PRIMARY OBJECTIVE:
I. To evaluate whether early treatment with venetoclax and obinutuzumab (V-O) extends overall
survival (OS) compared with delayed treatment with V-O in high-risk (Chronic Lymphocytic
Leukemia [CLL] International Prognostic Indicator [CLL-IPI] >= 4 or complex cytogenetics),
newly diagnosed asymptomatic CLL/small lymphocytic lymphoma (SLL) patients.
SECONDARY OBJECTIVES:
I. To compare overall response rates (complete response [CR] + partial response [PR]), CR
rates, progression-free survival (PFS), and event-free survival (EFS) between arms.
II. To evaluate safety and tolerability of each arm. III. To compare time to second
CLL-directed treatment (from randomization and from response) between arms.
IV. To compare relapse-free survival (RFS) and time to second objective disease progression
(PFS2) between arms.
V. To compare the rates of Richter's transformation between arms. VI. To describe
distribution of Cumulative Illness Rating Scale across the study, in each treatment arm, and
to estimate the interaction between the scale and treatment arm and OS.
PATIENT-REPORTED OUTCOMES OBJECTIVES:
I. To assess the impact of early intervention with V-O versus delayed therapy with V-O in CLL
patients in relation to Health-Related Quality of Life (HRQoL) using the Functional
Assessment of Cancer Therapy (FACT)-Leukemia scale.
II. To assess the impact of the two treatment arms on the specific domains of the
FACT-Leukemia, including physical, social, emotional, and functional well-being and
leukemia-specific HRQoL.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I (DELAYED V-O): Treatment begins once 2018 IWCLL indications are met. Patients receive
obinutuzumab intravenously (IV) over 4 hours on days 1, 2, 8, and 15 of cycle 1 and on day 1
of cycles 2-6. Patients also receive venetoclax orally (PO) once daily (QD) on days 22-28 of
cycle 1 and on days 1-28 of cycles 2-12. Treatment repeats every 28 days for 12 cycles in the
absence of disease progression or unacceptable toxicity.
ARM II (EARLY V-O): Treatment begins as soon as eligibility criteria are met. Patients
receive obinutuzumab IV over 4 hours on days 1, 2, 8, and 15 of cycle 1 and on day 1 of
cycles 2-6. Patients also receive venetoclax PO QD on days 22-28 of cycle 1 and on days 1-28
of cycles 2-12. Treatment repeats every 28 days for 12 cycles in the absence of disease
progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 10 years after
registration.
Inclusion Criteria:
- Patients must have a confirmed diagnosis of chronic lymphocytic leukemia (CLL) or
small lymphocytic lymphoma (SLL) (collectively referred to as CLL throughout)
according to the 2018 International Workshop on CLL. Patients must have been diagnosed
within 12 months prior to registration
- Patients must not meet any of the International Workshop on Chronic Lymphocytic
Leukemia (IWCLL) specified criteria for active CLL therapy
- Patients must have CLL-International Prognostic Index (CLL-IPI) score >= 4 and/or
complex cytogenetics (defined as 3+ chromosomal abnormalities)
- Cytogenetic and fluorescence in situ hybridization (FISH) analyses must be completed
at the site's Clinical Laboratory Improvement Act (CLIA)-approved laboratory within 12
months prior to registration. FISH panel should use probes to detect for abnormalities
in chromosomes 13q, 12, 11q, and 17p. TP53 mutation status (if completed) must be
obtained within 12 months prior to registration. Immunoglobulin heavy chain locus
variable (IgVH) mutational status must be obtained prior to registration (at any time
prior to registration). Serum beta-2 microglobulin level must be obtained within 28
days prior to registration
- Patients must not have received or be currently receiving any prior CLL-directed
therapy, including non-protocol-related therapy, anti-cancer immunotherapy,
experimental therapy, or radiotherapy
- The treating physician must have the intent of using V-O as initial therapy when the
patient requires initial treatment
- Treatment with high dose corticosteroids and/or intravenous immunoglobulin for
autoimmune complications of CLL 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. Prior therapy with anti CD20
monoclonal antibodies is not allowed
- Patients must not be receiving or planning to receive any other investigational agents
before completing protocol therapy
- Patients must be >= 18 years of age
- Patients must have Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Platelet count >= 100,000/mm^3 within 28 days prior to registration
- Absolute neutrophil count (ANC) >= 1,000/mm^3 within 28 days prior to registration
- Creatinine clearance >= 30mL/min (by Cockcroft Gault) within 28 days prior to
registration
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3.0 x upper
limit of normal (ULN) within 28 days prior to registration
- Total bilirubin =< 2.0 x ULN (or 5.0 x ULN if the patient has a history of Gilbert's
disease), within 28 days prior to registration
- Patients must not have current, clinically significant gastrointestinal malabsorption,
in the opinion of treating doctor
- Patients must be able to take oral medications
- Obinutuzumab has been associated with hepatitis reactivation. Participants must not
have uncontrolled active infection with hepatitis B or C. Participants with latent
hepatitis B infection must agree to take prophylaxis during and for 6 months following
active protocol therapy with V-O.
- Active infection with hepatitis B or C:
- Active infection is defined as detectable hepatitis B deoxyribonucleic acid
(DNA) or hepatitis C ribonucleic acid (RNA) by quantitative polymerase chain
reaction (PCR).
- Latent infection with hepatitis B:
- Latent infection is defined as meeting all of the following criteria:
- Hepatitis B surface antigen positive
- Anti-hepatitis B total core antibody positive
- Anti-hepatitis IgM core antibody undetectable
- Hepatitis B PCR undetectable
- Participants with latent hepatitis B infection must agree to take
prophylaxis with anti-hepatitis agents during and for 6 months following
active protocol therapy with V-O.
- Participants who have received intravenous immunoglobulin (IVIG) therapy
within 6 months who are hepatitis B core total antibody positive but PCR
undetectable are not mandated to take prophylaxis
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial
- Patients may not have had major surgery within 30 days prior registration or minor
surgery within 7 days prior to registration. Examples of major surgery include
neurosurgical procedures, joint replacements, and surgeries that occur inside the
thoracic or abdomino-pelvic cavities. Examples of minor surgery include dental
surgery, insertion of a venous access device, skin biopsy, or aspiration of a joint.
If there is a question about whether a surgery is major or minor, this should be
discussed with the study chair
- Patients must not have known bleeding disorders (e.g., von Willebrand's disease or
hemophilia)
- Patients must not have a history of stroke or intracranial hemorrhage within 6 months
prior to enrollment
- Patients must not require continued therapy with a strong inhibitor or inducer of
CYP3A4/5, as venetoclax is extensively metabolized by CYP3A4/5
- Patients must not have uncontrolled autoimmune hemolytic anemia or idiopathic
thrombocytopenia purpura
- Patients must not have any 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
prior to enrollment
- Patients with history of malignancy are allowed providing the cancer has not required
active treatment within 2 years prior to registration (hormonal therapy is
permissible). The following exceptions are permissible: basal cell, squamous cell
skin, or non-melanomatous skin cancer, in situ cervical cancer, superficial bladder
cancer not treated with intravesical chemotherapy or Bacillus Calmette-Guerin (BCG)
within 6 months, localized prostate cancer requiring no more than chronic hormonal
therapy, or localized breast cancer requiring no more than chronic hormonal therapy
- Patients must not be pregnant or nursing, as there are no safety data available for
these drug regimens during pregnancy. Women/men of reproductive potential must have
agreed to use an effective contraceptive method. A woman is considered to be of
"reproductive potential" if she has had menses at any time in the preceding 12
consecutive months. In addition to routine contraceptive methods, "effective
contraception" also includes heterosexual celibacy and surgery intended to prevent
pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy,
bilateral oophorectomy or bilateral tubal ligation. However, if at any point a
previously celibate patient chooses to become heterosexually active during the time
period for use of contraceptive measures outlined in the protocol, he/she is
responsible for beginning contraceptive measures
- Patients must be offered participation in banking for future research. With patient's
consent, specimens must be submitted
- Patients who are able to complete patient reported outcome (PRO) forms in English,
Spanish, French, German, Russian or Mandarin must agree to participate in the quality
of life assessments. (Those patients who are unable to read and write in English,
Spanish, French, German, Russian or Mandarin may be registered to S1925 without
contributing to the quality of life portion of the study.)
- Patients must be informed of the investigational nature of this study and must sign
and give written informed consent in accordance with institutional and federal
guidelines.
- As a part of the Oncology Patient Enrollment Network (OPEN) registration process the
treating institution's identity is provided in order to ensure that the current
(within 365 days) date of institutional review board approval for this study has been
entered in the system
