Rituximab is a chimeric mouse/human monoclonal antibody that binds to CD20, on pre-B and
mature B lymphocytes and eliminates these cells potentially via a number of different
mechanisms.
The R-GemOx regimen has been adopted by many sites internationally as therapy for older
patients or comorbid patients with relapsed or refractory DLBCL and as a back-bone for the
investigation of novel therapies in combination with chemotherapy.
The cytotoxic T-lymphocyte co-receptor PD-1 has been extensively studied and is recognised to
provide critical inhibitory signals that down-regulate T-cell function and provides a
mechanism for immune evasion for tumours. PD-L1, the ligand of PD-1 is expressed on DLBCL
tumour cells, along with infiltrating non-malignant cells, primarily macrophages, with PD-1
expressed on tumour infiltrating lymphocytes (TILs). Atezolizumab targets programmed PD-L1 on
immune and tumour cells and prevents interaction with either PD-1 receptor or B7.1 (CD80),
both of which function as inhibitory receptors expressed on T cells. Interference of the
PD-L1:PD-1 and PDL1:B7.1 interactions may enhance the magnitude and quality of the
tumour-specific T-cell response through increased T-cell priming, expansion, and/or effector
function.
This study of atezolizumab in combination with rituximab, gemcitabine and oxaliplatin aims to
address the unmet need of patients with relapsed and refractory DLBCL. It is based upon a
sound mechanistic approach, investigating the activity of novel agents and will aim to
compressively explore biomarkers of response.
The primary objective will be to document the durability of anti-tumour activity in patients
with relapsed or refractory DLBCL and to determine the safety and toxicity profile of the
combination. A maintenance phase of atezolizumab has been added as this may induce an
on-going T-cell response to neo-antigens released as a result of chemotherapy.
Inclusion Criteria:
- Histologically proven CD20 +ve diffuse large B-cell lymphoma with sufficient
diagnostic material, obtained either at diagnosis or relapse (the latter is
preferable) that is available to forward to the Haematological Malignancies Diagnostic
Service (HMDS) for gene expression profiling and central pathology review. (See
screening procedure for details on biopsy requirements)
- Refractory to, or relapsed following, first-line or second-line treatments with
rituximab concurrently with anthracycline or anthracenedione-based chemotherapy
(etoposide or gemcitabine allowed if comorbid).
Refractory disease must fulfil one of the following:
- Continuing partial response (PR) from termination of first-line treatment. It is
strongly recommended the lymphoma be reconfirmed by biopsy however, if these
procedures are deemed to be inappropriate, the CI may determine eligibility following
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 not mandatory.
- Progressive disease (PD). Biopsy or reconfirmation of the lymphoma is recommended but
not mandatory.
o Not eligible for high-dose therapy with peripheral blood progenitor cell rescue at
Investigator discretion as a result of:
- Age
- Co-morbidity
- Previous HDT. Rationale to be clearly documented on eCRF and medical notes.
- Baseline FDG-PET scans must demonstrate positive lesions compatible with CT
defined anatomical tumour sites.
- CT/PET scan showing at least:
- 2 or more clearly demarcated lesions/nodes with a long axis >1.5cm and short axis
≥1.0cm OR
- 1 clearly demarcated lesion/node with a long axis >2.0cm and short axis ≥1.0cm.
- Resolution of toxicities from previous therapy to a grade that in the opinion of
the investigator does not contraindicate study participation.
- Patients aged 16 years or over.
- Willingness to participate in appropriate pregnancy prevention measures.
- Female patients who are fertile and of childbearing potential must have a negative
serum or urine pregnancy test during screening (within 14 days prior to the start of
trial treatment) and agree to use two highly effective forms of contraception (oral,
injected or implanted hormonal contraception and condom; an intra-uterine device and
condom) effective from the first administration of all study drugs, throughout the
trial and for 12 months after last dose of study therapy are considered eligible.
Unless they are surgically sterile or ≥ 2 years after the onset of menopause.
- Male patients with partners of child-bearing potential who agree to take measures not
to father children by using one form of highly effective contraception (oral, injected
or implanted hormonal contraception and condom; an intra-uterine device and condom)
effective from the first administration of all study drugs, throughout the trial and
for 12 months after last dose of study therapy are considered eligible. Male subjects
must also refrain from donating sperm during this period. Unless they are surgically
sterile.
- Men with pregnant or lactating partners must be advised to use barrier method
contraception (for example: condom plus spermicidal gel) to prevent exposure to the
foetus or neonate
- Written informed consent using current version of Protocol, Patient Information
Sheet and Informed Consent Form.
- ECOG performance status ≤3
Exclusion Criteria:
- Received any of the following treatments within two weeks prior to start of study
therapy (unless otherwise stated):
- Anti-cancer cytotoxics (excluding corticosteroids)
- Radiotherapy unless it is to a limited field to control life/organ-threatening
symptoms.
- DLBCL that is refractory to or relapsed within 3 months of a gemcitabine regimen for
DLBCL
- Major surgery within 4 weeks of registration.
- Treatment with any known non-marketed drug substance or experimental therapy within 5
terminal half-lives or 4 weeks prior to registration.
- History of stroke or intracranial haemorrhage within 6 months prior to registration.
- Pre-existing peripheral neuropathy grade >2.
- Clinically significant cardiac disease including unstable angina, acute myocardial
infarction within six months prior to registration, congestive heart failure (NYHA
III-IV), a current LVEF of <40%
- Significant concurrent, uncontrolled medical condition that in the opinion of the
investigator contraindicates participation in this study
- Known lymphoma involvement of the CNS.
- Known or suspected hypersensitivity to study treatments that in the opinion of the
investigator contraindicates their participation. Patients with known history of
idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans),
drug induced pneumonitis or idiopathic pneumonitis, or evidence of active pneumonitis
will be excluded from study participation.
- Known HIV positivity; positive serology for Hep B (defined as positivity for Hepatitis
B surface antigen (HBsAg) or Hepatitis B core antibody (anti-HBc)) or C; chronic or
current infectious disease (except evidence of prior vaccination).
- Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection or
any major episode of infection requiring treatment with IV antibiotics or
hospitalization within 2 weeks of the start of Cycle 1. Suspected active or latent
tuberculosis needs to be confirmed by positive interferon gamma (IFN-gamma) release
assay.
- Other past or current malignancy within 2 years prior to registration unless in the
opinion of the investigator it does not contraindicate participation in the study.
Subjects who have a history of completely resected non-melanoma skin cancer, or
successfully treated in situ carcinoma, are eligible.
- 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 unless creatinine
clearance >60mL/min (should be calculated using Cockcroft and Gault equation))
- total bilirubin >1.5 times upper normal limit (unless due to lymphoma or a known
history of Gilbert's disease, no higher than >3 times upper normal limit)
- ALT/AST >2.5 times upper normal limit (unless due to lymphoma, no higher than >5 times
upper normal limit)
- alkaline phosphatase >2.5 times upper normal limit (unless due to lymphoma, no higher
than >5 times upper normal limit)
- Subjects known or suspected of being unable to comply with the study protocol.
- Pregnant or lactating women. Women of childbearing potential must have a negative
pregnancy test at screening.
- 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 antiphospholipid
syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome,
multiple sclerosis, vasculitis, or glomerulonephritis (Patients with a history of
autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone will
be eligible as will be patients with controlled Type I diabetes mellitus on a stable
dose of insulin). Patients with eczema, psoriasis, lichen simplex chronicus, or
vitiligo with dermatologic manifestations only (e.g., patients with psoriatic
arthritis are excluded) are eligible for the study provided all of following
conditions are met:
- Rash must cover <10% of body surface area
- Disease is well controlled at baseline and requires only low-potency topical
corticosteroids
- No occurrence of acute exacerbations of the underlying condition requiring psoralen
plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral
calcineurin inhibitors, or high potency or oral corticosteroids within the previous 12
months
- Patients who have previously undergone allogeneic transplantation.
- Vaccination with a live vaccine within 28 days of study treatment or anticipation of
need for such a vaccine during the course of the study and up to 5 months after the
last dose of atezolizumab.
- History of severe allergic anaphylactic reactions to chimeric, human or humanised
antibodies, or fusion proteins.
- Known hypersensitivity to CHO cell products or any component of the atezolizumab
formulation.
