Rituximab, Venetoclax, and Bortezomib for the Treatment of Relapsed or Refractory Diffuse Large B-Cell Lymphoma

• ClinicalTrials.gov Identifier: NCT04285268
• Recruitment Status: Withdrawn
• First Posted: February 26, 2020
• Last Update Posted: June 16, 2020
• Sponsor: Rutgers, The State University of New Jersey
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Rajat Bannerji, MD, PhD, Rutgers Cancer Institute of New Jersey

Study Description

Brief Summary:

This phase II trial studies how well rituximab, venetoclax, and bortezomib work in treating patients with diffuse large B-cell lymphoma that has come back (relapsed) or does not respond to treatment (refractory). Immunotherapy with monoclonal antibodies, such as rituximab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Venetoclax and bortezomib may stop the growth of tumor cells by blocking some of the proteins needed for cell growth. Giving rituximab, venetoclax, and bortezomib may slow or stop the growth of cancer cells in patients with diffuse large B-cell lymphoma.

Condition or disease	Intervention/treatment	Phase
High Grade B-Cell Lymphoma, Not Otherwise Specified; Recurrent Burkitt Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements; Refractory Burkitt Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Refractory High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements	Drug: Bortezomib; Biological: Rituximab; Drug: Venetoclax	Phase 2

Detailed Description:

PRIMARY OBJECTIVE:

I. To determine the overall response rate (ORR) of rituximab, venetoclax, and bortezomib in relapsed/refractory diffuse large B-cell lymphoma.

SECONDARY OBJECTIVES:

I. To describe the safety profile of rituximab, venetoclax, and bortezomib in diffuse large B-cell lymphoma (DLBCL).

II. To describe the progression free survival of subjects enrolled to the study.

III. To describe the median overall survival of subjects enrolled to the study. IV. To describe the complete remission (CR) rate, the partial remission (PR) rate and the duration of response (DoR) of rituximab, venetoclax, and bortezomib in relapsed/refractory DLBCL.

EXPLORATORY OBJECTIVE:

I. To describe the association of BCL2 expression status, measured by immunohistochemistry (IHC), with ORR, CR and PR rates.

OUTLINE:

Patients receive rituximab intravenously (IV) on day -1 of cycle 1, then on day 1 of cycles 2-6. Patients also receive venetoclax orally (PO) once daily (QD) on days 1-14 and bortezomib IV or subcutaneously (SC) on day -1 of cycle 1, then on days 1, 8, and 15 of subsequent cycles. Treatment repeats every 28 days for up to 6 cycles for rituximab and up to 26 cycles for venetoclax and bortezomib in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 0 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study of Rituximab, Venetoclax (ABT 199) and Bortezomib in Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
• Estimated Study Start Date: May 6, 2020
• Estimated Primary Completion Date: September 30, 2024
• Estimated Study Completion Date: September 30, 2024

Arms and Interventions

Arm

Intervention/treatment

Experimental: Treatment (rituximab, venetoclax, bortezomib); Patients receive rituximab IV on day -1 of cycle 1, then on day 1 of cycles 2-6. Patients also receive venetoclax PO QD on days 1-14 and bortezomib IV or SC on day -1 of cycle 1, then on days 1, 8, and 15 of subsequent cycles. Treatment repeats every 28 days for up to 6 cycles for rituximab and up to 26 cycles for venetoclax and bortezomib in the absence of disease progression or unacceptable toxicity.

Drug: Bortezomib; Given IV or SC; Other Names: [(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid; LDP 341; MLN341; PS-341; PS341; Velcade; Biological: Rituximab; Given IV; Other Names: ABP 798; BI 695500; C2B8 Monoclonal Antibody; Chimeric Anti-CD20 Antibody; CT-P10; IDEC-102; IDEC-C2B8; IDEC-C2B8 Monoclonal Antibody; MabThera; Monoclonal Antibody IDEC-C2B8; PF-05280586; Rituxan; Rituximab ABBS; 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 TQB2303; rituximab-abbs; RTXM83; Truxima; Drug: Venetoclax; Given PO; Other Names: ABT-0199; ABT-199; ABT199; GDC-0199; RG7601; Venclexta; Venclyxto

Outcome Measures

Primary Outcome Measures :

1. Overall response rate (ORR) [ Time Frame: Up to 4 years ]
   Defined as the proportion of subjects who achieve a best response of a partial response (PR) or better. The ORR (complete and partial responses) will be reported as a percentage with a 95% confidence interval. If response is missing for any patients, those patients will still be included in the denominator when reporting the response rate.

Secondary Outcome Measures :

1. Incidence of adverse events [ Time Frame: Up to 30 days post treatment ]
   Toxicity parameters will be defined by National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version (V) 5.0. Descriptive statistics will be provided for the safety data.
2. Progression free survival (PFS) [ Time Frame: From study enrollment to disease progression or death from any cause, assessed up to 4 years ]
   The Kaplan-Meier curve will be used to estimate the corresponding PFS distribution and median PFS for patients treated on this study.
3. Overall survival (OS) [ Time Frame: From study enrollment to the date of death from any cause, assessed up to 4 years ]
   The Kaplan-Meier curve will also be used to estimate the corresponding OS distribution and median OS for all treated patients. If a subject has not died, their survival time will be censored at the date of last contact ("last known alive date").
4. Complete response (CR) and partial response (PR) rates [ Time Frame: Up to 4 years ]
   Defined as the proportion of subjects who achieve a best response of CR or PR respectively.
5. Duration of response (DoR) [ Time Frame: From when measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 4 years ]
   The Kaplan-Meier curve will be used to estimate the corresponding DoR distribution and median DoR for patients treated on this study who achieve a CR or PR.

Other Outcome Measures:

1. BCL2 protein expression [ Time Frame: Up to 4 years ]
   BCL2 protein expression by immunohistochemistry will be defined as positive or negative based on the most recent available biopsy report of each patient's diffuse large B-cell lymphoma. Descriptive statistics will be provided for the exploratory analysis of BCL2 expression and response to treatment.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Relapsed/refractory DLBCL defined as any of the following:

  • Confirmed DLBCL/Burkitt lymphoma (BL)/B-cell lymphoma, unclassifiable (BCLU) by World Health Organization (WHO) 2016 classification
  • Double hit lymphoma (DHL) phenotype as confirmed by FISH (fluorescent in-situ hybridization) or IHC (immunohistochemistry)
• Relapsed or progression of disease after at least one prior line of standard rituximab-cyclophosphamide-hydroxydaunorubicin-oncovin-prednisone (R-CHOP), rituximab-etoposide-prednisone-oncovin-cyclophosphamide-hydroxydaunorubicin (R-EPOCH) or other R-CHOP-like therapy
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• No prior treatment with a proteasome inhibitor or prior BCL2 inhibitor
• No cytotoxic chemotherapy within 2 weeks prior to study treatment
• Patients who are not candidates for salvage stem cell transplant or patients who are not candidates for CAR-T (chimeric antigen receptor T-cell) therapy, patients who have progressed or relapsed after a salvage transplant or CAR-T therapy are eligible
• Patients must give informed consent
• Prior radiation therapy allowed to < 25% of the bone marrow and patients must have recovered from the toxic effects of the treatment prior to study enrollment (except for alopecia). Patients treated with standard postoperative adjuvant radiation therapy for other cancers are allowed. Prior radiotherapy must be completed 14 days before study entry. Lesions that have been radiated in the advanced setting cannot be included as sites of measurable disease unless clear tumor progression has been documented in these lesions since the end of radiation therapy
• Patients with lower blood counts due to marrow involvement by DHL will be eligible for the study
• Absolute neutrophil count (ANC) >= 1,000/uL
• Platelets >= 50,000/uL
• Total bilirubin within normal institutional limits
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 3 X institutional upper limit of normal (ULN)
• Creatinine < 1.5 the upper limit of normal

Exclusion Criteria:

• Patients who have had prior proteasome inhibitor therapy or prior therapy with venetoclax
• Patients with known brain metastases will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
• Serious concomitant systemic disorders (including active infections) that would compromise the safety of the patient or compromise the patient's ability to complete the study, at the discretion of the investigator
• Patients with history of hepatitis B with negative viral load are eligible (including latent carriers and patient with history of active disease who required treatment)
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to venetoclax and bortezomib or other agents used in the study
• Subjects with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) which is not well controlled on antiviral therapy
• Patients who have received autologous hematopoietic stem cell transplantation within 12 months
• Subject has received the following within 7 days prior to the first dose of study drug: Steroid therapy for anti-neoplastic intent, strong and moderate CYP3A inhibitors and/or strong and moderate CYP3A inducers
• The effects of combination venetoclax and bortezomib may cause fetal harm. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and for 12 weeks after. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately

Contacts and Locations

Locations

United States, New Jersey

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, United States, 08903

Sponsors and Collaborators

Rutgers, The State University of New Jersey

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Rajat Bannerji; Rutgers Cancer Institute of New Jersey

More Information

• Responsible Party: Rajat Bannerji, MD, PhD, Chief, Section Hematologic Malignancies. Associate Professor of Medicine Medical Oncology, Rutgers Cancer Institute of New Jersey
• ClinicalTrials.gov Identifier: NCT04285268
• Other Study ID Numbers: 011915; NCI-2020-00904 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 011915 ( Other Identifier: Rutgers Cancer Institute of New Jersey ); P30CA072720 ( U.S. NIH Grant/Contract )
• First Posted: February 26, 2020
• Last Update Posted: June 16, 2020
• Last Verified: June 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:

Burkitt Lymphoma; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, Non-Hodgkin; Epstein-Barr Virus Infections; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Tumor Virus Infections; Rituximab; Antineoplastic Agents, Immunological; Bortezomib; Venetoclax; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Immunologic Factors; Physiological Effects of Drugs; Antineoplastic Agents; Antirheumatic Agents