The primary objective for this study is to determine the safety profile of radiotherapy and
durvalumab, a PD-L1 inhibitor.
Toxicity, drug pharmacokinetics (PK), maximum tolerated dose (MTD) and recommended phase two
dose (RPTD) of simultaneous radiotherapy plus durvalumab in patients with relapsed or
refractory DLBCL or FL.
- Progression-free survival
- Overall survival
Exploratory endpoints include description of biological effects of combination radiotherapy
plus durvalumab (Imaging results, immune function, PK and PD-see 'research methodologies')
and in the PET-Sub-Study, biodistribution of 89Zr Durvalumab and 89Zr-IAB22M2C.
1. Male or Female subjects aged 18 years weighing more than 30 kg
2. Histologically proven CD20-positive relapsed or refractory diffuse large B cell
non-Hodgkin lymphoma (DLBCL) either de novo or DLBCL transformed from any indolent
B-non-Hodgkin lymphoma (including Richter's transformation) Or follicular lymphoma
grade 1-3A, or Grade 3B, according to the current World Health Organization
classification on tissue biopsy. Archived tissue is permitted however must have been
obtained after the last known therapy. The Trial Management Group retains the option
to limit the number of participants enrolled with a specific histology.
3. At least 1 line of previous treatment for lymphoma which must include a CD20
monoclonal antibody such as rituximab, with no curative option as determined by the
investigator. Prior radiotherapy is permitted.
4. Patients with DLBCL must not be eligible or willing to receive high-dose
(myeloablative) chemotherapy (HDC) and autologous stem cell transplant (ASCT) OR has
received prior ASCT.
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. Patients must have measurable disease (at least one bi-dimensionally measurable site
of disease that has not been previously irradiated OR has progressed after
radiotherapy: nodal disease >1.5 cm or an extranodal lesion > 1.0 cm in longest
perpendicular diameter). At least three disease sites must be FDG-avid on PET imaging
AND amenable to radiotherapy according to local radiation oncology investigator
7. One site of disease must be amenable to biopsy. It is preferable that this is a site
not planned for radiotherapy, but not mandated. A fresh tumor biopsy collected during
screening and /or archival tumor tissue collected after the last relapse/disease
progression (material which has been collected before the last line of treatment is
not accepted). In addition, a sufficient amount of the material is required for
acceptance of the archival material. If neither condition occurs, a fresh tumor biopsy
needs to be performed as stated above.
8. Adequate bone marrow function with platelets > 50 x109/l; neutrophils > 1.0x109/l at
the time of study entry unless attributed to bone marrow infiltration by lymphoma.
9. Adequate renal function defined by an estimated creatinine clearance ≥ 30 mL/min
according to the Cockcroft-Gault formula (or local institutional standard method).
10. Adequate hepatic function defined by a total bilirubin level ≤ 2 × the upper limit of
normal (ULN) range (excluding Gilbert's disease where a level of ≤ 3 ×ULN is
acceptable) and AST and alanine aminotransferase (ALT) levels ≤ 2.5 × upper limit of
institutional normal range unless attributed to lymphoma.
11. No concurrent uncontrolled medical condition as determined by the investigator.
12. Life expectancy > 3 months.
13. Negative blood pregnancy test at screening for women of childbearing potential.
Effective contraception for both male and female subjects if the risk of conception
(Note: The effects of the trial drug on the developing human fetus are unknown; thus, women
of childbearing potential and men must agree to use effective contraception, defined as 2
barrier methods, or 1 barrier method with an intrauterine device, or use of oral female
contraceptive. Should a woman become pregnant or suspect she is pregnant while she or her
partner is participating in this trial, the treating physician should be informed
immediately. Effective contraception at least 30 days prior and up to 3 months after
treatment is required for all women of childbearing potential and male subjects will be
advised not to father a child during the 3 months after treatment completion. Male subjects
will be requested to seek advice on conservation of sperm prior to treatment.) n) Signed
written informed consent before any trial-related procedure is undertaken that is not part
of the standard patient management.
1. T-cell lymphoma, Hodgkin lymphoma.
2. Central nervous system, meningeal or spinal cord involvement by lymphoma.
3. 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).
4. 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.
e) Current or prior use of immunosuppressive medication within 14 days before the first
dose of durvalumab. The following are exceptions to this criterion: i. Intranasal, inhaled,
topical steroids, or local steroid injections (e.g., intra articular injection) ii.
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisolone or
its equivalent iii. Steroids as premedication for hypersensitivity reactions (e.g., CT scan
.iv.Patients requiring steroids for symptom control during the screening period may receive
a single course of prednisolone at a dose of up to 100mg daily (or equivalent) for a
maximum of 5 days at the discretion of the local PI. Steroids must not be given within 5
days of radiotherapy. Note that steroids are optimally avoided due to the potential for
reduction in durvalumab activity
f) 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) g) Past history of interstitial lung disease. h) Prior organ
transplantation, including allogeneic stem-cell transplantation i) Prior malignancy active
within the previous 2 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.
j) 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
k) Any other serious active disease, including but not limited to; i) 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.
ii) uncontrolled active infection, iii) uncontrolled diabetes (e.g., haemoglobin A1c ≥
8.5%) l) 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) m) Medical or psychiatric conditions that compromise the patient's
ability to give informed consent.
o) Subject is pregnant, lactating or unwilling/unable to use adequate contraception p)
Subject weighs less than 30kg