| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed/Refractory Mantle Cell Lymphoma (MCL), Marginal Zone Lymphoma (MZL) and Waldenström Macroglobulinemia (WM) |
|
| E.1.1.1 | Medical condition in easily understood language |
| MCL is a B-cell non-Hodgkin lymphoma (lymph nodes, spleen, etc); MZL (B-cell lymphoma) arise from post-germinal center marginal zone B-cell; WM is a lymphoplasmacytic lymphoma in the bone marrow. |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10054697 |
| E.1.2 | Term | Waldenstrom's macroglobulinemia recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10054698 |
| E.1.2 | Term | Waldenstrom's macroglobulinemia refractory |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10077534 |
| E.1.2 | Term | Marginal zone lymphoma refractory |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10077533 |
| E.1.2 | Term | Marginal zone lymphoma recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10026801 |
| E.1.2 | Term | Mantle cell lymphoma refractory |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10026800 |
| E.1.2 | Term | Mantle cell lymphoma recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 efficacy of atezolizumab in combination with obinutuzumab or rituximab |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of atezolizumab in combination with obinutuzumab or rituximab
• To evaluate the safety and tolerability of atezolizumab in combination with obinutuzumab or rituximab
• To characterize the pharmacokinetics of atezolizumab and obinutuzumab when administered in combination in MCL and WM patients
• To characterize the pharmacokinetics of atezolizumab and rituximab when administered in combination in MZL patients
• To evaluate the immune response to atezolizumab with obinutuzumab or rituximab
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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).
|
|
| E.4 | Principal 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 entry
- Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA4, anti–PD-1, and anti–PD-L1 therapeutic antibodies
- Treatment with systemic immunostimulatory agents within 4 weeks or 5 half-lives of the drug, whichever is longer, prior to C1D1
- Treatment with systemic immunosuppressive medications within 2
weeks prior to C1D1 or anticipation of need for systemic immunosuppressive medication during study treatment
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. For MCL and nodal and extra-nodal MZL, objective response (OR) at end of Induction, defined as a complete response (CR) or partial response (PR) based on modified Cheson 2007 criteria (excluding PET)
2. For WM, best overall objective response (BOR), defined as a CR, very good partial response, PR, or minimum response, based on Owen 2013 criteria, at any time during the study
3. For gastric MZL, OR at end of Induction, defined as a CR or probable minimal residual disease or responding residual disease, based on the histological grading system of GELA 2003 criteria
4. For splenic MZL, OR at end of Induction, defined as a CR or PR based on Matutes (2008) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1, 3 & 4. At the end of induction
2. At any time during the study; up to approximately 54 months
|
|
| E.5.2 | Secondary end point(s) |
1. Progression-free survival (PFS), defined as the time from enrolment to the first occurrence of PD or death from any cause, whichever occurs
first, as determined by the investigator
2. BOR, defined as best response seen throughout study
3. Complete Response Rate defined as best response of CR
4. Duration of objective response, defined for responding patients as the
time from first occurrence of a documented objective response to the
time of progression or death from any cause, whichever occurs first as
determined by the investigator
5. Time to next treatment, defined as the time from the date of
enrolment to the start date of the next anti-lymphoma treatment (NALT)
or death from any cause, whichever occurs first
6. Overall survival, defined as the time from the enrolment to death from
any cause
7. Event free survival, defined as the time from enrolment to first
occurrence of disease progression or relapse, death from any cause, as
assessed by the investigator, or initiation of any non-protocol-specified
NALT, whichever occurs first.
8. Disease-free survival, defined as the time from the date of the first
occurrence of a documented CR to the date of disease progression,
relapse or death from any cause, whichever occurs first, as assessed by
the investigator, for the subgroup of patients with a BOR of CR
9. Safety: Incidence, nature and severity of adverse events (AEs),
graded according to the National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI CTCAE v4.03)
10. Pharmacokinetic parameters of atezolizumab, obinutuzumab, and
rituximab
11. Occurrence of anti-drug antibodies of atezolizumab, obinutuzumab,
and rituximab |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-9. Up to approximately 54 months
10. C1D1, C2D1, C3D1, C4D1, C8D1, C12D1, C16D1 (atezolizumab); C1D1, C2D1, C4D1 (obinutuzumab); C1D1, C2D1, C4D1, C8D1 (rituximab), end of treatment (EOT) and at Follow-up 1 (FU1)
11. C1D1, C2D1, C34D1, C4D1, C8D1, C12D1, C16D1 (atezolizumab); C1D1, C4D1 (obinutuzumab); C1D1, C4D1 (rituximab); EOT and at FU1 |
|
| 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 | 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 | 3 |
| 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 |
| Bosnia and Herzegovina |
| France |
| Germany |
| Greece |
| Italy |
| Korea, Republic of |
| Latvia |
| Russian Federation |
| Slovakia |
| Spain |
| Switzerland |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 the study is defined as the date when the last patient, last visit (LPLV) occurs. LPLV is expected to occur approximately 54 months after the first patient is enrolled. |
|
| 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 | 6 |
| 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 days | 0 |
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