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Trial registered on ANZCTR


Registration number
ACTRN12619001264178
Ethics application status
Approved
Date submitted
2/08/2018
Date registered
12/09/2019
Date last updated
22/04/2020
Date data sharing statement initially provided
12/09/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
PETReA: Phase 3 evaluation of PET-guided, Response-Adapted therapy in patients with previously untreated, high tumour burden follicular lymphoma
Scientific title
PETReA: Phase 3 evaluation of PET-guided, Response-Adapted therapy in patients with previously untreated, high tumour burden follicular lymphoma - PETReA
Secondary ID [1] 295726 0
EUCTR2016-004010-10-GB
Universal Trial Number (UTN)
Trial acronym
PETReA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Follicular Lymphoma 309124 0
Condition category
Condition code
Cancer 307999 307999 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Randomised Phase III PET -response adapted maintenance therapy

Based on PET response (negative or positive) patients are randomised in the following manner -
Group 1: PET +ve (Deauville 4-5)
Arm A: Rituximab maintenance
Rituximab: 375 mg/m2 intravenous (or 1400 mg subcutaneously) on day 1 of each cycle, repeated every 8 weeks for up to 12 cycles

Arm B: Rituximab + lenalidomide (R2)
Rituximab 375 mg/m2 intravenously (or 1400 mg subcutaneously) on day 1 of each cycle of, repeated every 8 weeks for up to 12 cycles, a cycle lasts 28 days
Lenalidomide oral tablet once daily on days 1 to 21 of every 28-day cycle (dose tailored to renal function and tolerance) for up to 24 cycles

Group 2: PET –ve (Deauville 1-3)
Arm A: Rituximab maintenance
Rituximab: 375 mg/m2 intravenously (or 1400 mg subcutaneously) on day 1 of each cycle, repeated every 8 weeks for up to 12 cycles, a cycle last 28 days

Arm B: No further treatment
Intervention code [1] 302050 0
Treatment: Drugs
Comparator / control treatment
For both PET positive and negative groups, the comparator arm is the SoC arm - rituximab maintenance
Rituximab 375 mg/m2 iv (or 1400 mg sc) on day 1 of each cycle, repeated every 8 weeks for up to 12 cycles
Control group
Active

Outcomes
Primary outcome [1] 306975 0
The primary outcome is progression-free survival (PFS). This is the time from randomisation until progression or death from any cause.
Timepoint [1] 306975 0
Timepoint(s) of evaluation of this end point: Patients will be assessed for disease progression by physical examination at the end of the induction phase of treatment and at every subsequent study visit. These visits occur every 4 weeks during the 2-year maintenance phase in the PET +ve group, every 8 weeks during the maintenance phase in the PET -ve group and every 24 weeks thereafter. Additional assessments will be performed between planned study visits if there is any suspicion of disease progression.
Secondary outcome [1] 350297 0
a) Anatomical response to induction therapy
Timepoint [1] 350297 0
Anatomical response to induction therapy will be based on a pre- and post-induction CT scan and bone marrow biopsy.
Secondary outcome [2] 354806 0
b) Metabolic response to induction therapy
Assessment of metabolic response will be based on the intensity of FDG uptake on whole-body PET-CT scans.
Timepoint [2] 354806 0
Assessment of metabolic response will occur post induction therapy
Secondary outcome [3] 354807 0
c) Conversion to PET negativity (PET +ve group only)
The PET +ve group will undergo additional imaging with a conventional ceCT and PET-CT scan
Timepoint [3] 354807 0
The additional imaging for the PET +ve group will occur 52 (+/- 2) weeks after day 1 of the first cycle of maintenance treatment and at least 2 weeks after the most recent administration of rituximab or G-CSF.
Secondary outcome [4] 354808 0
d) Overall survival

Timepoint [4] 354808 0
Overall survival will be assessed from randomisation until death by any cause. Pre-progression follow-up and post- progression follow-up will occur every 24 (+/-4) weeks.
Secondary outcome [5] 354809 0
e) Time to next treatment
This will be assessed through pre-progression follow-up assessments which includes vital signs, physical examination, blood tests, questionnaires, toxicity assessments and ceCT scan.
If disease progression is suspected on the basis of symptoms or physical examination findings, patients will undergo conventional CT scanning at the earliest opportunity.
By performing the above-mentioned assessments and confirming disease progression, this will indicate when patients will need to have further treatment.

The name of the questionnaires used are as follows:
QoL questionnaires - EQ-5D and EQ-VAS

Timepoint [5] 354809 0
Time to next treatment will be assessed during pre-progression follow-up.
Pre-progression follow-up will occur after maintenance therapy, every 24 (+/- 4 weeks) weeks. It finishes once progression is documented or at the end of the study, whichever is earlier.
Secondary outcome [6] 354810 0
f) Time to next chemotherapy
This will be assessed through pre-progression follow-up which includes vital signs, physical examination, blood tests, questionnaires, toxicity assessments and ceCT scan.
By performing the above-mentioned assessments and confirming disease progression, this will indicate when patients will need to have further subsequent chemotherapy.

The name of the questionnaires used are as follows:
QoL questionnaires - EQ-5D and EQ-VAS
Timepoint [6] 354810 0
Time to next treatment will be assessed during pre-progression follow-up
.The pre-progression follow-up phase starts immediately after the end of the last cycle of maintenance therapy (day 56 for rituximab monotherapy, day 28 for rituximab + lenalidomide), or after 96 weeks for patients in Arm B of the PET –ve group (no treatment). It finishes once progression is documented or at the end of the study, whichever is earlier.
Secondary outcome [7] 354811 0
g) Toxicity
Toxicity will be assessed through vital signs, physical examinations, blood tests, ECGs, questionnaires, CT scans and PET scans
Questionnaires used are QoL questionnaires - EQ-5D and EQ-VAS.
Timepoint [7] 354811 0
Toxicity will be assessed from the point of informed consent until 36 months post randomisation. Events felt to be a long term side effect of study treatment should be reported outside of this time limit at the discretion of the local investigator, if felt to be clinically relevant and serious.
Subjects will be evaluated for AEs at EACH VISIT with the NCI CTCAE Version 4.03 used as a guide for the grading of severity.


Eligibility
Key inclusion criteria
1. Must be greater than or equal to 18 years of age at the time of signing the informed consent form.
2. Must be able to adhere to the study visit schedule and other protocol requirements.
3. Must have a documented diagnosis of follicular lymphoma (grade 1, 2 or 3a).
4. Must be at non-contiguous stage II, stage III or stage IV.
5. Must fulfil at least one of the Groupe d'Etude des Lymphomas Folliculaires (GELF) GELF criteria for high tumour burden:
a. Systemic symptoms (> 10% weight loss, temperature greater than or equal to 38°C for more than 5 days, abundant night sweats)
b. Performance status (PS) greater than 1 according to the Eastern Cooperative Oncology Group (ECOG) scale
c. Elevated lactate dehydrogenase (LDH) level
d. ß2-microglobulin level greater than 25.5 nM/L (3 µg/mL)
e. A single lymph node larger than 7 cm
f. Involvement of at least 3 nodal sites, each with diameter greater than 3 cm
g. Marked splenomegaly
h. Organ failure
i. Pleural effusion or ascites
j. Orbital or epidural involvement
k. Blood infiltration
l. Cytopenia
6. Must not have received prior systemic therapy (local radiotherapy is permitted).
7. Must have a WHO performance status score of less than or equal to 2.
8. Must agree to adhere to the Celgene guidance on pregnancy prevention.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Any serious medical condition that would prevent the subject from participating in the study.
2. Known active infection with HIV, HBV or HCV.
3. Pregnant or lactating females.
4. Central nervous system involvement as documented by spinal fluid cytology or imaging.
5. History of active malignancy during the past 5 years with the exception of basal carcinoma of the skin, squamous cell carcinoma of the skin, carcinoma in situ of the cervix, carcinoma in situ of the breast, prostate cancer (TNM stage of T1a or T1b)
6. Any of the following laboratory abnormalities:
a. Absolute neutrophil count (ANC) <1,000/µL (1.0 X 10^9/L)
b. Platelet count <50,000/µL (50 X 10^9/L)
c. Serum alanine transaminase (ALT) > 3.0 x upper limit of normal (ULN)
d. Serum total bilirubin >1.5 x ULN unless due to Gilbert's Syndrome or biliary obstruction by lymphoma

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
In total, 840 patients will be recruited into the full study. An allowance is made for 10% to drop out in the induction phase. Of the remaining 756 patients, it is anticipated that 606 will be PET -ve and randomised to the de-escalation study and that 150 will be PET +ve and randomised to the escalation study. Sample size calculations are carried out for the PET -ve and PET +ve section of the trial separately.
PET -ve group: Following induction therapy, patients will be randomised on a 1:1 basis to receive either rituximab maintenance therapy (control arm) or no further therapy (experimental arm).
The null hypothesis is that removing rituximab maintenance results in a rate of PFS greater than the non-inferiority margin. That is for PFS rates in each treatment arm (PFS1 and PFS2)
H0: PFS1 – PFS2 = delta
The alternative hypothesis is that the change in PFS due to the removal of rituximab therapy will be less than the non-inferiority margin
H1: PFS1 – PFS2 < delta
The design parameters for the non-inferiority study were set after much discussion and use a one-sided alpha level of 0.5 and a Power of 85%.
The primary endpoint is PFS measured at 3 years with the hazard ratio between the two treatment arms the key efficacy parameter of interest. Based on historical data, it is estimated that the 3Y PFS rate will be approximately 76%. An estimate of the PFS rate in the control arm is characterized by a Weibull distribution with scale = 0.00133 and shape = 2.5 parameters. A non-inferiority margin of 8% was chosen via consultation with both clinicians and patient groups and with reference to EMA guidelines which state that larger non-inferiority margins should be considered when the experimental arm has some advantage in another aspect of its profile. Justifications in this instance are given as 1) frontline rituximab maintenance does not confer a survival advantage, 2) omitting rituximab maintenance should significantly reduce the risk of serious infection 3) there are substantial savings in cost to the NHS in not providing rituximab.
Based on a survival rate of 80% in the control arm, a non-inferiority margin of 8% relates to a hazard ratio of 1.47 which is obtained by having a second survival function with scale = 0.00188.
An allowance is also made for a single interim analysis to be carried out once 50% of the events have been observed (after approximately 5 years). Efficacy boundaries are set using O'Brien-Fleming boundaries. Here controlling the overall Type I error at 0.05 requires that assessment of non-inferiority is based on one-sided 99.1% and 95.3% confidence intervals at the interim and final analysis respectively.
Sample size calculations for the number of events are based on a one-side alpha level of 0.05 and 85% power, a total of 250 events are required after adjusting.
Based on these estimates, we anticipate recruiting a total of 840 patients over a period of 53 months. An allowance is made to account for 10% of patients leaving the study in the initial induction phase. Of the remaining patients, 80% are anticipated to be PET -ve giving an estimated 606 patients in this group. Based on this and the assumed PFS rate, it is projected that the required events will be obtained within 87 months following randomisation. Allowing for each patient to have a minimum of 3 years (36 months) follow-up from randomisation will ensure that enough events are available to power the analysis.

Recruitment
Recruitment status
Recruiting
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)
NSW,TAS,VIC
Recruitment hospital [1] 11562 0
Concord Repatriation Hospital - Concord
Recruitment hospital [2] 11563 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [3] 11565 0
Royal Hobart Hospital - Hobart
Recruitment hospital [4] 11566 0
Wollongong Hospital - Wollongong
Recruitment hospital [5] 11567 0
St George Hospital - Kogarah
Recruitment postcode(s) [1] 23606 0
2139 - Concord
Recruitment postcode(s) [2] 23607 0
3168 - Clayton
Recruitment postcode(s) [3] 23609 0
7000 - Hobart
Recruitment postcode(s) [4] 23610 0
2500 - Wollongong
Recruitment postcode(s) [5] 23611 0
2217 - Kogarah
Recruitment outside Australia
Country [1] 10724 0
United Kingdom
State/province [1] 10724 0
Liverpool

Funding & Sponsors
Funding source category [1] 300317 0
Charities/Societies/Foundations
Name [1] 300317 0
Snowdome Foundation
Address [1] 300317 0
Suite 4, 209 Toorak Road, South Yarra Vic 3141
Country [1] 300317 0
Australia
Funding source category [2] 305543 0
University
Name [2] 305543 0
The University of Sydney
Address [2] 305543 0
Level 3, F23 Administration Building, University of Sydney, NSW 2006
Country [2] 305543 0
Australia
Primary sponsor type
University
Name
University of Liverpool
Address
2nd Floor Block D Waterhouse Building
3 Brownlow Street
Liverpool
L69 3GL
Country
United Kingdom
Secondary sponsor category [1] 299749 0
Charities/Societies/Foundations
Name [1] 299749 0
Australiasian Leukaemia and Lymphoma Group
Address [1] 299749 0
Ground Floor, 35 Elizabeth St
Richmond, VIC 3121
Country [1] 299749 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301129 0
Sydney Local Health District Human Research Ethics Committee - Concord Repatriation Hospital [EC00118]
Ethics committee address [1] 301129 0
Hospital Road, Concord New South Wales 2139
Ethics committee country [1] 301129 0
Australia
Date submitted for ethics approval [1] 301129 0
06/08/2018
Approval date [1] 301129 0
27/09/2018
Ethics approval number [1] 301129 0

Summary
Brief summary
The purpose of this study is to determine the clinical utility of therapy based on the result of a PET-scan for patients with follicular lymphoma.

Who is it for?
You may be eligible for this study if you are aged over 18 and have a documented diagnosis of follicular lymphoma

What it involves
Participants in this study will be divided into groups (PET-ve and PET +ve) based on their PET-scan.
PET +ve patients will be randomised (by chance) into two groups. One group (called Arm A) will have the drug Rituximab through a needle in the arm every 8 weeks for up to 22 months. The other PET +ve group (called Arm B) will also have Rituximab, but will also receive a drug called Lenalidomide by orally every month for up to 24 months.
PET –ve patients will also be randomised (by chance) into two groups. One group (called Arm A) will have the drug Rituximab through a needle in the arm every 8 weeks for up to 22 months. The other PET –ve group (called Arm B) will receive no treatment.
All participants in all groups and arms will be monitored for disease progression by physical examination and PET scans throughout their time in the study.

It is hoped this study will demonstrate effectiveness of Lenalidomide in converting PET positive patients to PET negative patients. It is also hoped this research will show no treatment to be as effective as the current maintenance treatment (Rituximab) in PET negative patients.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 85954 0
A/Prof Judith Trotman
Address 85954 0
Department of Haematology
Concord Repatriation Hospital
Hospital road, Concord NSW 2137
Country 85954 0
Australia
Phone 85954 0
+612 9767 7243
Fax 85954 0
Email 85954 0
Judith.Trotman@health.nsw.gov.au
Contact person for public queries
Name 85955 0
A/Prof Judith Trotman
Address 85955 0
Department of Haematology
Concord Repatriation Hospital
Hospital road, Concord NSW 2137
Country 85955 0
Australia
Phone 85955 0
+612 9767 7243
Fax 85955 0
Email 85955 0
Judith.Trotman@health.nsw.gov.au
Contact person for scientific queries
Name 85956 0
A/Prof Judith Trotman
Address 85956 0
Department of Haematology
Concord Repatriation Hospital
Hospital road, Concord NSW 2137
Country 85956 0
Australia
Phone 85956 0
+612 9767 7243
Fax 85956 0
Email 85956 0
Judith.Trotman@health.nsw.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
No individual participant data will be publicly available as it is the aggregate data that is under investigation.
What supporting documents are/will be available?
No other documents available
Summary results
No Results