A Phase 2 Study of Venetoclax + Obinutuzumab Followed by Epcoritamab in Previously Untreated Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma (LonGEVity)
This phase II trial tests the effect of venetoclax and obinutuzumab followed by epcoritamab in treating patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) that have not previously received treatment. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Obinutuzumab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Epcoritamab, a bispecific monoclonal antibody, binds to a protein called CD3, which is found on T cells (a type of white blood cell). It also binds to a protein called CD20, which is found on B cells (another type of white blood cell) and some lymphoma cells. This may help the immune system kill cancer cells. The combination of venetoclax and obinutuzumab is a standard treatment for CLL/SLL and has been found to be safe and effective. Adding epcoritamab to standard treatment with venetoclax and obinutuzumab may lead to deeper and longer-lasting responses in patients with untreated CLL/SLL.
• Documented informed consent of the participant and/or legally authorized representative
‣ Assent, when appropriate, will be obtained per institutional guidelines
• Age: ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) ≤ 2
• Histologically confirmed 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)
• No prior treatment for CLL/SLL, except steroids and/or rituximab to treat autoimmune complications
• Evidence of CD20 positivity
• Active disease meeting criteria for requiring treatment per the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 guidelines
‣ A minimum of any one of the following constitutional symptoms:
• Unintentional weight loss \> 10% within the previous 6 months prior to screening
∙ Extreme fatigue (unable to work or perform usual activities)
∙ Fevers of greater than 100.5°F for ≥ 2 weeks without evidence of infection
∙ Night sweats without evidence of infection
⁃ 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)
• Participant must be able to swallow tablets or capsules. A participant with any gastrointestinal disease that would impair ability to swallow, retain, or absorb drug is not eligible
• Without bone marrow involvement: Absolute neutrophil count (ANC) ≥ 1,000/mm\^3
‣ NOTE: Growth factor is not permitted within 14 days of ANC assessment unless cytopenia is secondary to disease involvement.
• With bone marrow involvement: ANC ≥ 500/mm\^3
‣ NOTE: Growth factor is not permitted within 14 days of ANC assessment unless cytopenia is secondary to disease involvement.
• Without bone marrow involvement: Platelets ≥ 50,000/mm\^3
‣ NOTE: independent of transfusion support, with no active bleeding
• With bone marrow involvement: Platelets ≥ 30,000/mm\^3
‣ NOTE: independent of transfusion support, with no active bleeding
• Direct 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
• Estimated creatinine clearance of ≥ 40 mL/min using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 formula
• If not receiving anticoagulants: International normalized ratio (INR) OR prothrombin (PT) ≤ 1.5 x ULN
• If on anticoagulant therapy: PT must be within therapeutic range of intended use of anticoagulants
• If not receiving anticoagulants: Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN
• If on anticoagulant therapy: aPTT must be within therapeutic range of intended use of anticoagulants
• Women of childbearing potential (WOCBP): Negative serum pregnancy test
• Agreement by females of childbearing potential to either abstain from heterosexual activity or use an effective method of birth control (failure rate of \< 1% per year) during the treatment period and through at least 30 days after the last dose of venetoclax, 18 months after the last dose of obinutuzumab, 12 months after the last dose of epcoritamab, and at least 4 months after the last dose of tocilizumab (if applicable). Women must refrain from donating eggs during this same period
‣ Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for \> 1 year (women only)
⁃ Examples of contraceptive methods with a failure rate of \< 1% per year include tubal ligation, male sterilization, hormonal implants, established, proper use of combined oral or injected hormonal contraceptives, and certain intrauterine devices
• Agreement by males to either abstain from heterosexual activity or use a condom during the treatment period and through at least 30 days after the last dose of venetoclax, 4 months after the last dose of obinutuzumab, epcoritamab or tocilizumab (as applicable). Men with a pregnant partner must agree to remain abstinent or use a condom for the duration of the pregnancy. Men must refrain from donating sperm during this same period