Bendamustine, Obinutuzumab, and Venetoclax in Patients With Untreated Mantle Cell Lymphoma

PRIMARY OBJECTIVE:

I. To evaluate the efficacy of the combination of bendamustine, obinutuzumab and venetoclax
in patients with untreated mantle cell lymphoma.

SECONDARY OBJECTIVES:

I. To evaluate the safety and dose intensity of the combination of bendamustine, obinutuzumab
and venetoclax in untreated mantle cell lymphoma.

II. To explore methods of determining molecular remission for patients with untreated mantle
cell lymphoma (MCL).

III. To evaluate long-term outcomes including progression-free and overall survival for
patients with untreated MCL who receive the combination.

OUTLINE:

Patients receive venetoclax orally (PO) on days 1-28 of course 1 and days 1-10 of subsequent
courses, bendamustine intravenously (IV) on days 1 and 2, and obinutuzumab IV on days 1, 8,
and 15 of course 1 and day 1 of subsequent courses. Treatment repeats every 28 days for up to
6 courses in the absence of disease progression or unaccepted toxicity.

After completion of study treatment, patients are followed up at 45-60 days.

Inclusion Criteria:

- Signed informed consent form

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

- Histologic diagnosis of mantle cell lymphoma. This diagnosis must be confirmed at the
treating center and patients must have this diagnosis confirmed by at least one of the
following criteria:

- Fluorescent in situ hybridization (FISH) or conventional cytogenetics positive
for t(11;14)

- Cyclin D1 positive by immunohistochemistry

- Documentation by a hematopathologist at the treating institution that there is
pathologic evidence of mantle cell lymphoma if neither criteria above are met

- No previous therapy for diagnosis of lymphoma (note that in patients deemed to be
high-risk for tumor lysis syndrome or for rapid clinical deterioration due to
symptomatic disease by the investigator, a short course of steroids designed to
decrease tumor burden is permitted)

- Eastern Cooperative Oncology Group performance status of 0, 1, or 2

- Hemoglobin ≥ 9 g/dL

- Absolute neutrophil count ≥ 1.5 x 10⁹/L

- Platelet count ≥ 75 x 10⁹/L

- Serum creatinine ≤ 2.0 mg/dL or creatinine clearance ≥ 40 mL/min

- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2.5 x upper limit
of normal (ULN)

- Total bilirubin < 1.5 x ULN (or ≤ 3 x ULN for patients with documented Gilbert
syndrome)

- NOTE: Patients with renal or hepatic impairment that is disease-related (ie,
hydronephrosis, hepatic involvement) in the opinion of the investigator but who
meet all other eligibility criteria may be considered for enrollment in
consultation with the investigational new drug (IND) sponsor, Dr. Jonathon Cohen.
Documentation of prior adequate renal/hepatic function and clear association with
the disease will be required

- For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use a contraceptive method with a failure rate of < 1%
per year during the treatment period and for at least 30 days after the last dose of
venetoclax or 18 months after the last dose of obinutuzumab, whichever is longer

- A woman is considered to be of childbearing potential if she is postmenarcheal,
has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with
no identified cause other than menopause), and has not undergone surgical
sterilization (removal of ovaries and/or uterus)

- Examples of contraceptive methods with a failure rate of < 1% per year include
bilateral tubal ligation, male sterilization, hormonal contraceptives that
inhibit ovulation, hormone-releasing intrauterine devices, and copper
intrauterine devices

- The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or
postovulation methods) and withdrawal are not acceptable methods of contraception

- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use
contraceptive measures, and agreement to refrain from donating sperm, as defined
below:

- With female partners of childbearing potential, men must remain abstinent or use
a condom plus an additional contraceptive method that together result in a
failure rate of < 1% per year during the treatment period and for at least 6
months after the last dose of obinutuzumab. Men must refrain from donating sperm
during this same period

- With pregnant female partners, men must remain abstinent or use a condom during
the treatment period and for at least 6 months after the last dose of
obinutuzumab to avoid exposing the embryo

- The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or
postovulation methods) and withdrawal are not acceptable methods of contraception

Exclusion Criteria:

- 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 or
Stage 1 melanoma of the skin or in situ carcinoma of the cervix are eligible.

- Individuals in documented remission without treatment for ≥ 2 years prior to
enrollment may be included at the discretion of the investigator. Patients with
more recently treated low risk prostate cancer, thyroid cancer, or ductal
carcinoma in situ (DCIS) who are felt to be at low risk for progression and who
are not currently taking any chemotherapy, hormonal therapy or other anti-cancer
therapy are eligible. Patients who have been treated and been in remission for <
2 years must be cleared with the study chair prior to initiating study therapy

- Evidence of significant, uncontrolled concomitant diseases that could affect
compliance with the protocol or interpretation of results or that could increase risk
to the patient, including renal disease that would preclude chemotherapy
administration

- Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection
(excluding fungal infections of nail beds) at study enrollment

- Requires the use of warfarin (because of potential drug-drug interactions that may
potentially increase the exposure of warfarin)

- Received strong or moderate CYP3A inhibitors or inducers within 7 days of initiating
venetoclax. Consumed grapefruit, grapefruit products, Seville oranges (including
marmalade containing Seville oranges), or star fruit within 3 days prior to first dose
of venetoclax

- Clinically significant history of liver disease, including viral or other hepatitis,
current alcohol abuse, or cirrhosis

- Presence of positive test results for hepatitis B virus (HBV), hepatitis B surface
antigen (HBsAg), or hepatitis C (HCV) antibody

- Patients who are positive for HCV antibody must be negative for HCV by polymerase
chain reaction (PCR) to be eligible for study participation

- Patients with occult or prior HBV infection (defined as positive total hepatitis
B core antibody [HBcAb] and negative HBsAg) may be included if HBV
deoxyribonucleic acid (DNA) is undetectable. These patients must be willing to
undergo monthly DNA testing and to remain on hepatitis B prophylaxis during
therapy

- Patients with human immunodeficiency virus (HIV) are eligible if they have a CD4 count
> 400 and an undetectable viral load. They must be under the care of an infectious
disease physician and have no history of an acquired immune deficiency syndrome
(AIDS)-defining illness (except lymphoma)

- Receipt of live-virus vaccines within 28 days prior to the initiation of study
treatment or need for live-virus vaccines at any time during study treatment

- Pregnant or lactating, or intending to become pregnant during the study

- Women of childbearing potential must have a negative serum pregnancy test result
within 21 days prior to initiation of study drug

- Recent major surgery (within 6 weeks prior to the start of cycle 1, day 1) other than
for diagnosis or line placement

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

- Known allergy to both xanthine oxidase inhibitors (ie, allopurinol) and rasburicase