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.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

28 Aug 2018 → ongoing

Decision date (initial)

2023-02-10

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Roche

External identifiers

EU CT number

2022-501076-26-00

EudraCT number

2017-002605-35

ClinicalTrials.gov

NCT03463057

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

To evaluate the 2-year DFS for patients in complete metabolic remission after R-CHOP induction.

Secondary objectives 7

1. To evaluate toxicity and assess the relation of adverse events in time to recovery of the T-cell repertoire
2. To evaluate the 2-year OS.
3. To evaluate MRD status at the end of induction therapy, during consolidation treatment and at the end of consolidation.
4. To evaluate the recovery of the T-cell and NK cell repertoire after induction therapy and during consolidation treatment in relation to toxicity and efficacy.
5. To explore 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.
6. To explore the tumor characteristics and mutational dynamics in patients who relapse.
7. To assess the crossing of the blood-brain barrier of atezolizumab by measuring atezolizumab concentrations in het cerebrospinal fluid.

Conditions and MedDRA coding

high risk diffuse large B-cell lymphoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Age 18-75 (inclusive) years
2. 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.
3. Ann Arbor stages II-IV.
4. WHO performance status 0 – 1.
5. IPI >=3 at diagnosis.
6. 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.
7. Negative pregnancy test at study entry.
8. Patient is willing and able use adequate contraception during and until 5 months after the last protocol treatment.
9. Written informed consent.
10. Patient is capable of giving a written informed consent.

Exclusion criteria 29

1. 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
2. Clinical signs of severe pulmonary dysfunction.
3. Clinical signs of heart failure (NYHA classification II-IV)
4. Symptomatic coronary artery disease or cardiac arrhythmias not well controlled with medication.
5. Myocardial infarction during the last 6 months.
6. 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])
7. Inadequate hematological function: hemoglobin < 5.5 mmol/L ANC < 1.0x109/L or platelets < 75x109 /L.
8. Signs or known history of bleeding disorder.
9. Significant hepatic dysfunction (total bilirubin ≥ 1.5x upper limit of normal (ULN) or transaminases ≥ 2.5 x ULN), unless related to Gilberts syndrome.
10. Clinical signs of severe cerebral dysfunction.
11. 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.
12. Major surgery within the last 4 weeks
13. 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
14. Patients known to be HIV-positive.
15. Active chronic hepatitis B or C infection.
16. 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.
17. 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
18. 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.
19. Patients with uncontrolled asthma or allergy, requiring systemic steroid treatment.
20. 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.
21. 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)
22. Current participation in another clinical trial interfering with this trial
23. 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)
24. Life expectancy < 6 months
25. Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule
26. Prior treatment with atezolizumab, or anti PD-1 or PDL-1 antibodies.
27. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA4 therapeutic antibodies.
28. 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.
29. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Disease free survival measured from the date of registration to relapse or death from any cause whichever comes first.

Secondary endpoints 6

1. (Severe) Adverse Events and the relation of adverse events in time to the recovery of the T-cell repertoire.
2. Overall survival, calculated from registration until death from any cause. Patients still alive or lost to follow up are censored at the last date known to be alive.
3. The relationship between MRD status at the end-of-induction and endof- consolidation therapy.
4. The relation between MRD conversion and 2-years DFS and OS.
5. The relationship between T-cell repertoire, PDL1/HLA expression, mutational load, gene immune signature, microbiome and effect of atezolizumab on MRD conversion.
6. The relation between the T-cell and NK cell repertoire and adverse events.

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Sponsor organisation

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Address

Dr. Molewaterplein 40

City

Rotterdam

Postcode

3015GD

Country

Netherlands

Scientific contact point

Organisation

Haemato Oncology Foundation For Adults Netherlands (HOVON)

Contact name

Dr. M. Nijland

Public contact point

Organisation

Haemato Oncology Foundation For Adults Netherlands (HOVON)

Contact name

HOVON Data Center

Third parties 5

Locations

2 EU/EEA countries · 31 investigational sites

By country

Investigational sites

Country notifications

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

Application history

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