Safe Accelerated Venetoclax Escalation in CLL
Safe Accelerated Venetoclax Escalation in CLL
This research study is trying to determine which patients with newly diagnosed or
 relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL),
 as grouped by their risk for tumor lysis syndrome (TLS), are able to safely tolerate an
 accelerated, daily venetoclax dose ramp-up rather than the standard approved schedule (5-week
 dose ramp-up).

 The name of the study drug involved in this study is:

 -  Venetoclax

 The following drugs may also be included in some participants treatment regimen:

 -  Obinutuzumab

 -  Rituximab
This is an open label phase Ib study of an accelerated venetoclax ramp-up in patients with
 CLL/SLL in either the front-line or relapsed/refractory setting. This clinical trial is
 testing a new dosing schedule of a drug that is normally dosed in a different fashion. As
 such, venetoclax is considered an investigational drug when given in this new schedule.
 "Investigational" means that the drug is being studied. The U.S. Food and Drug Administration
 (FDA) has approved venetoclax as a treatment option for CLL or SLL but the approval is based
 on a different schedule.

 Venetoclax is an oral drug inhibitor of BCL-2, a protein that regulates the death of cells in
 the body. It has been FDA approved with or without rituximab for the treatment of adult
 patients with CLL/SLL who have received at least one prior therapy, with obinutuzumab for
 frontline therapy of CLL/SLL, as well in combination with azacitabine, decitabine, or
 low-dose cytarabine for the treatment of adults with newly diagnosed acute myeloid leukemia
 (AML).

 Venetoclax is typically started at a low dose and increased on a weekly basis, over 5 weeks,
 to the desired dose for patients with CLL/SLL.This study is trying to determine if patients
 can safely increase the venetoclax dose in the hospital on a daily basis, over 5 days rather
 than weekly, and which patients, grouped by their risk for TLS, with newly diagnosed or
 relapsed/refractory CLL/SLL, are able to safely tolerate this accelerated, daily venetoclax
 dose ramp-up.

 The research study procedures include screening for eligibility and study treatment including
 evaluations and follow up visits.

 All participants will be actively followed for approximately 3 months. Following completion
 of the active study period, participants will be encouraged to return for a response
 evaluation. Following this, patients will enter a long-term follow up period where they will
 be observed for a maximum of 5 years.

 It is expected that about 40 people will take part in this research study.
Inclusion Criteria:

 -  Must have a confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic
 lymphoma per IW-CLL 201814 requiring therapy based on at least one of the following
 criteria as listed below:

 -  Evidence of progressive marrow failure as manifested by the development of, or
 worsening of, anemia (hemoglobin <11.0 g/L) and/or thrombocytopenia (platelets
 <100 x 109/L)

 -  Massive (≥6 cm below the left costal margin), progressive, or symptomatic
 splenomegaly

 -  Massive nodes (at least 10 cm longest diameter), progressive, or symptomatic

 -  lymphadenopathy

 -  Progressive lymphocytosis with an increase of more than 50% over a 2-month period
 or LDT of <6 months. Lymphocyte doubling time may be obtained by linear
 regression extrapolation of absolute lymphocyte counts obtained at intervals of 2
 weeks over an observation period of 2 to 3 months.

 -  Autoimmune anemia and/or thrombocytopenia that is poorly responsive to
 corticosteroids or other standard therapy

 -  Documented constitutional symptoms, defined as 1 or more of the following disease
 related symptoms or signs: unintentional weight loss >10% within 6 months prior
 to screening, significant fatigue (inability to work or perform usual
 activities), fevers >100.5° F or 38.0° C for 2 or more weeks prior to screening
 without evidence of infection, night sweats for more than 1 month prior to
 screening without evidence of infection

 -  Both previously untreated and relapsed or refractory patients will be eligible,
 including those who will be receiving venetoclax as monotherapy or in combination with
 anti-CD20 monoclonal antibody therapy

 -  Age greater or equal to 18 years

 -  ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)

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

 -  Absolute neutrophil count ≥1000 cells/mm3. Growth factor is allowed in order to
 achieve this

 -  Platelet count ≥25,000 cells/mm3 (25 x 109/L) independent of transfusion within 7
 days of screening

 -  Adequate hepatic function defined as:

 -  Serum aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x upper
 limit of normal (ULN), bilirubin ≤1.5 x ULN (unless bilirubin rise is due to
 Gilbert's syndrome or of non-hepatic origin)

 -  Adequate renal function as defined as:

 -  Serum creatinine ≤1.5 times the ULN or creatinine clearance ≥ 50 mL/min using a
 24-hour urine collection

 -  Women of child-bearing potential and men must agree to use adequate contraception
 (hormonal, barrier method or abstinence) prior to study entry and for the duration of
 study participation

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

 Exclusion Criteria:

 -  Treatment with venetoclax within the past 6 months

 -  Transformation of CLL to aggressive NHL (Richter's transformation or pro-lymphocytic
 leukemia)

 -  Patients receiving cancer therapy (i.e., chemotherapy, radiation therapy,
 immunotherapy, biologic therapy, surgery within 2 weeks of Cycle 1/Day 1 with the
 following exceptions:

 -  CD20 antibody therapy (i.e. rituximab or obinutuzumab) if it is being used as
 part of the venetoclax regimen (see inclusion criteria 3.1.2)

 -  For patients on targeted therapies, a washout of least five half lives is
 required

 -  Patients who experience clinical deterioration may start therapy after a shorter
 washout period with prior approval by the PI

 -  Corticosteroid therapy (prednisone or equivalent <=20 mg daily) is allowed

 -  Confirmed central nervous system involvement

 -  Allogeneic hematologic stem cell transplant within 6 months of starting study
 treatment or active graft vs. host disease (GVHD) requiring treatment or prophylaxis

 -  Active malignancy requiring therapy that would interact with venetoclax as per the
 discretion of the treating investigator

 -  Any active systemic infection requiring IV antibiotics or other uncontrolled, active
 infections

 -  Known history of human immunodeficiency virus (HIV), hepatitis C virus (HCV), or
 hepatitis B virus (HBV)

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

 -  Currently active, clinically significant cardiovascular disease, such as uncontrolled
 arrhythmia or Class 3 or 4 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 of initial dosing on study

 -  Use of Coumadin for anticoagulation (other anticoagulants permitted)

 -  Lactating or pregnant

 -  Concurrent administration of medications or foods that are strong inhibitors or
 inducers of CYP3A . The concomitant use of drugs or foods that are strong or moderate
 inhibitors or inducers of CYP3A are not allowed beginning 1 week prior to the first
 dose of venetoclax.

 -  Patients with ongoing use of prophylactic antibiotics are eligible as long as there is
 no evidence of active infection and the antibiotic is not included on the list of
 prohibited medications

 -  Unable to swallow capsules or malabsorption syndrome, active disease significantly
 affecting gastrointestinal function, or resection of the stomach or small bowel,
 symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete
 bowel obstruction resulting in malabsorption or chronic diarrhea

 -  Active abuse of alcohol