A Phase Ib Study Evaluating the Safety, Efficacy, and Pharmacokinetics of Venetoclax in Combination With Polatuzumab Vedotin Plus Rituximab (R) and Cyclophosphamide, Doxorubicin, Prednisone (CHP) in Patients With Untreated BCL-2 Immunohistochemistry (IHC)-Positive Diffuse Large B-Cell Lymphoma
Overview
- Phase
- Phase 1
- Intervention
- Venetoclax
- Conditions
- Lymphoma, Large B-Cell, Diffuse
- Sponsor
- Hoffmann-La Roche
- Enrollment
- 50
- Locations
- 20
- Primary Endpoint
- Percentage of Participants with Dose-Limiting Toxicities (DLTs)
- Status
- Terminated
- Last Updated
- last year
Overview
Brief Summary
This Phase Ib, open-label, multicenter study evaluates the safety, efficacy, and pharmacokinetics of venetoclax in combination with Pola + R-CHP in previously untreated participants with BCL-2 IHC-positive DLBCL. Approximately 50 participants will be enrolled in this study in five consecutive cohorts each consisting of approximately 10 participants.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Previously untreated participants with CD20-positive DLBCL.
- •BCL-2 protein overexpression by IHC, as assessed by local testing.
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or
- •International Prognostic Index (IPI) 2-
- •Life expectancy of more than 6 months.
- •Left ventricular ejection fraction (LVEF) ≥ 50%, as determined on cardiac multiple-gated acquisition (MUGA) scan or cardiac echocardiogram (ECHO).
- •Availability of archival or freshly collected tumor tissue prior to study enrollment.
- •At least one bi-dimensionally fluorodeoxyglucose-avid measurable lymphoma lesion on PET/CT scan, defined as \> 1.5 cm in its longest dimension on CT scan.
- •Adequate hematopoietic function.
- •For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs.
Exclusion Criteria
- •Current diagnosis of unclassifiable B-cell lymphoma.
- •Prior treatment for indolent lymphoma.
- •Current Grade \> 1 peripheral neuropathy.
- •Prior organ transplantation.
- •Prior use of any monoclonal antibody within 3 months and any investigational therapy within 28 days prior to the start of Cycle
- •Vaccination with live vaccines within 28 days prior to the start of Cycle
- •Prior therapy for DLBCL and High-Grade B-cell Lymphoma (HGBCL) with the exception of palliative, short-term treatment with corticosteroids.
- •Recent major surgery (within 6 weeks prior to the start of Day 1 of Cycle 1), other than for diagnosis.
- •History of other cancers within 2 years prior to screening.
- •Any active infection that, in the opinion of the investigator, would impact participant safety within 7 days prior to Day 1 of Cycle
Arms & Interventions
Venetoclax (Schedule A)
Participants enrolled in dosing Schedule A will receive a total of six 21-day cycles of venetoclax treatment for 5 days in combination with Polatuzumab Vedotin + R-CHP (Rituximab, Cyclophosphamide, Doxorubicin and Prednisone) as described below: Schedule A: Participants will self-administer Venetoclax orally (PO) once daily (QD) at a dose of 800 mg for 5 consecutive days as follows: Cycle 1: 5 consecutive days of dosing on Days 4-8. Cycles 2-6: 5 consecutive days of dosing on Days 1-5.
Intervention: Venetoclax
Venetoclax (Schedule A)
Participants enrolled in dosing Schedule A will receive a total of six 21-day cycles of venetoclax treatment for 5 days in combination with Polatuzumab Vedotin + R-CHP (Rituximab, Cyclophosphamide, Doxorubicin and Prednisone) as described below: Schedule A: Participants will self-administer Venetoclax orally (PO) once daily (QD) at a dose of 800 mg for 5 consecutive days as follows: Cycle 1: 5 consecutive days of dosing on Days 4-8. Cycles 2-6: 5 consecutive days of dosing on Days 1-5.
Intervention: Polatuzumab Vedotin
Venetoclax (Schedule A)
Participants enrolled in dosing Schedule A will receive a total of six 21-day cycles of venetoclax treatment for 5 days in combination with Polatuzumab Vedotin + R-CHP (Rituximab, Cyclophosphamide, Doxorubicin and Prednisone) as described below: Schedule A: Participants will self-administer Venetoclax orally (PO) once daily (QD) at a dose of 800 mg for 5 consecutive days as follows: Cycle 1: 5 consecutive days of dosing on Days 4-8. Cycles 2-6: 5 consecutive days of dosing on Days 1-5.
Intervention: Rituximab
Venetoclax (Schedule A)
Participants enrolled in dosing Schedule A will receive a total of six 21-day cycles of venetoclax treatment for 5 days in combination with Polatuzumab Vedotin + R-CHP (Rituximab, Cyclophosphamide, Doxorubicin and Prednisone) as described below: Schedule A: Participants will self-administer Venetoclax orally (PO) once daily (QD) at a dose of 800 mg for 5 consecutive days as follows: Cycle 1: 5 consecutive days of dosing on Days 4-8. Cycles 2-6: 5 consecutive days of dosing on Days 1-5.
Intervention: Cyclophosphamide
Venetoclax (Schedule A)
Participants enrolled in dosing Schedule A will receive a total of six 21-day cycles of venetoclax treatment for 5 days in combination with Polatuzumab Vedotin + R-CHP (Rituximab, Cyclophosphamide, Doxorubicin and Prednisone) as described below: Schedule A: Participants will self-administer Venetoclax orally (PO) once daily (QD) at a dose of 800 mg for 5 consecutive days as follows: Cycle 1: 5 consecutive days of dosing on Days 4-8. Cycles 2-6: 5 consecutive days of dosing on Days 1-5.
Intervention: Doxorubicin
Venetoclax (Schedule A)
Participants enrolled in dosing Schedule A will receive a total of six 21-day cycles of venetoclax treatment for 5 days in combination with Polatuzumab Vedotin + R-CHP (Rituximab, Cyclophosphamide, Doxorubicin and Prednisone) as described below: Schedule A: Participants will self-administer Venetoclax orally (PO) once daily (QD) at a dose of 800 mg for 5 consecutive days as follows: Cycle 1: 5 consecutive days of dosing on Days 4-8. Cycles 2-6: 5 consecutive days of dosing on Days 1-5.
Intervention: Prednisone
Venetoclax (Schedule B)
Participants enrolled in dosing Schedule B will receive a total of six 21-day cycles of venetoclax treatment for 10 days in combination with Polatuzumab Vedotin + R-CHP as described below: Schedule B: Participants will self-administer Venetoclax orally (PO) once daily (QD) at a dose of 800 mg for 10 consecutive days as follows: Cycle 1: 10 consecutive days of dosing on Days 4-10. Cycles 2-6: 10 consecutive days of dosing on Days 1-10.
Intervention: Venetoclax
Venetoclax (Schedule B)
Participants enrolled in dosing Schedule B will receive a total of six 21-day cycles of venetoclax treatment for 10 days in combination with Polatuzumab Vedotin + R-CHP as described below: Schedule B: Participants will self-administer Venetoclax orally (PO) once daily (QD) at a dose of 800 mg for 10 consecutive days as follows: Cycle 1: 10 consecutive days of dosing on Days 4-10. Cycles 2-6: 10 consecutive days of dosing on Days 1-10.
Intervention: Polatuzumab Vedotin
Venetoclax (Schedule B)
Participants enrolled in dosing Schedule B will receive a total of six 21-day cycles of venetoclax treatment for 10 days in combination with Polatuzumab Vedotin + R-CHP as described below: Schedule B: Participants will self-administer Venetoclax orally (PO) once daily (QD) at a dose of 800 mg for 10 consecutive days as follows: Cycle 1: 10 consecutive days of dosing on Days 4-10. Cycles 2-6: 10 consecutive days of dosing on Days 1-10.
Intervention: Rituximab
Venetoclax (Schedule B)
Participants enrolled in dosing Schedule B will receive a total of six 21-day cycles of venetoclax treatment for 10 days in combination with Polatuzumab Vedotin + R-CHP as described below: Schedule B: Participants will self-administer Venetoclax orally (PO) once daily (QD) at a dose of 800 mg for 10 consecutive days as follows: Cycle 1: 10 consecutive days of dosing on Days 4-10. Cycles 2-6: 10 consecutive days of dosing on Days 1-10.
Intervention: Cyclophosphamide
Venetoclax (Schedule B)
Participants enrolled in dosing Schedule B will receive a total of six 21-day cycles of venetoclax treatment for 10 days in combination with Polatuzumab Vedotin + R-CHP as described below: Schedule B: Participants will self-administer Venetoclax orally (PO) once daily (QD) at a dose of 800 mg for 10 consecutive days as follows: Cycle 1: 10 consecutive days of dosing on Days 4-10. Cycles 2-6: 10 consecutive days of dosing on Days 1-10.
Intervention: Doxorubicin
Venetoclax (Schedule B)
Participants enrolled in dosing Schedule B will receive a total of six 21-day cycles of venetoclax treatment for 10 days in combination with Polatuzumab Vedotin + R-CHP as described below: Schedule B: Participants will self-administer Venetoclax orally (PO) once daily (QD) at a dose of 800 mg for 10 consecutive days as follows: Cycle 1: 10 consecutive days of dosing on Days 4-10. Cycles 2-6: 10 consecutive days of dosing on Days 1-10.
Intervention: Prednisone
Outcomes
Primary Outcomes
Percentage of Participants with Dose-Limiting Toxicities (DLTs)
Time Frame: Cycle 1 Day 1 up to but not including Cycle 3 Day 1 (Cycle length = 21 days)
Secondary Outcomes
- Percentage of Participants with Adverse Events (AEs)(Up to 4 years)
- Complete Response (CR) rate at the end of treatment(Up to 4 years)
- Objective Response Rate (ORR) at the end of treatment(Up to 4 years)
- Duration of Response (DOR)(Up to 4 years)
- Progression-Free Survival (PFS)(Up to 4 years)
- Plasma Concentrations of Venetoclax at specified timepoints(Up to 4 years)
- Plasma Concentrations of Polatuzumab Vedotin analytes at specified timepoints(Up to 4 years)