Principal Investigator
Enrollment Status
Clinical Trial ID
Clinical Trial Summary
This phase III trial compares adding a new anti-cancer drug (venetoclax) to the usual
treatment (ibrutinib plus obinutuzumab) in older patients with chronic lymphocytic leukemia
who have not received previous treatment. The addition of venetoclax to the usual treatment
might prevent chronic lymphocytic leukemia from returning. This trial also will investigate
whether patients who receive ibrutinib plus obinutuzumab plus venetoclax and have no
detectable chronic lymphocytic leukemia after 1 year of treatment, can stop taking ibrutinib.
Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell
growth. Immunotherapy with obinutuzumab may induce changes in body's immune system and may
interfere with the ability of cancer cells to grow and spread. Venetoclax is in a class of
medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer
cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving ibrutinib and
obinutuzumab with venetoclax may work better at treating chronic lymphocytic leukemia
compared to ibrutinib and obinutuzumab.
Phase
Phase 3
Funding Agency/Sponsor
National Cooperative Group
Disease
Leukemia/heme
Enrollment Eligibility
Inclusion Criteria:
- PRE-REGISTRATION ELIGIBILITY CRITERIA (STEP 0)
- Patients must have been diagnosed with chronic lymphocytic leukemia (CLL) (> 5000
B-cells per uL of peripheral blood at any point during the course of their disease) or
small lymphocytic lymphoma (SLL) with < 5000 B-cells per uL of blood but with
disease-associated lymphadenopathy
- This blood submission is mandatory prior to registration/randomization to perform
fluorescence in situ hybridization (FISH) centrally that will be used for
stratification. It should be obtained as soon after pre-registration as possible
- REGISTRATION ELIGIBILITY CRITERIA (STEP 1)
- Patients must be diagnosed with CLL or SLL in accordance with 2018 International
Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria that includes all of the
following:
- >= 5 x10^9 B lymphocytes (5000/uL) in the peripheral blood measured by flow
cytometry at any point in the course of the disease or less peripheral blood
involvement but disease-associated lymphadenopathy
- On local morphologic review, the leukemic cells must be small mature lymphocytes,
and prolymphocytes must not exceed 55% of the blood lymphocytes
- Neoplastic cells on immunophenotype (performed locally) must reveal a clonal
B-cell population, which express the B cell surface markers of CD19 and CD20, as
well as the T-cell antigen CD5. Patients with bright surface immunoglobulin
expression or lack of CD23 expression in >10% of cells must lack t(11;14)
translocation by interphase cytogenetics
- Patients must be intermediate or high-risk Rai stage CLL or SLL
- Intermediate risk (formerly stage I/II) is defined by lymphadenopathy and/or
hepatomegaly or splenomegaly without anemia or thrombocytopenia
- High risk (formerly stage III/IV) is defined by splenomegaly and/or anemia
(hemoglobin < 11g/dL) not attributable to autoimmune hemolytic anemia and/or
thrombocytopenia (platelets [plt] < 100 x10^9/L) not attributable to autoimmune
thrombocytopenia
- Patients must meet criteria for treatment as defined by 2018 IWCLL guidelines which
includes at least one of the following criteria:
- Evidence of marrow failure as manifested by the development or worsening of
anemia or thrombocytopenia (not attributable to autoimmune hemolytic anemia or
thrombocytopenia)
- Massive (>= 6 cm below the costal margin), progressive or symptomatic
splenomegaly
- Massive nodes (>= 10 cm) or progressive or symptomatic lymphadenopathy
- Progressive lymphocytosis with a lymphocyte doubling time < 6 months or an
increase of >= 50% over a 2 month period
- Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard
therapy
- Symptomatic or functional extranodal involvement (e.g. skin, kidney, lung, spine)
- Constitutional symptoms, which include any of the following:
- Unintentional weight loss of 10% or more within 6 months
- Significant fatigue
- Fevers > 100.5 degrees Fahrenheit (F) for 2 weeks or more without evidence
of infection
- Night sweats >= 1 month without evidence of infection
- Treatment with rituximab and/or high dose corticosteroids for autoimmune complications
of CLL/SLL must be complete at least 4 weeks prior to enrollment. Palliative steroids
must be at a dose not higher than 20 mg/day of prednisone or equivalent corticosteroid
at the time of registration
- Age >= 65 years
- Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- Absolute neutrophil count (ANC) >= 1,000/mm^3 except if due to bone marrow involvement
- Platelet count (untransfused) >= 30,000/mm^3 except if due to bone marrow involvement
- Calculated (Calc.) creatinine clearance >= 40 mL/min (by Cockcroft-Gault)
- Bilirubin =< 1.5 x upper limit of normal (ULN) except if due to liver involvement,
hemolysis, or Gilbert's disease
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit
of normal (ULN) except if due to liver involvement
- If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be
undetectable on suppressive therapy if indicated
- Please note: Intravenous immunoglobulin therapy (IVIG) can cause a false positive
hepatitis B serology. If patients receiving routine IVIG have core antibody or surface
antigen positivity without evidence of active viremia (negative hepatitis B
deoxyribonucleic acid [DNA]) they may still participate in the study, must have
hepatitis serologies and hepatitis B DNA monitored periodically by the treating
physician
- If history of hepatitis C virus (HCV) infection, must be treated with undetectable HCV
viral load
- Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral
therapy with undetectable viral load within 6 months are eligible for this trial
- Central fluorescent in situ hybridization (FISH) blood results are mandatory prior to
registration/randomization for it will be used for stratification
- Patients must be able to swallow capsules and not have the following conditions:
disease significantly affecting gastrointestinal absorption, resection of the stomach
or small bowel, partial or complete bowel obstruction
- Patients must be able to receive either a xanthine oxidase inhibitor or rasburicase
for prophylaxis/treatment of tumor lysis syndrome (TLS)
- RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2)
- Completion of treatment through cycle 14 day 28, and remain on ibrutinib therapy
- Receipt of central BM MRD results
- Response assessment completed with CR determination
Exclusion Criteria:
- Patients must not have had prior therapy for CLL/SLL (except palliative steroids or
treatment of autoimmune complications of CLL with rituximab or steroids)
- Patients must not have any history of Richter's transformation or prolymphocytic
leukemia (prolymphocytes in blood > 55%)
- Patients with class III or class IV heart failure by New York Heart Association, those
with unstable angina, and those with uncontrolled arrhythmia are not eligible
- Patients who have had a myocardial infarction, intracranial bleed, or stroke within
the past 6 months are not eligible
- Patients must not be receiving active systemic anticoagulation with heparin or
warfarin. Patients on warfarin must discontinue the drug for at least 10 days prior to
registration on the study
- Chronic concomitant treatment with strong inhibitors of CYP3A4/5 is not allowed on
this study. Patients on strong CYP3A inhibitors must discontinue the drug for 14 days
prior to registration on the study
- Chronic concomitant treatment with strong CYP3A4/5 inducers is not allowed. Patients
must discontinue the drug 14 days prior to registration on the study
- Patients must not require more than 20 mg prednisone or equivalent corticosteroid
daily
- Patients must not have uncontrolled active systemic infection requiring intravenous
antibiotics
- Patients must not have a known allergy to mannitol
- Patients must not have prior significant hypersensitivity to rituximab (not including
infusion reactions)
- Patients may not have had major surgery within 10 days prior to registration, or minor
surgery within 7 days prior to registration. Examples of minor surgery include dental
surgery, insertion of a venous access device, skin biopsy, or aspiration for a joint.
The decision about whether a surgery is major or minor can be made at the discretion
of the treating physician