A Study Evaluating the Safety, Efficacy and Pharmacokinetics of Venetoclax in Combination With Polatuzumab Vedotin Plus Rituximab (R) and Cyclophosphamide, Doxorubicin, Prednisone (CHP) in Participants With Untreated BCL-2 Immunohistochemistry (IHC)-Positive Diffuse Large B-Cell Lymphoma (DLBCL)

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.


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 2.
* International Prognostic Index (IPI) 2-5.
* 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.
* For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm.

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 1.
* Vaccination with live vaccines within 28 days prior to the start of Cycle 1.
* 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 1.
* Serious infection requiring oral or IV antibiotics within 4 weeks prior to Day 1 of Cycle 1.
* Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the participant's safe participation in and completion of the study.
* Positive test for Hepatitis B/C Viruses (HBV/HCV) and Human T-cell Leukemia Virus (HTLV)-1.
* Known infection with HIV.
* History of progressive multifocal leukoencephalopathy.
* Suspected active or latent tuberculosis.
* Clinically significant history of liver disease, including viral or other hepatitis or cirrhosis.
* Substance abuse, including non-prescription drug and alcohol dependence, within 12 months prior to screening.
* Pregnant or breastfeeding, or intending to become pregnant during the study within 6 months after the final dose of venetoclax, 9 months after the final dose of polatuzumab vedotin, or 12 months after the final dose of rituximab.
* History or presence of an abnormal ECG that is clinically significant in the investigator's opinion.
* Malabsorption syndrome or other condition that would interfere with enteral absorption.
* Blood transfusion within 14 days prior to screening.