Phase 2 Study of Fixed-Duration Zanubrutinib and Sonrotoclax (Z+S) All-Oral Combination Therapy in CLL/SLL Patients in 1st Relapse After Initial Fixed-Duration Novel Therapy (ZeuS-2 Trial)
Phase 2 Study of Fixed-Duration Zanubrutinib and Sonrotoclax (Z+S) All-Oral Combination Therapy in CLL/SLL Patients in 1st Relapse After Initial Fixed-Duration Novel Therapy (ZeuS-2 Trial)
This phase II trial tests how well giving zanubrutinib and sonrotoclax works for the treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) that has come back after a period of improvement (relapsed). Zanubrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Sonrotoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) and BCL-XL inhibitors. It may stop the growth of tumor cells and may kill them by blocking Bcl-2 and Bcl-XL, proteins needed for cell survival. Giving zanubrutinib and sonrotoclax may work well for the treatment of relapsed CLL/SLL.
PRIMARY OBJECTIVE:
I. Estimate overall response rate (ORR).
SECONDARY OBJECTIVES:
I. Estimate complete response (CR) rate. II. Estimate minimal residual disease (MRD) negativity by flow cytometry every 6 months.
III. Estimate progression-free survival (PFS) at 2, 3, and 5 years. IV. Estimate duration of response (DOR) at 2, 3, and 5 years. V. Estimate overall survival (OS) at 2, 3, and 5 years.
EXPLORATORY OBJECTIVES:
I. Identify mechanisms of resistance. II. Evaluate effect of treatment on immune cell repertoire. III. Evaluate clinical outcome stratified by first line therapy (anti-CD20 containing therapy: Yes versus [vs.] No) and time since stopping first line therapy (greater than 2 years: Yes vs. No).
OUTLINE:
CYCLE 1-4: Patients receive zanubrutinib orally (PO) once daily (QD) on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
CYCLE 5+: Patients receive zanubrutinib PO QD and sonrotoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.
Patients undergo bone marrow biopsy and aspiration, computed tomography (CT) scan/magnetic resonance imaging (MRI) and blood sample collection throughout the study. Patients may undergo lymph node biopsy during screening and optionally at time of progression.
After completion of study treatment, patients are followed up at 30 days. Patients who discontinue study drug due to reasons other than disease progression will be followed every 3 months until patient exhibits first progression for up to 5 years. Patients who discontinue study drug and have progressed are followed up every 6 months for up to 5 years.
Inclusion Criteria:
Documented informed consent of the participant and/or legally authorized representative.
Age: ≥ 18 years
Eastern Cooperative Oncology Group (ECOG) ≤ 2
Histological or flow cytometry confirmed diagnosis of B-CLL/SLL as documented by medical records and with histology based on criteria established by the World Health Organization (WHO)
CLL has progressed at least 6 months after completion of first-line fixed-duration novel drug (non-chemotherapy) regimen, including but not limited to venetoclax (V) + CD20 monoclonal antibody (monoclonal antibody [mAb], e.g., obinutuzumab (O); BTK inhibitor (zanubrutinib or acalabrutinib or ibrutinib) + V ± CD20 mAb
Active disease meeting criteria for requiring treatment per the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 guidelines (one of the following):
A minimum of any one of the following constitutional symptoms:
Evidence of progressive marrow failure as manifested by the development of, or worsening of anemia or thrombocytopenia.
Massive (i.e., > 6 cm below the left costal margin), progressive or symptomatic splenomegaly.
Massive nodes or clusters (i.e., > 10 cm in longest diameter) or progressive lymphadenopathy.
Progressive lymphocytosis with an increase of > 50% over a 2-month period, or an anticipated doubling time of less than 6 months.
Autoimmune anemia or thrombocytopenia that is poorly responsive to corticosteroids.
Symptomatic or functional extranodal involvement (e.g., skin, kidney, lung, spine)
Fully recovered from the acute toxic effects (except alopecia) to ≤ grade 1 to prior anti-cancer therapy
Without bone marrow involvement: absolute neutrophil count (ANC) ≥ 1,000/mm^3, with bone marrow involvement: ANC ≥ 500/mm^3
Neupogen or biosimilar may be administered for patients with ANC < 1000 with risk for development of febrile neutropenia as determined by treating physician. Dosing will be at 5 mcg/kg rounded to the nearest vial size
Without bone marrow involvement: Platelets ≥ 50,000/mm^3, with bone marrow involvement: platelets ≥ 30,000/mm^3
Hemoglobin ≥ 7 g/dL
Total bilirubin ≤ 2 X upper limit of normal (ULN) (unless has Gilbert's disease or compensated hemolysis directly attributable to CLL)
Aspartate aminotransferase (AST) ≤ 2.5 x ULN
Alanine aminotransferase (ALT) ≤ 2.5 x ULN
Creatinine clearance of ≥ 30 mL/min/ per 24-hour urine test or the Cockcroft-Gault formula
Fridericia's corrected QT interval (QTcB) ≤ 480 ms
Seronegative for hepatitis C virus (HCV), active hepatitis B virus (HBV) (Surface antigen negative) OR
Meets other institutional and federal requirements for infectious disease titer requirements
Women of childbearing potential (WOCBP): negative urine or serum pregnancy test
Agreement by females and males of childbearing potential* to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 1 week after the last dose of protocol therapy
Exclusion Criteria:
Chronic use of corticosteroids in excess of 20 mg/day prednisone
Major surgery (under general anesthesia) ≤4 weeks of the first dose of study drug
Prior chemotherapy
Refractory to prior BTK or BCL2 inhibitor (defined as relapsed within/< 6 months after completion of initial fixed duration regimen)
Vaccination with a live vaccine within 35 days prior to the first dose of study drug or at any time during planned study treatment
Requires ongoing treatment with a strong CYP3A inducer
Requires ongoing treatment with inhibitors of P-gp and BCRP
Requires ongoing treatment with warfarin or warfarin derivatives
Concurrent participation in another therapeutic clinical trial
Use of the following substances prior to the first dose of study drug:
Known current central nervous system involvement by lymphoma/leukemia
Known Richter's transformation
Any uncontrolled or clinically significant cardiovascular disease including the following:
Prior malignancy except:
Uncontrolled immune hemolysis or thrombocytopenia
Significant bleeding disorder (stable therapeutic anticoagulation acceptable)
History of stroke or intracranial hemorrhage within 6 months before first dose of study drug
Severe or debilitating pulmonary disease
Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction
Active fungal, bacterial and/or viral infection requiring systemic therapy
Underlying medical conditions that, in the investigator's opinion, will render the administration of study drugs hazardous or obscure the interpretation of toxicity or adverse events (AEs)
Known active infection with HIV
History of allergic reactions attributed to compounds of similar chemical or biologic composition to the study agents
Uncontrolled autoimmune anemia and/or autoimmune thrombocytopenia (e.g., idiopathic thrombocytopenia purpura)
Any condition which in the discretion of the investigator would compromise the ability to comply with study procedures
Females only: Pregnant or breastfeeding
Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)
tsiddiqi@coh.org626-803-3458
sayyappan@coh.org770-400-6568