Phase 2 Multicenter Study of Rituximab, Polatuzumab Vedotin, and Glofitamab in Untreated Aggressive B-cell Lymphoma Patients Aged >60 Ineligible for R-CHOP

Trial ID: 2024-513949-37-00
Sponsor: Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

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Diseases & Conditions

B-cell lymphoma

Objectives

The primary objective of this study is to evaluate an estimator of **efficacy** for the chemotherapy-light combination of glofitamab, polatuzumab vedotin, and rituximab in patients with previously untreated aggressive large B-cell lymphoma who are not eligible for a fully dosed R-CHOP regimen. This evaluation is clinically relevant as it aims to provide an alternative treatment option for a patient population that cannot tolerate standard chemotherapy, potentially improving outcomes and quality of life. The results from the first 80 patients enrolled will be used for initial effect estimation and planning of a subsequent phase III trial.

Secondary objectives include:

To further characterize the outcome of the treatment regimen.
To evaluate the safety and tolerability of the combination therapy.
To identify predictors for clinical outcome, which could guide personalized treatment approaches.
To assess the feasibility and safety of the R-Pola-Glo regimen in an outpatient setting, which could enhance patient convenience and reduce healthcare costs.

Participants

The clinical trial involves participants diagnosed with **previously untreated aggressive B-cell lymphoma**. The study population includes both male and female subjects, aged above 60 years, who are not eligible for a fully dosed R-CHOP regimen. The total number of participants is not specified as the sponsor has not provided this information. Participants were selected based on their ability to provide informed consent and comply with the study protocol, as well as their adequate liver, hematological, and renal function. They must have a life expectancy of at least 12 weeks and no active SARS-CoV-2 infection. Lifestyle considerations such as diet and physical activity are not detailed. The trial includes individuals with histologically confirmed aggressive B-cell lymphoma and at least one measurable FDG PET-positive lymphoma manifestation. Participants must not have received any prior systemic lymphoma therapy and should have an ECOG performance status of ≤ 2. The trial also considers vulnerable populations, although specific details are not provided.

Plans and Procedures

The clinical trial is a prospective, multicenter, phase II study designed to evaluate the efficacy of a chemotherapy-light combination therapy in patients with **previously untreated aggressive B-cell lymphoma** who are above 60 years of age and ineligible for a fully dosed R-CHOP regimen. The trial employs a single-arm design and involves the administration of intravenous **rituximab**, **polatuzumab vedotin**, and **glofitamab**. The study is expected to enroll 80 participants, with the primary objective being the estimation of efficacy, which will inform the planning of a subsequent phase III trial. The trial is anticipated to conclude by March 31, 2028, with recruitment having commenced on March 17, 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as adequate liver, renal, and hematological function, and the absence of active **SARS-CoV-2** infection. Following successful screening, participants will receive treatment over a maximum period of 36 months, with regular follow-up visits to monitor response rates, adverse events, and overall survival. The end-of-study visit will evaluate the primary endpoint of 1-year progression-free survival and secondary endpoints including event-free survival, overall survival, and response rates at various treatment phases.

The expected length of participant involvement is up to 36 months, with conditions for early termination including the development of unacceptable toxicity, withdrawal of consent, or investigator decision based on the participant's best interest. The trial is conducted under a controlled environment, with all medications administered via **intravenous infusion**. The study's rigorous design ensures the collection of robust data to assess the treatment's efficacy and safety profile, contributing valuable insights into the management of aggressive B-cell lymphoma in the specified patient population.

Treatment

The clinical trial involves the administration of several experimental medications, each with specific characteristics and administration protocols. **Gazyvaro** (obinutuzumab) is provided as a 1,000 mg concentrate for solution for infusion. It is administered via **intravenous infusion** with a maximum daily dose of 1,000 mg. The treatment period for Gazyvaro is limited to 2 days. The pharmaceutical form is a solution for infusion, and the product is manufactured by Roche Registration GmbH.

**Columvi** (glofitamab) is another experimental medication used in this trial. It is available as a 10 mg concentrate for solution for infusion and is also administered through intravenous infusion. The maximum daily dose is 30 mg, with a total maximum dose of 342.5 mg over a treatment period of 36 weeks. This product is also produced by Roche Registration GmbH.

**MabThera** (rituximab) is included in the study as a 500 mg concentrate for solution for infusion. The administration route is intravenous infusion, with a maximum daily dose of 375 mg/m² and a total maximum dose of 1,875 mg/m². The treatment period extends up to 15 weeks. Roche Registration GmbH is the manufacturer of this pharmaceutical product.

**Polivy** (polatuzumab vedotin) is provided as a 140 mg powder for concentrate for solution for infusion. It is administered via intravenous infusion, with a maximum daily dose of 1.8 mg/kg and a total maximum dose of 10.8 mg/kg over an 18-week treatment period. This product is also manufactured by Roche Registration GmbH.

All medications are administered in a controlled clinical setting, with compliance monitored throughout the study. The trial aims to evaluate the efficacy of these treatments in patients with previously untreated aggressive large B-cell lymphoma who are ineligible for a fully dosed R-CHOP regimen.

Efficacy

Efficacy in this clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoint is the 1-year progression-free survival (PFS) rate of the first 80 patients enrolled. Secondary endpoints include event-free survival (EFS), overall survival (OS), and response rates at various stages of the treatment cycle, specifically after 2 cycles, 6 cycles, and 12 cycles. These response rates will be categorized into complete remission (CR), partial remission (PR), overall remission rate (ORR: CR+PR), stable disease (SD), and progressive disease (PD). Additional secondary endpoints include relapse rate, conversion rate of PR to CR during different phases, duration of response (DoR), and rates of adverse events (AEs) and serious adverse events (SAEs).

Patient-reported outcomes for quality of life (QoL) will also be evaluated, alongside subgroup analyses based on age, IPI factors, geriatric scores, sex, and CD20 expression levels. The trial will further explore molecular and imaging-based predictors of response, such as total metabolic tumor volume (TMTV) at baseline and changes in standardized uptake values (delta SUV) between baseline and subsequent PET/CT scans. The rate of minimal residual disease (MRD)-negative patients will be assessed at the end of the target phase and at the end of treatment. Exploratory analyses will be conducted to identify predictive markers for investigational medicinal product (IMP)-related side effects at specified time points, including pretreatment and post-treatment cycles.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patient has provided written informed consent and is able and willing to comply with the study protocol and protocol mandated treatments according to ICH and local regulations.
Patient is above 60 years of age
Patient is not eligible for a fully dosed R-CHOP
Patient has histologically confirmed aggressive B-cell lymphoma.
Patient has at least one measurable FDG PET-positive lymphoma manifestation; defined as lesional maximum FDG uptake higher than the maximum FDG uptake in unaffected liver parenchyma as measured in a reference volume-of-interest with >10 mL
Baseline biopsy material is available for central review.
Female patients considered as women of childbearing potential (WOCBP, see section 5.2.7 for definition) and male patients with female partners considered as WOCBP must: a) agree to either remain completely abstinent (refrain from heterosexual intercourse) or to use at least one effective contraceptive methods that results in a failure rate of < 1% per year from screening until: o At least 4 months after last dose of glofitamab, 9 months after last dose of polatuzumab vedotin, 12 months after last dose of rituximab or 18 months after last dose of obinutuzumab, whichever is longer, if the patient is female o At least 4 months after last dose of rituximab, obinutuzumab and glofitamab or 6 months after last dose of polatuzumab vedotin, whichever is longer, if the patient is male b) refrain from donating ova (female patients) or donating sperm (male patients) during the same period as stated in a). c) in case of male patients with pregnant female partners, remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures such as a condom to avoid exposing the embryo. Female patients who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile, see section 5.2.7) as well as azoospermic male patients do not require contraception.
Patient did not receive any prior systemic lymphoma therapy.
Patient has an ECOG performance status of ≤ 2.
Patient has with treatment a life expectancy (in the opinion of the investigator) of at least 12 weeks.
Patient has adequate liver function: • Total bilirubin ≤1.5 x ULN (≤3 x ULN in patients with Gilbert’s syndrome). • AST (aspartate aminotransferase)/ALT (alanine aminotransferase), ALP (alkaline phosphatase) ≤3 x ULN. o Patients with bone marrow or liver involvement: ALP ≤5 x ULN. o Patients with documented liver involvement: AST and/or ALT ≤5 x ULN. • Albumin ≥ 2.5 g/dL.
Patient as adequate hematological function: • Neutrophil count of ≥1.5 x 109cells/L (1,500/μL). • Platelet count of ≥75 x 109cells/L (75,000/μL). • Hemoglobin (Hb) ≥9.0 g/dL. • For patients not receiving therapeutic anti-coagulation: INR or aPTT ≤ 1.5 x ULN).
Patient has adequate renal function: • Creatinine ≤ 1.5 x ULN, or • Creatinine clearance (CrCl) calculated by Cockcroft-Gault formula of ≥ 30 mL/min for patients in whom, in the Investigator’s judgment, serum creatinine levels do not adequately reflect renal function.
Patients has negative serologic and/or polymerase chain reaction (PCR) test results for: • Acute or chronic hepatitis B (HBV) infection. • Hepatis C virus (HCV) and human immunodeficiency virus (HIV)
Patient has no active SARS-CoV-2 infection. All potential subjects must be screened for SARS-CoV-2 with antigen and/or PCR testing within 7 days prior to enrolment. Investigators are strongly encouraged to test prior to study treatment administration at every cycle. PCR testing is preferred • Patients with positive SARS-CoV-2 antigen or PCR testing within 30 days prior to treatment initiation are not eligible • Patients with documented SARS-CoV-2 infection within 6 months prior to treatment initiation must have no persistent respiratory symptoms, no evidence of residual sequelae, and have negative PCR for SARS-CoV-2

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Exclusion Criteria

Patient with chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL) (including CD20+ ALL), lymphoblastic lymphoma, Richter`s transformation, Burkitt lymphoma.
Patient ≤ 60 years
Patient with known active infection, or reactivation of a latent infection, whether bacterial (e.g., tuberculosis), viral (including, but not limited to severe pneumonia, COVID-19, Epstein-Barr virus [EBV], cytomegalovirus [CMV], hepatitis B, hepatitis C, and HIV], fungal, mycobacterial, or other pathogens (excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with IV antibiotics (for IV antibiotics this pertains to completion of last course of antibiotic treatment) within 4 weeks prior to study enrollment.
Patient with current > Grade 1 peripheral neuropathy.
Patient with history of confirmed progressive multifocal leukoencephalopathy (PML).
Patient with history of leptomeningeal disease.
Patient with current or history of CNS lymphoma.
Patient with current or history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease. Following exceptions are allowed within this trial: • Patients with a history of stroke who have not experienced a stroke or transient ischemic attack in the past 2 years and have no residual neurologic deficits, as judged by the Investigator, • Patients with a history of epilepsy that are taking medication and/or had no seizure within a year , as judged by the Investigator
Patient with another invasive malignancy in the last 2 years (with the exception of basal cell carcinoma and tumors deemed by the Investigator to be of low likelihood for recurrence), with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate 90%), such as adequately-treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.
Patient with significant or extensive history of cardiovascular disease (such as New York Heart Association (NYHA) Class ≥ II cardiac disease, congestive heart failure, myocardial infarction or cerebrovascular accident within the past 3 months, unstable arrhythmias, or unstable angina or history of multiple cardiovascular events) or significant pulmonary disease (including obstructive pulmonary disease and history of bronchospasm).
Patient with active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, or multiple sclerosis (see addendum for a more comprehensive list of autoimmune diseases and immune deficiencies), with the following exceptions: • Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study. • Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study. • Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all following conditions are met: o Rash must cover < 10% of body surface area. o Disease is well controlled at baseline and requires only low-potency topical corticosteroids. o No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months.
Patient with uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently).
Patient with history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic.
Patient received treatment with any other standard anti-cancer radiotherapy/chemotherapy including investigational therapy (defined as treatment for which there is currently no regulatory authority approved indication) within 4 weeks or five times the elimination half-life of the product, whichever is longer, prior to study enrollment.
Patient with prior solid organ transplantation.
Patient with prior allogeneic stem cell transplantation.
Patient with prior treatment with targeted therapies (e.g., tyrosine kinase inhibitors, systemic immunotherapeutic/immunostimulating agents, including, but not limited to, CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies, radio-immunoconjugates, antibody-drug conjugates, immune/cytokines, and monoclonal antibodies) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to study enrollment.
Patient with toxicities from prior anti-cancer therapy including immunotherapy that did not resolve to ≤ Grade 1 except for alopecia, endocrinopathy managed with replacement therapy and stable vitiligo.
Patient with any history of immune related ≥ Grade 3 AE except for endocrinopathy managed with replacement therapy.
Patient with ongoing corticosteroid use 25 mg/day of prednisone or equivalent within 4 weeks prior and during study treatment: • Patients who received corticosteroid treatment with 25 mg/day of prednisone or equivalent must be documented to be on a stable dose of at least 4-week duration prior to treatment initiation. • Patients may have received a brief (max. 7 days) course of systemic steroids (100 mg prednisone equivalent per day) prior to initiation of study therapy for control of lymphoma-related symptoms as a prephase.
Patient with treatment with systemic immunosuppressive medication (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions: • Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.
Patient who received administration of a live, attenuated vaccine within 4 weeks prior to study enrollment infusion or anticipation that such a live, attenuated vaccine will be required during the study or within 5 months after the last dose of study treatment.
Patient with history of illicit drug or alcohol abuse within 12 months prior to screening, in the Investigator’s judgment.
Patient with history of severe allergic anaphylactic reactions to chimeric or humanized monoclonal antibodies or recombinant antibody-related fusion proteins. Please consult a Lead Investigator if the patient has documented history of CRS or HLH at previous treatments.
Patient with known hypersensitivity to Chinese hamster ovary (CHO) cell products or to any component of the rituximab, obinutuzumab, polatuzumab vedotin and/or glofitamab formulation and/or to the contrast agents used in the study.
Female patient is pregnant or breast feeding. Female patients of childbearing potential must have a negative serum pregnancy test result within 7 days prior to initiation of study treatment.
Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities.
Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts.
Patients who are dependent on the sponsor, the investigator or the trial site.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Not Recruiting	17 Mar 2023	52
Germany	Not Recruiting	17 Mar 2023	74

Sites & Investigators

Research sites

Noe LGA Gesundheit Region Mitte GmbH Universitaetsklinikum Regensburg AöR Universitaetsklinikum Erlangen AöR Medical University Of Vienna

Investigators

Christiane P.Angela Luise H.Ella W.Fabian M.

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
Glofitamab	Test	SOLUTION FOR INFUSION	INTRAVENOUS	30	36	PRD9870862
Gazyvaro 1,000 mg concentrate for solution for infusion.	Test	CONCENTRATE FOR SOLUTION FOR INFUSION	INTRAVENOUS INFUSION	1000	2	PRD1753415
MabThera 500 mg concentrate for solution for infusion	Test	CONCENTRATE FOR SOLUTION FOR INFUSION	INTRAVENOUS INFUSION	375	15	PRD2154043
Polivy 140 mg powder for concentrate for solution for infusion.	Test	POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION	INTRAVENOUS INFUSION	1.8	18	PRD7856215