Combination Immunotherapy for Non-Hodgkin's Lymphoma
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Lazaros Lekakis
Must not be taking: Antiepileptics, Immunosuppressants, Anticoagulants, others
Disqualifiers: CNS lymphoma, Uncontrolled infection, Autoimmune disorders, others
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?The purpose of this research study is to test if a combination treatment of chimeric antigen receptor (CAR) T-cell therapy, Mosunetuzumab, and Polatuzumab Vedotin will result in tumor reduction.
Will I have to stop taking my current medications?
The trial protocol does not specify if you must stop taking your current medications. However, it mentions that systemic immunosuppressive agents and certain biologic agents or chemotherapy are not allowed within specific time frames before starting the trial treatment. It's best to discuss your current medications with the trial team to understand any necessary adjustments.
What data supports the effectiveness of the drug polatuzumab vedotin for treating non-Hodgkin's lymphoma?
Polatuzumab vedotin has shown significant clinical activity and an acceptable safety profile in treating relapsed or refractory B-cell non-Hodgkin's lymphoma, particularly when combined with other therapies like rituximab and bendamustine, leading to its approval for use in patients who have tried at least two other treatments.
12345What safety data exists for CAR-T cell therapy in humans?
CAR-T cell therapy has been associated with some serious side effects, including cytokine release syndrome (a severe immune reaction) and neurotoxicity (nerve damage). These side effects can be more severe in patients with a high tumor burden (large amount of cancer). Efforts are ongoing to improve the safety of this treatment.
678910What makes the combination immunotherapy treatment for Non-Hodgkin's Lymphoma unique?
This treatment is unique because it combines CAR-T cell therapy, which uses modified immune cells to target cancer, with polatuzumab vedotin, an antibody-drug conjugate that delivers a toxin directly to cancer cells, and mosunetuzumab, which helps activate the immune system against the cancer. This combination aims to enhance the effectiveness of treatment by using different mechanisms to attack the lymphoma.
123411Eligibility Criteria
Adults aged 18-80 with aggressive Non-Hodgkin's Lymphoma that is resistant or has returned after treatment. They must have at least one measurable lesion, be in relatively good health (ECOG 0-2), and meet specific blood count criteria. Women of childbearing age need a negative pregnancy test and agree to use contraception.Inclusion Criteria
Signed informed consent and compliance with study requirements
I have at least one lymphoma lesion that can be measured.
My condition is primary mediastinal B cell lymphoma.
+22 more
Exclusion Criteria
I do not have severe heart disease.
You have an immune system disorder that is not related to the study.
My high blood pressure is not under control.
+18 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Induction Phase
Participants receive Mosunetuzumab on Days -42, -35, -28, and -7; and Polatuzumab on Day -28. Evaluation in clinic on Day -6.
5 weeks
5 visits (in-person)
CAR-T Treatment Phase
Participants receive lymphodepleting chemotherapy for three consecutive days beginning on Day -5, followed by CAR-T Cell therapy via infusion on Day 0.
1 week
4 visits (in-person)
Consolidation Phase
Participants receive Mosunetuzumab on Day +14; and combination Mosunetuzumab and Polatuzumab on Days +35, +56, and +77.
13 weeks
4 visits (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
Up to 2 years
Participant Groups
The trial tests if combining CAR-T Cell Therapy with Mosunetuzumab and Polatuzumab can shrink tumors in patients whose lymphoma didn't respond to previous treatments or came back after such treatments, including stem cell transplantation.
1Treatment groups
Experimental Treatment
Group I: Combination CAR-T Cell Therapy, Mosunetuzumab + PolatuzumabExperimental Treatment3 Interventions
Participants will receive study treatment in three phases: Induction Phase, CAR-T Treatment Phase and Consolidation Phase.
During the Induction Phase (Days -42, through -6), participants will receive Mosunetuzumab on Days -42, -35, -28, and -7; and Polatuzumab on Day -28. On Day -6, participants will be evaluated in clinic.
During the CAR-T Treatment Phase (Days -5, through Day 0), participants will receive lymphodepleting chemotherapy for three consecutive days beginning on Day -5, followed by CAR-T Cell therapy via infusion on Day 0.
During the Consolidation Phase (Days +1 through +90), participants will receive Mosunetuzumab on Day +14; and combination Mosunetuzumab and Polatuzumab on Days +35, +56 and +77.
CAR-T Cell Therapy is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as CAR-T Cell Therapy for:
- Relapsed or refractory large B-cell lymphoma (LBCL)
- Relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL)
- Relapsed or refractory mantle cell lymphoma (MCL)
- Relapsed or refractory multiple myeloma (MM)
- Relapsed or refractory follicular lymphoma (FL)
🇪🇺 Approved in European Union as CAR-T Cell Therapy for:
- Relapsed or refractory large B-cell lymphoma (LBCL)
- Relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL)
- Relapsed or refractory mantle cell lymphoma (MCL)
- Relapsed or refractory multiple myeloma (MM)
- Relapsed or refractory follicular lymphoma (FL)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of MiamiMiami, FL
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Who Is Running the Clinical Trial?
Lazaros LekakisLead Sponsor
Genentech, Inc.Industry Sponsor
References
Polatuzumab vedotin in combination with immunochemotherapy in patients with previously untreated diffuse large B-cell lymphoma: an open-label, non-randomised, phase 1b-2 study. [2023]Polatuzumab vedotin, an antibody-drug conjugate targeting the CD79b component of the B-cell receptor, has demonstrated activity as a single agent and in combination with rituximab in relapsed or refractory diffuse large B-cell lymphoma. In this study, we evaluated the safety and preliminary activity of polatuzumab vedotin in combination with rituximab or obinutuzumab and cyclophosphamide, doxorubicin, and prednisone (CHP) in patients with previously untreated diffuse large B-cell lymphoma.
Polatuzumab vedotin: an investigational anti-CD79b antibody drug conjugate for the treatment of diffuse large B-cell lymphoma. [2022]New agents for managing B-cell non-Hodgkin lymphomas (NHLs) are needed, particularly for high-risk and relapsed or refractory patients. Antibody-drug conjugates (ADCs) provide targeted drug delivery to tumors with a broaden therapeutic index of cytotoxic agent, reducing their systemic toxicity while increasing intracellular concentrations. Polatuzumab vedotin, an anti-CD79b conjugated to the microtubule inhibitor monomethyl auristatin E (MMAE) raises particular interest.
Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study. [2018]Patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) have an unfavourable prognosis with few treatment options. Polatuzumab vedotin is an antibody-drug conjugate containing an anti-CD79B monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the safety and clinical activity of polatuzumab vedotin in relapsed or refractory B-cell NHL and chronic lymphocytic leukaemia (CLL).
Polatuzumab vedotin in relapsed / refractory aggressive B-cell lymphoma. [2022]Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma histology. Outcomes for patients with relapsed or refractory (R/R) disease remain suboptimal. Polatuzumab vedotin (polatuzumab) is a recently approved antibody drug conjugate that targets CD79b, with a tubulin toxin payload, that has demonstrated significant clinical activity and an acceptable toxicity profile when administered with both anti-CD20 monoclonal antibodies and chemotherapy in clinical trials.
Integrated summary of immunogenicity of polatuzumab vedotin in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma. [2023]Polatuzumab vedotin, marketed under the trade name POLIVY®, is a CD79b-targeted antibody-drug conjugate that preferentially delivers a potent anti-mitotic agent (monomethyl auristatin E) to B cells, resulting in anti-cancer activity against B-cell malignancies. In 2019, polatuzumab vedotin in combination with rituximab and bendamustine was approved by the United States Food and Drug Administration for the treatment of adult patients with diffuse large B-cell lymphoma who have received at least two prior therapies. Recent Health Authority guidance recommendations for submitting an Integrated Summary of Immunogenicity were followed including a comprehensive immunogenicity risk assessment, bioanalytical strategy, and immunogenicity data to support the registration of polatuzumab vedotin. Key components of the polatuzumab vedotin Integrated Summary of Immunogenicity and data are presented. Validated semi-homogeneous bridging enzyme-linked immunosorbent assays were used to detect anti-drug antibodies (ADA) to polatuzumab vedotin and characterize the immune response in patients with non-Hodgkin's lymphoma. The overall incidence of ADA observed for polatuzumab vedotin was low across seven clinical trials. The low incidence of ADA is likely due to the mechanism of action of polatuzumab vedotin that involves targeting and killing of B cells, thereby limiting the development to plasma cells and ADA secretion. Furthermore, patients are co-medicated with rituximab, which also targets B cells and results in B-cell depletion. Therefore, the immunogenicity risk is considered low and not expected to impact the polatuzumab vedotin benefit/risk profile.
Chimeric Antigen Receptor T Cells: A Race to Revolutionize Cancer Therapy. [2020]For years, cancer treatment was dominated by chemotherapy, radiation therapy, and stem cell transplantation. New insights into genetic characteristics of leukemic cells have initiated the development of the chimeric antigen receptor (CAR) T-cell therapy. This type of adoptive cell immunotherapy has been a breakthrough in the treatment of aggressive B-cell lymphoma and B-cell precursor acute lymphoblastic leukemia. In August 2018, the European Commission has approved the first CAR T-cell products - tisagenlecleucel (Kymriah®, Novartis) and axicabtagene ciloleucel (Yescarta®, Gilead) - for hematological neoplasms in Europe. As CAR T cells are a living drug, its benefits can last for many years. The administration of CAR T cells is a complex and costly endeavor involving cell manufacture, shipping of apheresis products, and management of novel and severe adverse reactions. The most common toxicities observed after CAR T-cell therapy are cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. Current research focuses on improved safety and efficacy in hematological malignancies as well as the translation of CAR T-cell therapy to solid tumors. This review covers the development and current status of CAR T-cell therapy in a clinical setting with focus on challenges and future opportunities.
Treatment of Immune Checkpoint Inhibitor Induced Colitis with Infliximab. [2020]Several immunotherapeutic agents function against the T cell immune checkpoint inhibitor pathways thereby reestablishing immune response to elusive malignancies. Namely, the programmed death-1 co-receptor (PD-1) or ligand (PD-L1) and cytotoxic T lymphocyte- associated protein 4 (CTLA-4) are well known checkpoint targets of current FDA approved drugs. Among these drugs nivolumab, an IgG4 anti-PD-1 antibody, and ipilimumab, an anti-CTLA-4 antibody, are used to treat numerous malignancies but carry a large list of potential side effects termed immune-related adverse effects (irAEs). We describe the presentation, clinical course, and resolution of steroid-resistant immune checkpoint inhibitor-induced colitis secondary to administration of these two drugs in a 66-year-old female patient treated with infliximab.
Relapsed/Refractory Non-Hodgkin Lymphoma: Engineering T-Cells to Express Chimeric Antigen Receptors (CARs), a Salvage? [2021]For years, patients with B-cell non-Hodgkin lymphoma (NHL) have been treated with traditional first-line therapies with a fairly acceptable outcome. However, some individuals with relapsed or resistant lymphoma do not respond to those treatments, including chemotherapy, immunotherapy, radiotherapy, and (or) autologous stem cell transplantation. Based on the acquired immunotherapy knowledge, T-cells genetically engineered with chimeric antigen receptors (CARs) seem to offer complete, enduring clinical responses to patients with refractory or relapsed lymphomas. Currently, four autologous CD19-directed CAR T-cell therapies have gained approval by the U.S. Food and Drug Administration (FDA) for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, high-grade B-cell lymphoma, and transformed follicular lymphoma, while further CAR T-cell immunotherapies have entered the clinical trials pipeline. This review aims to summarize the efficacy and safety of the FDA-approved CAR T-cell treatments for the relapsed or refractory lymphomas.
Multiple autoimmune side effects of immune checkpoint inhibitors in a patient with metastatic melanoma receiving pembrolizumab. [2021]Immune agents including anti-programmed death receptor-1 and anti-cytotoxic T-lymphocyte antigen-4 have been associated with numerous immune-related complications. Pembrolizumab, a programmed death-1 inhibitor, has been associated with a number of immune-related adverse events such as pneumonitis, colitis, hepatitis, hypophysitis, hyperthyroidism, hypothyroidism, nephritis, and type 1 diabetes.
From bench to bedside: the history and progress of CAR T cell therapy. [2023]Chimeric antigen receptor (CAR) T cell therapy represents a major breakthrough in cancer care since the approval of tisagenlecleucel by the Food and Drug Administration in 2017 for the treatment of pediatric and young adult patients with relapsed or refractory acute lymphocytic leukemia. As of April 2023, six CAR T cell therapies have been approved, demonstrating unprecedented efficacy in patients with B-cell malignancies and multiple myeloma. However, adverse events such as cytokine release syndrome and immune effector cell-associated neurotoxicity pose significant challenges to CAR T cell therapy. The severity of these adverse events correlates with the pretreatment tumor burden, where a higher tumor burden results in more severe consequences. This observation is supported by the application of CD19-targeted CAR T cell therapy in autoimmune diseases including systemic lupus erythematosus and antisynthetase syndrome. These results indicate that initiating CAR T cell therapy early at low tumor burden or using debulking strategy prior to CAR T cell infusion may reduce the severity of adverse events. In addition, CAR T cell therapy is expensive and has limited effectiveness against solid tumors. In this article, we review the critical steps that led to this groundbreaking therapy and explore ongoing efforts to overcome these challenges. With the promise of more effective and safer CAR T cell therapies in development, we are optimistic that a broader range of cancer patients will benefit from this revolutionary therapy in the foreseeable future.
Profile of Polatuzumab Vedotin in the Treatment of Patients with Relapsed/Refractory Non-Hodgkin Lymphoma: A Brief Report on the Emerging Clinical Data. [2022]Polatuzumab vedotin is an anti-CD79b antibody conjugated to monomethyl auristatin E that has shown significant clinical activity in follicular and diffuse large B-cell lymphoma (DLBCL) and is currently FDA-approved in combination with bendamustine and rituximab for patients with relapsed/refractory DLBCL. This review article summarizes data from clinical trials of polatuzumab and discusses its current role and future directions in the treatment of patients with B-cell non-Hodgkin lymphoma.