The rationale and primary objective is to evaluate the feasibility of adding induction and
maintenance Avelumab into the standard Rituximab, Cyclophosphamide, Doxyrubicin, Vincristine
and Prednisolone (RCHOP) regimen in order to examine the effect of programmed death-ligand
1(PDL1) inhibition in patients with stage II, III and IV DLBCL.
• Immune related toxicity which requires discontinuation of Avelumab.
- Response rates (according to the Lugano classification for Response Criteria for
- Failure free survival;
- Overall survival;
- Overall toxicity of treatment (according to CTCAE v 4.0).
All patients (n=28) will receive Avelumab and rituximab 2 weekly for 2 cycles, then RCHOP
chemotherapy 3 weekly for 6 cycles then Avelumab 2 weekly for 6 cycles.
The sequential treatment schedule has been designed for several reasons: concurrent Avelumab
and RCHOP might result in reduced efficacy of Avelumab owing to the high dose prednisolone
component of RCHOP; immune related toxicities of Avelumab given concurrently with RCHOP might
result in chemotherapy dose delays and reduced chemotherapy efficacy; the Avelumab plus
rituximab prephase will allow for the preliminary assessment of nonchemotherapy agents
Avelumab plus rituximab in treatment naïve patients.
- Patients will be reviewed at baseline and prior to each cycle of treatment for toxicity
- Positron emission tomography-computed tomography (PET/CT) will be performed at baseline,
after induction phase, after cycle 2 RCHOP, at end of Avelumab (Av) RCHOP and at end of
maintenance phase Avelumab.
- Following completion of treatment, patients will be followed up for a total of 5 years
(at 3,6,9,12,18,24,36,48 and 60 months posttreatment). No formal routine imaging will be
performed during follow up. In patients with relapse, follow up only for survival will
be every 3 months.
1. Male or Female subjects aged 18 years.
2. Histologically proven CD20-positive diffuse large B cell non-Hodgkin lymphoma (DLBCL)
according to the current World Health Organization classification including all
3. No previous treatment for lymphoma including chemotherapy, radiotherapy or other
4. Stage II, III and IV disease (Ann Arbor criteria) (must be able to undergo PET/CT
imaging for staging purposes.)
5. Eastern Collaborative Oncology Group performance status 0, or 1, unless attributable
to lymphoma in which case patients of performance status 2 are also eligible.
6. Adequate bone marrow function with platelets > 100x109/l; neutrophils > 1.5x109/l at
the time of study entry unless attributed to bone marrow infiltration by lymphoma.
7. Adequate renal function defined by an estimated creatinine clearance ≥ 30 mL/min
according to the Cockcroft-Gault formula (or local institutional standard method)
8. Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × the upper limit
of normal (ULN) range and aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) levels ≤ 2.5 × upper limit of institutional normal range unless
attributed to lymphoma.
9. Patients must have an acceptable left ventricular ejection fraction (LVEF) i.e. within
the local normal range for multigated acquisition scan (MUGA) or ≥ 45% on
10. No concurrent uncontrolled medical condition as determined by the investigator.
11. Life expectancy > 3 months.
12. Negative blood pregnancy test at screening for women of childbearing potential.
Effective contraception for both male and female subjects if the risk of conception
13. Signed written informed consent before any trial-related procedure is undertaken that
is not part of the standard patient management.
1. T-cell lymphoma, transformed follicular lymphoma, grade 3B Follicular lymphoma.
2. Previous history of treated or non-treated indolent lymphoma. However, patients not
previously diagnosed with an indolent lymphoma, who have diffuse large B-cell lymphoma
with some small cell infiltration in bone marrow or lymph node may be included after
consultation with the sponsor.
3. Central nervous system, meningeal or spinal cord involvement by lymphoma.
4. Prior therapy with any antibody or drug targeting T-cell coregulatory proteins (immune
checkpoints) such as PD-1, PD-L1, or cytotoxic T-lymphocyte antigen-4 (CTLA-4).
5. Patients with active autoimmune disease that might deteriorate when receiving an
i) Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not
requiring immunosuppressive treatment are eligible ii) Subjects requiring hormone
replacement with corticosteroids are eligible if the steroids are administered only for the
purpose of hormonal replacement and at doses ≤ 10 mg or 10 mg equivalent prednisone per day
iii) Administration of steroids through a route known to result in a minimal systemic
exposure (topical, intranasal, intro-ocular, or inhalation) is acceptable.
f) Subjects with a condition requiring systemic treatment with either corticosteroids (> 15
mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of
study drug administration. Inhaled or topical steroids, and adrenal replacement doses > 15
mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
g) Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI-CTCAE v
4.03), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of
partially controlled asthma) h) Past history of interstitial lung disease. i) Prior organ
transplantation, including allogeneic stem-cell transplantation j) Prior malignancy active
within the previous 3 years except for locally curable cancers that have been apparently
cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma
in situ of the prostate, cervix, or breast.
k) Neurological contra-indication to vincristine (e.g. pre-existing diabetic neuropathy
>grade 1) l) Major surgery for any reason, except diagnostic biopsy, within 4 weeks of
enrolment and/or if the subject has not fully recovered from the surgery within 4 weeks of
enrolment m) Any other serious active disease, including but not limited to; i) pregnancy
or lactation, ii) clinically significant (i.e., active) cardiovascular disease: cerebral
vascular accident/stroke (< 6 months prior to enrolment), myocardial infarction (< 6 months
prior to enrolment), unstable angina pectoris, congestive heart failure (New York Heart
Association Classification Class ≥ II), or serious cardiac arrhythmia requiring medication
(including QTc prolongation of > 470 ms and/or pacemaker) or prior diagnosis of congenital
long QT syndrome.
iii) or, uncontrolled active infection, iv) or, uncontrolled diabetes (e.g., hemoglobin A1c
≥ 8%) n) Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS), Hepatitis B virus (HBV) or hepatitis C virus
(HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody
screening test positive) o) Medical or psychiatric conditions that compromise the patient's
ability to give informed consent.