Study of Venetoclax Plus DA-EPOCH-R for the Treatment of Aggressive B-Cell Lymphomas

This clinical trial is for men and women with aggressive B-Cell Lymphomas which includes:

- Diffuse large B-cell lymphoma (DLBCL),

- B-cell lymphoma unclassifiable with intermediate features between DLBCL and Burkitt
Lymphoma (BL),

- High grade B-cell lymphoma (HGBCL),

- Transformed indolent NHL (TiNHL). The aggressive B-cell lymphomas enrolling on this
study have been recognized to have a poor prognosis with the use of conventional
chemoimmunotherapy. DA-EPOCH-R is an alternative highly effective chemoimmunotherapy
platform for these lymphomas and may serve as an optimal chemotherapy backbone for the
incorporation of novel agents such as venetoclax.

The Bcl-2 protein plays a significant role in the regulation of cell death in malignant
cells. Overexpression of Bcl-2 family proteins is associated with chemo-resistance of a broad
variety of cancers, and BCL2 abnormalities are common in aggressive B-cell Lymphomas.
Venetoclax is a highly selective Bcl-2 family protein inhibitor that binds to Bcl-2 family
proteins to potentially overcome resistance and enhance responses to therapy. This study has
been designed to evaluate the safety and preliminary efficacy of venetoclax in combination
with DA-EPOCH-R.

Subjects will receive venetoclax in conjunction with six 21-day cycles of DA-EPOCH-R. Dosing
for DA-EPOCH-R will follow established protocols. Venetoclax will be administered on days 3
through 12 during cycle 1 and days 1 through 10 of each subsequent cycle. Following
completion of therapy, subjects will be followed every three months for up to two years.
Subjects removed from study due to toxicity will be followed until resolution or
stabilization of the toxicity.

Inclusion criteria:

- Adults age 18-80 years

- Histologically confirmed, biopsy-proven diagnosis of DLBCL, BCLu, HGBCL, or TiNHL.

Richter's transformation from Chronic Lymphocytic Leukemia (CLL) is not eligible.

- Subjects with DLBCL, BCLu, HGBCL NOS, or HGBCL with translocations of MYC and BCL2
and/or BCL6, must have had no prior chemotherapy for lymphoma. Steroids for palliation
prior to enrollment are allowed.

- Subjects with TiNHL are eligible if they have received no prior cytotoxic chemotherapy
for lymphoma. Steroids, rituximab, and external beam radiation therapy as prior
therapy for indolent lymphoma is allowed.

- Ann Arbor stage II-IV disease (Stage I primary mediastinal B-cell lymphoma will also
be eligible)

- Ability to provide signed Informed Consent Form

- Ability and willingness to comply with the requirements of the study protocol

- Measureable disease (defined as at least 1.5 cm in diameter).

- Adequate organ and bone marrow function:

- Absolute neutrophil count (ANC) at least 1,000/mm3

- Platelet count at least 100,000/mm3.

- Total bilirubin at most1.5 x the upper limit of the normal range (ULN), except
Gilbert's disease

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) at most 3 x ULN.

- Calculated creatinine clearance at least 30 mL/min.

Exclusion criteria:

- Known hypersensitivity to any of the study drugs

- History of other malignancy that could affect compliance with the protocol or
interpretation of results

- Patients with a history of curatively treated basal or squamous cell carcinoma of the
skin or in situ carcinoma of the cervix are generally eligible. Patients with a
malignancy that has been treated, but not with curative intent, will also be excluded,
unless the malignancy has been in remission without treatment for at least 2 years
prior to enrollment.

- Known CNS involvement at diagnosis

- Richter's transformation from CLL

- Evidence of other clinically significant uncontrolled condition(s) including, but not
limited to, uncontrolled systemic infection (viral, bacterial, or fungal)

- Major surgery within 3 weeks prior to the start of study treatment

- Infection with human immunodeficiency virus (HIV)

- Women who are pregnant or lactating

- Female patients who are not surgically sterile or postmenopausal (for at least 1 year)
must practice at least one of the following methods of birth control throughout the
duration of study participation and for at least 3 months after study treatment:

- Total abstinence from sexual intercourse

- A vasectomized partner

- Hormonal contraceptives (oral, parenteral, vaginal ring, or transdermal) that started
at least 3 months prior to study drug administration

- Double-barrier method (condom plus diaphragm or cervical cup with spermicidal
contraceptive sponge, jellies, or cream)

- Non-vasectomized male patients must comply with at least one of the following methods
of birth control throughout the duration of study participation and for at least 3
months after study treatment:

- A partner who is surgically sterile or postmenopausal (for at least 1 year) or who is
taking hormonal contraceptives (oral, parenteral, vaginal ring, or transdermal) for at
least 3 months prior to study drug administration

- Total abstinence from sexual intercourse

- Double-barrier method (condom plus diaphragm or cervical cup with spermicidal,
contraceptive sponge, jellies, or cream)

- Malabsorption syndrome or other condition that precludes enteral route of
administration

- Known allergy to both xanthine oxidase inhibitors and rasburicase

- Subjects with positive HBV core antibody or surface antigen are eligible as long as
they have an undetectable HBV DNA PCR, and receive concurrent antiviral therapy with
entecavir, tenofovir, or lamivudine, and continued for a minimum of 6 months after
completion of therapy.

- Active hepatitis C (defined as a positive HCV viral load)

- Chronic use of moderate or strong CYP3A4 modulators (inhibitor or inducer) or any
other prohibited medications. A washout period of 7 days is required prior to
venetoclax dosing if a prohibited medication is discontinued.

- Chronic use of a P-gp inhibitor, or a P-gp substrate with a narrow therapeutic index.
A washout period of 7 days is required prior to venetoclax dosing if a prohibited
medication is discontinued.