Venetoclax and Obinutuzumab Followed by Epcoritamab for the Treatment of Untreated Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma, LonGEVity Trial

NCT07218510 | Recruiting Phase 2 DMC FDA Drug

• 3 other identifiers: 24230NCI-2025-07205P30CA033572
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 7

Brief Summary

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.

Conditions

Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma

Outcome Measures

Primary Outcomes (1)

• Minimal residual disease (MRD) negative complete response (CR)

  MRD status will be assessed using ClonoSEQ® (Adaptive Biotechnologies™) on the blood (sensitivity at 10\^-4 and 10\^-6). The determination of MRD status (i.e. positive versus negative) will be defined as the presence or absence of measurable clonotypes, respectively, at a sensitivity of 10\^-6. Will be estimated along with the 95% exact binomial confidence interval.

  At beginning of cycle 12 (cycle length = 28 days)

Secondary Outcomes (5)

• Overall response rate

  After the start of protocol therapy and prior to disease progression and/or start of other anti-lymphoma therapy, assessed up to 5 years

• Progression-free survival (PFS)

  From start of protocol treatment to time of disease relapse/progression or death due to any cause, whichever occurs earlier, assessed up to 5 years

• Duration of response (DOR)

  From the first achievement of PR or CR to time of disease relapse/progression or death, whichever earlier, assessed up to 5 years

• Overall survival (OS)

  From start of protocol treatment to death due to any cause, assessed up to 5 years

• Incidence of adverse events

  Up to 60 days after last dose of study treatment

Study Arms (1)

Treatment (obinutuzumab, venetoclax, epcoritamab)

EXPERIMENTAL

Patients receive obinutuzumab IV on days 1, 2, 8 and 15 of cycle 1 and on day 1 of cycles 2-6, venetoclax PO QD on days 22-28 of cycle 1 and on days 1-28 of cycles thereafter, as well as epcoritamab SC on days 1, 8, 15, and 22 of cycles 7-9 and on day 1 of cycles thereafter. Cycles repeat every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. After completion of 12 cycles, patients who are MRD positive and have CR, PR, or SD continue receiving epcoritamab SC on day 1 of each cycle. Cycles of epcoritamab repeat every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. All patients also undergo blood sample collection and CT or MRI throughout the study. Additionally, patients may undergo bone marrow aspiration and biopsy throughout the study.

Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy; Procedure: Computed Tomography; Other: Electronic Health Record Review; Biological: Epcoritamab; Procedure: Magnetic Resonance Imaging; Biological: Obinutuzumab; Drug: Venetoclax

Interventions

Bone Marrow Aspiration PROCEDURE

Undergo bone marrow aspiration and biopsy

Treatment (obinutuzumab, venetoclax, epcoritamab)

Bone Marrow Biopsy PROCEDURE

Undergo bone marrow aspiration and biopsy

Also known as: Biopsy of Bone Marrow, Biopsy, Bone Marrow

Treatment (obinutuzumab, venetoclax, epcoritamab)

Computed Tomography PROCEDURE

Undergo CT

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, Diagnostic CAT Scan, Diagnostic CAT Scan Service Type, tomography

Treatment (obinutuzumab, venetoclax, epcoritamab)

Epcoritamab BIOLOGICAL

Given SC

Also known as: Anti-CD20/CD3 Bispecific Antibody GEN3013, DuoBody-CD3xCD20, Epcoritamab-bysp, Epkinly, GEN 3013, GEN-3013, GEN3013, Tepkinly

Treatment (obinutuzumab, venetoclax, epcoritamab)

Magnetic Resonance Imaging PROCEDURE

Undergo MRI

Also known as: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI

Treatment (obinutuzumab, venetoclax, epcoritamab)

Obinutuzumab BIOLOGICAL

Given IV

Also known as: Anti-CD20 Monoclonal Antibody R7159, GA 101, GA-101, GA101, Gazyva, huMAB(CD20), R 7159, R-7159, R7159, RO 5072759, RO-5072759, RO5072759

Treatment (obinutuzumab, venetoclax, epcoritamab)

Venetoclax DRUG

Given PO

Also known as: ABT 199, ABT-0199, ABT-199, ABT199, GDC 0199, GDC-0199, GDC0199, RG7601, Venclexta, Venclyxto

Treatment (obinutuzumab, venetoclax, epcoritamab)

Biospecimen Collection PROCEDURE

Undergo blood sample collection

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Treatment (obinutuzumab, venetoclax, epcoritamab)

Electronic Health Record Review OTHER

Ancillary studies

Treatment (obinutuzumab, venetoclax, epcoritamab)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• Chronic use of corticosteroids in excess of 20 mg/day prednisone or equivalent
• Major surgery (under general anesthesia) within 30 days prior to cycle 1 day 1 (C1D1)
• Uncontrolled coagulopathy or bleeding disorder. Direct oral anticoagulants are allowed
• Exposure to vaccination with live vaccine within 30 days prior to C1D1, or anticipated need for such vaccination during treatment
• Transformation of CLL to aggressive non-Hodgkin lymphoma (NHL) (Richter's transformation)
• Current evidence of central nervous system involvement by the CLL
• History of confirmed progressive multifocal leukoencephalopathy (PML)
• History of prior malignancy except:
• Malignancy treated with curative intent and no known active disease present for ≥ 2 years prior to initiation of therapy on current study
• Adequately treated non-melanoma skin cancer or lentigo maligna (melanoma in situ) without evidence of disease
• Adequately treated in situ carcinomas (e.g., cervical, esophageal, etc.) without evidence of disease
• Asymptomatic prostate cancer managed with "watch and wait" strategy
• Uncontrolled active systemic infection
• Known positive test result for hepatitis C (hepatitis C virus \[HCV\] antibody serology testing) and a positive test result for HCV ribonucleic acid (RNA). Participants with positive serology are eligible in case of negative HCV RNA test results
• Known positive test result for chronic hepatitis B virus (HBV) infection (defined by hepatitis B virus surface antigen \[HBsAg\] positivity)

Sponsors & Collaborators

• City of Hope Medical Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (7)

City of Hope Medical Center

Duarte, California, 91010, United States

RECRUITING

City of Hope at Irvine Lennar

Irvine, California, 92618, United States

RECRUITING

City of Hope at Long Beach Elm

Long Beach, California, 90813, United States

RECRUITING

University of Miami Miller School of Medicine-Sylvester Cancer Center

Miami, Florida, 33136, United States

NOT YET RECRUITING

City of Hope Atlanta Cancer Center

Newnan, Georgia, 30265, United States

RECRUITING

Laura and Isaac Perlmutter Cancer Center at NYU Langone

New York, New York, 10016, United States

NOT YET RECRUITING

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

NOT YET RECRUITING

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

Specimen Handling; Biopsy; Magnetic Resonance Spectroscopy; obinutuzumab; venetoclax

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Cytodiagnosis; Cytological Techniques; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Spectrum Analysis; Chemistry Techniques, Analytical

Study Officials

• Alexey V Danilov

  City of Hope Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 16, 2025
• First Posted: October 20, 2025
• Study Start: January 7, 2026
• Primary Completion (Estimated): June 8, 2029
• Study Completion (Estimated): June 8, 2029
• Last Updated: March 13, 2026

Record last verified: 2026-03

Locations

US (7)