Glofitamab + Obinutuzumab for Non-Hodgkin's Lymphoma
Recruiting in Palo Alto (17 mi)
+61 other locations
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Waitlist Available
Sponsor: Hoffmann-La Roche
No Placebo Group
Breakthrough Therapy
Approved in 1 jurisdiction
Trial Summary
What is the purpose of this trial?This trial tests glofitamab, a new drug given through an IV that helps immune cells attack cancer cells. It targets patients who need new treatment options because their cancer hasn't responded to existing treatments. The drug works by connecting immune cells to cancer cells, making it easier for the immune system to destroy the cancer. Glofitamab shows promise in treating certain types of blood cancers.
Will I have to stop taking my current medications?
The trial requires that participants stop taking certain medications before starting the study. Specifically, you must not have taken systemic immunotherapeutic agents, standard chemotherapy, or other investigational anti-cancer agents within 4 weeks prior to the study. Additionally, you should not have received systemic immunosuppressive medications within two weeks before the study, except for low-dose corticosteroids.
What data supports the effectiveness of the drug combination Glofitamab and Obinutuzumab for Non-Hodgkin's Lymphoma?
Research shows that Obinutuzumab, a part of this drug combination, has improved outcomes in follicular lymphoma, a type of Non-Hodgkin's Lymphoma, especially in patients who did not respond to the standard treatment, Rituximab. It has been shown to be more effective than Rituximab in some cases, suggesting potential benefits for similar conditions.
12345Is the combination of Glofitamab and Obinutuzumab safe for treating Non-Hodgkin's Lymphoma?
Glofitamab and Obinutuzumab have been studied for safety in treating Non-Hodgkin's Lymphoma. Common side effects include infusion-related reactions (mild to moderate reactions during or after the drug is given) and hematological toxicity (blood-related side effects). Serious side effects, such as cytokine release syndrome (a severe immune reaction) and febrile neutropenia (fever with low white blood cell count), have been reported, but these are less common.
678910What makes the drug Glofitamab unique for treating non-Hodgkin's lymphoma?
Glofitamab is unique because it is a bispecific antibody that simultaneously targets CD20 on B-cells and CD3 on T-cells, helping the immune system to directly attack cancer cells. Its novel 2:1 structure enhances its binding to CD20, potentially leading to more effective treatment outcomes for patients with relapsed or refractory B-cell non-Hodgkin's lymphoma who have limited options.
6791011Eligibility Criteria
This trial is for adults with relapsed/refractory B-Cell Non-Hodgkin's Lymphoma who've had at least one prior treatment and lack other survival-prolonging options. Participants must have measurable disease, be in good physical condition (ECOG 0 or 1), and have proper liver, kidney, and blood function. Pregnant women are excluded, as well as those with certain infections or a history of severe reactions to similar drugs.Inclusion Criteria
I have no treatment options left that could extend my life.
I have a tumor that can be measured with imaging tests.
I am fully active or restricted in physically strenuous activity but can do light work.
My blood cancer is likely to have CD20.
My condition did not improve after at least one treatment.
Exclusion Criteria
I have not had a serious infection or been on IV antibiotics in the last 4 weeks.
My condition did not improve after treatment with obinutuzumab.
I had a stem cell transplant using my own cells less than 100 days ago.
I have had progressive multifocal leukoencephalopathy or CNS lymphoma.
I've had side effects from previous immune therapy.
My condition is either CLL, Burkitt lymphoma, or lymphoplasmacytic lymphoma.
I have or might have had HLH.
I have a significant history of heart disease.
Participant Groups
The study tests Glofitamab alone or combined with Obinutuzumab in patients pre-treated with a fixed dose of Obinutuzumab. It's an early-phase trial to find the safest and most effective doses (Phase I/II). The trial includes escalating doses followed by expansion cohorts once optimal dosing is determined.
3Treatment groups
Experimental Treatment
Group I: Part III: Dose ExpansionExperimental Treatment3 Interventions
Part III will start once MTD/OBD is defined. Participants will receive Gpt 1000 mg single dose IV infusion on Day -7, followed by glofitamab at a fixed dose regimen or step-up dose regimen on a Q2W or Q3W dosing schedule as determined in Part II. A total of 12 cycles will be administered.
Combination Therapy: From Cycle 2 onwards, a fixed dose of 1000 mg obinutuzumab will be administered via IV infusion in combination with glofitamab at the dosing regimen determined in Part II.
Group II: Part II: Dose EscalationExperimental Treatment3 Interventions
In each treatment regimen, participants will receive Gpt 1000 mg IV infusion on Day -7; or 2000 mg either administered on Day -7, or split into two 1000 mg doses on Days -1 and -7. The first glofitamab IV infusion will be given on Day 1 of Cycle 1 and a total of 12 cycles will be administered.
Monotherapy, glofitamab as a single agent: ascending doses of glofitamab administered on Day 1 of Q2W or every 3 week (Q3W) cycle until either the MTD/OBD is defined.
Combination Therapy: From Cycle 2 onwards, a fixed dose of 1000 mg obinutuzumab will be administered via IV infusion in combination with ascending doses of glofitamab on Day 1 of Q3W cycle until either the MTD/OBD is defined.
Step-up dosing: Q3W, participants will receive an initial low dose of glofitamab on Cycle 1 Day 1, followed by a higher dose on Cycle 1 Day 8; the total dose in Cycle 1 will not exceed the previously determined MTD. Higher doses may be explored from Cycle 2 or later cycles.
Group III: Part I: Dose EscalationExperimental Treatment3 Interventions
Participants (single participant cohorts) will receive obinutuzumab pretreatment (Gpt) 1000 milligrams (mg) single dose IV infusion on Day -7 followed by glofitamab IV infusion on Day 1 and Day 8 of Cycle 1. From Cycle 2 onwards, ascending doses of glofitamab will be administered on Day 1 of every 2 week (Q2W) cycle up to Cycle 12 (24 weeks) or until unacceptable toxicity or disease progression. Glofitamab dosing will be initiated at 5 micrograms (mcg) (flat dose) followed by doses of 15 mcg, 45 mcg, 135 mcg, 405 mcg and 810 mcg.
Glofitamab is already approved in United States for the following indications:
🇺🇸 Approved in United States as COLUMVI for:
- Relapsed or refractory diffuse large B-cell lymphoma not otherwise specified (DLBCL), or large B-cell lymphoma (LBCL) arising from follicular lymphoma, after two or more lines of systemic therapy
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Washington University; Wash Uni. Sch. Of MedSaint Louis, MO
Washington UniversitySaint Louis, MO
University of MichiganAnn Arbor, MI
MSKCCNew York, NY
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Who is running the clinical trial?
Hoffmann-La RocheLead Sponsor
References
Obinutuzumab in follicular lymphoma. [2017]The CD20 marker continues to be exploited as a therapeutic target for non-Hodgkin's lymphoma. Obinutuzumab is part of a new generation of anti-CD20 monoclonal antibodies, which are synthesized using molecular engineering technology, resulting in novel target epitopes and unprecedented optimization of antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. Rituximab is the current gold standard for anti-CD20 therapy, yet despite outstanding results published over the past decade, many patients continue to relapse after anti-CD20 regimens. Obinutuzumab is slowly positioning itself in the treatment of CD20+ B-cell neoplasms. On the basis of favorable results from the phase III GADOLIN trial, obinutuzumab was recently approved by the U.S. Food and Drug Administration in combination with bendamustine followed by obinutuzumab maintenance, for the treatment of follicular lymphoma (FL) patients who relapsed or are refractory to a rituximab-containing regimen. Additional phase III trials are underway to test obinutuzumab as a first-line anti-CD20 agent in FL with good preliminary results (GALLIUM trial); thus, it is likely that obinutuzumab will soon achieve a first-line indication. It is plausible that obinutuzumab will replace rituximab as the gold standard for chemoimmunotherapy in FL, although some safety concerns still need to be resolved. This review will address the preclinical pharmacology and the main aspects of the clinical development of obinutuzumab for the treatment of FL.
Pharmacokinetics, exposure, efficacy and safety of obinutuzumab in rituximab-refractory follicular lymphoma patients in the GADOLIN phase III study. [2021]Rituximab is standard care in a number of lymphoma subtypes, including follicular lymphoma (FL), although many patients are resistant to rituximab, or develop resistance with repeated treatment, and a high proportion relapse. Obinutuzumab is a novel anti-CD20 monoclonal antibody with improved efficacy over rituximab. It is approved for previously untreated chronic lymphocytic leukaemia (CLL), and for use with bendamustine in patients with rituximab-relapsed/refractory FL.
Early efficacy and safety of obinutuzumab with chemotherapy in previously untreated patients with follicular lymphoma: A real-world retrospective report of the Polish Lymphoma Research Group. [2023]The first-line obinutuzumab-based immunochemotherapy improves the outcome of patients with follicular lymphoma (FL) compared with rituximab-based regimens. However, infusion-related reactions occur in almost half of patients during the 1st obinutuzumab administration.
Role of obinutuzumab exposure on clinical outcome of follicular lymphoma treated with first-line immunochemotherapy. [2021]Label="AIMS">Obinutuzumab (G) is a humanized type II, Fc-glycoengineered anti-CD20 monoclonal antibody used in various indications, including patients with previously untreated front-line follicular lymphoma. We investigated sources of variability in G exposure and association of progression-free survival (PFS) with average concentration over induction (CmeanIND ) in front-line follicular lymphoma patients treated with G plus chemotherapy (bendamustine, CHOP, or CVP) in the GALLIUM trial.
Cost-effectiveness analysis of treatment regimens with obinutuzumab plus chemotherapy in Japan for untreated follicular lymphoma patients. [2021]Obinutuzumab (GA101; G) is a new treatment for follicular lymphoma (FL) that is anticipated to have greater efficacy than the current treatment, rituximab (R). The aim of this study was to evaluate the cost-effectiveness of G plus chemotherapy (G + Chemo) against that of R plus chemotherapy (R + Chemo) for patients in Japan with previously untreated FL.
Glofitamab: First Approval. [2023]Glofitamab (Columvi®) is a CD20 × CD3 T-cell-engaging bispecific monoclonal antibody being developed by Roche for the treatment of B-cell non-Hodgkin lymphomas, including diffuse large B-cell lymphoma (DLBCL). Glofitamab received its first approval (with conditions) on 25 March 2023, in Canada, for the treatment of adult patients with relapsed or refractory DLBCL not otherwise specified, DLBCL arising from follicular lymphoma, or primary mediastinal B-cell lymphoma, who have received two or more lines of systemic therapy and are ineligible to receive or cannot receive CAR T-cell therapy or have previously received CAR T-cell therapy. Glofitamab is also under regulatory review for relapsed or refractory DLBCL in the EU and USA and in April 2023 received a positive opinion recommending the granting of a conditional marketing authorization in the EU. Clinical development of glofitamab, as a monotherapy and in combination with other agents for the treatment of non-Hodgkin lymphomas, is continuing worldwide. This article summarizes the milestones in the development of glofitamab leading to this first approval for relapsed or refractory DLBCL.
Glofitamab, a Novel, Bivalent CD20-Targeting T-Cell-Engaging Bispecific Antibody, Induces Durable Complete Remissions in Relapsed or Refractory B-Cell Lymphoma: A Phase I Trial. [2023]Label="PURPOSE">Glofitamab is a T-cell-engaging bispecific antibody possessing a novel 2:1 structure with bivalency for CD20 on B cells and monovalency for CD3 on T cells. This phase I study evaluated glofitamab in relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). Data for single-agent glofitamab, with obinutuzumab pretreatment (Gpt) to reduce toxicity, are presented.
Obinutuzumab (GA101) plus CHOP or FC in relapsed/refractory follicular lymphoma: results of the GAUDI study (BO21000). [2022]The safety and activity of obinutuzumab (GA101) plus chemotherapy in relapsed/refractory follicular lymphoma was explored in 56 patients. Participants received obinutuzumab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (G-CHOP; every 3 weeks for 6 to 8 cycles) or obinutuzumab plus fludarabine and cyclophosphamide (G-FC; every 4 weeks for 4 to 6 cycles). Patients were randomly assigned to either obinutuzumab 1600 mg on days 1 and 8 of cycle 1 followed by 800 mg on day 1 of subsequent cycles or 400 mg for all doses. Treatment responders were eligible for obinutuzumab maintenance every 3 months for up to 2 years. Grade 1/2 infusion-related reactions (IRRs) were the most common treatment-related adverse event (AE) (all grades: G-CHOP, 68%; G-FC, 82%). Grade 3/4 IRRs were rare (7%) and restricted to the first infusion. All patients received the planned obinutuzumab dose. Neutropenia was the most common treatment-related hematologic AE for G-CHOP (43%) and G-FC (50%). At induction end, 96% (27/28) of patients receiving G-CHOP (complete response [CR], 39% [11/28]) and 93% (26/28) receiving G-FC (CR, 50% [14 of 28]) achieved responses. G-CHOP and G-FC had an acceptable safety profile with no new or unexpected AEs, but G-FC was associated with more AEs than G-CHOP. Obinutuzumab plus chemotherapy resulted in 93% to 96% response rates, supporting phase 3 investigation. This trial was registered at www.clinicaltrials.gov as #NCT00825149.
Glofitamab CD20-TCB bispecific antibody. [2022]Bispecific T-cell recruiting antibodies are emerging as a potent immunotherapeutic class in the treatment of B-cell malignancies and act by simultaneously targeting antigens on T-cells and malignant cells to effect tumor cell death. Glofitamab is a novel full-length IgG-like CD20-CD3 bispecific with a unique 2:1 configuration that provides an extended half-life and superior CD20 binding. Phase 1 monotherapy and combination data demonstrate clear activity in heavily treated aggressive and indolent B-cell lymphoma, including >50% complete responses at the recommended phase 2 dose. In this review, we provide an overview of the structure, mechanism of action and pharmacokinetics of glofitamab. Available efficacy and safety data from ongoing clinical trials are also presented. Glofitamab appears to be a welcome addition to the treatment possibilities for patients with B-cell lymphomas who otherwise have limited therapeutic options. The current data are sufficient to evaluate its role in combination and in earlier lines of therapy.
Glofitamab in relapsed/refractory diffuse large B-cell lymphoma: Real-world data. [2023]Glofitamab is a CD3xCD20 bi-specific antibody with two fragments directed to the CD20 antigen and a single CD3-binding fragment. Encouraging response and survival rates were recently reported in a pivotal phase II expansion trial conducted in patients with relapsed/refractory (R/R) B-cell lymphoma. However, the real-world data of patients of all ages with no strict selection criteria are still lacking. Herein, this retrospective study aimed to evaluate the outcomes of diffuse large B-cell lymphoma (DLBCL) patients who received glofitamab via compassionate use in Turkey. Forty-three patients from 20 centers who received at least one dose of the treatment were included in this study. The median age was 54 years. The median number of previous therapies was 4, and 23 patients were refractory to first-line treatment. Twenty patients had previously undergone autologous stem cell transplantation. The median follow-up time was 5.7 months. In efficacy-evaluable patients, 21% and 16% of them achieved complete response and partial response, respectively. The median response duration was 6.3 months. The median progression-free survival (PFS) and overall survival (OS) was 3.3 and 8.8 months, respectively. None of the treatment-responsive patients progressed during the study period, and their estimated 1-year PFS and OS rate was 83%. The most frequently reported toxicity was hematological toxicity. Sixteen patients survived, while 27 died at the time of the analysis. The most common cause of death was disease progression. One patient died of cytokine release syndrome during the first cycle after receiving the first dose of glofitamab. Meanwhile, two patients died due to glofitamab-related febrile neutropenia. This is the largest real-world study on the effectiveness and toxicity of glofitamab treatment in R/R DLBCL patients. The median OS of 9 months seems promising in this heavily pretreated group. The toxicity related mortality rates were the primary concerns in this study.
Pharmacodynamics and molecular correlates of response to glofitamab in relapsed/refractory non-Hodgkin lymphoma. [2022]Glofitamab, a novel CD20xCD3, T-cell-engaging bispecific antibody, exhibited single-agent activity in Study NP30179, a first-in-human, phase 1 trial in relapsed/refractory B-cell non-Hodgkin lymphoma. Preclinical studies showed that glofitamab leads to T-cell activation, proliferation, and tumor cell killing upon binding to CD20 on malignant cells. Here, we provide evidence of glofitamab's clinical activity, including pharmacodynamic profile, mode of action, and factors associated with clinical response, by evaluating biomarkers in patient samples from the dose-escalation part of this trial. Patients enrolled in Study NP30179 received single-dose obinutuzumab pretreatment (1000 mg) 7 days before IV glofitamab (5 µg-25 mg). Glofitamab treatment lasted ≤12 cycles once every 2 or 3 weeks. Blood samples were collected at predefined time points per the clinical protocol; T-cell populations were evaluated centrally by flow cytometry, and cytokine profiles were analyzed. Immunohistochemical and genomic biomarker analyses were performed on tumor biopsy samples. Pharmacodynamic modulation was observed with glofitamab treatment, including dose-dependent induction of cytokines, and T-cell margination, proliferation, and activation in peripheral blood. Gene expression analysis of pretreatment tumor biopsy samples indicated that tumor cell intrinsic factors such as TP53 signaling are associated with resistance to glofitamab, but they may also be interlinked with a diminished effector T-cell profile in resistant tumors and thus represent a poor prognostic factor per se. This integrative biomarker data analysis provides clinical evidence regarding glofitamab's mode of action, supports optimal biological dose selection, and will further guide clinical development. This trial was registered at www.clinicaltrials.gov as #NCT03075696.