CRC043: A Phase II Study of Venetoclax in Combination With Dose-adjusted EPOCH-R for Patients With Richter's Syndrome

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, 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:

- Activated partial thromboplastin time (aPTT) and prothrombin time (PT) not to
exceed 1.5 × ULN;

- 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. Should a woman become
pregnant or suspect she is pregnant while participating in this study, she should
inform her treating physician immediately

- 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.

- 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 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. Those who are PCR positive will be excluded.

- Any uncontrolled active systemic infection.

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

- Any life-threatening illness, medical condition, or organ system dysfunction that, in
the investigator's opinion, could compromise the subject's safety or put the study
outcomes at undue risk.

- 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