Untersuchung der Sicherheit und Wirksamkeit von Atezolizumab (TECENTRIQ®) in Kombination mit Obinutuzumab (GAZYVARO®) oder Rituximab (MabThera®) bei Patienten mit rezidivierendem/refraktärem Mantelzelllymphom, Marginalzonenlymphom oder Makroglobulinämie Waldenström.

Product Name: Atezolizumab
Product Code: RO5541267
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: ATEZOLIZUMAB
CAS Number: 1380723-44
Current Sponsor code: RO5541267
Other descriptive name: TECENTRIQ
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 60-

Trade Name: Gazyvaro 1 000 mg
Product Name: Obinutuzumab
Product Code: RO5072759
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Obinutuzumab
CAS Number: 949142-50-1
Current Sponsor code: RO5072759
Other descriptive name: OBINUTUZUMAB
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1000-

Trade Name: MabThera 500 mg concentrate for solution for infusion
Product Name: MabThera 500 mg concentrate for solution for infusion
Product Code: RO0452294
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: RITUXIMAB
CAS Number: 174722-31-7
Current Sponsor code: RO452294
Other descriptive name: MabThera 500 mg concentrate for solution for infusion
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 500-

Trade Name: MabThera 1400 mg solution for subcutaneous injection
Product Name: MabThera 1400 mg solution for subcutaneous injection
Product Code: RO0452294
Pharmaceutical Form: Solution for injection
INN or Proposed INN: RITUXIMAB
CAS Number: 174722-31-7
Other descriptive name: MabThera 1400 mg solution for subcutaneous injection
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 120-

Trade Name: Tecentriq
Product Name: Atezolizumab
Product Code: RO5541267
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: ATEZOLIZUMAB
Current Sponsor code: RO5541267

Inclusion criteria:
- Ability to comply with the protocol
- Age >= 18 years
- Histologically documented, CD20 positive, relapsed or refractory MCL,
MZL and WM. Refractory is defined for the 3 indications as having
relapsed during or within 6 months after the last dose of the previous
treatment. For WM patients, the diagnosis of relapse/refractory will be
accompanied by evidence of reappearance of monoclonal IgM protein
and/or recurrence of bone marrow involvement, lymphadenopathy/splenomegaly with symptoms attributable to active
disease. Where ibrutinib is available in the selected country, patients
with MCL or WM must have relapsed or become refractory to its benefits,
or become intolerant of ibrutinib. All other patients must have failed at
least 1 prior line of systemic treatment.
- Bone marrow biopsy and/or other sites of disease at screening for tumor staging and response evaluation
- ECOG performance status of 0, 1 or 2
- Life expectancy>=12 weeks
- For mantle cell lymphoma (MCL) and nodal marginal zone lymphoma (MZL), at least one bi-dimensionally measurable lesion>=1.5 cm in its largest dimension by Computed Tomography scan or MRI, as defined by Revised Response Criteria for Malignant Lymphoma
- Adequate hematologic and end-organ function
- For women who are not postmenopausal or surgically sterile: agreement to remain abstinent or to use single highly effective or combined contraceptive methods that result in a failure rate of < 1% per year, starting at least 28 days prior to Day 1 of Cycle 1, during the treatment period and for at least 18 months after the last dose of combination therapy
- For women of childbearing potential, a negative serum pregnancy
test result within 3 days prior to Day 1 of Cycle 1 prior to dosing. In addition, a urine pregnancy test should be done prior to dosing on Day 1 of Cycle 1 to confirm the negative result if the serum test was not performed prior to dosing on D1 of C1. For all other women, documentation must be present in the medical history confirming that the patient is not of childbearing potential.
- 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 combination therapy
- Tumor tissue fresh sample preferred, archival tissue is acceptable
(only if a fresh sample is not available).

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 16
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 39

Exclusion criteria:
- Any approved anticancer therapy or hormonal therapy within 3 weeks prior to initiation of study treatment. Any radiotherapy within 4 weeks prior to initiation of study treatment.
- Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days or 5 half-lives prior to enrolment, whichever is longest.
- Known Central nervous system lymphoma, leptomeningeal lymphoma, or histologic evidence of transformation to a high-grade or diffuse large B-cell lymphoma
- Uncontrolled tumor-related pain
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures; patients with indwelling catheters are eligible
- Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab
- History of other malignancy
- History of severe allergic or anaphylactic or other hypersensitivity reactions to chimeric or humanized or murine monoclonal antibodies or fusion proteins or murine proteins or known sensitivity or allergy to murine products
- Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
- Regular treatment with corticosteroids within the 4 weeks prior to the start of C1 General Medical Exclusions
- Pregnant and lactating women, or intending to become pregnant during the study or within 18 months after the last dose of combination
therapy. Women who are not postmenopausal or surgically sterile must have a negative serum pregnancy test result within 3 days prior to D1 of C1 prior to dosing. In addition, a urine pregnancy test should be done prior to dosing on D1 of C1 to confirm the negative result if the serum test was not performed prior to dosing on D1 of C1
- History of autoimmune disease
- Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
- Significant cardiovascular disease, within 3 months prior to initiation of study treatment
- Patients with history of confirmed progressive multifocal leukoencephalopathy
- Patients with prior allogeneic bone marrow transplantation (allo
BMT) allogeneic stem cell transplant (ASCT), or prior solid organ
transplantation
- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis per chest CT scan at screening
- Serum albumin < 2.5 g/dL
- Positive test for HIV, human T-lymphotrophic 1 virus, and hepatitis B or C
- Active tuberculosis
- Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
- Major surgical procedure other than for diagnosis within 28 days prior to C1D1
- Administration of a live, attenuatedvaccine (e.g., FluMist®) within 4 weeks before C1D1 Exclusion Criteria Related to Medications
- Known hypersensitivity to obinutuzumab, rituximab or atezolizumab or their formulation excipients
- Prior treatment with obinutuzumab or atezolizumab, or anti progressive disease (PD)-1 or programmed death-ligand 1 (PDL-1) antibodies
- Fludarabine or Campath® within 12 months prior to study e