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 | 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 | 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 | 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., DEDLBCL) |
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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 RCHOP
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 GDC-0199
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 | 2 |
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 | |
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 |