Combination Therapy for Non-Hodgkin's Lymphoma

Recruiting in Palo Alto (17 mi)

+21 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Pfizer

Must not be taking: Anti-CD47, Glofitamab

Disqualifiers: High grade B-cell lymphoma, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

The purpose of this study is to learn about the effects of two study medicines (maplirpacept \[PF-07901801\] and glofitamab) when given together for the treatment of diffuse large B-cell lymphoma (DLBCL) that is relapsed or is refractory. Relapsed means has returned after last treatment. Refractory means that it has not responded to last treatment. The two study medicines are given after a single dose of obinutuzumab which is the third study medicine. DLBCL is a type of non-Hodgkin lymphoma (NHL). NHL is a cancer of the lymphatic system. It develops when the body makes abnormal B lymphocytes. These lymphocytes are a type of white blood cell that normally help to fight infections. This study is seeking adult participants who: * Have histologically confirmed diagnosis of DLBCL * Have received at least two first lines of treatment for NHL. * Are unable or unwilling to undergo a stem cell transplant or CAR-T cell therapy. Stem cell transplant is a procedure in which a patient receives healthy blood-forming cells to replace their own stem cells that have been destroyed by treatment. A CAR-T therapy is a type of treatment in which a patient's T cells are changed in the laboratory so they will attack cancer cells. Everyone in this study will receive all three medicines at the study site by intravenous (IV) infusion which is given directly into a vein. The two study medicines (maplirpacept \[PF-07901801\] and glofitamab) will be given in 21-day cycles. At Cycle 0, participants will receive a single dose of obinutuzumab pre-treatment followed by two step-up doses of glofitamab. The combination of maplirpacept (PF-07901801) with glofitamab full dose will be administered for the first time at Cycle 1 Day 1. Maplirpacept (PF-07901801) will be given weekly for the first three cycles and then every three weeks. Glofitamab will be given every 3 weeks for approximately 9 months. Thereafter participants will continue to receive maplirpacept alone. Maplirpacept (PF-07901801) will be given at different doses to different participants. Everyone taking part will receive the same fixed doses of glofitamab and obinutuzumab studied in patients with DLBCL. The study will compare the experiences of people receiving different doses of maplirpacept (PF-07901801). This will help to determine what dose is safe and effective when given with the other 2 study medicines.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug combination therapy for Non-Hodgkin's Lymphoma?

Glofitamab, a key component of the combination therapy, has shown promising results in treating relapsed or refractory B-cell non-Hodgkin lymphoma, with over 50% of patients achieving complete responses in clinical trials. It works by engaging T-cells to attack cancer cells, and has been approved in Canada for certain types of difficult-to-treat lymphomas.

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Is the combination therapy for Non-Hodgkin's Lymphoma, including Glofitamab, safe for humans?

Glofitamab has been studied for safety in patients with relapsed or refractory B-cell non-Hodgkin lymphoma. The most common side effects were related to blood cell counts, and some serious side effects included cytokine release syndrome (a severe immune reaction) and febrile neutropenia (fever with low white blood cell count). While some patients experienced severe side effects, the treatment was generally considered manageable with appropriate medical care.

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What makes the drug combination of Glofitamab, Maplirpacept, and Obinutuzumab unique for treating non-Hodgkin's lymphoma?

This drug combination is unique because Glofitamab is a bispecific antibody that engages T-cells to target and kill cancer cells, offering a novel approach for patients with relapsed or refractory non-Hodgkin's lymphoma who have limited treatment options.

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Eligibility Criteria

Adults with a confirmed diagnosis of diffuse large B-cell lymphoma (DLBCL) that has returned or hasn't responded to treatment, who have tried at least one therapy including an anti-CD20 antibody but can't or won't get stem cell or CAR-T cell therapy. They should be in good enough health as measured by specific medical standards.

Inclusion Criteria

I've had 1-2 treatments for my condition, including one with an anti-CD20 antibody.

My liver, kidneys, and bone marrow are functioning well.

I can take care of myself and am up and about more than 50% of my waking hours.

Exclusion Criteria

I currently have an active infection.

I have been treated with anti-CD47, glofitamab, or anti-CD20 x CD3 drugs and did not respond to obinutuzumab alone.

I had a stem cell transplant less than 12 weeks ago.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-Treatment

Participants receive a single dose of obinutuzumab followed by two step-up doses of glofitamab

1 week

1 visit (in-person)

Treatment

Participants receive maplirpacept (PF-07901801) weekly for the first three cycles and then every three weeks, and glofitamab every 3 weeks for approximately 9 months

9 months

Weekly visits for the first 3 cycles, then every 3 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Participant Groups

The trial is testing the combination of two drugs, maplirpacept and glofitamab, after an initial dose of obinutuzumab for relapsed/refractory DLBCL. Participants will receive these medications through IV infusions over several cycles to determine the safest and most effective dosage.

Group I: Phase 2 Experimental Treatment 3 Interventions

Participants will be randomized to 1 of 2 different dose levels of PF-07901801 which will be administered in combination with fixed doses of glofitamab after a dose of obinutuzumab. Approximately 50 participants will be enrolled (25 per dose).

Group II: Phase 1b Experimental Treatment 3 Interventions

Participants will be allocated to sequential dose levels of PF-07901801, administered in combination with fixed doses of glofitamab after a dose of obinutuzumab, to select two doses of PF-07901801 for further evaluation in Phase 2. Approximately 20 participants will be enrolled.

Group III: PK Bridging Sub-Study Experimental Treatment 3 Interventions

Participants will be allocated to 2 dose levels of PF-07901801 manufactured with process 3, administered in combination with fixed doses of glofitamab after a dose of obinutuzumab, to evaluate the pharmacokinetic of PF-07901801 using Process 3 material and determine a dose comparable to the recommended PF-07901801 dose for phase 3 determined in Phase 2. Approximately 20 participants will be enrolled.

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 Nearby Select from list below to view details:

The University of Kansas Clinical Research Center Fairway, KS

University of Kansas Hospital Cambridge North Tower A Kansas City, KS

The University of Kansas Hospital Kansas City, KS

Washington University School of Medicine Saint Louis, MO

More Trial Locations

Who Is Running the Clinical Trial?

Pfizer Lead Sponsor

Hoffmann-La Roche Industry Sponsor

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

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.

2. United States pubmed.ncbi.nlm.nih.gov

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.

3. England pubmed.ncbi.nlm.nih.gov

Glofitamab therapy for diffuse large B cell lymphoma: latest updates from the 2022 ASH Annual Meeting. [2023] Over one-third of B cell lymphomas are not effectively treated by R-CHOP chemotherapy. When lymphoma relapses or is refractory, the prognosis becomes very poor. Due to this fact, there is an urgent and clear requirement for a more effective, novel treatment option. Glofitamab is a CD20xCD3 T-cell-engaging, bispecific antibody capable of recruiting T cells to tumor cells. We have summarized several of the latest reports on glofitamab use in B cell lymphoma therapy from the 2022 ASH Annual Meeting (ASH2022).

4. United States pubmed.ncbi.nlm.nih.gov

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.

5. United States pubmed.ncbi.nlm.nih.gov

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.

6. England pubmed.ncbi.nlm.nih.gov

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.

7. United States pubmed.ncbi.nlm.nih.gov

Treatments for Relapsed-Refractory Diffuse Large B-cell Lymphoma: A Preliminary Evaluation of the Place in Therapy of Glofitamab, a Bispecific Monoclonal Antibody. [2023] Background and objectives Glofitamab, tafasitamab, loncastuximab tesirine, polatuzumab, and selinexor have been proposed for the treatment of relapsed-refractory diffuse large B-cell lymphoma (DLBCL). We studied the pattern of overall survival (OS) for these five agents. Methods We reconstructed patient-level data from the Kaplan-Meier OS graphs published in five pivotal trials. For this purpose, we used an artificial intelligence technique (the Shiny method). Reconstructed survival curves were subjected to standard statistics to perform cross-trial indirect comparisons; medians and hazard ratios (HRs) with 95% confidence interval (CI) were estimated for each treatment. Results Using glofitamab (a bispecific antibody) as a common comparator, our analysis of OS yielded the following results: a) tafasitamab plus lenalidomide, HR: 0.514 (95% CI: 0.341 to 0.776; P=0.0015); b) polatuzumab vedotin, HR: 0.822 (95% CI: 0.509 to 1.327); c) selinexor, HR: 1.170 (95% CI: 0.852 to 1.603); and d) loncastuximab tesirine, HR: 1.120 (95% CI: 0.868 to 1.659). Medians were estimated as follows: a) tafasitamab plus lenalidomide, 26.5 months (95% CI: 18.9 to NA); b) polatuzumab vedotin, 12.5 months (95% CI: 9.03 to NA); c) glofitamab, 11.7 months (95% CI: 7.96 to 18.0); d) loncastuximab tesirine, 10.2 months (95% CI: 6.97 to 11.6); and e) selinexor, 10.1 months (95% CI: 6.72 to 14.2). Conclusions These comparative results represent an original finding generated by the Shiny method. Although these comparisons are indirect, our analysis offers a useful synthesis of the outcomes of these treatments. According to these results, glofitamab, despite its improved mechanism of action, does not seem to confer any OS advantage compared with the other four treatments.