HOVON 151 DLBCL: A phase II study evaluating the feasibility and clinical efficacy of atezolizumab consolidation treatment in high risk diffuse large B-cell lymphoma.

Trial ID: 2022-501076-26-00
Protocol: HO151
Sponsor: Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

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Diseases & Conditions

Diffuse large B-cell lymphoma

Objectives

The primary objective of this phase II study is to evaluate the **2-year disease-free survival (DFS)** for patients with high-risk diffuse large B-cell lymphoma (DLBCL) who achieve complete metabolic remission following R-CHOP induction therapy. This objective is clinically relevant as it aims to determine the efficacy of atezolizumab consolidation treatment in prolonging DFS, which is a critical measure of treatment success and long-term patient outcomes in this high-risk population.

Secondary objectives include:

Evaluating toxicity and assessing the relation of adverse events in time to recovery of the T-cell repertoire.
Evaluating the 2-year overall survival (OS).
Evaluating minimal residual disease (MRD) status at the end of induction therapy, during consolidation treatment, and at the end of consolidation.
Evaluating the recovery of the T-cell and NK cell repertoire after induction therapy and during consolidation treatment in relation to toxicity and efficacy.
Exploring the PDL1/HLA expression, mutational load, gene expression immune profile, soluble PDL1, microbiome, and T-cell clonality of patients in relation to MRD status and MRD conversion.
Exploring the tumor characteristics and mutational dynamics in patients who relapse.
Assessing the crossing of the blood-brain barrier of atezolizumab by measuring its concentrations in the cerebrospinal fluid.

Participants

The clinical trial involves participants diagnosed with **high risk diffuse large B-cell lymphoma** (DLBCL-NOS), specifically targeting individuals aged 18 to 75 years. Both male and female subjects are included, and the study population encompasses a vulnerable group. Participants are required to have a confirmed histologic diagnosis of DLBCL-NOS, with Ann Arbor stages II-IV and a WHO performance status of 0-1. The trial focuses on individuals who have achieved complete metabolic remission after 6-8 cycles of R-CHOP induction therapy. The sponsor has not provided information regarding the total number of participants. Key lifestyle considerations include the requirement for a negative pregnancy test at study entry and the use of adequate contraception during and until five months after the last protocol treatment. The selection criteria ensure that participants are capable of providing written informed consent and have undergone specific treatment protocols, including the administration of rituximab and central nervous system prophylaxis. The trial aims to evaluate the 2-year disease-free survival (DFS) for patients in complete metabolic remission following R-CHOP induction.

Plans and Procedures

The clinical trial is designed to evaluate the feasibility and clinical efficacy of **atezolizumab** consolidation treatment in patients with high-risk diffuse large B-cell lymphoma (DLBCL). This is a Phase II, randomized, double-blind, controlled trial. The trial aims to assess the 2-year disease-free survival (DFS) for patients in complete metabolic remission after R-CHOP induction therapy. The trial is expected to run from September 2018 to January 2027, with a maximum treatment period of 54 weeks for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histologic diagnosis, and performance status. Following successful screening, participants will be randomized to receive the investigational product, Tecentriq 1,200 mg concentrate for solution for infusion, administered via infusion. Follow-up visits will be scheduled to monitor the primary endpoint of disease-free survival and secondary endpoints, including overall survival and adverse events. The end-of-study visit will conclude the participant's involvement, assessing the long-term effects of the treatment.

Participant involvement is expected to last up to 54 weeks, with conditions for early termination including withdrawal of consent, adverse events, or disease progression. The trial will adhere to rigorous scientific and ethical standards, ensuring the collection of high-quality data to evaluate the investigational treatment's efficacy and safety. The study will not encourage participation and will maintain an impersonal and factual approach throughout its conduct.

Treatment

The clinical trial involves the administration of **Tecentriq**, a concentrate for solution for infusion, containing the active substance **atezolizumab**. Atezolizumab is a monoclonal antibody classified under the ATC code L01FF05. The pharmaceutical form of Tecentriq is a solution for infusion, and it is administered intravenously. The dosage for this trial is set at 1,200 mg per infusion, with a maximum daily and total dose of 1,200 mg. The treatment period is defined as a maximum of 54 weeks. The product is manufactured by Roche Registration GmbH and has been re-labeled specifically for the purposes of this clinical trial.

In this study, Tecentriq is used as a consolidation treatment for patients with high-risk diffuse large B-cell lymphoma (DLBCL) who are in complete metabolic remission following R-CHOP induction therapy. The trial aims to evaluate the 2-year disease-free survival (DFS) of these patients. The administration of Tecentriq is conducted via infusion, and participant compliance is monitored throughout the study to ensure adherence to the dosing schedule. No additional non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified for this trial.

Efficacy

Efficacy in this clinical trial will be assessed primarily through the measurement of **disease-free survival (DFS)**. This parameter will be evaluated from the date of patient registration until the occurrence of relapse or death from any cause, whichever occurs first. Secondary endpoints include the assessment of overall survival, which will be calculated from registration until death from any cause, with patients still alive or lost to follow-up being censored at the last known date of being alive. Additionally, the trial will explore the relationship between minimal residual disease (MRD) status at the end of induction and consolidation therapy, as well as the correlation between MRD conversion and 2-year DFS and overall survival (OS).

Further secondary endpoints involve the analysis of the relationship between the T-cell repertoire, PDL1/HLA expression, mutational load, gene immune signature, microbiome, and the effect of **atezolizumab** on MRD conversion. The trial will also examine the relation between the T-cell and NK cell repertoire and adverse events. The collection and analysis of these efficacy parameters will be conducted at specified timepoints throughout the trial, ensuring a comprehensive evaluation of the treatment's impact on high-risk diffuse large B-cell lymphoma (DLBCL) patients.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Age 18-75 (inclusive) years
Patients with a confirmed histologic diagnosis of diffuse large B-cell lymphoma (DLBCL-NOS) based upon a representative histology specimen according to the WHO classification, revision 2016.
Ann Arbor stages II-IV.
WHO performance status 0 – 1.
IPI >=3 at diagnosis.
Complete metabolic remission (Deauville 1-3) after 6-8 cycles of RCHOP according to the Lugano criteria. Of note: 1. Rituximab may have been administered either intravenously or subcutaneously. A rituximab biosimilar may have been used when it is approved for the indication of DLBCL. 2. Patients should have received at least 6 cycles R-CHOP. Dose reductions for vincristine are allowed during R-CHOP. Dose reductions because of bone marrow toxicity are allowed but cannot exceed >15% of cumulative dose of doxorubicin and cyclophosphamide 3. Central nervous system prophylaxis (MTX) by intrathecal or IV therapy is allowed.4. 18F-FDG-PET scan should have been made 4-8 weeks after last induction cycle. 5. Histologically confirmed false positive EoT PET-scans are eligible.
Negative pregnancy test at study entry.
Patient is willing and able use adequate contraception during and until 5 months after the last protocol treatment.
Written informed consent.
Patient is capable of giving a written informed consent.

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Exclusion Criteria

All histopathological diagnoses other than DLBCL-NOS according to the WHO classification, revision 2016 (see appendix A), including: - High-grade B-cell lymphoma with a double/triple translocation with MYC, BCL2 and/or BCL6. Please note that patients with an isolated MYC translocation or an isolated BCL2 translocation or an isolated BCL-6 translocation are eligible (single hit translocation) - Testicular large B-cell lymphoma - Primary mediastinal B cell lymphoma - Transformed indolent lymphoma - Post-transplant lymphoproliferative disorder
Clinical signs of severe pulmonary dysfunction.
Clinical signs of heart failure (NYHA classification II-IV)
Symptomatic coronary artery disease or cardiac arrhythmias not well controlled with medication.
Myocardial infarction during the last 6 months.
Significant renal dysfunction (serum creatinine ≥ 150 umol/l or clearance ≤ 30ml/min Creatinine clearance may be calculated by Cockcroft –Gault formula: CrCl = (140 - age [in years]) x weight [kg] (x 0.85 for females) (0.815 x serum creatinine [μmol/L])
Inadequate hematological function: hemoglobin < 5.5 mmol/L ANC < 1.0x109/L or platelets < 75x109 /L.
Signs or known history of bleeding disorder.
Significant hepatic dysfunction (total bilirubin ≥ 1.5x upper limit of normal (ULN) or transaminases ≥ 2.5 x ULN), unless related to Gilberts syndrome.
Clinical signs of severe cerebral dysfunction.
Patients with a history of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant and adversely affecting compliance to study drugs.
Major surgery within the last 4 weeks
Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection or any major episode of infection requiring treatment with IV antibiotics or hospitalization within 4 weeks before date of registration. Suspected active or latent tuberculosis needs to be confirmed by positive interferon gamma (IFN-γ) release assay
Patients known to be HIV-positive.
Active chronic hepatitis B or C infection.
Administration of a live, attenuated vaccine within 4 weeks before date of registration or anticipation that such a live attenuated vaccine will be required during the study and for a period of 5 months after discontinuation of atezolizumab.
Any active or history of documented autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. The following exceptions are allowed: Patients with autoimmune-related hypothyroidism or type 1 diabetes mellitus who are on stable treatment
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis per chest CT scan at screening.
Patients with uncontrolled asthma or allergy, requiring systemic steroid treatment.
Regular treatment with corticosteroids within the 4 weeks prior to date of registration, unless administered for indications other than NHL at a dose equivalent to < 30 mg/day prednisone/prednisolone.
Serious underlying medical conditions, which could impair the ability of the patient to participate in the trial (e.g. ongoing infection, uncontrolled diabetes mellitus, gastric ulcers, active autoimmune disease)
Current participation in another clinical trial interfering with this trial
History of active cancer during the past 5 years, except basal cell carcinoma of the skin, stage 0 cervical carcinoma or carcinoma in situ (for which no systemic treatment was indicated)
Life expectancy < 6 months
Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule
Prior treatment with atezolizumab, or anti PD-1 or PDL-1 antibodies.
Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA4 therapeutic antibodies.
Treatment with systemic immunostimulatory agents (including but not limited to IFN, interleukin [IL]-2) within 6 weeks or 5 half-lives of the drug, whichever is shorter, prior to date of registration.
Treatment with systemic immunosuppressive medications, including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor (anti-TNF) agents within 2 weeks prior to date of registration; inhaled corticosteroids and mineralocorticoids are allowed.