Venetoclax, Rituximab and Nivolumab in Combination for the Treatment of Richter's Transformation Arising From Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

NCT06247540 | Withdrawn Phase 2 DMC FDA Drug

• 4 other identifiers: NU 23H01NCI-2023-08755STU00219856P30CA060553
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

This phase II trial tests how well venetoclax, rituximab and nivolumab works in treating patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with Richter's transformation. Richter's transformation can be described as the development of an aggressive lymphoma in the setting of underlying CLL/SLL that has a very poor prognosis with conventional therapies and represents a significant unmet medical need. 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. Immunotherapy with monoclonal antibodies, such as rituximab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of cancer cells to grow and spread. Giving venetoclax, rituximab and nivolumab together may work better than the conventional intensive immunochemotherapy to improve disease control in patients with Richter's transformation arising from CLL/SLL.

Conditions

Recurrent Transformed Chronic Lymphocytic Leukemia; Refractory Transformed Chronic Lymphocytic Leukemia; Richter Syndrome; Transformed Chronic Lymphocytic Leukemia to Diffuse Large B-Cell Lymphoma; Transformed Small Lymphocytic Lymphoma to Diffuse Large B-Cell Lymphoma

Outcome Measures

Primary Outcomes (3)

• Overall response rate

  Will be assessed using International Workshop on Chronic Lymphocytic Leukemia (iwCLL) and Lugano 2014 criteria for Richter's transformation (RT) patients. Will be calculated using proportions and exact 95% binomial confidence intervals.

  Up to 5 years

• Best response rate

  Will be assessed using iwCLL and Lugano 2014 criteria for RT patients. Will be calculated using proportions and exact 95% binomial confidence intervals.

  Up to 5 years

• Minimal residual disease (MRD) rate

  Will be assessed in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) patients in the peripheral blood and bone marrow by flow cytometry, polymerase chain reaction (PCR) and/or sequencing. MRD negativity is defined as less than one CLL/SLL cell per 10,000 leukocytes (or below 10-4) on peripheral blood and/or bone marrow based flow cytometry and/or PCR based methods. Rate of MRD status will be defined as the proportion of patients who have MRD negativity status. Will be calculated using proportions and exact 95% binomial confidence intervals.

  Up to 5 years

Secondary Outcomes (5)

• Incidence of adverse events

  Up to 100 days after last dose of study treatment

• Progression-free survival

  Up to 5 years

• Overall survival

  Up to 5 years

• Duration of response

  Up to 5 years

• Prognostic markers and biomarkers

  Up to 5 years

Study Arms (1)

Treatment (venetoclax, rituximab, nivolumab)

EXPERIMENTAL

Patients receive venetoclax PO QD on days 1-28, nivolumab IV over 30 minutes on days 2 and 15 of cycles 1-4 and day 1 of each subsequent cycle, and rituximab IV on day 2 of cycle 1 and day 1 of cycles 2-6. Treatment repeats every 28 days up to 6 cycles in the absence of disease progression or unacceptable toxicity. After the completion of 6 cycles, rituximab is discontinued and patients receive venetoclax PO QD on days 1-28 and nivolumab IV over 30 minutes on day 1 of each cycle. Treatment repeats every 28 days for up to 2 years total therapy in the absence of disease progression or unacceptable toxicity. Patients undergo tissue biopsy during screening. Patients undergo a bone marrow biopsy and blood sample collection as well as PET/CT and CT or MRI during screening and on the trial.

Procedure: Biopsy; Procedure: Biospecimen Collection; Procedure: Bone Marrow Biopsy; Procedure: Computed Tomography; Procedure: Magnetic Resonance Imaging; Biological: Nivolumab; Procedure: Positron Emission Tomography; Biological: Rituximab; Drug: Venetoclax

Interventions

Biopsy PROCEDURE

Undergo tissue biopsy

Also known as: BIOPSY_TYPE, Bx

Treatment (venetoclax, rituximab, nivolumab)

Biospecimen Collection PROCEDURE

Undergo blood sample collection

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

Treatment (venetoclax, rituximab, nivolumab)

Bone Marrow Biopsy PROCEDURE

Undergo bone marrow biopsy

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

Treatment (venetoclax, rituximab, nivolumab)

Computed Tomography PROCEDURE

Undergo PET/CT, CT

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

Treatment (venetoclax, rituximab, nivolumab)

Magnetic Resonance Imaging PROCEDURE

Undergo MRI

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

Treatment (venetoclax, rituximab, nivolumab)

Nivolumab BIOLOGICAL

Receive IV

Also known as: ABP 206, BMS-936558, CMAB819, MDX-1106, NIVO, Nivolumab Biosimilar ABP 206, Nivolumab Biosimilar CMAB819, ONO-4538, Opdivo

Treatment (venetoclax, rituximab, nivolumab)

Positron Emission Tomography PROCEDURE

Undergo PET/CT

Also known as: Medical Imaging, Positron Emission Tomography, PET, PET Scan, Positron emission tomography (procedure), Positron Emission Tomography Scan, Positron-Emission Tomography, proton magnetic resonance spectroscopic imaging, PT

Treatment (venetoclax, rituximab, nivolumab)

Rituximab BIOLOGICAL

Receive IV

Also known as: ABP 798, BI 695500, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, CT-P10, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, Ikgdar, Mabtas, MabThera, Monoclonal Antibody IDEC-C2B8, PF-05280586, Riabni, Rituxan, Rituximab ABBS, Rituximab ARRX, Rituximab Biosimilar ABP 798, Rituximab Biosimilar BI 695500, Rituximab Biosimilar CT-P10, Rituximab Biosimilar GB241, Rituximab Biosimilar IBI301, Rituximab Biosimilar JHL1101, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, Rituximab Biosimilar SAIT101, Rituximab Biosimilar SIBP-02, rituximab biosimilar TQB2303, Rituximab PVVR, Rituximab-abbs, Rituximab-arrx, Rituximab-pvvr, RTXM83, Ruxience, Truxima

Treatment (venetoclax, rituximab, nivolumab)

Venetoclax DRUG

Receive PO

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

Treatment (venetoclax, rituximab, nivolumab)

Eligibility Criteria

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

You may qualify if:

• Patients must have a confirmed diagnosis of one of Richter's transformation (to either diffuse large B cell lymphoma (DLBCL) or Hodgkin's lymphoma) with preceding CLL/SLL
• Richter's transformation refers to development of aggressive lymphoma (most commonly diffuse large B cell lymphoma (DLBCL), and less commonly Hodgkin's lymphoma) in a patient who has a pre-existing diagnosis of CLL/SLL. A pathologic diagnosis of DLBCL or Hodgkin's lymphoma in the setting of preceding CLL/SLL is required
• Patients with Richter's transformation arising from CLL/SLL may be newly diagnosed or have relapsed or progressed after prior treatment. Patients with newly diagnosed Richter transformation are eligible only if the treating physician believes they are not good candidates for standard immunochemotherapy or chemotherapy
• All patients must have measurable disease as defined by Lugano criteria 2014
• Patients must be age ≥ 18 years
• Patients must exhibit a/an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Absolute neutrophil count ≥ 1,000/mcL (independent of growth factor support for ≥ 14 days) (within 14 days prior to registration)
• Platelets ≥ 30,000/mcl (independent of transfusion for ≥ 14 days) (within 14 days prior to registration)
• Hemoglobin ≥ 8 g/dL (within 14 days prior to registration)
• Note: patients must be able to maintain this level without transfusion
• Total bilirubin \< 1.5 x institutional upper limit of normal (ULN) (within 14 days prior to registration)
• Note: Autoimmune hemolytic anemia (AIHA) and Gilbert's syndrome are exceptions and bilirubin value must be \< 5 x ULN
• Aspartate aminotransferase (AST) ( serum glutamic-oxaloacetic transaminase \[SGOT\]) ≤ 1.5 X ULN (within 14 days prior to registration)
• Alanine transaminase (ALT) (serum glutamic-pyruvic transaminase \[SPGT\]) ≤ 1.5 X ULN (within 14 days prior to registration)
• Creatinine clearance ≥ 50mL/min (within 14 days prior to registration)

You may not qualify if:

• Patients who have received prior nivolumab for treatment of Richter's transformation, or other PD-1/PD-L1 for the treatment of any indication.
• Note: Prior anti-CD-20 antibody treatment is allowed with ≥ 14 day washout period. Prior treatment with nivolumab is permissible if for a different disease indication. In such cases nivolumab must have been discontinued ≥ 3 months prior to registration
• Patients who have a history of life-threatening adverse reactions attributed to compounds of similar chemical or biologic composition to venetoclax, nivolumab, or rituximab
• Patients who are refractory to venetoclax (defined by disease progression while on venetoclax or within 3 months of discontinuing venetoclax)
• Patients who have had prior chimeric antigen receptor-modified T-cell (CAR-T) therapy within the 45 days prior to registration or with any remaining CAR-T related cytokine-release syndrome or neurotoxicity
• Patients who have adverse events due to agents administered ≥ 30 days prior to registration that have not recovered to ≤ grade 2
• Patients who have had chemotherapy, radiotherapy or immunotherapy ≤ 14 days prior to registration
• Patients receiving any other investigational agents within ≤ 30 days or 5 half-lives prior to registration, whichever is shorter
• Patients who have received B-cell receptor pathway inhibitor (such as ibrutinib or idelalisib) ≤ 3 days prior to receiving study treatment
• Patients who have undergone an autologous stem cell transplant ≤ 120 days prior to registration
• Patients who have undergone an allogeneic stem cell transplant ≤ 180 days prior to registration.
• Note: Patients must be off all immunosuppressive therapies \> 30 days prior to registration, with no active graft versus host disease (GVHD)
• Patients with acute or extensive chronic graft-versus-host disease (GVHD)
• Patients who have received any of the following agents ≤ 7 days prior to receiving study treatment:
• Steroid therapy with anti-neoplastic intent

Sponsors & Collaborators

• Northwestern University: lead
• National Cancer Institute (NCI): collaborator
• Bristol-Myers Squibb: collaborator
• AbbVie: collaborator

Study Sites (1)

Northwestern University

Chicago, Illinois, 60611, United States

Location

MeSH Terms

Interventions

Biopsy; Specimen Handling; Magnetic Resonance Spectroscopy; Nivolumab; Rituximab; CT-P10; venetoclax

Intervention Hierarchy (Ancestors)

Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Investigative Techniques; Spectrum Analysis; Chemistry Techniques, Analytical; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Antibodies, Monoclonal, Murine-Derived

Study Officials

• Shuo Ma, MD, PhD

  Northwestern University

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: December 8, 2023
• First Posted: February 8, 2024
• Study Start: March 29, 2024
• Primary Completion (Estimated): December 29, 2029
• Study Completion (Estimated): December 29, 2031
• Last Updated: February 29, 2024

Record last verified: 2024-02

Locations

US (1)