Acalabrutinib, Venetoclax, and Obinutuzumab in Treating Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
- Subjects must meet iwCLL 2018 guidelines for the diagnosis of CLL or small lymphocytic lymphoma (SLL), or World Health Organization (WHO) 2017 guidelines for the diagnosis of B-prolymphocytic leukemia (B-PLL)
- In cohort 2, subjects must have TP53-aberrant disease defined as: * Del(17p) detected on karyotype and/or fluorescence in situ hybridization (FISH); OR * TP53 mutation
- Participants must have measurable disease (lymphocytosis > 5,000/ul, or palpable or computed tomography [CT] measurable lymphadenopathy >= 1.5 cm, or bone marrow involvement >= 30%)
- Subjects must not have received any prior systemic therapy for CLL or SLL due to previously meeting IWCLL 2018 guidelines and must currently have an indication for treatment as defined by the IWCLL 2018 guidelines, or must not have received therapy for B-PLL and must currently have an indication for treatment: * Massive or progressive or symptomatic splenomegaly; OR * Massive lymph nodes, nodal clusters, or progressive lymphadenopathy; OR * Significant fatigue (i.e. Eastern Cooperative Oncology Group [ECOG] performance status [PS] 2 or worse; cannot work or unable to perform usual activities); OR * Fever >= 100.5 degrees Fahrenheit (F) for 2 or more weeks without evidence of infection; OR * Night sweats for >= 1 months without evidence of infection; OR * Presence of weight loss >= 10% over the preceding 6 months; OR * Progressive lymphocytosis with an increase of >= 50% over a 2-month period or lymphocyte doubling time of less than 6 months; OR * Evidence of progressive marrow failure as manifested by the development of or worsening of anemia and/or thrombocytopenia. * Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids and another standard therapy such as rituximab * Symptomatic or functional extranodal involvement; OR
- ECOG performance status =< 2
- Total bilirubin =< 1.5 times upper limit of normal, unless there is disease involvement of the liver, hemolysis, or a known history of Gilbert’s disease, in which case direct bilirubin must be =< 3 times the upper limit of normal
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 times the upper limit of normal. If there is hemolysis or documented disease involvement of the liver, then patients with any AST or ALT abnormalities remain eligible
- Creatinine clearance (CrCl) >= 50 mL/min using 24-hour urine collection for creatinine clearance or calculated CrCl OR calculated glomerular filtration rate (GFR) >= 50 mL/min/1.73m^2 using the chronic kidney disease epidemiology (CKD-EPI) equation
- Prothrombin time (PT)/institutional normalized ratio (INR) =< 2 times the upper limit of normal and partial thromboplastin time (PTT) =< 2 times the upper limit of normal
- Absolute neutrophil count >= 750 cells/mm^3 (0.75 x 10^9/L) or >= 500 cells/mm^3 in subjects with documented bone marrow involvement
- Platelet count without transfusional support must be >= 50,000 cells/mm^3 or >= 30,000 cells/mm^3 in subjects with documented bone marrow involvement
- The effects of the study drugs on the developing human fetus are unknown. Women of child-bearing potential must agree to remain abstinent or use highly effective contraception (defined as contraceptive measures that result in a failure rate of < 1% per year) during the treatment period and for at least 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. Men with female sexual partners of childbearing potential should agree to remain abstinent or use contraceptive measures which include a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for at least 30 days after the last dose of venetoclax or 6 months after the last dose of obinutuzumab, whichever is longer. Men should refrain from donating sperm during the same period. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
- Ability to understand and the willingness to sign a written informed consent document
- Participants who have a history of other malignancies except: * Malignancy treated with curative intent and with no known active disease present and felt to be at low risk for recurrence by treating physician. Current adjuvant hormonal therapy for disease treated with curative intent is permissible * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease * Adequately treated carcinoma in situ without evidence of disease * Low-risk prostate cancer on active surveillance
- Participants who are receiving any other investigational agents
- History of severe allergic reactions attributed to compounds of similar chemical or biologic composition to obinutuzumab, venetoclax, or acalabrutinib. Patients with reactions to other CD20 monoclonal antibodies (e.g. rituximab, ofatumumab) are not excluded
- Unable to receive prophylactic treatment for pneumocystis, herpes simplex virus (HSV), and herpes zoster (VZV) at start of treatment
- Known or suspected Richter’s transformation or known central nervous system (CNS) involvement
- Concurrent systemic immunosuppressant therapy (e.g., cyclosporine A, tacrolimus, etc., within 28 days of the first dose of study drug or chronic administration of > 20 mg/day of prednisone within 7 days of the first dose)
- Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug
- Ongoing or recent infection requiring intravenous antimicrobials at time of screening. 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
- Known bleeding disorders (e.g. von Willebrand’s disease) or hemophilia
- Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening
- History of stroke or intracranial hemorrhage within 6 months prior to enrollment
- Major surgery within 4 weeks of first dose of study drug. If a subject had major surgery greater than 4 weeks prior to the first dose, they must have recovered adequately from any toxicity and/or complications from the intervention before the 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 prior to randomization. Patients with atrial fibrillation are allowed as long as they are adequately rate controlled
- Baseline corrected QT interval by Fridericia's correction formula (QTcF) > 480 ms. NOTE: This criterion does not apply to patients with a left bundle branch block
- Patients who require warfarin or other vitamin K antagonists for anticoagulation (other anticoagulants are allowed)
- Patients who require treatment with proton pump inhibitors. Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment on this study
- Patients who require concurrent treatment with strong CYP3A inhibitors or strong CYP3A inducers are excluded from the study. If patients are receiving strong CYP3A inhibitors/inducers at time of screening but do not require continuous administration of these agents, these patients are eligible if there is a 3-day washout period between discontinuation of the strong CYP3A inhibitor/inducer and initiation of the first study drug, acalabrutinib
- Patients who require concurrent treatment with P-gp inhibitors or narrow therapeutic index P-gp substrates are excluded from the study. If patients are receiving P-gp inhibitors or narrow therapeutic index P-gp substrates at time of screening but do not require continuous administration of these agents or can be switched to alternative agents, these patients are eligible if there is a 3-day washout period between discontinuation of the P-gp inhibitor and initiation of venetoclax.
- Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel if thought by the investigator to compromise systemic absorption, active, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction
- Lactating or pregnant women are excluded from this study because venetoclax has been shown to decrease implantation, litter size, live fetuses, and fetal body weight in animal models. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with venetoclax, breastfeeding should be discontinued if the mother is treated with venetoclax. These potential risks may also apply to other agents used in this study
- Patients with human immunodeficiency virus (HIV) or active hepatitis C virus (HCV) or hepatitis B virus (HBV) infection. HIV-positive participants are ineligible because of the potential for pharmacokinetic interactions between certain components of anti-retroviral therapy and venetoclax. Patients who are positive for hepatitis B core antibody or hepatitis B surface antigen must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded. Those who are positive for either hepatitis B surface antigen and/or hepatitis B core antibody but negative for HBV DNA will be managed as detailed. Patients who are positive for HCV antibody must be negative for HCV by polymerase chain reaction (PCR) to be eligible for study participation
- Unwilling or unable to participate in all required study evaluations and procedures
- Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations)
- Significant co-morbid condition or disease which in the judgment of the principal investigator would place the patient at undue risk or interfere with the study
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements, compromise the subject’s safety, or put the study outcomes at undue risk
I. To assess the rate of complete response with bone marrow minimal residual disease (MRD)-negativity, as determined by four color flow cytometry, after 15 cycles of treatment with acalabrutinib, venetoclax, and obinutuzumab (AVO) in previously untreated chronic lymphocytic leukemia (CLL) patients.
I. Safety and tolerability of the AVO combination.
II. Rate of partial response after 15 cycles of therapy, as defined by 2018 International Workshop on Chronic Lymphocytic Leukemia (IW-CLL) criteria.
III. Rate of complete remission (including complete remission with incomplete count recovery, CRi) after 15 cycles of therapy.
IV. Median progression free survival (PFS), 2-year and 3-year PFS.
V. Median overall survival (OS), 2-year and 3-year OS.
VI. Rates of complete remission with bone marrow MRD negativity at 8 cycles and 24 cycles.
VII. Rates of therapy discontinuation after 15 cycles and corresponding reasons for therapy discontinuation (e.g. disease progression, achievement of MRD-negative complete response [CR], or intolerability).
VIII. Time to MRD-positive disease recurrence, in patients who have achieved MRD negativity after 8, 15, or 24 cycles.
IX. Time to clinical progression as defined by IWCLL criteria.
X. Association between established CLL prognostic factors (including fluorescence in situ hybridization [FISH] cytogenetics and IGHV mutation status) and rates of MRD-negativity, CR, partial response [PR], recurrence, PFS, and OS.
XI. Rate of peripheral blood MRD-negativity at 8, 15, and 24 cycles.
XII. Rate of infusion reactions with obinutuzumab.
XIII. Rate of clinical and laboratory tumor lysis syndrome, as defined by the Cairo-Bishop Classification system.
XIV. Correlation between MRD-negativity as measured in the blood with MRD-negativity as measured in the bone marrow after 8, 15, and 24 cycles of treatment.
XV. To perform the above efficacy and safety analyses on cohort 1, cohort 2 plus the patients with TP53 aberrant disease in cohort 1, and in the entire group of cohort 1 plus cohort 2.
I. Association between novel CLL prognostic factors (including BH3 profiling and somatic mutations such as SF3B1, TP53, NOTCH1, and other mutations in the BCR/NFkappaB pathway) and rates of MRD-negativity, CR, PR, PFS, and OS.
II. The development and kinetics of BTK, PLCG2, CARD11, and BCL2 acquired somatic resistance mutations.
III. MRD measurements by four-color flow cytometry as compared to those of the Adaptive ClonoSEQ sequencing technology at the primary response (15 cycle) endpoint.
Patients receive acalabrutinib orally (PO) twice daily (BID) on days 1-28 of cycles 1-15, obinutuzumab intravenously (IV) over 4 hours on days 1, 2, 8, and 15 of cycle 2 and on day 1 of cycles 3-7, and venetoclax PO daily on days 1-28 of cycles 4-15. After cycle 15, patients with MRD positive or in PR continue to receive acalabrutinib and venetoclax. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study, patients are followed up every 3 months for up to 5 years.
Trial Phase Phase II
Trial Type Treatment
Dana-Farber Harvard Cancer Center
Matthew Steven Davids
- Primary ID 18-226
- Secondary IDs NCI-2018-02439
- Clinicaltrials.gov ID NCT03580928