Venetoclax + Rituximab for Mantle Cell Lymphoma
Recruiting in Palo Alto (17 mi)
Overseen ByLode Swinnen, MD
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Approved in 2 jurisdictions
Trial Summary
What is the purpose of this trial?The proposed study is an open-label, single arm phase II study of venetoclax in combination with rituximab in patients over the age of 60 with previously untreated mantle cell lymphoma. The primary objective of the trial is to determine whether the combination of venetoclax with rituximab in this patient population yields a clinically acceptable proportion of overall responses (ORR, assessed by PET/CT with Lugano criteria) without chemotherapy.
What makes the drug combination of Venetoclax and Rituximab unique for treating Mantle Cell Lymphoma?
The combination of Venetoclax and Rituximab is unique because Venetoclax is a first-in-class oral drug that specifically targets and inhibits BCL-2, a protein that helps cancer cells survive, and when combined with Rituximab, it has shown a synergistic effect, enhancing treatment effectiveness and prolonging progression-free survival in similar conditions like chronic lymphocytic leukemia.
24589Do I need to stop my current medications for the trial?
The trial protocol does not specify if you need to stop taking your current medications. However, if you are taking warfarin, you cannot participate in the trial.
Is the combination of Venetoclax and Rituximab safe for treating Mantle Cell Lymphoma?
Venetoclax, when used alone or with Rituximab, has been generally well tolerated in clinical trials for various types of lymphoma, including Mantle Cell Lymphoma. Most side effects were mild to moderate, but some patients experienced more serious blood-related issues like anemia (low red blood cell count), neutropenia (low white blood cell count), and thrombocytopenia (low platelet count).
13456What data supports the effectiveness of the drug Venetoclax combined with Rituximab for Mantle Cell Lymphoma?
A study showed that adding Venetoclax to a combination of Lenalidomide and Rituximab was safe and effective for patients with untreated Mantle Cell Lymphoma, achieving high response rates and undetectable disease in most patients.
24579Eligibility Criteria
This trial is for people over 60 with a new diagnosis of mantle cell lymphoma who need treatment but haven't had any yet. They should be in fairly good health, able to perform daily activities, and have decent blood counts and organ function. Pregnant or breastfeeding women can't join, nor can those with certain types of the disease, uncontrolled infections, HIV, hepatitis B or C.Inclusion Criteria
I am 60 years old or older.
I am using birth control as required.
My diagnosis is mantle cell lymphoma, confirmed by a biopsy.
I can care for myself but may not be able to do heavy physical work.
Exclusion Criteria
My lymphoma is in the early stages (stage I or II).
I have an infection that isn't responding to treatment.
I am currently pregnant or breastfeeding.
I need to take warfarin.
My lymphoma has spread to my brain or spinal cord.
I am HIV positive.
I have a type of cancer called blastoid-variant mantle cell lymphoma.
I need immediate treatment to reduce my cancer cells.
Participant Groups
The study tests Venetoclax tablets combined with Rituximab injections as an initial therapy for older patients with mantle cell lymphoma. It's an open-label phase II trial aiming to see if this drug combo works well without chemotherapy by measuring overall response rates using PET/CT scans.
1Treatment groups
Experimental Treatment
Group I: venetoclax and rituximab in patients over 60 yrs old with previously untreated mantle cell lymphomaExperimental Treatment1 Intervention
Venetoclax dose escalation for Cycles 1-4. If Complete response (CR) at Cycle 4, continue with cycles 5-12 at fixed venetoclax 400mg dose. If partial response (PR) at Cycle 4, continue with cycles 5-8 at fixed venetoclax 800mg dose. If CR at Cycle 8 after PR, continue with cycles 9-12 at fixed venetoclax 800mg dose. If continued PR at Cycle 8, reduce venetoclax to 400mg and add bendamustine 90 mg/m2.
Venetoclax is already approved in United States, European Union for the following indications:
๐บ๐ธ Approved in United States as Venclexta for:
- Chronic lymphocytic leukemia (CLL)
- Small lymphocytic lymphoma (SLL)
- Acute myeloid leukemia (AML)
๐ช๐บ Approved in European Union as Venclyxto for:
- Chronic lymphocytic leukemia (CLL)
- Small lymphocytic lymphoma (SLL)
- Acute myeloid leukemia (AML)
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimore, MD
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Who is running the clinical trial?
Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsLead Sponsor
AbbVieIndustry Sponsor
References
Venetoclax: First Global Approval. [2018]Venetoclax (Venclextaโข) is an oral selective inhibitor of the prosurvival protein BCL-2 and therefore restores the apoptotic ability of malignant cells. The drug arose from research by Abbott Laboratories (now AbbVie) during a collaboration with Genentech and is being co-developed by AbbVie and Genentech/Roche primarily for the treatment of haematological malignancies. Venetoclax is approved in the USA for use as monotherapy in patients with chronic lymphocytic leukaemia (CLL) with the 17p deletion (as detected by an approved FDA test) who have received at least one prior therapy, and is awaiting approval for similar indications in the EU and Canada. Venetoclax is also in phase I-III development as combination therapy for CLL, phase I/II development as monotherapy and/or combination therapy for non-Hodgkin lymphomas (including diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma) and acute myeloid leukaemia, and phase I development for multiple myeloma, systemic lupus erythematosus and breast cancer. This article summarizes the milestones in the development of venetoclax leading to this first approval for CLL.
Relationship between venetoclax exposure, rituximab coadministration, and progression-free survival in patients with relapsed or refractory chronic lymphocytic leukemia: demonstration of synergy. [2018]Venetoclax is indicated at a dosage of 400 mg daily (QD) for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least 1 prior therapy. Ongoing trials are evaluating venetoclax in combination with CD20 targeting monoclonal antibodies, such as rituximab. The objective of this research was to characterize the relationship between venetoclax exposures and progression-free survival (PFS) and to evaluate the effect of rituximab coadministration on PFS in patients with relapsed or refractory (R/R) CLL/small lymphocytic lymphoma (SLL). A total of 323 patients from 3 clinical studies of venetoclax, with and without rituximab coadministration, were pooled for the analyses. A time-variant relative risk survival model was used to relate plasma venetoclax concentrations and rituximab administration to PFS. Demographics and baseline disease characteristics were evaluated for their effect on PFS. A concentration-dependent effect of venetoclax on PFS and a prolonged synergistic effect of 6 cycles of concomitant rituximab were identified. The 17p deletion chromosomal aberration was not identified to affect the PFS of patients treated with venetoclax. A venetoclax dose of 400 mg daily QD was estimated to result in a substantial median PFS of 1.8 years (95% confidence interval [CI], 1.7-2.1), whereas the addition of 6 cycles of rituximab was estimated to increase the median PFS to 3.9 years (95% CI, 2.8-5.6). The analysis demonstrates a concentration-dependent effect of venetoclax on PFS and also a synergistic effect with rituximab. Combining venetoclax with the CD20 targeting monoclonal antibody rituximab in R/R CLL/SLL patients provides substantial synergistic benefit compared with increasing the venetoclax monotherapy dose.
Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma. [2018]Purpose B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non-Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts. Treatment commenced with a 3-week dose ramp-up period for most patients in dose-escalation cohorts and for all patients in safety expansion. Results NHL subtypes included mantle cell lymphoma (MCL; n = 28), follicular lymphoma (FL; n = 29), diffuse large B-cell lymphoma (DLBCL; n = 34), DLBCL arising from chronic lymphocytic leukemia (Richter transformation; n = 7), Waldenstrรถm macroglobulinemia (n = 4), and marginal zone lymphoma (n = 3). Venetoclax was generally well tolerated. Clinical tumor lysis syndrome was not observed, whereas laboratory tumor lysis syndrome was documented in three patients. Treatment-emergent adverse events were reported in 103 patients (97%), a majority of which were grade 1 to 2 in severity. Grade 3 to 4 events were reported in 59 patients (56%), and the most common were hematologic, including anemia (15%), neutropenia (11%), and thrombocytopenia (9%). Overall response rate was 44% (MCL, 75%; FL, 38%; DLBCL, 18%). Estimated median progression-free survival was 6 months (MCL, 14 months; FL, 11 months; DLBCL, 1 month). Conclusion Selective targeting of BCL-2 with venetoclax was well tolerated, and single-agent activity varied among NHL subtypes. We determined 1,200 mg to be the recommended single-agent dose for future studies in FL and DLBCL, with 800 mg being sufficient to consistently achieve durable response in MCL. Additional investigations including combination therapy to augment response rates and durability are ongoing.
Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . [2018]Venetoclax (Venclextaโข) is a potent, selective, orally available, small-molecule B-cell lymphoma 2 inhibitor that achieves response rates of about 80% and has an acceptable safety profile for patients with relapsed or refractory chronic lymphocytic leukemia (CLL). .
Venetoclax: A Review in Relapsed/Refractory Chronic Lymphocytic Leukemia. [2020]Venetoclax (Venclyxto®; Venclexta®) is a first-in-class, oral, selective B cell lymphoma-2 (BCL-2) inhibitor. The drug is approved in numerous countries, including those of the EU and in the USA, for the treatment of adults with relapsed or refractory (RR) chronic lymphocytic leukemia (CLL); the specific indication(s) for venetoclax may vary between individual countries. Venetoclax monotherapy or combination therapy with rituximab was an effective treatment, provided durable responses, and had a manageable safety profile in pivotal clinical trials in adults with RR CLL, including in patients with adverse prognostic factors. In combination with 6 cycles of rituximab, venetoclax (fixed 24 months' treatment) was more effective than bendamustine plus rituximab (6 cycles) in prolonging progression-free survival (PFS) and inducing undetectable minimal residual disease (uMRD) in peripheral blood (PB) and bone marrow (BM), with these benefits sustained during 36 months' follow-up. Hence, with its novel mechanism of action and convenient oral once-daily regimen, venetoclax monotherapy or fixed 24-month combination therapy with rituximab represents an important option for treating RR CLL, including in patients with del(17p) or TP53 mutation and those failing a B cell receptor (BCR) inhibitor and/or chemotherapy.
Treatment of Patients With Relapsed/Refractory Non-Hodgkin Lymphoma With Venetoclax: A Single-Center Evaluation of Off-Label Use. [2020]Venetoclax is a highly effective agent in chronic lymphocytic leukemia and acute myeloid leukemia. Phase I/II clinical trials have shown it to be safe and effective in non-Hodgkin lymphoma (NHL). Adverse events were consistent with package labeling despite escalation to high doses. To the best of our knowledge, venetoclax use outside the setting of a clinical trial of NHL has not been reported.
Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. [2021]Venetoclax (Venclexta®; Venclyxto®) is a first-in-class, oral, selective inhibitor of B cell lymphoma 2 (BCL2). In several countries, including the USA and those of the EU, venetoclax is indicated in combination with obinutuzumab for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL). Approval was based on the results of the phase III CLL14 trial in patients with previously untreated CLL and co-existing conditions. In this study, fixed-duration (12 months) targeted treatment with venetoclax + obinutuzumab resulted in significantly longer progression-free survival (PFS; primary endpoint) relative to fixed-duration chemoimmunotherapy with chlorambucil + obinutuzumab. Venetoclax + obinutuzumab was also associated with significantly higher rates of undetectable minimal residual disease (MRD), complete response and overall response than chlorambucil + obinutuzumab. Improvements in clinical outcomes with venetoclax + obinutuzumab were maintained during long-term follow-up, when all patients had been off treatment for ≥ 2 years. No significant between-group difference was observed in overall survival (OS). Venetoclax had an acceptable tolerability profile. Notable adverse events such as grade 3 or 4 neutropenia can be managed with supportive therapy and venetoclax dose modifications. In conclusion, fixed-duration venetoclax + obinutuzumab represents an important chemotherapy-free first-line treatment option for patients with CLL, particularly those who are not fit enough to receive intensive chemoimmunotherapy.
Addition of rituximab in relapsed/refractory chronic lymphocytic leukemia after progression on venetoclax monotherapy. [2022]Venetoclax is approved as monotherapy and in combination with rituximab for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Two Phase 1 studies (M12-175 [NCT01328626]; M13-365 [NCT01682616]) were conducted in which patients who initially responded and then progressed on venetoclax monotherapy could receive added rituximab. Ten patients were evaluated (M12-175, n = 8; M13-365, n = 2), and five (50%) responded again upon addition of rituximab, including three complete and two partial responses. Responses were ongoing after 5-10 months of follow-up. Addition of rituximab was well tolerated. These findings indicate potential clinical benefit with rituximab added to venetoclax post-progression in some patients with R/R CLL.
Adding venetoclax to lenalidomide and rituximab is safe and effective in patients with untreated mantle cell lymphoma. [2023]Mantle cell lymphoma (MCL) is a rare, incurable hematological malignancy with a heterogeneous presentation and clinical course. A wide variety of chemotherapy-based regimens are currently used in patients who are untreated. Over the last several years, several targeted or small-molecule therapies have shown efficacy in the relapsed/refractory setting and have since been explored in the frontline setting. Lenalidomide plus rituximab was explored in a phase 2 study of 38 patients with MCL who were untreated and ineligible to receive transplantation, in which the combination produced durable remissions. We looked to build upon this regimen by adding venetoclax to the combination. We conducted a multicenter, open-label, nonrandomized, single-arm study to evaluate this combination. We enrolled 28 unselected patients with untreated disease irrespective of age, fitness, or risk factors. Lenalidomide was dosed at 20 mg daily from days 1 to 21 of each 28-day cycle. The dose of venetoclax was determined using the time-to-event continual reassessment method. Rituximab was dosed at 375 mg/m2 weekly, starting on cycle 1, day 1 until cycle 2, day 1. No dose-limiting toxicities were noted. All patients were treated with venetoclax at the maximum tolerated dose of 400 mg daily. The most common adverse events were neutropenia and thrombocytopenia. The overall and complete response rates were 96% and 86%, respectively. In total, 86% of patients achieved minimal residual disease undetectability via next-generation sequencing. The median overall and progression-free survivals were not reached. The combination of lenalidomide, rituximab, and venetoclax is a safe and effective regimen in patients with untreated MCL. This trial was registered at www.clinicaltrials.gov as #NCT03523975.