ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12624001105538p

Ethics application status

Not yet submitted

Date submitted

28/08/2024

Date registered

13/09/2024

Date last updated

13/09/2024

Date data sharing statement initially provided

13/09/2024

Type of registration

Prospectively registered

Titles & IDs

Public title

Understanding the Abscopal Effect of Low-Dose Localised Radiotherapy in Follicular Lymphoma: The AFL study

Scientific title

Understanding the Abscopal Effect of Involved-Site Radiotherapy in Patients with Follicular Lymphoma Aged 40 years and over: The AFL study

Secondary ID [1]

None

Universal Trial Number (UTN)

Trial acronym

The AFL Study

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Follicular Lymphoma

Condition category

Condition code

Cancer

Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Consented patients with Follicular Lymphoma (either disease recurrence or slow growing/stable lymphoma) in more than one site of disease will receive low dose localised radiotherapy (involved-site radiotherapy or ISRT) to some (not all) of their known lymphoma disease sites at the discretion of the treating radiation oncologist.
Along with standard of care FDG-PET/CT scans prior to radiotherapy (within 60 days), a single 89Zr-durvalumab PET/CT and two (at 1-2 hours and 24 hours post 89Zr- IAB22M2C infusion) 89Zr- IAB22M2C PET/CT scans will be performed – all given over a 5-10 minute infusion and each scan will take 30-45 mins spent on the PET/CT scanner. Patients will be administered 3.0mCi/8ml of89Zr- IAB22M2C during the infusion using a syringe pump. 10 mg of unlabeled durvalumab will be infused over 30 min. After 60 min of observation, the patient will receive 89Zr-durvalumab (60 mBq/70 k up to no more than 74MBq with a concentration of 4 ug/MBq). All PET scans will be acquired according to current departmental guidelines on an integrated PET/CT. This will be reported by a qualified PET physician who will also administer these tracers. The delayed timing of PET image acquisition (4-5 days after tracer administration) is due to the long physical and physiological half-lives of the tracer, and timing.
20ml routine and study blood samples will also be taken at this timepoint. Then, ISRT will be delivered to lesions that are selected and will receive 4 Gy in 2 fractions, delivered on consecutive days. 2 weeks post ISRT, study and routine bloods will be collected along with another two 89Zr- IAB22M2C PET/CT scan’s (again 1-2 hrs and 24hrs post infusion). Lastly, at 6-8 weeks post ISRT, standard of care bloods will be collected along with standard management FDG-PET scans. Following completion of the imaging and pathology phase of the study participants will return to standard of care follow up with their radiation oncologist and/or haematologist approximately 3 months post involvement.

Intervention code [1]

Diagnosis / Prognosis

Comparator / control treatment

No control group

Control group

Uncontrolled

Outcomes

Primary outcome [1]

Composite primary outcome: Local abscopal response per lesion or nodal station on FDG-PET and overall (whole body abscopal response on FDG PET)

Timepoint [1]

Baseline (pre-treatment) and follow up FDG-PET imaging 6 weeks after ISRT

Secondary outcome [1]

Uptake of tracer in each known lymphoma site

Timepoint [1]

At baseline and 2-6 weeks post ISRT, translational bloods will be collected and CD8 and PD-L1 imaging will be assessed.

Eligibility

Key inclusion criteria

1) Eligible to receive palliative ISRT for histologically confirmed low grade (WHO grade1,2 or 3a) follicular lymphoma,
2) Requiring ISRT to local disease for palliation or prevention of local disease progression, or eligible for a “watchful waiting” approach to management
3) >2 lymphoma lesions visualized on FDG-PET scan, with FDG uptake > liver (not including spleen or bone marrow disease)
4) >1 FDG-avid lesion(s) located outside planned ISRT volume, with FDG uptake > liver (not including spleen or bone marrow disease)
5) No systemic therapy (chemo or immunotherapy) delivered in the 2 months before radiation therapy
6) No systemic therapy planned for at least 2 months after ISRT
7) Capable of giving informed consent
8) Life expectancy > 12 months
9) ECOG performance status 0-1 (or 2 if impairment is not related to lymphoma)
10) Available FFPE biopsy specimen confirming diagnosis of FL, suitable for translational studies
11) Age >40

Minimum age

40 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

1) Initial presentation of stage II disease suitable for curative intent RT
2) Any active high grade lymphoma
3) Any prior history of aggressive or transformed lymphoma
4) >2 prior systemic therapy regimens
5) Taking any immunosuppressive medication (e.g. steroids)
6) Active autoimmune disease
7) Neutropaenia (<1.0 x 109)
8) All FDG-avid disease sites are considered to be high priority for early treatment with ISRT and no lesion can safely be left untreated
9) Irradiation of a lesion selected for ISRT would inadvertently irradiate all nominally “untreated” lesions, intended for observation, to > 0.4 Gy
10) Palliative ISRT is required within 7 days for rapid symptom relief
11) Women who are pregnant or who are breastfeeding

Study design

Purpose of the study

Treatment

Allocation to intervention

Non-randomised trial

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

Single group

Other design features

Phase

Not Applicable

Type of endpoint/s

Bio-availability

Statistical methods / analysis

The primary endpoint is the abscopal regression rate. This is the proportion of patients who after ISRT experience regression of any unirradiated, previously FDG-avid lymphoma lesions, as detected on follow up FDG-PET imaging 6 weeks after ISRT. The abscopal regression rate will be assessed both per lesion/nodal station and overall per patient as follows.
Local abscopal response per lesion or nodal station on FDG-PET; Complete metabolic response (CMR) defined by a Deauville score of 1-3, Partial metabolic response (PMR) analysed by a visually appreciable reduction in FDG uptake, therefore reduction of SUV max, stable metabolic disease (SMD) or progressive metabolic disease (defined by Deauville score of 4 or 5).

Overall (whole body) abscopal response on FDG PET will also be analysed by:
Allocating patients to one of the following overall abscopal response categories based on a consideration of all disease sites in pre and post treatment FDG-PET scans.
a) Complete abscopal response: CMR in all unirradiated lesions and no new lesions
b) Partial abscopal response: at least a PMR in all unirradiated lesions but without a CMR in all unirradiated lesions and no new lesions
b) Mixed abscopal response: CMR or PMR in one or more unirradiated lesions but SMD, or PMD in any other lesion(s). May have one or more new lesions.
c) No abscopal response: No CMR or PMR in any unirradiated lesion

Recruitment

Recruitment status

Not yet recruiting

Date of first participant enrolment

Anticipated

1/01/2025

Actual

Date of last participant enrolment

Anticipated

1/01/2027

Actual

Date of last data collection

Anticipated

1/04/2027

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Varian

Address [1]

Country [1]

Australia

Primary sponsor type

Hospital

Name

Peter MacCallum Cancer Centre

Address

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Not yet submitted

Ethics committee name [1]

Peter MacCallum Cancer Centre Human Research Ethics Committee

Ethics committee address [1]

https://www.petermac.org/research/doing-research-us/ethics-governance

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

01/11/2024

Approval date [1]

Ethics approval number [1]

Summary

Brief summary

This study is investigating if low-dose localised radiotherapy (involved-site radiation therapy or “ISRT”) can sometimes activate the immune system to cause shrinkage or even disappearance of disease in other parts of the body, outside of the treated region, in patients with advanced Follicular lymphoma (FL) Patients in this study will receive very low dose radiotherapy to some, but not all, of their known lymphoma disease sites. This trial will systematically explore the potential of low dose ISRT as a single modality to engage anti-tumour immunity in advanced FL through investigating both the frequency and the biology of abscopal regression in FL. It will utilise serial imaging and correlative analyses with serial blood (+/- tissue) samples, to explore the underlying mechanisms that may be responsible for this important phenomenon.  
Who is it for?
This study is open both to patients who have had recurrence of disease after previous treatments, and patients who have slow growing or stable lymphoma that would be otherwise be managed by close observation without any current active therapy.  You must be aged 40 and over. 
Study details
All participants will undergo a Positron Emission Tomography (PET)/Computed Tomography (CT) with fluoro-deoxyglucose (FDG) which is a standard type of scan to detect FL. PET scanning is performed by injecting a small amount of radioactive material (called a tracer) into your bloodstream followed by imaging your body by passing you through a PET/CT scanner. 
As well as standard FDG-PET scans, this study will involve the use of two new PET scan tracers that allow us to see different aspects of the immune system.  These tracers are called 89Zr- IAB22M2C and 89Zr-durvalumab respectively.  They need 1- 5 days to be taken up in the tumour after injection and therefore PET imaging scans are performed 1-5 days after the tracer is given.  PET scanning with 89Zr-IAB22M2C allows CD8+ T lymphocytes to be tracked in the body. CD8 T cells can be involved in killing tumour cells in patients with cancer and there is evidence from laboratory studies that CD8 T cells accumulate in tumours before abscopal regression occurs. The other new tracer, 89Zr-durvalumab, enables a molecule called PD-L1 to be imaged in patients. PD-L1 is a target for Immune Checkpoint Immunotherapy and can be found on some tumour cells and on cells of the immune system.  
 
Using these novel PET tracers we hope to increase our understanding of the effects of radiation on immunity in general and on the abscopal effect in particular.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Michael MacManus

Address

Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne Victoria 3000

Country

Australia

Phone

+61 03 8559 7761

Fax

michael.macmanus@petermac.org

Contact person for public queries

Name

Michael MacManus

Address

Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne Victoria 3000

Country

Australia

Phone

+61 03 8559 7761

Fax

michael.macmanus@petermac.org

Contact person for scientific queries

Name

Michael MacManus

Address

Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne Victoria 3000

Country

Australia

Phone

+61 03 8559 5000

Fax

michael.macmanus@petermac.org

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

No additional documents have been identified.

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