Venetoclax + Lenalidomide + Rituximab for Mantle Cell Lymphoma
Recruiting in Palo Alto (17 mi)
+4 other locations
Overseen ByTycel Phillips, M.D.
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: City of Hope Medical Center
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?The purpose of this study is to determine if giving an experimental drug called venetoclax in combination with lenalidomide and rituximab is safe and effective for treating people with Mantle Cell Lymphoma (MCL).
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications, but you cannot take certain drugs that affect liver enzymes (CYP3A inhibitors or inducers) within one week before starting the trial treatment.
What makes the drug combination of Venetoclax, Lenalidomide, and Rituximab unique for treating Mantle Cell Lymphoma?
This drug combination is unique because it combines Venetoclax, a BCL-2 inhibitor, with Lenalidomide and Rituximab to enhance treatment effectiveness for untreated Mantle Cell Lymphoma, achieving high response rates and minimal residual disease undetectability, which is not commonly seen with other treatments.
23478Is the combination of Venetoclax, Lenalidomide, and Rituximab safe for humans?
The combination of Venetoclax, Lenalidomide, and Rituximab has been found to be safe in patients with untreated mantle cell lymphoma, with common side effects including low white blood cell counts (neutropenia) and low platelet counts (thrombocytopenia). Venetoclax, when used alone or with Rituximab, has also shown a manageable safety profile in patients with chronic lymphocytic leukemia.
34678What data supports the effectiveness of the drug combination of Venetoclax, Lenalidomide, and Rituximab for treating Mantle Cell Lymphoma?
A study showed that adding Venetoclax to Lenalidomide and Rituximab was safe and effective for patients with untreated Mantle Cell Lymphoma, with 96% of patients responding to the treatment and 86% achieving complete response.
14578Eligibility Criteria
This trial is for adults over 18 with untreated Mantle Cell Lymphoma, who are in relatively good health (ECOG ≤2), not pregnant or breastfeeding, and can take oral medication. They must join the Revlimid REMS® program, agree to pregnancy testing if applicable, use contraception, and have no recent strong drug interactions or other cancers within 2 years.Inclusion Criteria
My tests show I have mantle cell lymphoma.
I can take care of myself but might not be able to do heavy physical work.
I am 18 years old or older.
My diagnosis is mantle cell lymphoma confirmed by tissue examination.
I am registered and can follow the Revlimid REMS program requirements.
Exclusion Criteria
My cancer has spread to my brain or spinal cord.
I have received chemotherapy for mantle cell lymphoma.
I have taken a strong or moderate drug that affects liver enzymes within the last week.
I have a serious heart condition.
I do not have an active Hepatitis B or C infection.
I have moderate to severe numbness, tingling, or pain in my hands or feet.
Participant Groups
The study tests a combination of venetoclax with lenalidomide and rituximab for safety and effectiveness against MCL. Participants will receive this experimental treatment to see how well it works compared to current treatments.
1Treatment groups
Experimental Treatment
Group I: Venetoclax, Lenalidomide, RituximabExperimental Treatment3 Interventions
Rituximab 375 mg/m2 IV day 1, 8, 15, 22 of 1st cycle then on day 1 for cycles 2, 4, 6, 8, 10, 12 Lenalidomide 10 mg day 1-7 of and 15 mg day 8-14 cycle #1. 20 mg PO day day 15-21 of cycle #1 and days 1-21 cycles 2-12. Venetoclax PO days 8 - 28 cycles during cycle 1 only. Starting with ramp-up dose as follows (50 mg x 7 days then 100mg x 7 days then 200 mg x 7 days then 400 mg for remainder of therapy). Will be given days 1-28 at a dose of 400 mg cycle 2-12.
Lenalidomide is already approved in European Union, United States for the following indications:
🇪🇺 Approved in European Union as Revlimid for:
- Multiple myeloma
- Myelodysplastic syndromes
- Mantle cell lymphoma
- Follicular lymphoma
- Marginal zone lymphoma
🇺🇸 Approved in United States as Revlimid for:
- Multiple myeloma
- Myelodysplastic syndromes
- Mantle cell lymphoma
- Follicular lymphoma
- Marginal zone lymphoma
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
University of Michgan Comprehensive Cancer CenterAnn Arbor, MI
University of MichiganAnn Arbor, MI
City of Hope Medical centerDuarte, CA
City of Hope Comprehensive Cancer CenterDuarte, CA
More Trial Locations
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Who is running the clinical trial?
City of Hope Medical CenterLead Sponsor
University of Michigan Rogel Cancer CenterLead Sponsor
References
Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial. [2023]The combination of rituximab and lenalidomide has shown promise for the treatment of mantle-cell lymphoma (MCL) in preclinical studies. We aimed to identify the maximum tolerated dose (MTD) of lenalidomide when combined with rituximab in a phase 1 trial and to assess the efficacy and safety of this combination in a phase 2 trial in patients with relapsed or refractory MCL.
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.
Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . [2018]Venetoclax (Venclexta™) 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.
Lenalidomide: A Review in Previously Treated Follicular Lymphoma. [2021]Lenalidomide (Revlimid®) is a targeted immunomodulatory drug with multiple mechanisms of action. In the USA and the EU, oral lenalidomide is indicated in combination with rituximab or a rituximab product for the treatment of patients with previously treated follicular lymphoma. In the pivotal, phase III AUGMENT trial, lenalidomide + rituximab significantly prolonged progression-free survival (PFS; primary endpoint) relative to placebo + rituximab in patients with relapsed or refractory indolent non-Hodgkin lymphoma, with the PFS benefit appearing to be specific to patients with follicular lymphoma and extending to elderly patients with this subtype. Lenalidomide + rituximab also demonstrated activity in an interim analysis of the phase III MAGNIFY trial in patients with relapsed or refractory indolent non-Hodgkin lymphoma, including those with rituximab-refractory disease. Lenalidomide had an acceptable tolerability profile. Although grade 3 or 4 neutropenia occurred more frequently with lenalidomide + rituximab than with placebo + rituximab, this was generally well managed with dosage adjustments and growth factor support. In conclusion, lenalidomide in combination with rituximab represents an important new treatment option for previously treated follicular lymphoma, including patients whose disease has become refractory to rituximab.
Phase 1/2 study of venetoclax, a BCL-2 inhibitor, in Japanese patients with relapsed or refractory chronic lymphocytic leukemia and small lymphocytic lymphoma. [2021]Patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have limited treatment options. Venetoclax is a potent BCL-2 inhibitor that induces apoptosis in CLL cells. This open-label, phase 1/2 study (NCT02265731) evaluated the safety, pharmacokinetics, and efficacy of venetoclax in Japanese patients with R/R CLL/SLL. Patients enrolled in phase 1 received 400 mg/day venetoclax monotherapy. Patients enrolled in phase 2 received 400 mg/day venetoclax, plus rituximab. Venetoclax was administered with a weekly stepwise ramp-up in doses. In phase 2, efficacy was evaluated by objective response rate (ORR). Twelve patients were enrolled, six in each arm. The most common grade ≥ 3 adverse events were neutropenia (83%), lymphopenia (67%), leukopenia (33%), and thrombocytopenia (17%). Patients receiving venetoclax monotherapy achieved an ORR of 100%, including a complete remission (CR) rate of 17%. Patients receiving combination therapy had an ORR of 67% and a CR rate of 50%. The venetoclax pharmacokinetics profile in Japanese patients was similar to that of Western patients. Venetoclax 400 mg/day monotherapy or in combination with rituximab was well-tolerated and induced promising responses in Japanese patients with R/R CLL/SLL. Although patient numbers were small, the safety profile was largely consistent with other Western studies. Clinical trial registration: clinicaltrials.gov; NCT02265731.
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.