MO28543

F. Hoffmann-La Roche AG

Grenzacherstrasse 124, Basel, Switzerland, CH4070

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com

No

No

No

Final

08 Oct 2018

No

Yes

08 Oct 2018

No

To evaluate the safety and tolerability of obinutuzumab alone or in combination with chemotherapy.

All study subjects were required to read and sign an Informed Consent Form.

04 Nov 2013

Yes

Yes

Argentina: 8

Belgium: 18

Brazil: 34

Bosnia and Herzegovina: 7

Canada: 69

Estonia: 10

Finland: 10

France: 137

Germany: 117

Greece: 27

Ireland: 18

Israel: 20

Italy: 81

Korea, Republic of: 9

Latvia: 10

Lithuania: 15

Mexico: 21

Poland: 37

Portugal: 18

Romania: 3

Russian Federation: 35

Serbia: 10

Slovakia: 15

Slovenia: 9

Spain: 67

Sweden: 16

Switzerland: 41

Thailand: 20

Turkey: 75

Macedonia, the former Yugoslav Republic of: 3

Egypt: 12

972

608

0

0

0

0

0

0

434

523

15

Overall Study (overall period)

Not applicable

Obinutuzumab

Concentrate for solution for infusion

Intravenous use

Obinutuzumab was administered by intravenous (i.v.) infusion at a dose of 1000 mg on Day 1/2, 8 and 15 of Cycle 1. From Cycle 2 to Cycle 6, it was administered at the same dose on Day 1 only. A treatment cycle was defined as lasting 28 days.

Bendamustine

Powder for solution for infusion

Intravenous use

Bendamustine: 90 milligram per millilitre square (mg/m^2) I.V. over 60 minutes once daily (QD) Day 1–2 in subjects previously untreated or 70 mg/m^2 I.V. over 60 minutes QD Day 1–2 in subjects with relapsed/refractory disease. In nonfit subjects only, investigators may opt at their own discretion to use lower initial doses of bendamustine, i.e., bendamustine 70 mg/m^2 in previously untreated subjects, and bendamustine 50 mg/m^2 in relapsed/refractory subjects (over 60 minutes qd Day 1–2 for each administration).

Fludarabine

Concentrate for solution for infusion, Powder for oral suspension

Intravenous use, Oral use

Fludarabine 25 mg/m^2 I.V. over 30 minutes QD Day 1–3 or Fludarabine 40 mg/m^2 per os (p.o.) QD Day 1–3 in fit subjects only.

Cyclophosphamide

Concentrate for solution for infusion, Powder for solution for infusion, Powder for oral suspension

Intravenous use, Oral use

Cyclophosphamide 250 mg/m^2 I.V. over 15-30 minutes qd Day 1-3 or Cyclophosphamide 250 mg/m^2 p.o. QD Day 1–3 in fit subjects only.

Chlorambucil

Tablet

Oral use

Chlorambucil 0.5 mg/kg p.o. qd on Day 1 and Day 15 in non-fit subjects only.

Obinutuzumab

G mono: Previously Untreated Fit

Participants with obinutuzumab monotherapy who were previously untreated fit. Fit participants were defined as having a total Cumulative Illness Rating Scale (CIRS) score ≤6 and creatinine clearance (CrCl) ≥70 mL/min.

G mono: Previously Untreated Unfit

Participants with obinutuzumab monotherapy who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.

G mono: Relapsed/refractory

Participants with obinutuzumab monotherapy who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).

G-Benda: Previously Untreated Fit

Participants with obinutuzumab in combination with bendamustine who were previously untreated fit. Fit participants were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.

G-Benda: Previously Untreated Unfit

Participants with obinutuzumab in combination with bendamustine who were previously untreated unfit. Non fit Participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.

G-Benda: Relapsed/refractory

Participants with obinutuzumab in combination with bendamustine who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).

G-FC: Previously Untreated Fit

Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who were previously untreated fit. Fit subjects were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.

G-FC: Previously Untreated Unfit

Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min. This is a Protocol deviation: unfit subjects were incorrectly assigned to the G-FC treatment regimen.

G-FC: Relapsed/refractory

Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who had documented relapsed/refractory chronic lymphocytic leukemia (CLL). This is a Protocol deviation: 5 unfit subjects were incorrectly assigned to this relapsed/refractory G-FC treatment regimen.

G-Clb: Previously Untreated Fit

Participants with obinutuzumab in combination with chlorambucil who were previously untreated fit. Fit participants were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.

G-Clb: Previously Untreated Unfit

Participants with obinutuzumab in combination with chlorambucil who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.

G-Clb: Relapsed/refractory

Participants with obinutuzumab in combination with chlorambucil who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).

Obinutuzumab

G mono: Previously Untreated Fit

Participants with obinutuzumab monotherapy who were previously untreated fit. Fit participants were defined as having a total Cumulative Illness Rating Scale (CIRS) score ≤6 and creatinine clearance (CrCl) ≥70 mL/min.

G mono: Previously Untreated Unfit

Participants with obinutuzumab monotherapy who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.

G mono: Relapsed/refractory

Participants with obinutuzumab monotherapy who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).

G-Benda: Previously Untreated Fit

Participants with obinutuzumab in combination with bendamustine who were previously untreated fit. Fit participants were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.

G-Benda: Previously Untreated Unfit

Participants with obinutuzumab in combination with bendamustine who were previously untreated unfit. Non fit Participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.

G-Benda: Relapsed/refractory

Participants with obinutuzumab in combination with bendamustine who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).

G-FC: Previously Untreated Fit

Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who were previously untreated fit. Fit subjects were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.

G-FC: Previously Untreated Unfit

Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min. This is a Protocol deviation: unfit subjects were incorrectly assigned to the G-FC treatment regimen.

G-FC: Relapsed/refractory

Participants with obinutuzumab in combination with fludarabine and cyclophosphamide who had documented relapsed/refractory chronic lymphocytic leukemia (CLL). This is a Protocol deviation: 5 unfit subjects were incorrectly assigned to this relapsed/refractory G-FC treatment regimen.

G-Clb: Previously Untreated Fit

Participants with obinutuzumab in combination with chlorambucil who were previously untreated fit. Fit participants were defined as having a total CIRS score <=6 and CrCl >=70 mL/min.

G-Clb: Previously Untreated Unfit

Participants with obinutuzumab in combination with chlorambucil who were previously untreated unfit. Non fit participants were defined as having a CIRS score >6 and/or CrCl <70 mL/min.

G-Clb: Relapsed/refractory

Participants with obinutuzumab in combination with chlorambucil who had documented relapsed/refractory chronic lymphocytic leukemia (CLL).

An adverse event 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 adverse event 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 adverse events. AEs, including AEs of Special Interest and AEs of Particular Interest, were reported based on the national cancer institute common terminology criteria for AEs, Version 4.0 (NCI-CTCAE, v4.0). Reported are the number of subjects with AEs, Grade 3-5 AEs, and Serious Adverse Events (SAEs). The safety population was defined as all subjects who have received at least one dose of study medication.

Primary

Baseline up to time of primary completion (3 years)

The following AEs were defined as AESIs: AEs with the preferred term Tumour Lysis Syndrome (TLS), Infusion-Related Reactions (IRRs) defined as AEs that occurred during or within 24 hours of the completion of obinutuzumab infusion and were assessed as related to obinutuzumab by the Investigator, Infections defined as AEs from System Organ Class (SOC) “Infections and infestations” and AEs with the preferred term Neutropenia. Reported are number of participants with total AESIs, IRRs, Infections, Neutropenia and TLS. The safety population was defined as all subjects who have received at least one dose of study medication.

Primary

Baseline up to time of primary completion (3 years)

The following AEs were defined as AEPIs: AEs with the preferred term Progressive multifocal leukoencephalopathy, hepatitis B reactivation defined as AEs with preferred term containing “Hepatitis B” or “hepatitis acute", thrombocytopenia defined via Roche MedDRA basket subgroup “haematopoietic thrombocytopenia”, second malignancies defined as AEs from the SOC “Neoplasms benign, malignant and unspecified” starting 6 months after the first study drug intake, second malignancies based on standardised MedDRA queries (SMQ) starting 6 months after the first study drug intake based on the MedDRA SMQ “Malignant or unspecified tumours”, in which benign neoplasms are not included, Cardiac events including AEs from the SOC “Cardiac disorders”, and hemorrhagic events defined via Roche MedDRA basket subgroup “Haemorrhagic events”. The safety population was defined as all subjects who have received at least one dose of study medication.

Primary

Baseline up to time of primary completion (3 years)

OR: percentage of participants with complete response (CR) or CR with incomplete marrow recovery (CRi), or partial response (PR), determined by investigator based on International Workshop on Chronic Lymphocytic Leukemia (IWCLL) tumor response criteria. CR: Peripheral blood lymphocytes 4,000/mcL, no significant lymphadenopathy, no hepatomegaly and splenomegaly, no disease symptoms, blood counts: neutrophils >1,500/mcL, platelets > 100,000/mcL, hemoglobin > 110 g/L and bone marrow normocellular for age. Cri: CR with persistent cytopenia. PR: >/= 50% decrease in peripheral blood lymphocyte count AND >/= 50% reduction in lymphadenopathy OR >/= 50% reduction of liver enlargement OR >/= 50% reduction of spleen PLUS one of the following: neutrophils >1,500/mcL, platelets > 100,000/mcL, Hb > 110 g/L OR >/= 50% increase in neutrophils, platelets or Hb. ITT population was defined as all subjects enrolled in the study regardless of whether or not they received any study drug.

Secondary

3 months after the last dose of study treatment (up to approximately 5 years)

MRD-negativity was defined as the presence of less than 1 chronic lymphocytic leukemia (CLL) cell per 10,000 leukocytes in blood and bone marrow as assessed by flow cytometry 3 months after last dose of study treatment (i.e. at final response assessment [FRA] visit). The intent-to-ship (ITS) population included all participants from the ITT population whose MRD samples at the FRA could be shipped to the central laboratory within 48 hours. MRD ITS population was a part of the intent-to-treat population. Number of subjects analyzed indicates subjects who took part in the analysis. 9999 = Not estimable.

Secondary

3 months after the last dose of study treatment (up to approximately 5 years)

BOR was defined as percentage of participants with best response obtained throughout the trial with CR, CRi, or PR, as determined by the investigator based on IWCLL tumor response criteria. CR: Peripheral blood lymphocytes 4,000/mcL, no significant lymphadenopathy, no hepatomegaly and splenomegaly, no disease symptoms, blood counts: neutrophils >1,500/mcL, platelets > 100,000/mcL, hemoglobin > 110 g/L and bone marrow normocellular for age. Cri: CR with persistent cytopenia. PR: >/= 50% decrease in peripheral blood lymphocyte count AND >/= 50% reduction in lymphadenopathy OR >/= 50% reduction of liver enlargement OR >/= 50% reduction of spleen PLUS one of the following: neutrophils >1,500/mcL, platelets > 100,000/mcL, Hb > 110 g/L OR >/= 50% increase in neutrophils, platelets or Hb. ITT population was defined as all subjects enrolled in the study regardless of whether or not they received any study drug. Number of subjects analysed indicates subjects who took part in the analysis.

Secondary

Baseline, Day 85, end of treatment or early termination, and follow-up, assessed up to disease progression or death, whichever occurs first (up to approximately 5 years)

PFS was defined as time from the date of enrollment until the first documented progressive disease(PD) based on IWCLL tumor response criteria or death from any cause, whichever occurred first. PD: at least one of the following: >/= 50% increase in the absolute number of circulating lymphocytes to at least 5,000/mcL, appearance of new palpable lymph nodes, >/= 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 more aggressive histology, progression of any cytopenia, decrease of Hb levels by > 20 g/L or to less than 100 g/L, decrease of platelet counts by > 50% or to < 100,000 /mcL, decrease of neutrophil counts by > 50% or to < 1,000/mcL. The ITT population was defined as all subjects enrolled in the study regardless of whether or not they received any study drug. 0000/9999 = Not estimable.

Secondary

Baseline, Day 85, end of treatment or early termination, and follow-up, assessed up to disease progression or death, whichever occurs first (up to approximately 5 years)

Kaplan Meier estimate of median TTR was defined as the time at which half of the participants reached CR or PR based on IWCLL tumor response criteria. CR: Peripheral blood lymphocytes 4,000/mcL, no significant lymphadenopathy, no hepatomegaly and splenomegaly, no disease symptoms, blood counts: neutrophils >1,500/mcL, platelets > 100,000/mcL, hemoglobin > 110 g/L and bone marrow normocellular for age. PR: >/= 50% decrease in peripheral blood lymphocyte count AND >/= 50% reduction in lymphadenopathy OR >/= 50% reduction of liver enlargement OR >/= 50% reduction of spleen PLUS one of the following: neutrophils >1,500/mcL, platelets > 100,000/mcL, hemoglobin > 110 g/L OR >/= 50% increase in neutrophils, platelets or hemoglobin. 0000/9999 = Not estimable. The ITT population was defined as all subjects enrolled in the study regardless of whether or not they received any study drug.

Secondary

Baseline, Day 85, end of treatment or early termination, and follow-up, assessed up to disease progression or death, whichever occurs first (up to approximately 5 years)

EFS: time from enrollment to first event of PD or relapse, as assessed by the investigator based on IWCLL criteria, or start of a non-protocol-specified anti-leukemia therapy or death, whichever occurs first. PD: at least one of the following: >/= 50% increase in the absolute number of circulating lymphocytes to at least 5,000/mcL, appearance of new palpable lymph nodes, >/= 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 more aggressive histology, progression of any cytopenia, decrease of Hb levels by more than 20 g/L or to less than 100 g/L, decrease of platelet counts by more than 50% or to < 100,000 /mcL, decrease of neutrophil counts by > 50% or to < 1,000/mcL. 0000/9999 = Not estimable. ITT population was defined as all subjects enrolled in the study regardless of whether or not they received any study drug.

Secondary

Baseline, Day 85, end of treatment or early termination, and follow-up, assessed up to disease progression or death, whichever occurs first (up to approximately 5 years)

Kaplan Meier estimate of median OS was defined as the time at which half of the participants had died, regardless of the cause of death. 9999 = Not estimable. The ITT population was defined as all subjects enrolled in the study regardless of whether or not they received any study drug.

Secondary

Baseline until death (Approximately up to 5 years)

Kaplan Meier estimate of median TTNT was defined as the time at which half of the participants have initiated a new anti-leukemic therapy. 9999 = Not estimable. The ITT population was defined as all subjects enrolled in the study regardless of whether or not they received any study drug.

Secondary

Baseline until end of study (up to approximately 5 years)

DoR was defined as the period from the date of initial confirmed PR or CR until the date of PD or death from any cause. PR: >/= 50% decrease in peripheral blood lymphocyte count AND >/= 50% reduction in lymphadenopathy OR >/= 50% reduction of liver enlargement OR >/= 50% reduction of spleen PLUS one of the following: neutrophils >1,500/mcL, platelets > 100,000/mcL, hemoglobin > 110 g/L OR >/= 50% increase in neutrophils, platelets or hemoglobin. CR: Peripheral blood lymphocytes 4,000/mcL, no significant lymphadenopathy, no hepatomegaly and splenomegaly, no disease symptoms, blood counts: neutrophils >1,500/mcL, platelets > 100,000/mcL, hemoglobin > 110 g/L and bone marrow normocellular for age. PD: as defined in the description for Event-Free Survival outcome measure. 0000/9999 = Not estimable. The ITT population was defined as all subjects enrolled in the study regardless of whether or not they received any study drug.

Secondary

Baseline, Day 85, end of treatment or early termination, and follow-up, assessed up to disease progression or death, whichever occurs first (up to approximately 5 years)

Up to 5 years

The safety population was defined as all participants who received at least one dose of study medication. AEs that were entered into the data base at the time of the data base lock were included in the AE analysis.

21.1

G-Mono

G-FC

G-Clb

G-Benda