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Diffuse Large B Cell LymphomaPhase 1RaDDNCT03610061

A Trial of Radiotherapy and Durvalumab in DLBCL and FL

A Phase 1 study testing Durvalumab, Radiotherapy and Radiotherapy (cohort 6 only) in people with Diffuse Large B Cell Lymphoma and Follicular Lymphoma, run by Austin Health at 3 sites in Australia.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Durvalumab, Radiotherapy and Radiotherapy (cohort 6 only)
Could I receive a placebo?
No, everyone receives an active treatment
How many people
34 participants
Where
3 sitesAustralia
Study dates
1 Nov 2018to 8 Apr 2024
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Male or Female subjects aged 18 years weighing more than 30 kg
  • 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.
  • 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.
  • 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.
  • Eastern Collaborative Oncology Group performance status 0, or 1, unless attributable to lymphoma in which case patients of performance status 2 are also eligible.
  • 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.
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  • 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.
  • 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.
  • Adequate renal function defined by an estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method).
  • 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.
  • No concurrent uncontrolled medical condition as determined by the investigator.
  • Life expectancy > 3 months.
  • 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.) n) Signed written informed consent before any trial-related procedure is undertaken that is not part of the standard patient management.

Who cannot join

  • T-cell lymphoma, Hodgkin lymphoma.
  • Central nervous system, meningeal or spinal cord involvement by lymphoma.
  • 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).
  • Patients with active autoimmune disease that might deteriorate when receiving an immunostimulatory agent:
  • 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.
  • 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 premedication)
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  • .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
  • 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.
  • 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.
  • 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.
  • Subject is pregnant, lactating or unwilling/unable to use adequate contraception p) Subject weighs less than 30kg

Trial locations and contacts

3 sites in 1 country.

Australia3 sites

  • Princess Alexandra Hospital

    Brisbane, Queensland, 4000

  • Monash Health

    Clayton, Victoria

  • Austin Health

    Heidelberg, Victoria, 3084

Other trials in Australia

About this study

Official title: Phase I Dose Escalation Study of Radiotherapy and Durvalumab in Relapsed/Refractory Diffuse Large B-cell Lymphoma (DLBCL) and Follicular Lymphoma (FL): The RaDD Study

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 or FL.

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.

Read the detailed description

Diffuse large B cell lymphoma (DLBCL) and Follicular Lymphoma (FL) are the most common non Hodgkin lymphomas. Standard first line treatment achieves cure in approximately half of patients. However 30% die from relapsed lymphoma.

Durvalumab (an antibody which blocks programmed cell death ligand 1) and other immunotherapies fight cancer by blocking barriers to immune system activity. Immune control of lymphoma provides the prospect of cure, even when chemotherapy has failed. Radiotherapy has striking effects on the immune system and can boost responses to these immunotherapies. The effect of concurrent radiotherapy and durvalumab in DLBCL and FL is unproven.

This study will evaluate the safety and effect of simultaneous radiotherapy plus durvalumab (a PD-L1 inhibitor) in relapsed DLBCL and FL patients.

Being tested
Durvalumab, Radiotherapy, Radiotherapy (cohort 6 only)
Medical subject headings
Lymphoma, Large B-Cell, Diffuse, Lymphoma, Follicular

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • DurvalumabDrug

    Also called MEDI4736

    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.

  • RadiotherapyRadiation

    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.

  • Radiotherapy (cohort 6 only)Radiation

    Cohort 6 patients (only) will receive:

    Day 8-Day 10: External Beam Radiotherapy to target site(s)- daily (ie. 5 further fractions to a total of 10 fractions)

Study groups in NCT03610061
Study groupRoleWhat they receive
Radiotherapy plus DurvalumabExperimentalA 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.
Receives: Drug: Durvalumab; Radiation: Radiotherapy; Radiation: Radiotherapy (cohort 6 only)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: First 28 days of treatment

Secondary outcomes (3)

  1. Response rates (according to the Lugano classification for Response Criteria for Non-Hodgkin Lymphoma)

    Response rates

    Measured: 0-12 months

  2. Progression free survival

    Progression free survival in patients who cease treatment due to toxicity.

    Measured: From ceasing treatment annually up to 5 years

  3. Overall survival

    Overall survival

    Measured: Every 6 months from PD up to two years.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 Aug 2018
  2. Study start1 Nov 2018
  3. Primary completion5 Apr 2023
  4. Study completion8 Apr 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Sequential
Model description
Dose Escalation
Masking
None (open label)
Enrolment
34 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03610061
Sponsor's protocol ID
ONJ2017-003-DV-008259
Other IDs
TRP16-006
Acronym
RaDD
Status last verified
Apr 2024
First submitted
14 Nov 2017
Last updated
12 Apr 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Undecided: IPD is the property of the Sponsor (Olivia Newton John Cancer Research Institute). Results from the research intends to be published/presented in relevant publications/conferences for colleague review

Publications

  • Hawkes EA, Palmer JB, Khor R, Lee ST, Burgess M, Law SC, Gandhi MK, Chong G, Shortt J, Chowdhury R, Swain F, Churilov L, MacManus M, Smith C, Scott FE, Martynchyk A, Barraclough A, Manos K, Scott AM, Keane C. T-cell dysregulation informs radiotherapy-immunotherapy response in B-cell lymphoma: results from a phase 1 trial. Blood Adv. 2025 Oct 28;9(20):5263-5273. doi: 10.1182/bloodadvances.2025016505.

    PubMed 40540795

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Durvalumab, Radiotherapy and Radiotherapy (cohort 6 only) in people with Diffuse Large B Cell Lymphoma and Follicular Lymphoma, run by Austin Health at 3 sites in Australia.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 14 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 12 Apr 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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). (time frame: First 28 days of treatment). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03610061, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Apr 2024.

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