Tafasitamab + Lenalidomide + Venetoclax for Mantle Cell Lymphoma (V-MIND Trial)
Palo Alto (17 mi)Overseen byYucai Wang
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Academic and Community Cancer Research United
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This phase II trial tests how well tafasitamab, lenalidomide and venetoclax work in treating patients with mantle cell lymphoma that has come back (after a period of improvement) (relapsed) or that has not responded to previous treatment (refractory). Tafasitamab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Lenalidomide is in a class of medications called immunomodulatory agents. It works by helping the immune system kill cancer cells. 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. Giving tafasitamab, lenalidomide and venetoclax together may kill cancer cells more efficiently in patients with relapsed or refractory mantle cell lymphoma.
What safety data exists for the combination of Tafasitamab, Lenalidomide, and Venetoclax in treating Mantle Cell Lymphoma?The safety data for the combination of Tafasitamab, Lenalidomide, and Venetoclax specifically for Mantle Cell Lymphoma is not directly available in the provided research. However, related studies provide some insights: 1) A study on Lenalidomide and Venetoclax with Rituximab in untreated Mantle Cell Lymphoma showed no dose-limiting toxicities, with common adverse events being neutropenia and thrombocytopenia. 2) Tafasitamab plus Lenalidomide has been studied in relapsed/refractory diffuse large B-cell lymphoma, showing improved survival outcomes compared to other treatments, with no specific safety concerns highlighted. 3) Venetoclax, when used in other combinations, has been associated with serious adverse events, particularly infections, at higher doses. Overall, while these studies suggest the components have been used safely in various combinations, specific safety data for the exact combination in Mantle Cell Lymphoma is not detailed in the provided research.45689
Is the drug combination of Lenalidomide, Tafasitamab, and Venetoclax promising for treating Mantle Cell Lymphoma?Yes, the combination of Lenalidomide, Tafasitamab, and Venetoclax is promising for treating Mantle Cell Lymphoma. Research shows that these drugs can work well together, leading to high response rates and effective treatment outcomes in patients. Venetoclax, in particular, has shown strong anticancer activity, and when combined with other drugs, it can improve overall survival rates.12378
What data supports the idea that Tafasitamab + Lenalidomide + Venetoclax for Mantle Cell Lymphoma is an effective treatment?The available research shows that adding venetoclax to lenalidomide and rituximab is safe and effective for patients with untreated mantle cell lymphoma. In a study with 28 patients, 96% responded to the treatment, and 86% had no detectable disease after treatment. This suggests that the combination of lenalidomide, rituximab, and venetoclax is effective for mantle cell lymphoma. However, there is no specific data on the combination of Tafasitamab, Lenalidomide, and Venetoclax for mantle cell lymphoma in the provided information.34689
Do I need to stop my current medications to join the trial?The trial protocol does not specify if you must stop all current medications, but certain medications are restricted. You cannot take anticoagulants like vitamin K antagonists within 7 days before joining, and you must avoid strong CYP3A inhibitors or inducers during the study. If you recently took MCL treatment, at least 5 half-lives of the drug or 14 days must pass before joining. Check with your doctor for specific guidance.
Eligibility Criteria
Adults with relapsed or refractory mantle cell lymphoma, who've had at least one prior treatment and have measurable disease. They must be in relatively good health, with adequate blood counts and organ function, not pregnant, willing to use contraception, and able to take daily aspirin or anticoagulants. Excluded are those recently receiving certain treatments like stem cell transplants or CAR T-cell therapy, those with CNS involvement by MCL or severe concurrent diseases.Treatment Details
The trial is testing a combination of three drugs: tafasitamab (a monoclonal antibody), lenalidomide (an immunomodulatory agent), and venetoclax (a Bcl-2 inhibitor) for treating mantle cell lymphoma that has returned after treatment or hasn't responded to previous therapies. The goal is to see if this drug combo can more effectively kill cancer cells.
1Treatment groups
Experimental Treatment
Group I: Treatment (Tafasitamab, lenalidomide, venetoclax)Experimental Treatment11 Interventions
Patients receive tafasitamab IV, lenalidomide PO and venetoclax PO while on study. Patients may undergo lumbar puncture during screening. Patients undergo CT scan and blood sample collection and may undergo MRI and tumor biopsy on study and during follow-up. Patients undergo PET/CT, bone marrow biopsy, and bone marrow aspirate throughout the study.
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:
Mayo Clinic in RochesterRochester, MN
M D Anderson Cancer CenterHouston, TX
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Who is running the clinical trial?
Academic and Community Cancer Research UnitedLead Sponsor
National Cancer Institute (NCI)Collaborator
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.
Cotargeting of BCL2 with Venetoclax and MCL1 with S63845 Is Synthetically Lethal In Vivo in Relapsed Mantle Cell Lymphoma. [2020]Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin lymphomas characterized by (over)expression of BCL2. A BCL2-targeting drug, venetoclax, has promising anticancer activity in MCL. We analyzed molecular mechanisms of venetoclax resistance in MCL cells and tested strategies to overcome it.
Efficacy of venetoclax in high risk relapsed mantle cell lymphoma (MCL) - outcomes and mutation profile from venetoclax resistant MCL patients. [2020]Venetoclax is effective in relapsed patients with mantle cell lymphoma (MCL). Mechanisms of resistance to venetoclax in MCL are poorly understood. We describe the clinical outcomes and genomic characteristics of 24 multiply relapsed patients (median of five prior lines of therapy) who received venetoclax-based therapies; 67% had progressed on BTK inhibitors (BTKi) and 54% had blastoid or pleomorphic histology. Median follow up after venetoclax treatment was 17 months. The overall response rate was 50% and complete response (CR) rate was 21%, 16 patients had progressed and 15 died. The median progression free, overall and post venetoclax survival were 8, 13.5 and 7.3 months respectively. Whole-exome sequencing (WES) was performed on samples collected from seven patients (including five pairs; before starting venetoclax and after progression on venetoclax). The SMARCA4 and BCL2 alterations were noted only after progression, while TP53, CDKN2A, KMT2D, CELSR3, CCND1, NOTCH2 and ATM were altered 2-4-fold more frequently after progression. In two patients with serial samples, we demonstrated clonal evolution of novel SMARCA4 and KMT2C/D mutations at progression. Mutation dynamics in venetoclax resistant MCL is demonstrated. Our data indicates that venetoclax resistance in MCL is predominantly associated with non-BCL2 gene mutations. Further studies are ongoing in MCL patients to evaluate the efficacy of venetoclax in combination with other agents and understand the biology of venetoclax resistance in MCL.
Tafasitamab: First Approval. [2022]Tafasitamab (tafasitamab-cxix; MONJUVI®) is an Fc-modified (i.e. two amino acid substitutions within the Fc region, resulting in increased Fcγ receptor affinity), humanized, anti-CD19 monoclonal antibody. Developed by MorphoSys AG, under a license from Xencor, it received accelerated approval (in July 2020) for use in combination with lenalidomide as a treatment for adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, including DLBCL arising from low grade lymphoma, and who are not eligible for autologous stem cell transplantation (ASCT). It is the first therapy to be approved as a second-line treatment for this patient population in the USA. The recommended dose of tafasitamab is 12 mg per kg of bodyweight, administered via an intravenous infusion. A regulatory assessment for tafasitamab plus lenalidomide for the treatment of adults with relapsed or refractory DLBCL is currently underway in the EU. Tafasitamab is also being clinically investigated as a therapeutic option in various other B-cell malignancies, including follicular lymphoma and other indolent non-Hodgkin's lymphoma. This article summarizes the milestones in the development of tafasitamab leading to this first approval for its use in combination with lenalidomide in adults with relapsed or refractory DLBCL.
Low dose venetoclax in combination with bortezomib, daratumumab, and dexamethasone for the treatment of relapsed/refractory multiple myeloma patients-a single-center retrospective study. [2021]Venetoclax is a BCL-2 inhibitor currently indicated for use in treating hematologic malignancies with recommended doses ranging from 400 to 600 mg/day. Although currently not FDA-approved to treat multiple myeloma (MM) patients, there is a growing number of reports indicating its efficacy as a salvage therapy for these patients, especially for those with the t(11;14) chromosomal marker. These studies, however, have also indicated that venetoclax given at doses ≥ 400 mg/day can cause serious adverse events (SAEs) especially when administered with bortezomib, commonly related to infections. The purpose of this single-center retrospective study was to determine the efficacy of low dose venetoclax (defined as ≤ 250 mg/day) in combination with low dose bortezomib (defined as 1.0 mg/m2 per dose), daratumumab, and dexamethasone (Dvvd) as a salvage therapy for relapsed/refractory myeloma (RRMM) patients. Twenty-two RRMM patients were given venetoclax orally at doses ranging from 100 to 250 mg daily using this four-drug regimen. While the low doses resulted in reduced venetoclax efficacy among those lacking t(11;14) (overall response rate [ORR] = 31%), those harboring the t(11;14) marker exhibited an ORR of 80%. Notably, this response was without frequent infection-related SAEs as reported in previous studies. Together, the results of this study demonstrate that treatment of t(11;14) positive RRMM patients with Dvvd is both effective and well-tolerated.
Tafasitamab Plus Lenalidomide Versus 3 Rituximab-Based Treatments for Non-Transplant Eligible Relapsed/Refractory Diffuse Large B-Cell Lymphoma: A Matching-Adjusted Indirect Comparison. [2022]Tafasitamab plus lenalidomide (TAFA + LEN) received accelerated US Food and Drug Administration approval and conditional European Medicines Agency approval for treatment of adults with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) not eligible for autologous stem cell transplant. This study investigates the relative efficacy of TAFA + LEN versus comparator treatments.
A multicenter analysis of the outcomes with venetoclax in patients with relapsed mantle cell lymphoma. [2023]To report the activity of venetoclax in patients with relapsed mantle cell lymphoma (MCL), we identified 81 patients treated with venetoclax monotherapy (n = 50, 62%) or in combination with a Bruton tyrosine kinase inhibitor (BTKi) (n = 16, 20%), an anti-CD20 monoclonal antibody (n = 11, 14%), or other active agents at 12 US academic medical centers. Patients had high-risk disease features including Ki67 >30% (61%), blastoid/pleomorphic histology (29%), complex karyotype (34%), and TP53 alterations (49%), and received a median of 3 prior treatments including BTKis in 91%. Venetoclax alone or in combination resulted in an overall response rate (ORR) of 40% and median progression-free (PFS) and overall survival (OS) of 3.7 and 12.5 months, respectively. The receipt of ≤3 prior treatments was associated with higher odds of response to venetoclax in a univariable analysis. In a multivariable analysis, having a high-risk Mantle Cell Lymphoma International Prognostic Index score before receiving venetoclax and disease relapse or progression within 24 months of diagnosis were associated with inferior OS whereas the use of venetoclax in combination was associated with superior OS. Although most patients (61%) had low risk for tumor lysis syndrome (TLS), 12.3% of patients developed TLS despite the implementation of several mitigation strategies. In conclusion, venetoclax resulted in good ORR but short PFS in patients with MCL who are at high risk, and may have a better role in earlier lines of treatment and/or in conation with other active agents. TLS remains an important risk in patients with MCL who initiate treatment with venetoclax.
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.
RE-MIND2: comparative effectiveness of tafasitamab plus lenalidomide versus polatuzumab vedotin/bendamustine/rituximab (pola-BR), CAR-T therapies, and lenalidomide/rituximab (R2) based on real-world data in patients with relapsed/refractory diffuse large B-cell lymphoma. [2023]RE-MIND2 (NCT04697160) compared patient outcomes from the L-MIND (NCT02399085) trial of tafasitamab+lenalidomide with those of patients treated with other therapies for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who are autologous stem cell transplant ineligible. We present outcomes data for three pre-specified treatments not assessed in the primary analysis. Data were retrospectively collected from sites in North America, Europe, and the Asia Pacific region. Patients were aged ≥18 years with histologically confirmed DLBCL and received ≥2 systemic therapies for DLBCL (including ≥1 anti-CD20 therapy). Patients enrolled in the observational and L-MIND cohorts were matched using propensity score-based 1:1 nearest-neighbor matching, balanced for six covariates. Tafasitamab+lenalidomide was compared with polatuzumab vedotin+bendamustine+rituximab (pola-BR), rituximab+lenalidomide (R2), and CD19-chimeric antigen receptor T-cell (CAR-T) therapies. The primary endpoint was overall survival (OS). Secondary endpoints included treatment response and progression-free survival. From 200 sites, 3,454 patients were enrolled in the observational cohort. Strictly matched patient pairs consisted of tafasitamab+lenalidomide versus pola-BR (n = 24 pairs), versus R2 (n = 33 pairs), and versus CAR-T therapies (n = 37 pairs). A significant OS benefit was observed with tafasitamab+lenalidomide versus pola-BR (HR: 0.441; p = 0.034) and R2 (HR: 0.435; p = 0.012). Comparable OS was observed in tafasitamab+lenalidomide and CAR-T cohorts (HR: 0.953, p = 0.892). Tafasitamab+lenalidomide appeared to improve survival outcomes versus pola-BR and R2, and comparable outcomes were observed versus CAR-T. Although based on limited patient numbers, these data may help to contextualize emerging therapies for R/R DLBCL. CLINICAL TRIAL REGISTRATION: NCT04697160 (January 6, 2021).