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Accelerated Dose Venetoclax Ramp-Up for the Treatment of Newly Diagnosed, Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma, SAVE Study

Trial Status: Active

This phase Ib trial studies the side effects of an accelerated dose ramp-up of venetoclax in treating patients with chronic lymphocytic leukemia or small lymphocytic lymphoma that is newly diagnosed, has come back (relapsed) or does not respond to treatment (refractory). Venetoclax is an oral drug inhibitor of BCL-2, a protein that regulates the death of cells in your body. Venetoclax is typically started at a low dose and increased on a weekly basis until the desired dose is reached. Giving an increased dose of venetoclax over a shorter period of time may be safe in treating patients with chronic lymphocytic leukemia or small lymphocytic lymphoma.

Inclusion Criteria

  • Must have a confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic lymphoma per International Workshop-Chronic Lymphocytic Leukemia (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 10^9/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 lymphocyte doubling time (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 degree F or 38.0 degree 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 antiCD20 monoclonal antibody therapy
  • Age greater or equal to 18 years
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Absolute neutrophil count >=1000 cells/mm^3. Growth factor is allowed in order to achieve this (unless they have significant bone marrow involvement of CLL confirmed on biopsy)
  • Platelet count >= 25,000 cells/mm^3 (25 x 10^ 9/L) independent of transfusion within 7 days of screening (unless they have significant bone marrow involvement of CLL confirmed on biopsy)
  • 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)
  • 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 non-Hodgkin lymphoma (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 * 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 principal investigator (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

Massachusetts

Boston
Brigham and Women's Hospital
Status: ACTIVE
Contact: Jennifer Crombie
Phone: 617-632-4106
Dana-Farber Cancer Institute
Status: ACTIVE
Contact: Jennifer Crombie
Phone: 617-632-4106

PRIMARY OBJECTIVE:

I. To determine the highest risk tumor lysis syndrome (TLS) group among patients with newly diagnosed or relapsed/refractory chronic lymphocytic leukemia (CLL) who are able to safely tolerate an accelerated, daily venetoclax dose ramp-up.

SECONDARY OBJECTIVES:

I. To assess the safety and tolerability of an accelerated, daily venetoclax dose ramp-up.

II. To evaluate preliminary efficacy, including best objective response rate (ORR), complete response (CR) rate after approximately 3 months of venetoclax-based therapy, progression free survival (PFS), and overall survival (OS).

III. To determine the rate of undetectable minimal residual disease (uMRD) in the peripheral blood.

EXPLORATORY OBJECTIVES:

I. Determine the rate of uMRD in the bone marrow.

II. To determine if overall mitochondrial priming, dependency on specific anti-apoptotic BCL-2 family members, or protein expression is associated with efficacy or toxicity, including risk of TLS.

OUTLINE: This is a dose-escalation study of venetoclax.

Beginning day 1 or 22 of cycle 1, patients receive venetoclax orally (PO) once daily (QD) for up to 5 weeks. Before or after venetoclax and depending on their treatment schedule, patients may also receive rituximab intravenously (IV) on day 1 (starting during cycle 2) or obinutuzumab IV on days 1, 2, 8, and 15 of cycle 1 and on day 1 of subsequent cycles per standard of care. Treatment with rituximab or obinutuzumab repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 5 years.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Jennifer Crombie

  • Primary ID 20-415
  • Secondary IDs NCI-2021-03547
  • Clinicaltrials.gov ID NCT04843904