A prospective multicenter phase 2 study of the chemotherapy-light combination of intravenous rituximab with the antibody-drug conjugate polatuzumab vedotin and the bispecific antibody glofitamab in previously untreated aggressive B-cell lymphoma patients above 60 years of age ineligible for a fully dosed R-CHOP

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

16 Mar 2023 → ongoing

Decision date (initial)

2024-11-13

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

ROCHE Pharma AG · ROCHE Austria GmbH

External identifiers

EU CT number

2024-513949-37-00

EudraCT number

2022-003398-51

ClinicalTrials.gov

NCT05798156

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy

The primary objective of the trial is to evaluate an estimator of efficacy of the chemotherapy-light combination of glofitamab, polatuzumab vedotin and rituximab in patients with previously untreated aggressive large B-cell lymphoma not eligible for a fully dosed R-CHOP. The results shall be generated from the first 80 patients enrolled and can be used for initial effect estimation and planning of a subsequent phase III trial.

Secondary objectives 4

1. to further characterize the outcome
2. to evaluate the safety and tolerability
3. to evaluate identify predictors for clinical outcome
4. to assess feasibility and safety of the R-Pola-Glo regimen in an outpatient setting

Conditions and MedDRA coding

previously untreated aggressive B-cell lymphoma

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. 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.
2. Patient is above 60 years of age
3. Patient is not eligible for a fully dosed R-CHOP
4. Patient has histologically confirmed aggressive B-cell lymphoma.
5. 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
6. Baseline biopsy material is available for central review.
7. 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.
8. Patient did not receive any prior systemic lymphoma therapy.
9. Patient has an ECOG performance status of ≤ 2.
10. Patient has with treatment a life expectancy (in the opinion of the investigator) of at least 12 weeks.
11. 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.
12. 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).
13. 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.
14. 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)
15. 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

Exclusion criteria 29

1. Patient with chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL) (including CD20+ ALL), lymphoblastic lymphoma, Richter`s transformation, Burkitt lymphoma.
2. Patient ≤ 60 years
3. 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.
4. Patient with current > Grade 1 peripheral neuropathy.
5. Patient with history of confirmed progressive multifocal leukoencephalopathy (PML).
6. Patient with history of leptomeningeal disease.
7. Patient with current or history of CNS lymphoma.
8. 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
9. 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.
10. 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).
11. 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.
12. Patient with uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently).
13. Patient with history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic.
14. 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.
15. Patient with prior solid organ transplantation.
16. Patient with prior allogeneic stem cell transplantation.
17. 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.
18. 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.
19. Patient with any history of immune related ≥ Grade 3 AE except for endocrinopathy managed with replacement therapy.
20. 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.
21. 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.
22. 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.
23. Patient with history of illicit drug or alcohol abuse within 12 months prior to screening, in the Investigator’s judgment.
24. 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.
25. 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.
26. 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.
27. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities.
28. 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.
29. Patients who are dependent on the sponsor, the investigator or the trial site.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 1 year progression-free survival (PFS) rate of first 80 patients enrolled

Secondary endpoints 21

1. Event-free survival (EFS)
2. Overall survival (OS)
3. Response rates after 2 cycles (during target dose phase), 6 cycles (end of target dose phase before start of consolidation phase) and 12 cycles (end of treatment following completion of consolidation phase). i.e., complete remission (CR) rate, partial remission (PR) rate, overall remission rate (ORR: CR+PR), stable disease (SD) rate and progressive disease (PD) rate
4. Relapse rate
5. Conversion rate of PR to CR during target dose phase (C2-C6) and consolidation phase (C7-C12)
6. Duration of response (DoR)
7. Rate and type of adverse events (AEs) and serious adverse events (SAEs)
8. Rate of secondary malignancies
9. Treatment-related death rate
10. Protocol adherence
11. Patient-reported outcomes for quality of life (QoL)
12. Subgroup analysis with respect to age groups, IPI factors, IPI score, geriatric scores, sex, and CD20 expression level (as centrally assessed)
13. Subgroup analysis for disease entities (DLBCL, rFL, HGBCL with MYC and BCL2 translocation), transcriptional subtypes (ABC vs. GCB) and genetic subtypes of DLBCL (DLBclass and LymphGen).
14. Identification of molecular and imaging-based (investigator vs central review of images) predictors of response and sensitivity, including TMTV at baseline, delta SUV between baseline and C2 and C6 PET/CTs, rate of mCR at C2 and C6 (defined as a Deauville score ≤ 3)
15. Rate of minimal residual disease (MRD)-negative patients after end of target phase (before start of consolidation phase) and at end of treatment (including consolidation phase)
16. Duration of molecular remission for MRD negative patients
17. Identification of molecular and imaging-based (investigator vs central review of images) predictors of PR to CR conversion.
18. Proportion of patients in whom R-Pola-Glo medication can be administered in the outpatient setting as recommended by the safety board (judged before treatment and including modification after cycle 1 or 2) and no hospitalization occurs following 24hrs after last administration.
19. Proportion of patients in whom R-Pola-Glo medication can be administered in the outpatient setting as recommended by the safety board (judged before treatment and including modification after cycle 1 or 2) but are hospitalized within 24hrs after last administration for timely medical assistance from treating physician for symptoms developed following treatment with R-Pola-Glo.
20. Cycles safely administered in an outpatient setting per patient.
21. Exploratory analysis for predictive markers for IMP-related side effects from the safety board parameter assessment at the following time points: pretreatment, post cycle 1 and post cycle 2

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

Sponsor organisation

Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

Address

Steinbacher Hohl 2-26, Praunheim Praunheim

City

Frankfurt Am Main

Postcode

60488

Country

Germany

Scientific contact point

Organisation

Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

Contact name

Clinical Trial project manager

Public contact point

Organisation

Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

Contact name

Clinical Trial project manager

Third parties 4

Locations

2 EU/EEA countries · 29 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 13 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications