E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Follicular lymphoma (FL) is one of the most common common B cell-indolent non-Hodgkin's lymphomas (NHL) [type of blood cell cancer of the immune system] |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10016903 |
E.1.2 | Term | Follicle centre lymphomas, follicular grade I, II, III |
E.1.2 | System Organ Class | 100000004851 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061170 |
E.1.2 | Term | Follicle centre lymphoma, follicular grade I, II, III |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the safety of obinutuzumab administered as a short duration infusion (SDI) during cycle 2 and in patients with previously untreated advanced FL on the basis of the incidence of Grade >=3 infusion-related reactions (IRRs) during cycle 2 in patients who had previously received obinutuzumab at the standard infusion rate without experiencing a Grade 3 or 4 IRR |
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety and efficacy of obinutuzumab administered as an SDI from cycle 2 in patients with previously untreated advanced FL on the basis of objective response rate and complete response rate, progression-free survival rate and overall survival, as determined by the investigator. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age >= 18 years
- Able and willing to comply with all study related procedures including completion of patient-reported outcome endpoints
- Ability to comply with the study protocol, in the investigator's judgment
- Patients with previously untreated Stage III or IV FL or Stage II bulky disease scheduled to receive obinutuzumab and chemotherapy due to at least one of the following criteria:
o Bulky disease
o Local symptoms or compromise of normal organ function due to progressive nodal disease or extranodal tumor mass
o Presence of B symptoms
o Presence of symptomatic extra nodal disease
o Cytopenias due to underlying lymphoma
o Involvement of >= 3 nodal sites, each with a diameter of >= 3 cm
o Symptomatic splenic enlargement
- Histologically documented CD-20-positive FL, as determined by the local laboratory
- Eastern Cooperative Oncology Group performance status 0−2
- Adequate hematologic function
- Life expectancy of >= 12 months
- For women who are not postmenopausal or surgically sterile: agreement to remain abstinent 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 cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or cyclophosphamide, vincristine, and prednisone chemotherapy, whichever is longer
- For men: agreement to remain abstinent or use contraceptive measures and agreement to refrain from donating sperm, with female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for at least 3 months after the last dose of study treatment |
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E.4 | Principal exclusion criteria |
- Relapsed / refractory FL
- Prior treatment for FL with chemotherapy 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 and 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, hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or any of the study drugs and history of HIV positive status
- 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, hepatitis C
- History of progressive multifocal leukoencephalopathy and prior other malignancy
- 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
- Evidence of any significant, uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease or significant pulmonary disease
- 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
- For patients who will be receiving CHOP: left ventricular ejection fraction < 50% by multigated acquisition scan or echocardiogram
- Any of the following abnormal laboratory values
o Creatinine > 1.5 × the upper limit of normal (ULN) or creatinine clearance < 40 mL/min
o AST or ALT > 2.5 × ULN
o Total bilirubin ≥ 1.5 × the ULN: Patients with documented Gilbert disease may be enrolled if total bilirubin is <= 3.0 × the ULN
o International normalized ratio (INR) > 1.5 in the absence of therapeutic anticoagulation
o Partial thromboplastin time or activated partial thromboplastin time > 1.5 × ULN in the absence of a lupus anticoagulant
- 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), evaluated in endemic Countries
- Development of a Grade >=4 infusion-related reaction (IRR) during Cycle 1
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E.5 End points |
E.5.1 | Primary end point(s) |
1. The incidence of Grade >=3 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, with severity determined according to NCI CTCAE Version 5.0 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Safety
1. Incidence, nature, and severity of all AEs
2. Time to IRR (in hours) from infusion to onset of the IRR during cycle 2
3. Incidence of IRRs regardless of grade by cycle (separately)
4. Duration (in minutes) of obinutuzumab administration by cycle (all cycles including maintenance)
5. Type and duration of Grade >=3 IRRs, during all cycles, where obinutuzumab was administered as an SDI.
Efficacy
6. Objective response rate at the end of induction therapy as determined by the investigator and according to the guidelines used at the site
7. Progression-free survival rate at the end of the study
8. Overall survival at the end of the study
9. Complete response rate at 30 months as assessed by the investigator and according to the guidelines used at the site
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Approximately 2.75 years
2-5. Day 1, 8, 15 of Cycle 1; Day 1 of Cycle 2; Day 1 of Cycle 3-6/8 and Maintenance (every 8 weeks +-10 days)
6-8. Up to 2.75 years
9. At 30 months
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Brazil |
Japan |
United States |
Germany |
Netherlands |
Slovakia |
Spain |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the study is defined as the Last Patient, Last Visit (LPLV) which will occur when all patients have completed 3 months of follow-up for safety, or earlier, if one of the following is documented:
Withdrawal of consent, completed the safety follow-up after discontinuing obinutuzumab for patients in the maintenance or induction phase, Lost to follow-up or death.
In addition, the Sponsor may decide to terminate the study at any time.
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |