| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Follicular Lymphoma (FL) or Diffuse Large B-cell Lymphoma (DLBCL) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Lymphoma is a type of cancer of the white blood cells (these cells are part of the body's immune system) |
|
| 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 | LLT |
| E.1.2 | Classification code | 10016904 |
| E.1.2 | Term | Follicle centre lymphoma, follicular grade I, II, III NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 determine the recommended Phase II dose (RP2D) for polatuzumab
vedotin (Pola) when given in combination with fixed doses of obinutuzumab (G) and atezolizumab (Atezo)
• To evaluate the safety and tolerability of the G + Atezo + Pola treatment group and the Rituximab (R) + Atezo + Pola treatment group
• To evaluate the efficacy of induction treatment with G + Atezo + Pola in relapsed or refractory FL and R+ Atezo + Pola in relapsed or refractory DLBCL on the basis of the following endpoint:
o Complete Response (CR) at end of induction (EOI), as
determined by the investigator on the basis of positron emission
tomography-computed tomography (PET-CT) scans |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of induction treatment with G + Atezo + Pola and maintenance treatment with G + Atezo in relapsed or refractory FL and of induction treatment with R + Atezo + Pola and consolidation treatment with R + Atezo in relapsed or refractory DLBCL
• To characterize the pharmacokinetics (PK) of obinutuzumab, atezolizumab, rituximab and polatuzumab vedotin when given in combination
• To evaluate the immune response to obinutuzumab, atezolizumab, rituximab and polatuzumab vedotin |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Age >=18 years
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2
- For G + Atezo + Pola treatment group: relapsed or refractory FL after treatment with at least one prior chemoimmunotherapy regimen that included an anti-CD20 monoclonal antibody and for which no other more appropriate treatment option exists as determined by the investigator
- For R + Atezo + Pola treatment group: relapsed or refractory DLBCL after treatment with at least one prior chemoimmunotherapy regimen that included an anti-CD20 monoclonal antibody in patients who are not eligible for second line combination (immuno-)chemotherapy and autologous stem-cell transplantation or who have failed second line combination (immuno-)chemotherapy or experienced disease progression (DP) following autologous stem-cell transplantation
- Histologically documented CD20-positive lymphoma as determined by the local laboratory
- Fluorodeoxyglucose (FDG)-avid lymphoma (i.e., PET-positive lymphoma)
- At least one bi-dimensionally measurable lesion (>1.5 cm in its largest dimension by computed tomography (CT) scan or magnetic resonance imaging [MRI])
- Availability of a representative tumour specimen and the corresponding pathology report for retrospective central confirmation of the diagnosis of FL or DLBCL
- For women of childbearing potential, agreement to remain abstinent or to use single highly effective or combined contraceptive methods that result in a failure rate of <1% per year during the treatment period for >= 5 months after the last dose of atezolizumab, >= 12 months after last dose of rituximab, >= 12 months after the last dose of polatuzumab vedotin, and >=18 months after the last dose of obinutuzumab
- For men, agreement to remain abstinent or to 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 obinutuzumab, rituximab and atezolizumab, and 5 months after the last dose of (polatuzumab vedotin) and to refrain from donating sperm during this same period |
|
| E.4 | Principal exclusion criteria |
- Grade 3b follicular lymphoma
- History of transformation of indolent disease to DLBCL
- Known CD20-negative status at relapse or progression
- Central nervous system (CNS) lymphoma or leptomeningeal infiltration
- Prior allogeneic stem-cell transplantation (SCT)
- Completion of autologous SCT within 100 days prior to Day 1 of Cycle 1
- Prior standard or investigational anti-cancer therapy
- Clinically significant toxicity (other than alopecia) from prior treatment that has not resolved to Grade <= 2 (as per National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE], v4.0) prior to Day 1 of Cycle 1
- Treatment with systemic immunosuppressive medications within 2 weeks prior to Day 1 of Cycle 1
- History of solid organ transplantation and severe allergic or anaphylactic reaction to humanized, chimeric, or murine monoclonal antibodies
- Known hypersensitivity or allergy to murine products and biopharmaceuticals or any component of the atezolizumab, obinutuzumab, rituximab or polatuzumab vedotin formulations
- Known history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis or evidence of active pneumonitis on screening chest CT scan
- Active bacterial, viral, fungal, or other infection
- Positive for hepatitis B surface antigen (HBsAg), total hepatitis B core antibody (HBcAb), or hepatitis C virus (HCV) antibody at screening
- History of HIV positive status
- History of progressive multifocal leukoencephalopathy
- Vaccination with a live virus vaccine or live attenuated vaccine within 28 days prior to Day 1 of Cycle 1
- History of other malignancy
- History of autoimmune disease
- Grade > 1 peripheral neuropathy present at screening
- Any significant, uncontrolled concomitant disease
- Major surgical procedure other than for diagnosis within 28 days prior to Day 1 of Cycle 1
- Inadequate haematologic and liver function (unless due to underlying lymphoma) defined as aspartate aminotransferase (AST) > upper limit of normal (ULN) or serum total bilirubin > ULN for patients enrolled in dose escalation phase and for the patients enrolled in the expansion phase the defined criteria is AST or alanine transaminase (ALT) > 2.5 x ULN and serum total bilitrubin > 1.5 x ULN (or > 3 x ULN for patients with Gilberts syndrome)
- Abnormal laboratory values (unless due to underlying lymphoma)
- Pregnant or lactating, or intending to become pregnant during the study
- Life expectancy < 3 months |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety:
1. Incidence of dose-limiting toxicities (DLTs) during Cycles 1 and 2 of study treatment
2. Nature, frequency, severity, and timing of adverse events
3. Changes in clinical laboratory results during and following study treatment administration
Efficacy:
4. CR at EOI, as determined by the investigator on the basis of PET-CT scans based on Lugano 2014 criteria |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Day (D) 1-28 during Cycles (C) 1 and 2 of study treatment
2. Up to 90 days after the last dose (LD) of study treatment
3. Up to 90 days after the last dose (LD) of study treatment
4. 6-8 weeks after Day 1 of the last induction cycle |
|
| E.5.2 | Secondary end point(s) |
Efficacy:
1. CR at EOI, as determined by the investigator on the basis of CT scans
alone
2. Objective response [CR or partial response (PR)] at EOI, as
determined by the investigator on the basis of PET-CT scans
3. Objective response at EOI, as determined and by the investigator on
the basis of CT scans alone
4. Best response during the study, as determined by the investigator on
the basis of CT scans alone
PK:
5. Observed serum obinutuzumab concentration at specified timepoints
6. Observed serum atezolizumab concentration at specified timepoints
7. Observed serum and plasma concentrations of polatuzumab vedotin
and relevant analytes [total antibody, antibody conjugated mono-methyl
auristatin E (acMMAE), and unconjugated MMAE] at specified timepoints
8. Observed serum rituximab concentration at specified timepoints
Immunogenicity:
9. Incidence of human anti-chimeric antibodies (HACAs) to rituximab
during the study relative to the prevalence of HACAs at baseline
10. Incidence of human anti-human antibodies (HAHAs) to
obinutuzumab during the study relative to the prevalence of HAHAs at
baseline
11. Incidence of anti-therapeutic antibodies (ATAs) to atezolizumab
during the study relative to the prevalence of ATAs at baseline
12. Incidence of ATAs to polatuzumab vedotin during the study relative
to the prevalence of ATAs at baseline |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-3. 6−8 weeks after D1 of the last induction cycle
4. Every 6 months after the induction treatment,until DP,initiation of
another anti-lymphoma treatment or end of study, whichever occurs first
5. D1, of C1, C2, C4, C6, D1 of Month (M)1,and of 7, 13, 19 in
FL,treatment discontinuation (TD),120 days after LD
6. At TD, 120 days after the LD
7. Serum: D1 of C1, C2, C4, M1D1, TD, 120 days, and 1 yr after LD
Plasma: C1D1, C1D8, C1D15, D1 of C2, C4, C6
8-9. D1 of C1, C2, C4, C6, TD, 120 days, after LD
10. C1D1, C6D1, TD, 120 days, after LD
11. At TD and 120 days after LD
12. D1 of C1, C2, C4, TD, 120 days, and 1 yr after LD |
|
| 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 | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| 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 | No |
| 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.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| 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 |
| Germany |
| Poland |
| United States |
|
| 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
|
The end of this study is defined as the time when both of the following criteria are met:
• All enrolled FL patients have completed or discontinued study treatment (including induction treatment and maintenance treatment, as applicable).
• All enrolled patients with DLBCL have been followed for at least 1 year after they have completed or discontinued study treatment (including induction treatment and consolidation treatment, as applicable). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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