A phase II study of venetoclax in combination with dose-adjusted R-EPOCH or R-CHOP for patients with Richter's syndrome

This research study is evaluating the combination of a study drug, venetoclax, and a standard
chemotherapy regimen, R-EPOCH or R-CHOP, as a possible treatment for Richter's Syndrome.

The drugs involved in this study are:

- Venetoclax

- R-EPOCH:

- Rituximab

- Etoposide

- Prednisone

- Vincristine Sulfate (Oncovin)

- Cyclophosphamide

- Doxorubicin Hydrochloride (Hydroxydaunomycin)

- R-CHOP:

- Rituximab

- Cyclophosphamide Vincristine

- Doxorubicin Hydrochloride (Hydroxydaunomycin)

- Sulfate (Oncovin)

- Prednisone

Inclusion Criteria:

- Must have a confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic
lymphoma as per IW-CLL 2008 criteria (Hallek et al, 2008) with biopsy proven
transformation to diffuse large B cell lymphoma (DLBCL), consistent with Richter's
Syndrome.

- Age greater than or equal to 18 years. Because CLL and Richter's Syndrome are
extremely rare in persons <18 years of age, children are excluded from this study.

- ECOG performance status <2 (see Appendix A)

- Patients must meet the following hematologic criteria at screening, unless they have
significant bone marrow involvement of their malignancy confirmed on biopsy:

- Absolute neutrophil count ≥1000 cells/mm3 (0.5 x 109/L). Growth factor allowed to
achieve

- Platelet count ≥40,000 cells/mm3 (40 x 109/L) independent of transfusion within 7
days of screening

- Subject must have adequate coagulation, renal, and hepatic function, per laboratory
reference range at Screening as follows:

- Creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min using 24-hour urine
collection for creatinine clearance

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × ULN;

- Bilirubin ≤ 1.5 × ULN;

- Subjects with Gilbert's Syndrome or resolving autoimmune hemolytic anemia may
have a bilirubin up to 3.0 × ULN and are still eligible

- The effects of venetoclax on the developing human fetus are unknown. For this reason,
women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and for
the duration of study participation. Contraception must continue for an additional 30
days post last dose of venetoclax for women, and an additional 90 days post last dose
in men. Should a woman become pregnant or suspect she is pregnant while participating
in this study, she should inform her treating physician immediately and venetoclax
must be discontinued immediately.

- For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraception and agreement to refrain from
donating eggs, as defined below:

- Women must remain abstinent or use contraceptive methods with a failure rate of
<1% per year during the treatment period and for at least 30 days after the last
dose of venetoclax and 12 months after the last dose of chemotherapy, whichever
is later. Women must refrain from donating eggs during this same period.

- A woman is considered to be of childbearing potential if she is postmenarchal,
has not reached a postmenopausal state (≥12 continuous months of amenorrhea with
no identified cause other than menopause), and is not permanently infertile due
to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another
cause as determined by the investigator (e.g., Müllerian agenesis). The
definition of childbearing potential may be adapted for alignment with local
guidelines or regulations. 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.

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

- With a female partner of childbearing potential who is not pregnant, men who are
not surgically sterile 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 90 days after the last dose of
venetoclax or 12 months after completion of chemotherapy, whichever is later. Men
must refrain from donating sperm during this same period. With a pregnant female
partner, men must remain abstinent or use a condom during the treatment period
and for at least 90 days after the last dose of venetoclax or 12 months after the
last dose of chemotherapy, whichever is later, to avoid exposing the embryo.

- Patients who have undergone prior allogeneic transplantation are eligible provided
they do not have significant active graft versus host disease and that their
transplant day 0 is > 6 months from their first dose of chemotherapy

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients with the Hodgkin variant transformation of CLL will be excluded

- History of severe allergic or anaphylactic reactions to monoclonal antibody therapy or
to the chemotherapy drugs used in this study (see Appendix D), unless the antibody can
be given through a desensitization program in consultation with an allergist

- Subject has received any of the following within 14 days or 5 drug half-lives
(whichever is shortest) prior to the first dose of chemotherapy, or has not recovered
to less than Grade 2 clinically significant adverse effect(s)/toxicity(s) of the
previous therapy:

--Any anti-cancer therapy including chemotherapy, biologic agents for anti-neoplastic
treatment (e.g. monoclonal antibodies) or radiotherapy, investigational therapy,
including targeted small molecule agents. Patients who are currently receiving
treatment with ibrutinib or acalabrutinib may continue this agent until the day prior
to starting venetoclax, to reduce the risk of tumor flare on treatment cessation.

- Received previous treatment with R-CHOP, R-EPOCH, or R-hyper-CVAD

- History of other malignancies, except:

- Malignancy treated with curative intent and with no known active disease present
before the first dose of study drug and felt to be at low risk for recurrence by
treating physician.

- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease.

- Adequately treated carcinoma in situ without evidence of disease

- Low-risk prostate cancer on active surveillance

- Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc.)
within 28 days of the first dose of study drug.

- Corticosteroids are allowed, but must be dosed at prednisone 20 mg (or equivalent) or
lower prior to the start of chemotherapy.

- Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.

- Known bleeding disorders (eg, von Willebrand's disease) or hemophilia.

- History of stroke or intracranial hemorrhage within 6 months prior to enrollment.

- History of human immunodeficiency virus (HIV) or Human T-Cell Leukemia Virus 1
(HTLV-1), or active hepatitis C virus (HCV) or hepatitis B virus (HBV). Patients who
are positive for hepatitis B core antibody or hepatitis B surface antigen must have a
negative polymerase chain reaction (PCR) result before enrollment, i.e. HBV DNA must
be undetectable, provided that they are willing to undergo monthly DNA testing. Those
who are PCR positive will be excluded. Patients who are positive for HCV antibody are
eligible only if PCR is negative for HCV RNA.

- Any uncontrolled active systemic infection.

- Major surgery within 4 weeks of first dose of study drug.

- Currently active, clinically significant cardiovascular disease, such as uncontrolled
arrhythmia or Class 2 or higher congestive heart failure as defined by the New York
Heart Association Functional Classification; or a history of myocardial infarction,
unstable angina, or acute coronary syndrome within 6 months prior to randomization.

- Unable to swallow capsules or malabsorption syndrome, symptomatic inflammatory bowel
disease or ulcerative colitis, or partial or complete bowel obstruction at time of
screening.

- Breastfeeding or pregnant. Serum pregnancy test will be conducted.

- Male subject who is considering fathering a child or donating sperm during the study
or for approximately 90 days after the last dose of study drugs.

- Unwilling or unable to participate in all required study evaluations and procedures.
Unable to understand the purpose and risks of the study and to provide a signed and
dated informed consent form (ICF) and authorization to use protected health
information (in accordance with national and local subject privacy regulations)

- Patients receiving any other study agents

- Patients with known CNS involvement

- Baseline QTcF >480 ms. NOTE: This criterion does not apply to patients with a left
bundle branch block.

- Patients who require warfarin or other vitamin K antagonists for anticoagulation
(other anticoagulants are allowed).

- Concurrent administration of medications or foods that are strong inhibitors or
inducers of CYP3A (see Appendix B).

- Patients with ongoing use of prophylactic antibiotics are eligible as long as there is
no evidence of active infection and the antibiotic is not a prohibited medication

- Unable to receive prophylactic treatment for pneumocystis, herpes simplex virus (HSV),
and herpes zoster (VZV) at start of treatment

- Significant co-morbid condition or disease which in the judgment of the Principal
Investigator would place the patient at undue risk or interfere with the study