Phase II Study of Glofitamab-Based Induction Followed by CAR‑T Cell Therapy in High‑Risk Relapsed/Refractory Large B‑Cell Lymphoma
- Trial ID
- 2025-523806-34-00
- Protocol
- UKD-IKF-Double-T
Trial statistics
Diseases & Conditions
Objectives
The primary objective is to assess the preliminary efficacy of a double T‑cell therapy approach that employs glofitamab combined with gemcitabine/oxaliplatin (Glofi‑GemOx) as induction before standard‑of‑care CAR‑T cell therapy, followed by glofitamab monotherapy consolidation, aiming to improve outcomes in high‑risk second‑line patients with relapsed/refractory Large B-Cell Lymphoma. Secondary objectives include further characterization of the efficacy of the Glofi‑GemOx induction and glofitamab consolidation, evaluation of the impact of glofitamab consolidation on CAR‑T cell expansion, persistence, and functional durability, assessment of safety and tolerability of the combined regimen, determination of patient‑reported outcomes after induction and consolidation, and exploratory analysis of T‑cell exhaustion markers and activation profiles.
Participants
The trial enrolled adult patients, both male and female, aged 18 to 80 years with histologically confirmed relapsed/refractory Large B‑Cell Lymphoma. Eligible participants had previously received R‑CHOP‑based first‑line therapy, exhibited measurable disease on imaging, and demonstrated an Eastern Cooperative Oncology Group performance status of 0–2 with adequate organ function (renal, hepatic, hematologic, cardiac and pulmonary) as defined by specified laboratory thresholds. All subjects were required to have undergone successful leukapheresis for a commercially available CAR‑T‑cell product and to provide baseline tumor tissue for central review. Contraceptive use was mandated for individuals of childbearing potential throughout the study and for a defined period after treatment. The sponsor did not provide information regarding the total number of participants. Selection was based on the outlined inclusion criteria, without emphasis on additional lifestyle factors beyond contraception requirements.
Plans and Procedures
The study is a phase II, open‑label, single‑arm trial evaluating a Glofitamab‑based induction (Glofi‑Gem/Ox) followed by standard‑of‑care CAR‑T‑cell therapy and subsequent Glofitamab consolidation in patients with relapsed/refractory Large B‑Cell Lymphoma. Recruitment is planned from April 2026 to April 2030. After written informed consent, participants undergo a screening visit to confirm eligibility, including baseline biopsy collection and organ‑function assessments. Eligible patients receive the induction regimen, after which a leukapheresis is performed for CAR‑T manufacturing. The CAR‑T infusion constitutes the primary treatment phase, followed by a predefined number of Glofitamab consolidation infusions. Follow‑up visits are scheduled at regular intervals (e.g., every 4 weeks) to monitor efficacy endpoints such as complete response rate and progression‑free survival, as well as safety parameters per NCI CTCAE 6.0. The end‑of‑study visit occurs after the final consolidation dose or at the predefined assessment time point, concluding participant involvement, which typically spans approximately 12–18 months. Early termination may occur due to disease progression, unacceptable adverse events, failure to meet organ‑function criteria, or patient withdrawal of consent.
Treatment
The investigational agent Glofitamab is supplied as Columvi 10 mg concentrate for solution for infusion. It is administered intravenously at a dose of 30 mg per infusion. Each dose is given as an IV infusion over the prescribed duration according to the study schedule, and repeated according to the protocol‑defined induction and consolidation phases.
Obinutuzumab is provided as Gazyvaro 1,000 mg concentrate for solution for infusion. The drug is delivered by intravenous infusion at a single dose of 1,000 mg. Infusions are performed on the days specified in the treatment regimen and may be repeated as required by the study protocol.
Lisocabtagene maraleucel is marketed as Breyanzi dispersion for infusion. The product is administered intravenously as a cell suspension at a target dose of 1.2 × 10⁸ cells per infusion. The cell product is infused in a single administration, following standard manufacturing and release criteria.
Axicabtagene ciloleucel is supplied as YESCARTA dispersion for infusion and designated as an orphan drug. The intended dose is 2 × 10⁶ cells per infusion, delivered intravenously as a single-dose cell infusion.
Standard‑of‑care CAR‑T cell therapy serves as the comparator treatment in this study. Eligible participants receive either Breyanzi or YESCARTA according to the approved dosing regimen for relapsed/refractory large B‑cell lymphoma. The CAR‑T product is administered as a single intravenous infusion following lymphodepleting chemotherapy, in line with current clinical practice.
All study medications are administered in a controlled clinical setting. Dosing schedules are defined by the protocol and include pre‑treatment assessments, infusion monitoring, and post‑infusion observation. Participant compliance is monitored through drug accountability logs, infusion records, and scheduled safety assessments. Adverse events and laboratory parameters are evaluated regularly to ensure adherence to the treatment plan.
Efficacy
The primary efficacy assessment is the Complete response rate at the end of treatment (CCR@EOT), defined as the proportion of patients achieving a complete response according to the Lugano classification.
Secondary efficacy evaluations include:
- CRR after induction treatment (CCR@pIT) and at 3 months post‑CAR‑T infusion (CRR@3MpCT)
- Overall Objective response rate and CRR across all time points
- Best overall response rate (BORR)
- Progression‑free survival with PFS rates at one and two years from treatment start
- Overall survival with OS rates at one and two years from treatment start
- Quantification of peak CAR‑T cell expansion in peripheral blood by flow cytometry and/or qPCR for the CAR transgene
- Time to peak CAR‑T cell expansion and duration of CAR‑T cell persistence
- Correlation of CAR‑T cell expansion/persistence with clinical responses (CR, PR, PFS)
- Quality of life over time assessed with the EORTC QLQ‑C30 questionnaire
Efficacy parameters are measured using validated imaging criteria (Lugano classification) for response categorization, laboratory assays (flow cytometry, qPCR) for cellular kinetics, and patient‑reported outcomes (EORTC QLQ‑C30). Assessments are performed after the induction phase, at 3 months following CAR‑T cell infusion, and at the end of trial treatment, with long‑term follow‑up for survival and disease progression endpoints.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient has given written informed consent.
- Patient is 18-80 years of age at time of signing the written informed consent
- Patient has histologically confirmed diagnosis of large B-cell lymphoma by local pathologist at time of relapse.
- Patient received R-CHOP based first-line therapy containing a CD20-antibody and anthracyclines.
- Patient has relapsed/refractory disease, defined as follows: - Relapsed: disease that had recurred following partial or complete response (PR/CR) within 12 months of adequate first-line therapy - Refractory: disease that did not respond to, or that progressed <6 months after, completion of first-line therapy
- Patient has at least one FDG-PET positive bi-dimensionally measurable (≥1.5 cm) nodal lesion, or one bi dimensionally measurable (>1 cm extranodal lesion, as measured on computed tomography (CT) scan
- Patient has Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 - 2
- Patient has an absolute lymphocyte count > 200/µL
- Patient is eligible for CAR-T cell therapy as per investigator´s discretion meeting all of the following criteria of adequate organ function: a. Adequate kidney function, defined as: Serum creatinine estimated glomerular filtration rate (MDRD) ≥ 60 mL/min. b. Adequate hepatic function, defined as: ALAT and ASAT ≤ 5 ULN. Bilirubin ≤ 2.0 mg/dl (except for Meulengracht disease) c. Adequate bone marrow function, defined as: Absolute neutrophil count (ANC) ≥ 1000/µL, Platelets ≥ 50.000/µL and Hemoglobin > 8.0 g/dL. d. Adequate cardiac function, defined as: Cardiac ejection fraction ≥ 45%. e. Adequate pulmonary function as per investigators discretion
- Patient successfully performed MNC-leucapheresis procedure for a commercially available CAR-T-cell product
- Patient is willing and able to provide baseline biopsy material (archival or fresh tumor sample) for central review
- Male patients with female partners of childbearing potential are eligible to participate if they agree to contraceptive methods throughout the duration of the trial and at least 18 months after obinutuzumab administration, 12 months after lost dose oxaliplatin, 6 months after lymphodepletion or 2 months after last dose glofitamab, whatever is last
- Female participants of childbearing potential must agree to use a highly effective method of contraception (e.g., hormonal contraception, intrauterine device (IUD), or surgical sterilization) throughout the duration of the trial and at least 18 months after obinutuzumab administration, 15 months after lost dose oxaliplatin, 6 months after lymphodepletion or 2 months after last dose glofitamab, whatever is last.
Exclusion Criteria
- Patient has HIV infection of any stage as determined by presence of anti-HIV antibodies (confirmatory test) and / or presence of RNA confirmed by PCR during screening
- Patient has previous or concurrent malignancies with the following exceptions: a. Surgically cured carcinoma in-situ b. Other kinds of cancer without evidence of disease for at least 3 years
- Patient has known hypersensitivity to any component of the Glofitamab, Obinutuzumab, Yescarta® and/or Breyanzi® formulation as well as a known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion protein and/or any known contraindication (including hypersensitivity) to one of the other trial drugs
- Patient has severe active infection requiring iv treatment within 14 days prior first dose of study drugs
- Patient has congenital or acquired immunodeficiency including previous organ or allogeneic stem cell transplantation
- Patient received prior treatment with glofitamab or other bispecific antibodies targeting both CD20 and CD3
- Patient received prior treatment with gemcitabine and oxaliplatin in prior lymphoma treatment line
- Patient had a major surgery within 4 weeks prior to first dose of study drugs
- Patient has primary or secondary central nervous system (CNS) lymphoma at the time of enrollment or history of CNS lymphoma
- Patient has current or history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease
- Patient has significant or extensive cardiovascular disease such as New York Heart Association Class III or IV cardiac disease, myocardial infarction within the last 3 months, unstable arrhythmias, or unstable angina
- Patient has an active autoimmune disease requiring systemic treatment
- Patient receives ongoing corticosteroid use >20 mg/day of prednisone or equivalent. Patients on stable low-dose corticosteroids (≤20 mg/day of prednisone or equivalent for at least 7–14 days prior to first IMP administration) or on short courses of higher-dose corticosteroids that are completed before first IMP administration are eligible.
- Female patients who are pregnant or breast feeding or planning to become pregnant within 18 months after start of trial treatment. Female patients of childbearing potential must have a negative serum pregnancy test result within 3 days prior to initiation of trial treatment.
- Patient has a relationship of dependence or employer-employee relationship to the sponsor or the investigator
- Patient lacks accountability and inability to appreciate the nature, meaning and consequences of the trial and to formulate their own wishes correspondingly
- Patient is non-compliant, for reasons including, but not limited to the following: - Increased alcohol consumption, drug dependency or substance abuse that would interfere with cooperation with requirements of the trial - Refusal of blood products during treatment - Any similar circumstances that appear to make protocol treatment or follow-up impossible
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Recruiting | 15 Apr 2026 | 20 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Columvi 10 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 30 | 39 | PRD10561232 |
Gazyvaro 1,000 mg concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 1000 | 2 | PRD1753415 |
Breyanzi 1.1-70 × 106 cells/mL / 1.1-70 × 106 cells/mL dispersion for infusion | Test | DISPERSION FOR INFUSION | INTRAVENOUS | 120000000 | 1 | PRD9615667 |
YESCARTA 0.4 – 2 x 10e8 cells dispersion for infusion | Test | DISPERSION FOR INFUSION | INTRAVENOUS | 2000000 | 1 | PRD6563423 |