Phase 2
Completed N=56
A Study Evaluating the Safety, Efficacy and Pharmacokinetics of Venetoclax Combined With Chemotherapy in Participants With B-Cell Non-Hodgkin's Lymphoma (NHL) and DLBCL
Lymphoma, Non-Hodgkin
Source: ClinicalTrials.gov NCT02055820 ↗
Enrolled (actual)
56
Serious AEs
57.6%
Results posted
Dec 2018
Primary outcomePrimary: Safety: Number of Participants With Dose-Limiting Toxicities (DLTs) — 1; 0; 1; 0 Participants
Summary
This is a multicenter, open-label, dose-finding study of venetoclax administered orally in combination with rituximab (R) or obinutuzumab (G) and standard doses of cyclophosphamide, doxorubicin, vincristine and oral prednisone (CHOP) in participants with Non-Hodgkin's Lymphoma (NHL). The study consisted of 2 stages: a dose-finding Phase Ib stage and a Phase II expansion stage. In the Phase I portion of the study, participants were randomized to one of 2 treatment arms venetoclax in combination with R-CHOP (Arm A) and venetoclax in combination with G-CHOP (Arm B) and explored the doses of venetoclax in combination with R-CHOP and G-CHOP. The maximum tolerated dose (MTD) of venetoclax in combination with R-CHOP and G-CHOP was determined during the dose-finding stage. For the Phase II portion of the study, the venetoclax dose for venetoclax + R-CHOP was on a non-continuous dosing schedule as determined by the Phase Ib portion of the study based on safety and tolerability observed in participants treated in the dose escalation portion of the study. On 17 July 2016, Roche/Genentech as the sponsor of Study BO21005 (Goya study), a Phase III study that evaluated G CHOP versus R-CHOP in 1L DLBCL, informed through a press release that the primary endpoint of investigator-assessed PFS was not met. Given these results, Arm B (venetoclax + G-CHOP) was not expanded in Phase II in patients who are first-line with DLBCL.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Safety: Number of Participants With Dose-Limiting Toxicities (DLTs) |
1; 0; 1; 0; 2; 1 | — |
| PRIMARY Percentage of Previously Untreated DLBCL Participants With Complete Response (CR) Defined by Positron Emission Tomography-Computed Tomography (PET/CT) Scan Using the Modified Lugano Classification Assessed by Independent Review Committee (IRC) |
68.2 | — |
| PRIMARY Percentage of Participants With CR Defined by PET/CT Scan in Previously Untreated DLBCL Co-Expressing Both Bcl-2 and c-Myc Proteins (DE-DLBCL) Participants Assessed by IRC |
66.7 | — |
| SECONDARY Venetoclax Plasma PK: Area Under the Plasma Concentration-Time Curve (AUC) |
.66; 2.51; 3.87; 3.70; 4.51; 2.55 | — |
| SECONDARY Venetoclax Plasma PK: Time to Maximum Observed Plasma Concentration (Tmax) |
4.0; 4.59; 6.50; 5.52; 5.53; 5.72 | — |
| SECONDARY Venetoclax Plasma PK: Maximum Observed Plasma Concentration (Cmax) |
.09; .58; .92; .85; 1.15; .52 | — |
| SECONDARY Venetoclax Plasma PK: Minimum Plasma Concentration (Cmin) Within the Dosing Interval |
0.0714; 0.522; 0.253; 0.387; 0.640; 0.134 | — |
| SECONDARY Prednisone Plasma PK: AUC |
195; 184 | — |
| SECONDARY Prednisone Plasma PK: Tmax |
2.19; 3.80 | — |
| SECONDARY Prednisone Plasma PK: Cmax |
49.9; 43.2 | — |
| SECONDARY Rituximab PK: Cmax |
173 | — |
| SECONDARY Rituximab PK: Cmin Within the Dosing Interval |
26.1 | — |
| SECONDARY Obinutuzumab PK: Cmax |
326 | — |
| SECONDARY Cyclophosphamide PK: Cmax |
32.1 | — |
| SECONDARY Doxorubicin PK: Cmax |
1260 | — |
| SECONDARY Vincristine PK: Cmax |
54.0 | — |
| SECONDARY Percentage of Participants With Objective Response Defined as Partial Response (PR) or Complete Response (CR) Defined by Positron Emission Tomography-Computed Tomography (PET/CT) Using the Modified Lugano Classification Assessed by IRC |
81.5 | — |
| SECONDARY Percentage of Participants Who Are Alive and Without Disease Progression at Month 12 |
85.71; 100.00; 87.50; 66.67; 88.99; 100.00 | — |
| SECONDARY Percentage of Participants With CR Defined by Computed Tomography (CT) Scan Using the Modified Lugano Classification |
37.4 | — |
| SECONDARY Safety: Percentage of Participants With Adverse Events |
100.00; 100.00; 100.00; 100.00; 99.0; 100.00 | — |
| SECONDARY Safety: Percentage of Participants Maintaining Relative Dose Intensity of CHOP Chemotherapy |
89.5; 77.4; 88.6; 77.4; 86.6; 78.1 | — |
| SECONDARY Relative Dose Intensity of Venetoclax |
71.4; 0.00; 12.5; 0.00; 26.0; 100.00 | — |
Eligibility Criteria
Inclusion Criteria
General Inclusion Criteria:
- At least one bi-dimensionally measurable lymphoma lesion on CT scan defined as > 1.5 cm in its longest dimension, which is also FDG avid by screening PET scan.
- Confirmed availability of archival or freshly biopsied tumor tissue prior to study enrollment
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
- Adequate hematologic function
- For female participants of childbearing potential, agreement to use highly effective forms of contraception
Dose-Escalation Portion of the Study:
- Participants must have histologically confirmed B-cell NHL, except MCL or SLL
- Participants must have never received previous R-CHOP treatment
- Any relapsed/refractory participants that are enrolled during the dose escalation should have received only a single previous treatment regimen
Expansion Portion of the Study:
- Participants must have previously untreated CD20-positive DLBCL and IPI score must be 2-5
Exclusion Criteria
General Exclusion Criteria:
- History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products
- Contraindication to receive any of the individual components of CHOP, rituximab or obinutuzumab
- Prior anthracycline therapy
- Participants with ongoing corticosteroid use >30 mg per day of prednisone or equivalent
- CNS lymphoma or primary mediastinal DLBCL
- Vaccination with live vaccines within 28 days prior to randomization
- Chemotherapy or other investigational therapy within 28 days prior to the start of Cycle 1
- History of other malignancy that could affect compliance with the protocol or interpretation of results
- Evidence of significant, uncontrolled concomitant disease
- Significant cardiovascular disease or significant pulmonary disease
- Left ventricular ejection fraction less than (<) 50% as defined by multiple-gated acquisition (MUGA)
- Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 weeks prior to Cycle 1 Day 1
- Received the following agents within 7 days prior to the first dose of venetoclax: steroid therapy for anti-neoplastic intent; strong and moderate cytochrome P450 (CYP) 3A4 inhibitors or inducers; grapefruit/grapefruit products, seville oranges or star fruit within 3 days prior to the first dose of venetoclax
- Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis
- Recent major surgery
- Women who are pregnant or lactating
Dose-Escalation Portion of the Study:
- Participants with confirmed mantle cell lymphoma (MCL) or small lymphocytic lymphoma (SLL)
Expansion Portion of the Study:
- Participants with transformed lymphoma (participants 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 NHL
Data sourced from ClinicalTrials.gov (NCT02055820). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.