| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| aggressive large B-cell lymphoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| aggressive large B-cell lymphoma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10012819 |
| E.1.2 | Term | Diffuse large B-cell lymphomas |
| E.1.2 | System Organ Class | 100000004851 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of the trial is to evaluate an estimator of efficacy of the chemotherapy-light combination of glofitimab, polatuzumab vedotin and rituximab in patients with previously untreated aggressive large B-cell lymphoma. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objectives of the trial are designed to i.) further characterize the outcome, ii.) to evaluate the safety and tolerability of the chemotherapy-light combination R-Pola-Glo in patients with previously untreated DLBCL and only for extension cohort iii) to assess feasibility and safety of the R-Pola-Glo regimen in an outpatient setting. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
(1) Patient has provided written informed consent and is able and willing to comply with the study protocol and protocol mandated hospitalizations 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.
Note: transformed follicular lymphoma and composite B-cell lymphoma can be included as long as the low-grade component had not obtained systemic treatment.
(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 WOCPB 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 lymphoma therapy.
Note: Except for a corticosteroid prephase or local radiation to low grade lymphoma.
(9) Patient has a ECOG performance status of ≤ 2.
(10) Patient has a life expectancy (in the opinion of the investigator) of at least 12 weeks.
(11) Patient has adequate liver function:
a) Total bilirubin ≤1.5 x ULN (≤3 x ULN in patients with Gilbert’s syndrome).
b) 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.
c) Albumin ≥ 2.5 g/dL.
(12) Patient has adequate hematological function:
a) Neutrophil count of ≥1.5 x 109 cells/L (1,500/μL).
b) Platelet count of ≥75 x 109 cells/L (75,000/μL).
c) Hemoglobin (Hb) ≥9.0 g/dL.
Note: Transfusion of RBCs and platelets is allowed to reach the inclusion criteria. In case screening procedures are leading to situations that would exclude the patient from study participation (such as Hb value below entry criteria), the patient may still be enrolled into the trial after consultation with the sponsor.
d) For patients not receiving therapeutic anti-coagulation: INR or aPTT ≤ 1.5 x ULN).
(13) Patient has adequate renal function:
a) Creatinine ≤ 1.5 x ULN, or
b) Creatinine clearance (CrCl) calculated by Cockroft-Gault formula of ≥ 40 mL/min for patients in whom, in the Investigator’s judgment, serum creatinine levels do not adequately reflect renal function.
(14) Patient has negative serologic and/or polymerase chain reaction (PCR) test results for:
a) Acute or chronic hepatitis B (HBV) infection.
Note: Patients whose HBV infection status cannot be determined by serologic test results (https://www.cdc.gov/hepatitis/hbv/pdfs/serologicchartv8.pdf) must be negative for HBV by PCR to be eligible for study participation.
b) Hepatitis 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
Note: In case of CT (Threshold Cycle) value >30 in repeated PCR tests in a patient without symptoms the patient may still be enrolled into the trial after consultation with the sponsor.
• 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 |
|
| E.4 | Principal exclusion criteria |
(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, fungal, mycobacterial, or other pathogens (excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with IV antibiotics 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. Exceptions are allowed fot this trial.
(9) Patient with another invasive malignancy in the last 2 years.
(10) Patient with significant or extensive history of cardiovascular disease or significant pulmonary disease.
Note: Congestive heart failure NYHA II patients can be included if they provide an LVEF >40%.
(11) Patient with active or history of autoimmune disease or immune deficiency (see addendum for a comprehensive list of autoimmune diseases and immune deficiencies), with exceptions.
(12) Patient with uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently).
Note: Patients with indwelling catheters (e.g., PleurX) are allowed.
(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 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.
(21) Patient with treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with exceptions.
(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 antibodyrelated 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1 year progression-free survival (PFS) rate of the first 80 patients.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Analysis of the primary outcome endpoint and the secondary endpoints will be performed following recruitment of all analyzable patients and with adequate observation time to assess the 1-years PFS rate.
|
|
| E.5.2 | Secondary end point(s) |
i.) Outcome-related corresponding endpoints
• Event-free survival (EFS)
• Overall survival (OS)
• Response rates after 2 cycles (during target dose phase), 6 cycles (end of target dose phase before start of maintenance) and 12 cycles (end of treatment following completion of maintenance). i.e., complete remission rate , partial remission (PR) rate, overall remission rate (ORR: CR+PR), stable disease (SD) rate and progression disease (PD) rate
• Relapse rate
• Conversion rate of PRs to mCRs during target dose (C2-C6) and maintenance phase (C6-C12)
• Duration of response (DoR)
ii.) Safety, tolerability and protocol adherence-relpated corresponding endpoints:
• Rate and type of adverse events (AEs) and serious adverse events (SAEs)
• Rate of secondary malignancies
• Treatment-related death rate
• Protocol adherence
• Patient-reported outcomes for quality of life (QoL) as measured by EORTC QLQ-C30 and FACT-Lym
iii.) additional endpoints for extension cohort
o 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.
Note: These patients and cycles will be defined as "safely treated in outpatient setting"
o 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.
Note: These patients and cycles will still be defined as "safely treated in outpatient setting"
o Cycles safely administered in outpatient setting per patient.
Note: We will define the aggregate statistics in the SAP.
o 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. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoint for analysis for toxicity and response assessment of the initial cohort
Analysis of the secondary endpoints regarding response and toxicity will be performed after completion of the final end of treatment staging of the last patient.
Timepoints for analysis of the endpoints of the extension cohort
A first analysis assessing the feasibility to apply R-Pola-Glo in an outpatient setting and safety data will be performed when the last of the 45 patients recruited in this cohort has finished cycle 6.
A second analysis for efficacy, safety and feasibility in an outpatient setting will be performed following recruitment of all analyzable patients of the extension cohort and with adequate observation time to assess the 1-years PFS rate. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The date of database closure is defined as the global end of the trial to ensure the collection of survival data of patients and the active involvement of sites in the data cleaning process. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 60 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 60 |
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