PRIMARY OBJECTIVES:
I. Demonstrate improvement in bone marrow (BM) undetectable-minimal residual disease,10-4
sensitivity (MRD4) from 40% to 70% after 7 courses of combined acalabrutinib (ACA) and
venetoclax (VEN) (end of C9 overall) with addition of early obinutuzumab (OBIN).
(Treatment-naive [TN] cohort) II. Demonstrate improvement in BM undetectable-MRD4 from 40% to
70% after 12 courses of combined acalabrutinib (ACA) and venetoclax (VEN) (end of cycle [C]14
overall) with addition of early obinutuzumab (OBIN). (Relapsed/refractory [R/R] cohort)
SECONDARY AND EXPLORATORY OBJECTIVES:
I. Determine the safety of combined acalabrutinib, venetoclax obinutuzumab. II. Determine the
overall best response rates (complete response [CR], partial response [PR], overall response
[OR]) for each cohort and each treatment arm by International Workshop on Chronic Lymphocytic
Leukemia (iwCLL) 2018 criteria.
III. Estimate the time to best response for each cohort and each treatment arm with this
combination.
IV. Estimate the progression-free (PFS) for each cohort and each treatment arm. V. Estimate
proportion of patients with blood/BM undetectable-MRD4, blood/BM undetectable-MRD6 (10-6
sensitivity), CR after 12 and 24 courses combination with VEN (end of C14 and C26 overall)
(by cohort and OBIN status).
VI. Determine the proportion of patients who receive late OBIN (C15-C20 overall) and
conversion rate for blood/BM undetectable-MRD4 and blood/BM undetectable-MRD6 and CR in those
who receive late OBIN.
VII. Correlate plasma cell-free deoxyribonucleic acid (DNA) (cfDNA) with cell-based blood/BM
undetectable-MRD4, blood/BM undetectable-MRD6 status at all response assessment time points.
VIII. Determine proportion of patients who discontinue treatment early based on
undetectable-MRD results.
IX. Determine time-to-blood MRD6 relapse for those who achieve undetectable-MRD6.
X. Determine response to re-treatment upon relapse. XI. Assess clonal evolution at relapse
and correlate with plasma cell-free DNA (cfDNA).
XII. Determine OBIN pharmacokinetics - free drug level assessments to optimize dosing.
XIII. Determine VEN pharmacokinetics - free drug levels to assess changes in exposure with
combination.
XIV. Determine ACA pharmacokinetics - free drug levels to assess changes in exposure with
combination.
XV. Identify predictive markers for response and outcomes.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive acalabrutinib orally (PO) twice daily (BID) on days 1-28. Beginning
cycle 3, patients receive venetoclax PO BID on days 1-28. Patients who are BM MRD4-positive
or in PR also receive obinutuzumab intravenously (IV) over 4-6 hours on days 1, 2, 8, and 15
of cycle 15 and day 1 of cycles 16-20. Treatment repeats every 28 days (or 42 days for cycle
14) for up to 26 cycles in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive acalabrutinib PO BID on days 1-28 beginning cycle 2 and venetoclax
PO BID on days 1-28 beginning cycle 3. Patients also receive obinutuzumab IV over 4-6 hours
on days 1, 2, 8, and 15 of cycle 1 and day 1 of cycles 2-6. Patients who are BM MRD4-positive
or in PR receive obinutuzumab IV over 4-6 hours on day 1 cycles 15-20. Treatment repeats
every 28 days (or 42 days for cycle 14) for up to 26 cycles in the absence of disease
progression or unacceptable toxicity.
After completion of study treatment, patients are followed up periodically.
Inclusion Criteria:
- Patients with a diagnosis of chronic lymphocytic leukemia (CLL)/small lymphocytic
lymphoma (SLL) and indication for treatment by 2018 iwCLL criteria:
- Cohort 1: Untreated patients with at least 1 high-risk feature (del(17p) or
mutated TP53 or del(11q) or unmutated immunoglobulin heavy chain variable [IGHV]
or complex karyotype) OR >= 65 years of age
- Cohort 2: Relapsed after and/or refractory to at least one prior therapy
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Total bilirubin =< 1.5 x upper limit of normal (ULN) or =< 3 x ULN for patients with
Gilbert's disease
- Creatinine clearance > 50 mL/min (calculated according to institutional standards or
using Cockcroft-Gault, Modification of Diet in Renal Disease [MDRD], or Chronic Kidney
Disease-Epidemiology Collaboration [CKD-EPI] formula)
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3.0 x ULN,
unless clearly due to disease involvement
- Absolute neutrophil count greater than 750 neutrophils/μL, unless thought to be due to
marrow infiltration with CLL
- Platelet count of greater than 30,000/ul, with no platelet transfusion in 2 weeks
prior to registration
- Women of childbearing potential must have a negative serum or urine beta human
chorionic gonadotropin (b-hCG) pregnancy test result within 7 days prior to the first
dose of study drugs and must agree to use an effective contraception method during the
study and for 2 days after the last dose of acalabrutinib, 30 days after the last dose
of venetoclax, or 18 months after the last dose of obinutuzumab, whichever is longer.
Women of non-childbearing potential are those who are postmenopausal greater than 1
year or who have had a bilateral tubal ligation or hysterectomy. Men who are sexually
active must agree to use highly effective forms of contraception with the addition of
a barrier method (condom) during the study and for 30 days after the last dose of
venetoclax and for 18 months after the last dose obinutuzumab, whichever is longer
- Free of prior malignancies for 2 years with exception of patients diagnosed with basal
cell or squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or
breast, who are eligible even if they are currently treated or have been treated
and/or diagnosed in the past 2 years prior to study enrollment. If patients have
another malignancy that was treated within the last 2 years, such patients may be
enrolled, if the likelihood of requiring systemic therapy for this other malignancy
within 2 years is less than 10%, as determined by an expert in that particular
malignancy at MD Anderson Cancer Center, and after consultation with the principal
investigator
- Patients or their legally authorized representative must provide written informed
consent
- Patients taking proton pump inhibitors must be willing to switch to H2-receptor
antagonist or antacid prior to starting treatment
Exclusion Criteria:
- Prior treatment with combined BTKi and BCL2i
- Major surgery, radiotherapy, chemotherapy, biologic therapy, immunotherapy,
investigational therapy or live virus vaccination within 3 weeks prior to the first
dose of the study drugs, unless patients have rapidly progressive disease, in which
case, washout will be 3 drug half-lives
- History of severe allergic or anaphylactic reactions to humanized or murine monoclonal
antibodies or known sensitivity or allergy to murine products
- Uncontrolled clinically significant active infection (viral, bacterial, and fungal)
- Known positive serology for human immunodeficiency virus (HIV), due to potential
drug-drug interactions between anti-retroviral medications and the study drugs
- Active hepatitis B infection (defined as the presence of detectable hepatitis B virus
[HBV] DNA, hepatitis B virus e [HBe] antigen or hepatitis B virus surface [HBs]
antigen). Subjects with serologic evidence of prior vaccination (hepatitis B virus
surface antigen [HBsAg] negative, anti-HBs antibody positive, anti-HBc antibody
negative) are eligible. Patients who are HBsAg negative/hepatitis B virus surface
antibody ([HBsAb) positive but hepatitis B virus core antibody (HBcAb) positive are
eligible, provided HBV DNA is negative
- Active hepatitis C, defined by the detectable hepatitis C ribonucleic acid (RNA) in
plasma by polymerase chain reaction (PCR)
- Active, uncontrolled autoimmune phenomenon (autoimmune hemolytic anemia or immune
thrombocytopenia) requiring steroid therapy with > 20 mg daily of prednisone dose or
equivalent
- Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias,
congestive heart failure, or myocardial infarction within 6 months of screening, or
any class 3 or 4 cardiac disease as defined by the New York Heart Association
Functional Classification
- Patient is pregnant or breast-feeding
- Concurrent use of warfarin
- Received strong CYP3A inhibitors or strong CYP3A inducers within 7 days of starting
study drugs and throughout venetoclax administration
- Consumed grapefruit, grapefruit products, Seville oranges, or star fruit within 3 days
of starting venetoclax
- Known bleeding disorder or history of stroke or intracranial hemorrhage within past 6
months
- Malabsorption syndrome or other condition that precludes enteral route of
administration
- Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that in the opinion of the investigator may increase the risk associated
with study participation or investigational product administration or may interfere
with the interpretation of study results and/or would make the patient inappropriate
for enrollment into this study
