An Open-Label, Single Arm Study of Obinutuzumab Short Duration Infusion in Patients With Previously Untreated Advanced Follicular Lymphoma

Study Overview
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Brief Summary
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This open-label, single arm study will evaluate the safety of obinutuzumab administered as a short duration infusion (SDI; target 90-minute infusion) during cycle 2 and from cycle 2 onwards in combination with chemotherapy in participants with previously untreated advanced follicular lymphoma (FL). The study has two phases: in the first phase, participants will receive the first cycle of obinutuzumab-based chemotherapy (G-chemo) induction therapy as usual with the first three infusions of obinutuzumab (1000 mg) administered at the regular infusion rate on Day 1, 8, and 15 of cycle 1. Phase 2 starts when participants who do not experience any Grade ≥ 3 infusion related reactions during the first cycle receive their first obintuzumab infusion given at the faster infusion rate in Cycle 2. For Cycle 2, Day 1 and all other following infusions (including maintenance), obinutuzumab will be administered at a faster infusion of 90-minute SDI, as long as the participant does not experience any Grade ≥ 3 infusion related reactions. The investigator is free to choose the chemotherapy for each participant (bendamustine, CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone/prednisolone/methylprednisolone], or CVP [cyclophosphamide, vincristine, and prednisone/prednisolone/methylprednisolone]). The total number of cycles of G-chemo induction therapy and the cycles length depends on the chemotherapy chosen for each participant.

Official Title
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A Multicentric, Open-Label, Single Arm Study of Obinutuzumab Short Duration Infusion (SDI) in Patients With Previously Untreated Advanced Follicular Lymphoma

Conditions
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Advanced Follicular Lymphoma

Intervention / Treatment
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* Drug: Obinutuzumab
* Drug: Bendamustine
* Drug: Cyclophosphamide
* Drug: Doxorubicin
* Drug: Prednisone/Prednisolone/Methylprednisolone
* Drug: Vincristine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with previously untreated Stage III or IV FL or Stage II bulky disease scheduled to receive obinutuzumab plus chemotherapy due to at least one of the following criteria: a.) Bulky disease, defined as a nodal or extranodal (except spleen) mass ≥ 7 cm in the greatest diameter b.) Local symptoms or compromise of normal organ function due to progressive nodal disease or extranodal tumor mass c.) Presence of B symptoms (fever [> 38ºC], drenching night sweats, or unintentional weight loss of > 10% of normal body weight over a period of 6 months or less) d.) Presence of symptomatic extranodal disease (e.g., pleural effusions, peritoneal ascites) e.) Cytopenias due to underlying lymphoma (i.e., absolute neutrophil count < 1.0 × 109/L, hemoglobin < 10 g/dL, and/or platelet count < 100 × 109/L) f.) Involvement of ≥ 3 nodal sites, each with a diameter of ≥ 3 cm g.) Symptomatic splenic enlargement Histologically documented CD-20-positive FL, as determined by the local laboratory Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Adequate hematologic function (unless abnormalities are related to FL) Life expectancy of ≥ 12 months For women who are not postmenopausal (≥ 12 consecutive months of non-therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 18 months after the last dose of obinutuzumab, for at least 3 months after the last dose of bendamustine or according to institutional guidelines for CHOP or CVP chemotherapy, whichever is longer For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm Exclusion Criteria: Relapsed / refractory FL Prior treatment for FL with chemotherapy, radiotherapy, or immunotherapy Grade IIIb FL Histological evidence of transformation of FL into high-grade B-cell NHL Treatment with systemic immunosuppressive medications, including, but not limited to, prednisone/prednisolone/methylprednisolone (at a dose equivalent to >30 mg/day prednisone), azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents within 2 weeks prior to Day 1 of Cycle 1 History of solid organ transplantation History of anti-CD20 antibody therapy History of severe allergic or anaphylactic reaction to humanized, chimeric, or murine monoclonal antibodies Known sensitivity or allergy to murine products Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or any of the study drugs Active bacterial, viral, fungal, or other infection or any major episode of infection requiring treatment with IV antibiotics within 4 weeks of Day 1 of Cycle 1 Positive test results for chronic HBV infection (defined as positive HBsAg serology) Positive test results for hepatitis C (hepatitis C virus [HCV] antibody serology testing) Known history of HIV positive status History of progressive multifocal leukoencephalopathy (PML) Vaccination with a live virus vaccine within 28 days prior to Day 1 of Cycle 1 or anticipation that such a live, attenuated vaccine will be required during the study History of prior other malignancy with the exception of: a. Curatively treated carcinoma in situ of the cervix, good-prognosis ductal carcinoma in situ of the breast, basal- or squamous-cell skin cancer, Stage I melanoma, or low-grade, early-stage localized prostate cancer b. Any previously treated malignancy that has been in remission without treatment for ≥ 2 years prior to enrollment Evidence of any significant, uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, myocardial infarction within the previous 6 months, unstable arrhythmia, or unstable angina) or significant pulmonary disease (such as obstructive pulmonary disease or history of bronchospasm) Major surgical procedure other than for diagnosis within 28 days prior to Day 1 of Cycle 1, Day 1, or anticipation of a major surgical procedure during the course of the study Any of the following abnormal laboratory values: Creatinine > 1.5 × the upper limit of normal (ULN) (unless creatinine clearance normal) or creatinine clearance < 40 mL/min Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × ULN Total bilirubin ≥ 1.5 × the ULN: Patients with documented Gilbert disease may be enrolled if total bilirubin is ≤ 3.0 × the ULN. International normalized ratio (INR) > 1.5 in the absence of therapeutic anticoagulation Partial thromboplastin time or activated partial thromboplastin time > 1.5 × ULN in the absence of a lupus anticoagulant For patients who will be receiving CHOP: left ventricular ejection fraction (LVEF) < 50% by multigated acquisition (MUGA) scan or echocardiogram Pregnant or lactating, or intending to become pregnant during the study Any investigational therapy within 28 days prior to the start of Cycle 1 Positive test results for human T-lymphotropic virus 1 (HTLV-1)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Obinutuzumab+Chemotherapy<br>Participants received 6-8 cycles of obinutuzumab, combined with 6 or 8 cycles of standard chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone/prednisolone/methylprednisolone [CHOP - 21-day cycle) or bendamustine (28-day cycle), or cyclophosphamide, vincristine, and prednisone/prednisolone/methylprednisolone [CVP - 21-day cycle]). Participants received an additional two doses of obinutuzumab on Days 8 and 15 of Cycle 1. The investigator is free to choose the chemotherapy for each patient. Obinutuzumab and chemotherapy is administered during induction phase and obinutuzumab monotherapy is administered during maintenance phase. | Drug: Obinutuzumab<br>* Obinutuzumab 1000 mg IV infusion, administered on Day 1, 8 and 15 during Cycle 1, and on Day 1 of subsequent cycles, for 6-8 cycles. Each cycle is 21 or 28 days long depending on the chemotherapy regimen allocated. Maintenance obinutuzumab monotherapy in patients who achieve at least a partial response, after induction therapy will be administered a dose of 1000 mg once every 8 weeks for 2 years or until disease progression (whichever occurs first).<br>* Other names: GA101, RO5072759;Drug: Bendamustine<br>* Bendamustine will be administered on Days 1 and 2 for Cycles 1-6 at a dose of 90 mg/m2/day, for six 28-day cycles.<br>Drug: Cyclophosphamide<br>* Cyclophosphamide 750 milligrams per square metre (mg/m^2), administered intravenously (IV) on Day 1 of each 21-day cycle, for six cycles for CHOP treatment or eight cycles for CVP treatment.<br>Drug: Doxorubicin<br>* Doxorubicin 50 mg/m^2 IV, administered on Day 1 of each 21-day cycle, for six cycles.<br>Drug: Prednisone/Prednisolone/Methylprednisolone<br>* Prednisone 100 mg (or equivalent prednisolone or methylprednisolone), administered orally on Days 1-5 of each 21-day cycle, for six cycles for CHOP treatment or eight cycles for CVP treatment.<br>Drug: Vincristine<br>* Vincristine 1.4 mg/m^2 (maximum 2 mg) IV, administered on Day 1 of each 21-day cycle, for six cycles for CHOP treatment or eight cycles for CVP treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Grade >=3 Infusion-Related Reactions (IRRs) During Cycle 2 in Patients Who Had Previously Received Obinutuzumab at the Standard Infusion Rate During Cycle 1 Without Experiencing a Grade 3 or 4 IRR | IRRs were defined as all adverse events (AEs) that occurred during or within 24 hours from the end of study treatment infusion and were judged as related to infusion of study treatment components by the investigator. | Within 24 hours from the end of study treatment infusion of Day 1 in Cycle 2 (1 cycle: 21 or 28 days depending on the chemotherapy selected) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Adverse Events (AEs) | An AE was defined as any untoward medical occurrence in a clinical investigation participant who was administered a pharmaceutical product, regardless of causal attribution. An AE was therefore any unfavourable 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. Pre-existing conditions which worsened during the study, recurrence of an intermittent medical condition, deterioration in a laboratory value or other clinical test or were related to a protocol-mandated intervention were also considered AEs. Grading was completed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0. | Baseline up to clinical cut off date (up to approximately 1.5 years) | 
| Percentage of IRRs Regardless of Grade by Cycle | IRRs were defined as all adverse events (AEs) that occurred during or within 24 hours from the end of study treatment infusion and were judged as related to infusion of study treatment components by the investigator. | Within 24 hours from the end of study treatment infusion in all cycles, including maintenance ((1 cycle: 21 or 28 days depending on the chemotherapy selected); up to approximately 2.5 years) | 
| Time to IRR From Infusion to Onset of the IRR During Cycle 2 | Time to IRR (of any grade) in Cycle 2 was defined as the time from the start of infusion (i.e., start date/time of infusion of the first component of study treatment) in Cycle 2 to the onset of the IRR (of any grade) during Cycle 2. | From infusion to onset of IRR during Cycle 2 (1 cycle: 21 or 28 days depending on the chemotherapy selected) | 
| Duration (In Minutes) of Obinutuzumab Administration by Cycle | The duration of obinutuzumab administration (in minutes) by cycle was defined as the difference between the end time and the start time of obinutuzumab administration. | All cycles including maintenance (1 cycle: 21 or 28 days depending on the chemotherapy selected; up to approximately 2.5 years) | 
| Type of Grade >=3 IRRs Associated With the Obinutuzumab Administered as an SDI by Cycle |  | All cycles including maintenance (1 cycle: 21 or 28 days depending on the chemotherapy selected; up to approximately 2.5 years) | 
| Duration of Grade >=3 IRRs Associated With the Obinutuzumab Administered as an SDI by Cycle | The duration, in minutes, of IRRs during all cycles, where obinutuzumab was administered as an SDI. | All cycles including maintenance (1 cycle: 21 or 28 days depending on the chemotherapy selected; up to approximately 2.5 years) | 
| Objective Response Rate (ORR) at the End of Induction (EOI) Therapy | ORR at EOI therapy was defined as the percentage of particpants with either a CR, CR unconfirmed or PR at the EOI visit, as determined by the investigator and according to the guidelines used at the site. | Baseline up to end of induction therapy (up to approximately 6 months) | 
| Progression-Free Survival (PFS) Rate at the End of the Study | PFS was defined as the time from start of treatment to the first occurrence of disease progression as assessed by the investigator according to the guidelines used at the site or death from any cause. | Baseline up to end of study (up to approximately 4 years) | 
| Overall Survival (OS) at the End of the Study | OS was defined as the time from start of treatment (date of first intake of any study treatment component) to death from any cause. | Baseline up to end of study (up to approximately 4 years) | 
| Complete Response (CR) Rate at 30 Months (CR30), as Assessed by the Investigator and According to the Guidelines Used at the Site | The CR30 rate was defined as the percentage of participants with a CR at 30 months from study treatment initiation (date of first intake of any study treatment component), as determined by the investigator according to the guidelines used at the site. | Baseline up to 30 months |