 g/L and/or decrease of platelet counts by more than 50% or to below 100 x 10^9/L and/or decrease in the neutrophil counts by more than 50% or to below 1.0 x 10^9/L if the marrow biopsy also shows infiltration of clonal CLL cells. | From start of treatment up to disease progression or relapse or death or start of a new anti-leukemic therapy, whichever occurred first (up to approximately 4.5 years) | 
| Disease Free Survival (DFS) | DFS was defined for all participants who achieved complete response (CRi or CR). DFS lasted from the date on which CRi or CR was recorded until the date on which the first DP or death from any cause occurred. DP: at least one of the following characteristics: increase ≥ 50% in lymphocytes up to at least 5 x 10^9/L, appearance of new palpable lymph nodes, increase ≥ 50% of the longest diameter of any previous area of clinically significant lymphadenopathy, increase ≥ 50% of the size of the liver and/or spleen, transformation to a more aggressive histology, after treatment, progression of any cytopenia: decrease of hemoglobin levels of more than 20 g/L or to below 100 g/L and/or decrease of platelet counts by more than 50% or to below 100 x 10^9/L and/or decrease in the neutrophil counts by more than 50% or to below 1.0 x 10^9/L if the marrow biopsy also shows infiltration of clonal CLL cells. | From occurrence of complete response up to disease progression or death, whichever occurred first (up to approximately 4.5 years) | 
| Duration of Response (DR) | DR was defined for participants with CRi, CR or PR. DR spanned from the date on which response was recorded until the date on which DP or death from any cause occurred. DP: at least one of the following characteristics: increase ≥ 50% in lymphocytes up to at least 5 x 10^9/L, appearance of new palpable lymph nodes, increase ≥ 50% of the longest diameter of any previous area of clinically significant lymphadenopathy, increase ≥ 50% of the size of the liver and/or spleen, transformation to a more aggressive histology, after treatment, progression of any cytopenia: decrease of hemoglobin levels of more than 20 g/L or to below 100 g/L and/or decrease of platelet counts by more than 50% or to below 100 x 10^9/L and/or decrease in the neutrophil counts by more than 50% or to below 1.0 x 10^9/L if the marrow biopsy also shows infiltration of clonal CLL cells. | From occurrence of CR or PR up to disease progression or death, whichever occurred first (up to approximately 4.5 years) | 
| Time to Re-treatment/New Anti-leukemia Therapy | Time to re-treatment/new leukemia therapy was defined as the time between the start of treatment and the date of the first administration of re-treatment or new leukemia therapy. | Up to 4.5 years | 
| Percentage of Participants With Minimal Residual Disease (MRD) Negativity | MRD negativity was defined as the presence of less than 1 cell of CLL per 10,000 leukocytes (= category 0, <0.01%) assessed in bone marrow (BM) and peripheral blood (PB) by flow cytometry after the end of the treatment at the final response assessment. | At approximately 9 months | 
| Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE 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 AEs. An SAE was any AE that was any of the following: fatal, life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/ birth defect, and was considered a significant medical event by the investigator. | Up to approximately 4.5 years | 
| Percentage of Participants With AEs of Special Interest (AESIs) | AESIs included any of the following: SAEs associated with the infusion of obinutuzumab: obinutuzumab serious infusion-related reactions, which were defined as AEs occurring during or within 24 hours following the administration of an infusion of obinutuzumab and considered related to obinutuzumab; serious infection; serious neutropenia; any tumor lysis syndrome (TLS); second malignancies. | Up to approximately 4.5 years | 
| Percentage of Participants With Infusion-related Reactions (IRRs) | IRRs were defined as AEs occurring during or within 24 hours following the administration of an infusion and considered related to drug treatment. | Up to end of treatment at 6 months | 
| Percentage of Participants Who Discontinued Treatment Prematurely |  | Up to end of treatment at 6 months | 
| Percentage of Participants With Previous/Concomitant Diseases |  | Up to approximately 4.5 years | 
| Percentage of Participants With Concomitant Medication | Concomitant therapies included any medication (prescription medication, over-the-counter medications, herbal/homeopathic remedies, nutritional supplements) used by subjects in the 7 days prior to screening until the end of treatment. The following treatments were not permitted during the study treatment period: investigational or unauthorized or unapproved medicinal products, immunotherapy or radioimmunotherapy (other than the trial immunotherapy, obinutuzumab), chemotherapy (other than the trial chemotherapy, bendamustine) and radiotherapy. | From 7 days prior to screening to the end of treatment at 6 months |