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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT03610061




Registration number
NCT03610061
Ethics application status
Date submitted
14/11/2017
Date registered
1/08/2018
Date last updated
15/01/2019

Titles & IDs
Public title
A Trial of Radiotherapy and Durvalumab in DLBCL
Scientific title
Phase I Dose Escalation Study of Radiotherapy and Durvalumab in Relapsed/Refractory Diffuse Large B-cell Lymphoma (DLBCL): The RaDD Study
Secondary ID [1] 0 0
TRP16-006
Secondary ID [2] 0 0
ONJ2017-003-DV-008259
Universal Trial Number (UTN)
Trial acronym
RaDD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Diffuse Large B Cell Lymphoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Durvalumab
Treatment: Other - Radiotherapy

Experimental: Radiotherapy plus Durvalumab - A minimum of 3 patients will initially be enrolled in each cohort of this arm. Patients will be allocated to a radiotherapy dose and site cohort from the schedule at registration. There will be no intra-patient dose or site escalations.
Cohorts will escalate in number of anatomical sites of radiotherapy and dose of radiotherapy given subject to safety. Durvalumab will be administered at a fixed dose every 4 weeks IV.


Treatment: Drugs: Durvalumab
All patients will receive:
Day 1-Day 5: External Beam Radiotherapy to target site(s)-daily for 5 days (i.e. 5 fractions).
D2: Commence durvalumab. Continue 4-weekly until disease progression. Patients can continue until a second radiological progression if clinical benefit is ongoing.

Treatment: Other: Radiotherapy
All patients will receive:
Day 1-Day 5: External Beam Radiotherapy to target site(s)-daily for 5 days (i.e. 5 fractions).
D2: Commence durvalumab. Continue 4-weekly until disease progression. Patients can continue until a second radiological progression if clinical benefit is ongoing.

Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Treatment: Other
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Number of participants treated with radiotherapy and durvalumab with treatment-related adverse events as assessed using CTCAE v4.0. To determine the maximum tolerated dose (MTD). - A minimum of 3 patients will initially be enrolled in each cohort, if none of the first 3 patients experiences a dose limiting toxicity (DLT), the doses in that cohort will be deemed safe and tolerable and escalation may continue. DLTs will be grade 4 neutropenia or thrombocytopenia, grade 3 hemolysis, grade 4 immune related AEs.
If 1 of the first 3 evaluable patients in a cohort experiences a DLT, the cohort will be expanded to at least 6 patients. If there are no further DLTs in the first 6 DLT-evaluable patients, the doses in that cohort will be deemed safe and tolerable and escalation may continue.
If a DLT is observed in = 33% of patients (e.g., 2 or more of up to 6 patients), the dose combination at which this occurs will be considered intolerable and the MTD will have been exceeded for radiotherapy If the MTD is exceeded in any cohort, the highest dose combination at which fewer than 33% experience a DLT will be declared the combination MTD.
Timepoint [1] 0 0
First 28 days of treatment
Secondary outcome [1] 0 0
Response rates (according to the Lugano classification for Response Criteria for Non-Hodgkin Lymphoma) - Response rates
Timepoint [1] 0 0
0-12 months
Secondary outcome [2] 0 0
Progression free survival - Progression free survival in patients who cease treatment due to toxicity.
Timepoint [2] 0 0
From ceasing treatment annually up to 5 years
Secondary outcome [3] 0 0
Overall survival - Overall survival
Timepoint [3] 0 0
Every 6 months from PD up to two years.

Eligibility
Key inclusion criteria
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 follicular
lymphoma, according to the current World Health Organization classification26 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 transformed FL.

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. Not eligible or not 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
review.

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
exists.

(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.)

14. Signed written informed consent before any trial-related procedure is undertaken that
is not part of the standard patient management.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. T-cell lymphoma, grade 3B Follicular 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
immunostimulatory agent:

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) 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.

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

Study design
Purpose of the study
Treatment
Allocation to intervention
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD,VIC
Recruitment hospital [1] 0 0
Princess Alexandra Hospital - Brisbane
Recruitment hospital [2] 0 0
Austin Health - Heidelberg
Recruitment postcode(s) [1] 0 0
4000 - Brisbane
Recruitment postcode(s) [2] 0 0
3084 - Heidelberg

Funding & Sponsors
Primary sponsor type
Other
Name
Austin Health
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Olivia Newton-John Cancer Research Institute
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Commercial sector/Industry
Name [2] 0 0
AstraZeneca
Address [2] 0 0
Country [2] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
The primary objective for this study is to determine the safety profile of radiotherapy and
durvalumab, a PD-L1 inhibitor.

Primary endpoint:

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.

Secondary endpoints:

- ORR

- 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.
Trial website
https://clinicaltrials.gov/show/NCT03610061
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Eliza Hawkes, MD
Address 0 0
Austin Health
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Eliza Hawkes, MD
Address 0 0
Country 0 0
Phone 0 0
+61 3 94965763
Fax 0 0
Email 0 0
eliza.hawkes@onjcri.org.au
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT03610061