Venetoclax + Lenalidomide + Rituximab for Non-Hodgkin's Lymphoma
Recruiting in Palo Alto (17 mi)
Overseen byUbaldo R Martinez-Outschoorn, MD
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Thomas Jefferson University
Must be taking: Aspirin
Must not be taking: Warfarin, CYP3A inhibitors
Disqualifiers: CNS involvement, Other malignancy, Infections, others
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This phase I trial studies the side effects and best dose of venetoclax when given together with lenalidomide and rituximab hyaluronidase in treating patients with follicular lymphoma and marginal zone lymphoma that has come back after treatment (relapsed) or has not responded to treatment (refractory). Venetoclax may stop the growth of cancer cells by blocking the action of a protein called Bcl-2, that helps cancer cells survive. Immunotherapy with lenalidomide, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Immunotherapy with monoclonal antibodies, such as rituximab and rituximab hyaluronidase, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. The purpose of this research is to determine if the combination of three drugs, venetoclax, lenalidomide, and rituximab hyaluronidase are safe to administer in patients whose low-grade lymphoma (follicular or marginal zone) has come back after initial therapy or was not responsive to initial therapy.
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 use warfarin or certain other drugs like strong CYP3A inhibitors or inducers. It's best to discuss your current medications with the trial team to see if any adjustments are needed.
What data supports the effectiveness of the drug combination Venetoclax, Lenalidomide, and Rituximab for Non-Hodgkin's Lymphoma?
Venetoclax, when used with rituximab, has shown effectiveness in treating chronic lymphocytic leukemia (CLL), providing durable responses and prolonging progression-free survival. Additionally, venetoclax has demonstrated activity in multiple myeloma, suggesting potential benefits when combined with other agents.
12345Is the combination of Venetoclax, Lenalidomide, and Rituximab generally safe for humans?
Venetoclax, when used alone or with Rituximab, has shown a manageable safety profile in patients with chronic lymphocytic leukemia. Rituximab, including its subcutaneous form with hyaluronidase, has comparable adverse events to its intravenous form, suggesting it is generally safe for use in humans.
14678What makes the drug combination of Venetoclax, Lenalidomide, and Rituximab unique for treating Non-Hodgkin's Lymphoma?
This drug combination is unique because Venetoclax is a first-in-class oral BCL-2 inhibitor that, when combined with Rituximab, has shown a synergistic effect, enhancing progression-free survival in other conditions like chronic lymphocytic leukemia. This suggests potential benefits in Non-Hodgkin's Lymphoma, especially when combined with Lenalidomide, which modulates the immune system.
12349Eligibility Criteria
This trial is for adults with certain slow-growing lymphomas, like follicular and marginal zone lymphoma, that have either returned after treatment or haven't responded to previous therapy. Participants must have had at least one prior systemic therapy, be able to swallow pills whole, take daily aspirin or equivalent for blood clot prevention, and meet specific health criteria.Inclusion Criteria
I agree to follow the pregnancy testing schedule as required.
You must have a certain type of lymphoma and have visible disease on a CT scan with at least one lymph node larger than 1.5 cm.
I have a specific type of slow-growing lymphoma and have had at least one treatment.
+7 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Patients receive venetoclax, lenalidomide, and rituximab hyaluronidase in a dose-escalation study. Venetoclax is administered daily, lenalidomide starting from cycle 2, and rituximab in cycles 2, 4, 6, 8, 10, and 12.
12 months
Monthly visits for 12 cycles
Follow-up
Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 days and then for up to 5 years.
5 years
Participant Groups
The study tests a combination of three drugs: Venetoclax (which blocks proteins helping cancer cells survive), Lenalidomide (an immunotherapy that may alter the immune system to hinder tumor growth), and Rituximab/Hyaluronidase (antibodies aiming to boost the immune attack on cancer). The goal is to find safe doses for patients with relapsed/refractory low-grade lymphoma.
1Treatment groups
Experimental Treatment
Group I: Treatment (venetoclax, lenalidomide, rituximab, hyaluronidase)Experimental Treatment4 Interventions
Patient receive venetoclax PO QD on days 1-28. Beginning cycle 2, patients receive lenalidomide PO QD on days 1-21. Patients also receive rituximab IV on days 1, 8, 15, and 22 of cycle 2 and rituximab hyaluronidase (if no significant infusion reaction to rituximab) SC on day 1 of cycles 4, 6, 8, 10, and 12. Patients may receive rituximab IV (instead of rituximab hyaluronidase) on days 1, 8, 15, and 22 of cycles 4, 6, 8, 10, and 12 if the patient requires rituximab IV in the opinion of the treating physician. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
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:
Sidney Kimmel Cancer Center at Thomas Jefferson UniversityPhiladelphia, PA
Loading ...
Who Is Running the Clinical Trial?
Thomas Jefferson UniversityLead Sponsor
National Cancer Institute (NCI)Collaborator
References
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.
Phase I Study of Venetoclax Plus Daratumumab and Dexamethasone, With or Without Bortezomib, in Patients With Relapsed or Refractory Multiple Myeloma With and Without t(11;14). [2022]Venetoclax is an oral BCL-2 inhibitor with single-agent activity in patients with relapsed or refractory multiple myeloma (RRMM) with t(11;14) translocation. Venetoclax efficacy in RRMM may be potentiated through combination with agents including bortezomib, dexamethasone, and daratumumab.
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.
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). .
Efficacy and safety of venetoclax in patients with relapsed/refractory multiple myeloma: a meta-analysis. [2023]Venetoclax is clinically active in treating relapsed/refractory multiple myeloma (RRMM). This study evaluated the efficacy and safety of venetoclax or venetoclax with other agents in treating RRMM.
A Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Recombinant Human Hyaluronidase PH20 Administered Intravenously in Healthy Volunteers. [2022]Recombinant human hyaluronidase PH20 (rHuPH20) is used in subcutaneous formulations (eg, RITUXAN HYCELA [rituximab and hyaluronidase human], HERCEPTIN HYLECTA [trastuzumab and hyaluronidase-oysk], PHESGO [pertuzumab/trastuzumab/hyaluronidase-zzxf], and Darzalex FASPRO [daratumumab and hyaluronidase-fihj]) to increase the dispersion and absorption of coadministered therapeutics. Although unlikely, subcutaneous products that include rHuPH20 could be mistaken for the intravenous formulation of the corresponding drugs (eg, RITUXAN [rituximab], HERCEPTIN [trastuzumab], and DARZALEX [daratumumab]). To understand the potential effects of inadvertent intravenous injection of rHuPH20, we investigated the safety profile, pharmacokinetics (PK), and pharmacodynamics (PD) of rHuPH20 administered intravenously.
Subcutaneous Rituximab in Follicular Lymphoma, Chronic Lymphocytic Leukemia, and Diffuse Large B-Cell Lymphoma. [2020]Rituximab and hyaluronidase human is a new subcutaneous formulation of rituximab that was recently approved by the US Food and Drug Administration for the treatment of adults with follicular lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia. With data to support noninferior pharmacokinetics, similar outcomes, and comparable adverse events, rituximab and hyaluronidase human may offer a suitable alternative to intravenous rituximab that could improve convenience for patients and better utilize health-care resources.
Clinical considerations of hyaluronidase as an adjunct to subcutaneous rituximab injection. [2019]Subcutaneous rituximab injectables are formulated with recombinant human hyaluronidase as an adjunct to facilitate the absorption of the large volume of rituximab. We review the clinical considerations regarding the potential for systemic hyaluronidase toxicity and increased systemic absorption of subcutaneous or topical drugs administered subsequent to rituximab.
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.