A Study on Limiting Treatment Time with Acalabrutinib Combined with Obinutuzumab in Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
This phase II trial studies the effect of acalabrutinib and obinutuzumab in treating patients with chronic lymphocytic leukemia or small lymphocytic lymphoma. Acalabrutinib blocks a protein called Bruton tyrosine kinase (BTK) that can help lymphoma cells multiply and survive. Blocking BTK may slow or stop the growth of the disease. Obinutuzumab targets a protein called CD20 that is found on the surface of B cells, the white blood cells affected by chronic lymphocytic leukemia. When obinutuzumab attaches to CD20, it helps the immune system recognize and attack the cancerous B cells. A usual treatment for chronic lymphocytic leukemia or small lymphocytic lymphoma is to give the acalabrutinib and obinutuzumab continuously until the cancer progresses, even if the disease is in remission. But when patients receive these drugs for long periods of time, they can have serious side effects, and their cancer can become resistant to treatment. The purpose of this study is to find out whether stopping acalabrutinib and obinutuzumab when the cancer responds to the treatment, followed by a period of observation in which no treatment is given, is better than, the same as, or worse than the usual approach.
Inclusion Criteria
- Signed informed consent form (ICF). Legally authorized representatives are permitted
- Ability and willingness to comply with requirements of the study protocol
- >= 18 years-old
- Have documented previously untreated CLL or SLL per World Health Organization (WHO) criteria and require treatment per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2, with no deterioration over the previous 2 weeks prior to baseline or day of first dosing
- Total bilirubin =< 1.5 times upper limit of normal (ULN), unless there is a disease involvement of the liver, hemolysis, or a known history of Gilbert’s disease
- Hemoglobin >= 8 g/dL without transfusion support, unless anemia is due to marrow involvement of CLL
- Absolute neutrophil count (ANC) >= 1.0 x 10^9/L
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 times the ULN
- Creatinine clearance (CrCl) > 30 mL/min as calculated using modified Cockcroft-Gault or Modification of Diet in Renal Disease (MDRD) formula
- Prothrombin time (PT)/international normalized ration (INR) =< 2 times the ULN and activated partial thromboplastin time (aPTT) =< 2 times the ULN unless the elevation in PT/INR or aPTT is solely attributable to direct oral anticoagulant
- Platelet count without transfusion support must be >= 50,000 cells/mm^3 or >= 30,000 cells/mm^3 in subjects with documented bone marrow involvement, as determined locally
- For women of childbearing potential: Agreement to remain abstinent (refrain from heterosexual intercourse) or use a highly effective contraceptive method (failure rate of < 1%) per year during the treatment period and for at least 18 months after the last dose of study medication. Women of childbearing potential must have a negative serum pregnancy test result within 3 days prior to initiation of study drug * Women must refrain from donating eggs during this same period * A woman is considered of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (>= 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus) * Examples of contraceptive methods with a failure rate of < 1 % per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices
- For men: Agreement to remain abstinent (refrain from heterosexual intercourse) or use highly effective contraceptive measures, and agreement to refrain from donating sperm, as defined below * With female partners of childbearing potential, men must remain abstinent or use 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 6 months after the last dose of obinutuzumab; men must refrain from donating sperm during this same period * With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 6 months after the last dose of obinutuzumab to avoid exposing the embryo * The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient; periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception
Exclusion Criteria
- Prior CLL-directed therapy * Excluding corticosteroid therapy started for non-CLL related reasons or brief courses for disease related symptom management
- Received any investigational drug within 30 days or 5 half-lives (whichever is shorter) before first dose of study drug
- History of prior malignancy that could affect compliance with the protocol or interpretation of results, except for the following: * Curatively treated basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or carcinoma in situ of the prostate at any time prior to study * Other cancers not specified above that have been curatively treated by surgery and/or radiation therapy from which subject is disease-free for >= 3 years without further treatment
- Transformation of CLL to aggressive lymphoma (Richter’s transformation to non-Hodgkin's lymphoma [NHL] or Hodgkin’s lymphoma, or pro-lymphocytic leukemia)
- CLL with deletion of chromosome 17p and/or TP53 mutation. Patients must have fluorescence in situ hybridization (FISH) and/or array comparative genomic hybridization (CGH) analysis and TP53 mutational testing locally within 365 days of cycle C1D1 (peripheral blood, bone marrow or lymph node with disease involvement are acceptable sources) as SOC
- History of ongoing confirmed central nervous system (CNS) lymphoma
- Known hypersensitivity to any active ingredient in the study drugs
- Active bleeding, or presence of known bleeding disorder (e.g. von Willebrand’s disease) or hemophilia
- Any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as: * Clinically significant cardiac disease that includes symptomatic arrhythmia (subjects with controlled, asymptomatic atrial fibrillation or other atrial arrhythmias during screening are allowed to enroll on study) * Intracranial hemorrhage, stroke within 6 months of study enrollment * Symptomatic, or history of documented congestive heart failure (New York [NY] Heart Association functional classification III-IV * Myocardial infarction within 6 months of enrollment * Concomitant use of medication known to cause QT prolongation or torsade’s de pointes should be used with caution and at investigator’s discretion * Angina not well-controlled by medication * Poorly controlled or clinically significant atherosclerotic vascular disease including cerebrovascular accident (CVA), transient ischemic attack (TIA), angioplasty, cardiac/vascular stenting within 6 months of study enrollment
- Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 2 weeks prior to cycle 1 day 1 including subjects with positive cytomegalovirus (CMV) deoxyribonucleic acid (DNA) polymerase chain reaction (PCR)
- Requires the use of warfarin or equivalent vitamin K antagonist
- Requires or received the following agents within 7 days prior to the first dose of acalabrutinib-obinutuzumab combination therapy: * Strong and/or moderate CYP3A inhibitors * Strong and/or moderate CYP3A inducers * Treatment with proton pump inhibitors (PPIs)
- Presence of positive test results for hepatitis B virus (HBV), hepatitis B surface antigen (HBsAg), or hepatitis C (HCV) virus * Patients who are positive for HCV antibody must be negative for HCV by polymerase chain reaction (PCR) to be eligible for study participation * Patients with occult or prior HBV infection (defined as positive total hepatitis B core antibody [HBcAb] and negative HBsAg) may be included if HBV deoxyribonucleic acid (DNA) is undetectable by PCR. These patients must be willing to undergo sequential DNA testing as per institutional standards (every 1-3 months) and antiviral prophylaxis as per institutional standards
- Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic purpura)
- Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening, this is subject to investigator’s discretion
- Known infection with human immunodeficiency virus (HIV)
- Receipt of live-virus vaccines within 28 days prior to the initiation of study treatment
- Pregnant or lactating, or intending to become pregnant during the study
- Major surgical procedures within 28 days of first dose of study drug. Note: if a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug
- Malabsorption syndrome or other condition that precludes enteral route of administration; this is subject to investigator discretion
- Has difficulty with or is unable to swallow oral medication
- Concurrent participation in the treatment phase of an interventional clinical trial
- Unwilling or unable to participate in all required study evaluations and procedures. Unable to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local patient privacy regulations)
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04722172.
PRIMARY OBJECTIVE:
I. Estimate 36-month progression-free survival (PFS) to acalabrutinib (administered for 13 to 26 cycles; duration based on depth of response) plus obinutuzumab (administered for 6 cycles) in the front-line setting.
SECONDARY OBJECTIVES:
I. To investigate the safety of acalabrutinib plus obinutuzumab as first-line therapy for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
II. To estimate the overall response rate (ORR), complete response (CR) rate, and undetectable- minimal residual disease (U-MRD) rate in peripheral blood using next generation sequencing (clonoSEQ; 10^-4 sensitivity) in patients treated with acalabrutinib plus obinutuzumab for a maximum of 26 cycles.
III. To estimate median PFS from start of acalabrutinib / obinutuzumab therapy.
IV. To estimate PFS at 65 cycles (approximately 5 years) from start of acalabrutinib / obinutuzumab therapy.
V. To estimate median PFS as measured from the start of treatment-free observation.
VI. To estimate ORR, CR rate, and U-MRD rate in peripheral blood using next generation sequencing (clonoSEQ; 10^-4 sensitivity) in the subset of patients who require retreatment with acalabrutinib/ obinutuzumab during study observation period.
VII. To assess for BTK resistance mutations at the time of discontinuation of acalabrutinib and at time of retreatment.
OUTLINE:
Patients receive acalabrutinib orally (PO) twice daily (BID) on days 1-28. Patients also receive obinutuzumab intravenously (IV) on days 1, 2, 8 and 15 of cycle 2, and day 1 of cycles 3-7. Treatment repeats every 28 days for up to 13 cycles in the absence of disease progression or unacceptable toxicity. Patients who achieve stable disease (SD), partial response (PR) or CR with detectable MRD continue acalabrutinib PO BID for a maximum of 26 cycles. Patients who achieve CR or PR with U-MRD after 13 or 26 cycles undergo observation for a maximum of 65 cycles from cycle 1 day 1.
After completion of study treatment, patients are followed up at 35 days.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center
Principal InvestigatorMeghan Caitlin Thompson
- Primary ID20-503
- Secondary IDsNCI-2021-06310
- ClinicalTrials.gov IDNCT04722172