A Phase II Study of Venetoclax in Combination With Dose-adjusted EPOCH-R or R-CHOP for Patients With Richter's Syndrome
A Phase II Study of Venetoclax in Combination With Dose-adjusted EPOCH-R 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
This research study is a Phase II clinical trial. Phase II clinical trials test the safety
 and effectiveness of an investigational drug to learn whether the drug works in treating a
 specific disease. "Investigational" means that the drug is being studied.

 Tumor cells from patients with Richter's Syndrome are often resistant to chemotherapy. One
 reason for this may be that a protein called BCL-2 can prevent cancer cells from dying after
 being exposed to chemotherapy. Venetoclax is an oral drug that specifically targets BCL-2. It
 has already been shown to be highly effective at killing tumor cells from CLL patients whose
 cells are resistant to chemotherapy, leading to its FDA (the U.S. Food and Drug
 Administration) approval for these patients. A small number of patients with Richter's
 Syndrome have been treated with venetoclax as a single drug, and some of these patients had
 improvement of their cancer with this treatment.

 In this research study, the investigators are looking to see whether adding venetoclax to a
 standard chemotherapy regimen, R-EPOCH or R-CHOP, will help this chemotherapy work better to
 more effectively kill tumor cells in patients with Richter's Syndrome. Venetoclax is not
 approved for Richter's Syndrome or for use in combination with chemotherapy, which is why its
 use in this trial is considered to be investigational.
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