E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
B-cell non-hodgkin's lymphoma (NHL) and diffuse large B-cell lymphoma (DLBCL) |
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E.1.1.1 | Medical condition in easily understood language |
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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 | PT |
E.1.2 | Classification code | 10012821 |
E.1.2 | Term | Diffuse large B-cell lymphoma recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10029601 |
E.1.2 | Term | Non-Hodgkin's lymphoma refractory |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10012822 |
E.1.2 | Term | Diffuse large B-cell lymphoma refractory |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10029600 |
E.1.2 | Term | Non-Hodgkin's lymphoma recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10029547 |
E.1.2 | Term | Non-Hodgkin's lymphoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10012818 |
E.1.2 | Term | Diffuse large B-cell lymphoma |
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 |
The primary objective of the Phase I portion of the study is:
• To estimate the maximum tolerated dosing schedule for venetoclax given in combination with R-CHOP or G-CHOP to patients with B-cell NHL, either previously untreated or relapsed/refractory after a maximum of one prior therapy
The primary objectives of the Phase II portion of the study are:
• To assess the safety and tolerability of the combination of venetoclax and R-CHOP or G-CHOP administered to patients with previously untreated DLBCL
• To make a preliminary assessment of efficacy as measured by CR rate at end of treatment determined by positron emission tomography and/or computed tomography (PET-CT) scans of the combination of venetoclax and R-CHOP administered to patients with previously untreated DLBCL co-expressing both Bcl-2 and c-Myc proteins (i.e., DE-DLBCL) |
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E.2.2 | Secondary objectives of the trial |
The PK objectives of this study are:
• To characterize the PK of Venetoclax when administered in combo with R-CHOP or G-CHOP in the relapsed/refractory or previously untreated setting in NHL
• To characterize the PK of rituximab, obinutuzumab, and prednisone when administered in combo with venetoclax in relapsed/refractory or previously untreated B-cell NHL
• To confirm exposure to cyclophosphamide, doxorubicin, and vincristine when given in combination with rituximab, obinutuzumab, and/or venetoclax
The efficacy objective of this study includes:
• To make a preliminary assessment of efficacy when venetoclax and R-CHOP are administered in combination to patients with previously untreated DLBCL, as measured by
• OR rate
• CR rate determined by CT scan
• DOR
• PFS
• 12 month PFS estimate
• OS
Please see section 2.2.3 of the protocol for additional explotatory objectives |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
General Inclusion Criteria:
- Patients, age >= 18 years
- At least one bi-dimensionally measurable lymphoma lesion defined as > 1.5 cm in its longest dimension which is also FDG avid by screening PET scan
- Ability and willingness to comply with the study protocol procedures
- Confirmed availability of archival or freshly biopsied tumor tissue prior to study enrollment
- ECOG performance status of 0, 1, or 2
- Adequate hematologic function
- For female patients of childbearing potential and male patients with female partners of childbearing potential, agreement to use highly effective forms of contraception
Dose Finding Portion of the Study:
- Patients must have histologically confirmed B-cell non-Hodgin's Lymphoma (NHL)
- Patients must have never received previous R-CHOP treatment
- Any relapsed/refractory patients that are enrolled during the dose escalation should have received only a single previous treatment regimen
Phase II Portion of the Study:
- Patients must have previously-untreated CD20-positive diffuse large, B-cell lymphoma
- International prognostic index (IPI) score must be 2-5 |
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E.4 | Principal exclusion criteria |
General Exclusion Criteria:
- Contraindication to receive any of the individual components of CHOP, rituximab or obinutuzumab
- CNS lymphoma or primary mediastinal DLBCL
- Vaccination with live vaccines within 28 days prior to randomization
- History of other malignancy that could affect compliance with the protocol or interpretation of results
- Evidence of significant, concomitant disease or illness
- Use of CYP3A inhibitors or inducers within 7 days of the first dose of venetoclax
- Recent major surgery
- Women must not be pregnant or breastfeeding
Dose Finding Portion of the Study:
- Histologically confirmed mantle cell lymphoma (MCL) or small lymphocytic lymphoma (SLL)
Phase II Portion of the Study:
- Patients with transformed lymphoma (patients with discordant bone marrow involvement [i.e., low grade histology in bone marrow] may be considered after discussion with the Medical Monitor)
- Prior therapy for non-hodgkin's lymphoma (NHL) |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Safety: Incidence of dose-limiting toxicities
2. Complete response (CR) defined by PET/CT scan and bone marrow examination
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Approximately 9 months
2. Approximately 9 months |
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E.5.2 | Secondary end point(s) |
1. Pharmacokinetics: plasma concentration-time profile of venetoclax
2. Objective response (partial or complete response) rate
3. Response duration, defined as time from first documented response until relapse or death
4. Incidence of adverse events
5. Progression-free survival
6. Overall survival
7. CR defined by CT scan and bone marrow examination
8. Relative dose intensity |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Approximately 9 months
2. Approximately 9 months
3. Approximately 1 year
4. Approximately 1 year
5. Approximately 1 year
6. Approximately 1 year
7. Approximately 9 months
8. Approximately 9 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 | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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) | 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 |
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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 | Yes |
E.8.1.1 | Randomised | Yes |
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 | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 41 |
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 |
Australia |
Austria |
Canada |
Czech Republic |
France |
Hungary |
Italy |
Netherlands |
Spain |
United States |
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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 study will be defined as one year following initiation of treatment of the last patient enrolled |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |