First-line Treatment of P53 Mutation With PD-L1 Expression in DLBCL With Anti-PD-1 Mab and R-CHOP

Official title

First-line Treatment of P53 Mutation With PD-L1 Expression in DLBCL With Anti-PD-1 Mab and R-CHOP: a Randomized, Open, Multicenter Clinical Study

Overview

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma。The majority of refractory patients have PD-L1 expression due to P53 mutations, some of which account for about 10% of DLBCL.Our department has found that in refractory DLBCL with high PD-L1 expression, cedilizumab monotherapy is also more effective and has reversed chemotherapy resistance.The aim of this study was to determine whether the addition of sindilizumab to the R-CHOP regimen could improve the objective efficiency of DLBCL patients with P53 mutation with PD-L1 expression and to see if it could prolong patient survival.

Detailed description

This study is a randomized, open, multicenter clinical study to determine whether the addition of sindilizumab to the R-CHOP regimen could improve the objective efficiency of DLBCL patients with P53 mutation with PD-L1 expression and to see if it could prolong patient survival.In this study, patients with P53 mutation with PD-L1 expressing DLBCL were selected to be randomised 1:1 into 2 groups: group A Sindilizumab + R-CHOP and group B R-CHOP. Sindilizumab was administered on day 10 after chemotherapy to avoid interference from prednisone.At the end of 6 cycles, Group A treatment effective maintenance treatment with Sindilizumab for 6 months as indicated.Each patient's tumour tissue was tested for mutations and ctDNA after allocation, and ctDNA and peripheral blood free PD-L1 levels were monitored dynamically during and after treatment.

Interventions

• Drug Sintilimab
  After one cycle of standard R-CHOP chemotherapy, Group A uses Sintilimab with R-CHOP, with Sintilimab administered on day 10 post-chemotherapy, scheduled for 5 cycles. After 5 cycles CR patients in group A continue Sindilizumab treatment for 8 times, once every 21 days.
• Drug Rituximab
  After one cycle of standard R-CHOP chemotherapy, Group B uses R-CHOP for 5 cycles. After 5 cycles, CR patients in group B are followed up for observation.

Primary outcome measures

• CRR [Time frame: 1 year]

Secondary outcome measures (3)

• PFS [Time frame: 1 year]
• ORR [Time frame: 1 year]
• OS [Time frame: 1 year]

Eligibility criteria

Inclusion criteria

• Ages≥18 years, ≤ 80 years.
• Patients with primary treatment of DLBCL.
• Histopathologically confirmed diagnosis of diffuse large B-cell lymphoma.
• At least one measurable lesion according to the 2014 Lugano criteria.
• ECOG physical status score of 0, 1 or 2.
• Laboratory tests meet the following criteria unless judged to be due to lymphoma:

• Routine blood tests: (in the absence of growth factor support therapy or blood transfusion within 7 days) haemoglobin ≥ 90 g/L, absolute neutrophil value ≥ 1.5 x 109/L, platelet count ≥ 90 x 109/L.
• Liver biochemistry: serum creatinine ≤ 1.5 x upper limit of normal; total bilirubin ≤ 1.5 x upper limit of normal; glutamate transaminase and glutamic oxalacetic transaminase ≤ 2.5 x upper limit of normal.
• Coagulation: INR and APTT ≤ 2.5 times the upper limit of normal values.
• Consent to use contraception during the trial and for 3 months after its completion.
• Expected survival ≥ 3 months.

Exclusion criteria

• Suffering from other untreated malignant tumours.
• Cardiovascular disease that remains unstable under pharmacological control .
• With severe interstitial lung disease.
• With cognitive impairment.
• Patients with uncontrolled autoimmune disease.
• Presence of uncontrolled active infection.
• Expected survival time < 3 months.
• Lactating women and subjects of childbearing age who do not wish to use contraception.
• With poor adherence or unable to follow up regularly.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Coiffier B, Thieblemont C, Van Den Neste E, Lepeu G, Plantier I, Castaigne S, Lefort S, Marit G, Macro M, Sebban C, Belhadj K, Bordessoule D, Ferme C, Tilly H. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood. 2010 Sep 23;116(12):2 PMID 20548096
• Young KH, Leroy K, Moller MB, Colleoni GW, Sanchez-Beato M, Kerbauy FR, Haioun C, Eickhoff JC, Young AH, Gaulard P, Piris MA, Oberley TD, Rehrauer WM, Kahl BS, Malter JS, Campo E, Delabie J, Gascoyne RD, Rosenwald A, Rimsza L, Huang J, Braziel RM, Jaffe ES, Wilson WH, Staudt LM, Vose JM, Chan WC, Weisenburger DD, Greiner TC. Structural profiles of TP53 gene mutations predict clinical outcome in di PMID 18559976
• McDermott DF, Atkins MB. PD-1 as a potential target in cancer therapy. Cancer Med. 2013 Oct;2(5):662-73. doi: 10.1002/cam4.106. Epub 2013 Jul 21. PMID 24403232
• Ansell SM, Minnema MC, Johnson P, Timmerman JM, Armand P, Shipp MA, Rodig SJ, Ligon AH, Roemer MGM, Reddy N, Cohen JB, Assouline S, Poon M, Sharma M, Kato K, Samakoglu S, Sumbul A, Grigg A. Nivolumab for Relapsed/Refractory Diffuse Large B-Cell Lymphoma in Patients Ineligible for or Having Failed Autologous Transplantation: A Single-Arm, Phase II Study. J Clin Oncol. 2019 Feb 20;37(6):481-489. doi PMID 30620669
• McCord R, Bolen CR, Koeppen H, Kadel EE 3rd, Oestergaard MZ, Nielsen T, Sehn LH, Venstrom JM. PD-L1 and tumor-associated macrophages in de novo DLBCL. Blood Adv. 2019 Feb 26;3(4):531-540. doi: 10.1182/bloodadvances.2018020602. PMID 30770362
• Pascual M, Mena-Varas M, Robles EF, Garcia-Barchino MJ, Panizo C, Hervas-Stubbs S, Alignani D, Sagardoy A, Martinez-Ferrandis JI, Bunting KL, Meier S, Sagaert X, Bagnara D, Guruceaga E, Blanco O, Celay J, Martinez-Baztan A, Casares N, Lasarte JJ, MacCarthy T, Melnick A, Martinez-Climent JA, Roa S. PD-1/PD-L1 immune checkpoint and p53 loss facilitate tumor progression in activated B-cell diffuse la PMID 30975638

Identifiers

NCT: NCT05280626 · CIBI308Y047

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗