A Study of Obinutuzumab [RO5072759 (GA101)] in Combination With CHOP Chemotherapy in Patients With Previously Untreated Advanced Diffuse Large B-Cell Lymphoma (GATHER)

A Phase II, Open-Label, Multicenter Study of Efficacy, Safety, and Biomarkers in Patients With Previously Untreated Advanced Diffuse Large B-Cell Lymphoma Treated With GA101 (RO5072759) in Combination With CHOP Chemotherapy

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01414855

Enrollment

100

Registered

2011-08-11

Start date

2011-08-31

Completion date

2016-12-23

Last updated

2018-04-25

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Lymphoma, B-Cell

Brief summary

This open-label, multicenter study will evaluate the efficacy and safety of obinutuzumab \[RO5072759 (GA101)\] in combination with CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone) chemotherapy in patients with advanced diffuse large B-cell lymphoma. Patients will receive 8 cycles of obinutuzumab (1000 mg intravenously on Day 1 of each 21-day cycle, during Cycle 1 obinutuzumab will also be infused on Days 8 and 15) in combination with CHOP chemotherapy on Day 1 of cycles 1 to 6. A substudy will investigate the drug-drug interaction of obinutuzumab with CHOP chemotherapy agents. For the substudy, an additional cohort of approximately 15 patients are planned to be enrolled at a subset of investigational sites.

Interventions

DRUGobinutuzumab

1000 mg intravenously on Day 1 of each 21-day cycle, 8 cycles; during Cycle 1 administration also on Days 8 and 15.

DRUGcyclophosphamide

750 mg/m\^2 intravenous (IV), Day 1 of each 21-day cycle, 6 cycles.

DRUGdoxorubicin

50 mg/m\^2 IV, Day 1 of each 21-cycle, 6 cycles.

DRUGprednisone

100 mg/day, Days 1 through 5 of each 21-day cycle, 6 cycles.

DRUGvincristine

1.4 mg/m\^2 IV, Day 1 of each 21-day cycle, 6 cycles.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Adult patients, ≥18 years of age * Previously untreated cluster of differentiation antigen 20 (CD20)-positive diffuse large B-cell lymphoma * Ann Arbour Stage III/IV and bulky II (mass \>10 cm) * At least one bi-dimensionally measurable lesion defined as \>1.5 cm in its largest dimension by CT scan * Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 * Left ventricular ejection fraction ≥50% * Adequate hematologic function

Exclusion criteria

* Transformed lymphoma (follicular IIIB) if previously treated with chemotherapy or immunotherapy * Prior therapy for diffuse large B-cell lymphoma except for nodal biopsy or local irradiation * Central nervous system (CNS) lymphoma, primary mediastinal large cell lymphoma, primary cutaneous lymphoma, primary effusion lymphoma * Patients who received cytotoxic drugs or rituximab as part of their treatment for another condition (e.g. rheumatoid arthritis) or prior use of an anti-CD20 antibody * Chemotherapy or other investigational therapy within 28 days prior to the start of Cycle 1 * Contraindication to any of the individual components of CHOP, including prior receipt of anthracyclines * History of severe allergic or anaphylactic reactions to monoclonal antibody therapy * History of other malignancy, except for curatively treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix, or malignancy treated with or without curative intent and in remission without treatment for ≥2 years prior to enrolment * Positive for hepatitis B, hepatitis C, human immunodeficiency virus (HIV) or human T-cell leukemia virus (HTLV-1) infection * Pregnant or lactating women

Design outcomes

Primary

Measure	Time frame	Description
Complete Response (CR) Rate as Assessed by the Investigator at the End of Treatment	From the first dose of study treatment to end of treatment response assessment (approximately 228 to 258 days)	Complete response rate is defined as the percentage of participants with Complete Response (CR) according to the Revised Response Criteria for Malignant Lymphoma (Cheson et al., 2007). Disease response was evaluated by the investigator using regular clinical and laboratory examinations, fluorodeoxyglucose-positron emission tomography (FDG-PET) and computed tomography (CT). CR is the disappearance of all evidence of disease.
Overall Response Rate (ORR) as Assessed by the Investigator at the End of Treatment	From the first dose of study treatment to end of treatment response assessment (approximately 228 to 258 days)	Overall response rate was defined as the percentage of participants with Complete Response (CR) or Partial Response (PR) according to the Revised Response Criteria for Malignant Lymphoma (Cheson et al., 2007). Disease response was evaluated by the investigator using regular clinical and laboratory examinations, FDG-PET and computed tomography (CT). CR is the disappearance of all evidence of disease. PR is at least 50% regression of measurable disease compared to tumors measured by a baseline scan and no new sites.

Secondary

Measure	Time frame	Description
Progression-Free Survival (PFS) as Assessed by the Investigator	From the first dose of study treatment to PFS assessment (up to 64 months)	PFS was defined as the time from the date of the first dose of study treatment until the date of disease progression, relapse, or death from any cause.
Duration of Response (DOR)	From the response assessment to relapse, progression, or death (up to 64 months)	DOR is defined as first occurrence of documented response (CR or PR) until the first occurrence of relapse or progression or death of any cause. CR: disappearance of all evidence of disease. PR: at least 50% regression of measurable disease compared to tumors measured by a baseline scan and no new sites.
Percentage of Participants With Adverse Events as a Measure of Safety	From the first dose of study treatment to end of study (up to 5 years 4 months)	An adverse event was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug or other protocol-imposed intervention. Preexisting conditions that worsened during the study were reported as adverse events.
Number of Participants With Grade 3 to 4 Infusion-Related (IRR) Adverse Events (AE) in Participants Receiving Shorter Duration Infusion (SDI)	From the first dose of study treatment to end of treatment response assessment (approximately 228 to 258 days)	SDI 120 is a shorter duration infusion of 120 minutes and SDI 90 is shorter duration infusion of 90 minutes. Grade 3 IRR AE: Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae. Grade 4 IRR AE: Life-threatening consequences; urgent intervention indicated.
Pharmacokinetics (PK): Maximum Concentration Observed (Cmax) for Obinutuzumab	Cycle 1 Day 1 pre and post dose, Days 3,5, Day 8 pre and post-dose, Day 15 pre-dose. Cycle 8 Day 1 pre and post-dose, Days 5,8,12	Blood was collected for PK Parameters. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in micrograms per milliliter (μg/mL).
Complete Response (CR) Rate as Assessed by the Independent Review Facility (IRF) at the End of Treatment	From the first dose of study treatment to end of treatment response assessment (approximately 228 to 258 days)	Complete response rate is defined as the percentage of participants with Complete Response (CR) according to the Revised Response Criteria for Malignant Lymphoma (Cheson et al., 2007). Disease response was evaluated by the IRF using CT scans, PET scans and pertinent clinical information. CR is the disappearance of all evidence of disease.
Pharmacokinetics: Clearance (Cl) for Obinutuzumab	Cycle 1 Day 1 pre and post dose, Days 3,5, Day 8 pre and post-dose, Day 15 pre-dose. Cycle 8 Day 1 pre and post-dose, Days 5,8,12	Cl is the volume of serum cleared of the drug per unit of time. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in milliliters/day (mL/day).
Pharmacokinetics: Volume of Distribution (V) for Obinutuzumab	Cycle 1 Day 1 pre and post dose, Days 3,5, Day 8 pre and post-dose, Day 15 pre-dose. Cycle 8 Day 1 pre and post-dose, Days 5,8,12	V is the apparent volume in which a drug is distributed in the body. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in milliliters (mL).
Pharmacokinetics: Area Under the Concentration-Time Curve 7 Day (AUC7day)	Cycle 1 Day 1 pre and post dose, Days 3,5, Day 8 pre and post-dose, Day 15 pre-dose. Cycle 8 Day 1 pre and post-dose, Days 5,8,12	Blood was collected for PK parameters. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in in day times micrograms per milliliter (day\*μg/mL).
Pharmacodynamics: Peripheral Blood CD19-positive B-cell Count	Up to approximately 24 months	—
Pharmacokinetics: Terminal Half-Life (t1/2) for Obinutuzumab	Cycle 1 Day 1 pre and post dose, Days 3,5, Day 8 pre and post-dose, Day 15 pre-dose. Cycle 8 Day 1 pre and post-dose, Days 5,8,12	T1/2 is the time required for the concentration of the drug to reach half of its original value. Blood was collected for PK Parameters. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in days
Overall Response Rate (ORR) as Assessed by the IRF at the End of Treatment	From the first dose of study treatment to end of treatment response assessment (approximately 228 to 258 days)	Overall response rate was defined as the percentage of participants with Complete Response (CR) or Partial Response (PR) according to the Revised Response Criteria for Malignant Lymphoma (Cheson et al., 2007). Disease response was evaluated by the IRF using CT scans, PET scans and pertinent clinical information. CR is the disappearance of all evidence of disease. PR is at least 50% regression of measurable disease compared to tumors measured by a baseline scan and no new sites.

Countries

United States

Participant flow

Participants by arm

Arm	Count
Obinutuzumab + CHOP Participants received 1000 mg obinutuzumab intravenously on Day 1 of each 21-day cycle for 8 cycles; during Cycle 1 administration also on Days 8 and 15. Participants also received standard CHOP therapy for 6 cycles.	100
Total	100

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Death	17
Overall Study	Lost to Follow-up	5
Overall Study	Withdrawal by Subject	7

Baseline characteristics

Characteristic	Obinutuzumab + CHOP
Age, Continuous	57.9 years STANDARD_DEVIATION 14.4
Sex: Female, Male Female	43 Participants
Sex: Female, Male Male	57 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	100 / 100
serious Total, serious adverse events	38 / 100

Outcome results

Primary

Complete Response (CR) Rate as Assessed by the Investigator at the End of Treatment

Complete response rate is defined as the percentage of participants with Complete Response (CR) according to the Revised Response Criteria for Malignant Lymphoma (Cheson et al., 2007). Disease response was evaluated by the investigator using regular clinical and laboratory examinations, fluorodeoxyglucose-positron emission tomography (FDG-PET) and computed tomography (CT). CR is the disappearance of all evidence of disease.

Time frame: From the first dose of study treatment to end of treatment response assessment (approximately 228 to 258 days)

Population: All participants.

Arm	Measure	Value (NUMBER)
Obinutuzumab + CHOP	Complete Response (CR) Rate as Assessed by the Investigator at the End of Treatment	55.0 percentage of participants

Primary

Overall Response Rate (ORR) as Assessed by the Investigator at the End of Treatment

Overall response rate was defined as the percentage of participants with Complete Response (CR) or Partial Response (PR) according to the Revised Response Criteria for Malignant Lymphoma (Cheson et al., 2007). Disease response was evaluated by the investigator using regular clinical and laboratory examinations, FDG-PET and computed tomography (CT). CR is the disappearance of all evidence of disease. PR is at least 50% regression of measurable disease compared to tumors measured by a baseline scan and no new sites.

Time frame: From the first dose of study treatment to end of treatment response assessment (approximately 228 to 258 days)

Population: All participants

Arm	Measure	Value (NUMBER)
Obinutuzumab + CHOP	Overall Response Rate (ORR) as Assessed by the Investigator at the End of Treatment	82.0 percentage of participants

Secondary

Complete Response (CR) Rate as Assessed by the Independent Review Facility (IRF) at the End of Treatment

Complete response rate is defined as the percentage of participants with Complete Response (CR) according to the Revised Response Criteria for Malignant Lymphoma (Cheson et al., 2007). Disease response was evaluated by the IRF using CT scans, PET scans and pertinent clinical information. CR is the disappearance of all evidence of disease.

Time frame: From the first dose of study treatment to end of treatment response assessment (approximately 228 to 258 days)

Population: All participants.

Arm	Measure	Value (NUMBER)
Obinutuzumab + CHOP	Complete Response (CR) Rate as Assessed by the Independent Review Facility (IRF) at the End of Treatment	58.0 percentage of participants

Secondary

Duration of Response (DOR)

DOR is defined as first occurrence of documented response (CR or PR) until the first occurrence of relapse or progression or death of any cause. CR: disappearance of all evidence of disease. PR: at least 50% regression of measurable disease compared to tumors measured by a baseline scan and no new sites.

Time frame: From the response assessment to relapse, progression, or death (up to 64 months)

Population: All participants with data available. Participants who had not progressed, relapsed, or died at the time of analysis were censored for duration of response at the date of the last valid response assessment.

Arm	Measure	Value (MEDIAN)
Obinutuzumab + CHOP	Duration of Response (DOR)	45.6 months

Secondary

Number of Participants With Grade 3 to 4 Infusion-Related (IRR) Adverse Events (AE) in Participants Receiving Shorter Duration Infusion (SDI)

SDI 120 is a shorter duration infusion of 120 minutes and SDI 90 is shorter duration infusion of 90 minutes. Grade 3 IRR AE: Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae. Grade 4 IRR AE: Life-threatening consequences; urgent intervention indicated.

Time frame: From the first dose of study treatment to end of treatment response assessment (approximately 228 to 258 days)

Population: Participants from the Safety population, all randomized participants who received at least 1 dose of study drug, who received shorter duration infusions.

Arm	Measure	Group	Value (NUMBER)
Obinutuzumab + CHOP	Number of Participants With Grade 3 to 4 Infusion-Related (IRR) Adverse Events (AE) in Participants Receiving Shorter Duration Infusion (SDI)	SDI 120 (n=5)	0 participants
Obinutuzumab + CHOP	Number of Participants With Grade 3 to 4 Infusion-Related (IRR) Adverse Events (AE) in Participants Receiving Shorter Duration Infusion (SDI)	SDI 90 (n=70)	0 participants

Secondary

Overall Response Rate (ORR) as Assessed by the IRF at the End of Treatment

Overall response rate was defined as the percentage of participants with Complete Response (CR) or Partial Response (PR) according to the Revised Response Criteria for Malignant Lymphoma (Cheson et al., 2007). Disease response was evaluated by the IRF using CT scans, PET scans and pertinent clinical information. CR is the disappearance of all evidence of disease. PR is at least 50% regression of measurable disease compared to tumors measured by a baseline scan and no new sites.

Time frame: From the first dose of study treatment to end of treatment response assessment (approximately 228 to 258 days)

Population: All participants

Arm	Measure	Value (NUMBER)
Obinutuzumab + CHOP	Overall Response Rate (ORR) as Assessed by the IRF at the End of Treatment	75.0 percentage of participants

Secondary

Percentage of Participants With Adverse Events as a Measure of Safety

An adverse event was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug or other protocol-imposed intervention. Preexisting conditions that worsened during the study were reported as adverse events.

Time frame: From the first dose of study treatment to end of study (up to 5 years 4 months)

Population: Safety population included all randomized participants who received study drug.

Arm	Measure	Value (NUMBER)
Obinutuzumab + CHOP	Percentage of Participants With Adverse Events as a Measure of Safety	100.0 percentage of participants

Secondary

Pharmacodynamics: Peripheral Blood CD19-positive B-cell Count

Time frame: Up to approximately 24 months

Secondary

Pharmacokinetics: Area Under the Concentration-Time Curve 7 Day (AUC7day)

Blood was collected for PK parameters. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in in day times micrograms per milliliter (day\*μg/mL).

Time frame: Cycle 1 Day 1 pre and post dose, Days 3,5, Day 8 pre and post-dose, Day 15 pre-dose. Cycle 8 Day 1 pre and post-dose, Days 5,8,12