Description:
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.
Title
- Brief Title: Rituximab, Venetoclax, and Bortezomib for the Treatment of Relapsed or Refractory Diffuse Large B-Cell Lymphoma
- Official Title: A Phase 2 Study of Rituximab, Venetoclax (ABT 199) and Bortezomib in Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
Clinical Trial IDs
- ORG STUDY ID:
011915
- SECONDARY ID:
NCI-2020-00904
- SECONDARY ID:
011915
- SECONDARY ID:
P30CA072720
- NCT ID:
NCT04285268
Conditions
- 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
Interventions
Drug | Synonyms | Arms |
---|
Bortezomib | [(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid, LDP 341, MLN341, PS-341, PS341, Velcade | Treatment (rituximab, venetoclax, bortezomib) |
Rituximab | 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 | Treatment (rituximab, venetoclax, bortezomib) |
Venetoclax | ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, Venclyxto | Treatment (rituximab, venetoclax, bortezomib) |
Purpose
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.
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.
Trial Arms
Name | Type | Description | Interventions |
---|
Treatment (rituximab, venetoclax, bortezomib) | Experimental | 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. | - Bortezomib
- Rituximab
- Venetoclax
|
Eligibility 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
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Overall response rate (ORR) |
Time Frame: | Up to 4 years |
Safety Issue: | |
Description: | 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
Measure: | Incidence of adverse events |
Time Frame: | Up to 30 days post treatment |
Safety Issue: | |
Description: | 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. |
Measure: | Progression free survival (PFS) |
Time Frame: | From study enrollment to disease progression or death from any cause, assessed up to 4 years |
Safety Issue: | |
Description: | The Kaplan-Meier curve will be used to estimate the corresponding PFS distribution and median PFS for patients treated on this study. |
Measure: | Overall survival (OS) |
Time Frame: | From study enrollment to the date of death from any cause, assessed up to 4 years |
Safety Issue: | |
Description: | 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"). |
Measure: | Complete response (CR) and partial response (PR) rates |
Time Frame: | Up to 4 years |
Safety Issue: | |
Description: | Defined as the proportion of subjects who achieve a best response of CR or PR respectively. |
Measure: | 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 |
Safety Issue: | |
Description: | 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. |
Details
Phase: | Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Withdrawn |
Lead Sponsor: | Rutgers, The State University of New Jersey |
Last Updated
June 16, 2020