Pembrolizumab in Combination With R-ICE Chemotherapy in Relapsed/Refractory Diffuse Large B-cell Lymphoma

Inclusion Criteria:

• Histologically proven CD20 +ve diffuse large B-cell lymphoma, preferably withsufficient diagnostic material, obtained either at diagnosis or relapse (the latteris preferable) that is available to forward to the Haematological MalignanciesDiagnostic Service (HMDS) for gene expression profiling and central pathology review

• Refractory to, or relapsed following, first-line or second-line treatments withrituximab concurrently with anthracycline or anthracenedione-based chemotherapy orsimilar (etoposide allowed if comorbid).

Refractory disease must fulfil one of the following:

• Continuing partial response (PR) from termination of first-line treatment. It isstrongly recommended the lymphoma be reconfirmed by biopsy however, if theseprocedures are deemed to be inappropriate, the CI may determine eligibilityfollowing review of the imaging results and disease history.

• Continuing stable disease (SD) from termination of first-line treatment.Reconfirmation of the lymphoma by biopsy (preferred) is recommended but notmandatory.

• Progressive disease (PD). Biopsy or reconfirmation of the lymphoma is recommendedbut not mandatory.

• Potentially eligible for high-dose therapy and peripheral blood progenitor cellrescue in the event of response

• Positive lesions shown on baseline PET-CT must be compatible with CT definedanatomical tumour sites.

• At least 2 demarcated lesions/nodes with a long axis >1.5 cm and a short axisequal to 1.0cm or 1 clearly demarcated lesion/node with a long axis >2.0cm andshort axis of 1.0cm

• Previous therapy related toxicity should have resolved to a grade that theinvestigator deems appropriate to commence further treatment

• ECOG Performance Status 0 - 1

• Has provided written informed consent

• Willing to use acceptable contraception (see Section 4.6)

• Aged 18 or over

Exclusion Criteria:

• Previous lymphoma cancer treatment beyond third line

• Radiotherapy or cytotoxic drugs within two weeks of trial treatment

• Major surgery within 4 weeks of trial registration. If a subject had major surgery,more than 4 weeks ago, they must have recovered adequately from any toxicity and/orcomplications from the intervention before the first dose of study drug.

• Treatment with any unlicensed drug within 4 weeks of trial treatment

• History of stroke or intracranial haemorrhage within 6 months prior to registration

• Pre-existing peripheral neuropathy grade >2

• Clinically significant cardiac disease (inc. unstable angina, acute myocardialinfarction, congestive heart failure, a current LVEF of <40%) within 6 months ofregistration

• Any significant uncontrolled medical condition or known hypersensitivity to thestudy drugs

• Chronic or current infectious disease requiring systemic antibiotics, antifungal, orantiviral treatment such as, but not limited to, chronic renal infection, chronicchest infection with bronchiectasis and tuberculosis.

• Other past or current malignancy within 2 years prior to registration unless in theopinion of the investigator it does not contraindicate participation in the study.Subjects who have a history of completely resected non-melanoma skin cancer, orsuccessfully treated in situ carcinoma, are eligible

• Known CNS involvement

• Serological positivity for Hepatitis B, C, or known HIV infection. As per standardof care, prior to initiation of immunochemotherapy, the results of hepatitisserology should be known prior to commencement of therapy.

Positive test results for chronic HBV infection (defined as positive HBsAg serology) will not be eligible.

Patients with occult or prior HBV infection (defined as negative HBsAg and positive total HBcAb) will not be eligible.

Patients who have protective titres of hepatitis B surface antibody (HBsAb) after vaccination will be eligible.

Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA

• Screening laboratory values :

• platelets <75x109/L (unless due to lymphoma involvement of the bone marrow)

• neutrophils <1.0x109/L (unless due to lymphoma involvement of the bone marrow)

• creatinine >2.0 times upper normal limit (unless due to lymphoma or unlesscreatinine clearance >50mL/min)

• total bilirubin >1.5 times upper normal limit (unless due to lymphoma or aknown history of Gilbert's disease)

• ALT/AST >2.5 times upper normal limit (unless due to lymphoma)

• alkaline phosphatase >2.5 times upper normal limit (unless due to lymphoma)

• History of autoimmune disease, including but not limited to myasthenia gravis,myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,inflammatory bowel disease, vascular thrombosis associated with antiphospholipidsyndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome,multiple sclerosis, vasculitis, or glomerulonephritis (Patients with a history ofautoimmune-related hypothyroidism on a stable dose of thyroid replacement hormonewill be eligible as will be patients with controlled Type I diabetes mellitus on astable dose of insulin).

• Patients who have previously undergone allogeneic transplantation.

• Live vaccination within 28 days of study treatment.

• Pregnant or lactating females. Women of child-bearing potential should have negativepregnancy test.

• History of severe allergic anaphylactic reactions to chimeric, human or humanisedantibodies, or fusion proteins.

• History of (non-infectious) pneumonitis that required steroids or has currentpneumonitis.

• Known hypersensitivity to CHO cell products or any component of the pembrolizumabformulation.

• Previous treatment with an anti-PD-1, anti-PD-L1 or anti-PD-L2 agent or with anagent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4,OX 40, CD137).

• Corticosteroid use >10 mg/day of prednisolone or equivalent, for purposes other thanfor lymphoma symptom control.

Patients receiving corticosteroid treatment with <10 mg/day of prednisolone or equivalent must be documented to be on a stable dose of at least 4 weeks' duration prior to the start of Cycle 1. If glucocorticoid treatment is urgently required for lymphoma symptom control prior to the start of study treatment, prednisolone 100 mg or equivalent could be given for a maximum of 14 days as a pre-phase. A dose of up to 10mg or prednisolone or equivalent may be used during the screening phase to control symptoms.