The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12618001667202p
Ethics application status
Not yet submitted
Date submitted
12/09/2018
Date registered
10/10/2018
Date last updated
10/10/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Treatment of recurrent prostate cancer with 177Lutetium-prostate specific membrane antigen (177Lu-PSMA) theranostic and external beam radiation therapy
Scientific title
A Randomised Trial of External Beam Radiation Therapy (EBRT) Alone versus EBRT in Combination with 177Lu-PSMA Theranostic in Patients with Biochemically Recurrent Prostate Cancer (to determine the proportion of participants in each group with a 50% decline in PSA through to the end of the trial) - a phase 3 study
Secondary ID [1] 296005 0
None
Universal Trial Number (UTN)
U1111-1220-0289
Trial acronym
TARGET
Linked study record
None

Health condition
Health condition(s) or problem(s) studied:
Prostate cancer (recurrent) 309525 0
Condition category
Condition code
Cancer 308354 308354 0 0
Prostate

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
External beam radiation therapy (EBRT): For patients receiving EBRT, radiotherapy will consist of a conventionally fractionated course of treatment that aims to deliver 66-70 Gy in 33-35 fractions to gross tumour volume and 54 Gy in 33-35 fractions subclinical target volume concomitantly over 6.5-7 weeks using either intensity modulation radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) techniques (as per physician discretion). In general, treatments are delivered daily for a minimum of 9 and a maximum of 11 fractions per fortnight according to departmental policies, except where interruptions are unavoidable (due to, for example) hospital holidays. Treatments will occur on weekdays only, except for on public holidays.

177Lutetium-prostate specific membrane antigen (177Lu-PSMA): No more than 8 GBq of 177Lu-PSMA is administered intravenously as infusion over 15 to 30 minutes by syringe pump. Dose is administered 8 weekly, over 3 treatment cycles. Patients will receive a dose of 80MBq/kg 177Lu-PSMA at each treatment visit.
**This is the approximate mean dose used for all 177Lu-PSMA at all centres administering this therapy around the world. It is based on dosimetric calculation relating to dose limiting organs/dose limiting toxicity (e.g. dose to bone marrow, kidneys, salivary glands etc). The 80 MBq/kg dose is used to prevent (if not - in the worst case scenario - minimise) bone marrow and other toxicity. (NB - this is the same principle used in EBRT).

All EBRT and 177Lu-PSMA treatments will take place at GenesisCare treatment sites. Authorised medical personnel will deliver each treatment.

**Patients will not receive EBRT and 177Lu-PSMA concurrently. Patients on the combination therapy arm will first receive EBRT. Four weeks later, they will commence 177Lu-PSMA treatment.
Intervention code [1] 312336 0
Treatment: Other
Comparator / control treatment
EBRT consist of a conventionally fractionated treatment course that aims to deliver 66-70 Gy in 33-35 fractions to gross tumour volume and 54 Gy in 33-35 fractions subclinical target volume concomitantly over 6.5-7 weeks using either Intensity-modulated radiation therapy (IMRT) or Volumetric-modulated arc therapy (VMAT) techniques as per physician discretion.

Treatments will be delivered daily (on weekdays) for a minimum of 9 and a maximum of 11 fractions per fortnight according to departmental policies, except where interruptions are unavoidable (due to, for example, hospital holidays).
Control group
Active

Outcomes
Primary outcome [1] 307344 0
Proportion of patients with at least a 50% decline in prostate specific antigen (PSA)
Timepoint [1] 307344 0
A nadir and stabilisation of PSA within four months of close of treatment is expected. Follow up visits will occur every 3 months for 24 months. At each visit, PSA levels of patients will be determined.
Secondary outcome [1] 351545 0
To determine if Objective Tumour Response Rate (OTRR) is improved when 177Lu-PSMA targeted radiotherapy is used in combination with EBRT relative to EBRT alone (where Objective Tumour Response is based on 68Ga-PSMA-PET/CT avidity of lesions, and number of lesions and as per RECIST 1.1 and PERCIST criteria). As the OTRR is dependent upon the collective measure of each of these parameters, this is a composite secondary outcome.
Timepoint [1] 351545 0
At each 3-monthly follow up visit, which will occur from the end of treatment for a total period of 24 months.
Secondary outcome [2] 351891 0
To determine Progression Free Survival (PFS), defined as the time from randomisation to
time of PSA increase on based serum analysis; or radiographic progression (RECIST 1.1 or PERCIST for bone and soft tissue involvement respectively); or pain progression as per QLQC30 quality of life questionnaire.
Timepoint [2] 351891 0
At each 3-monthly follow up visit, which will occur from the end of treatment for a total period of 24 months.
Secondary outcome [3] 351892 0
To monitor and record health-related quality of life during EBRT therapy and combined 177Lu-PSMA+EBRT treatment as per QLQC30 quality of life questionnaire.
Timepoint [3] 351892 0
At each 3-monthly follow up visit, which will occur from the end of treatment for a total period of 24 months.
Secondary outcome [4] 351893 0
To determine and document the frequency and severity of adverse events, as assessed by CTCAE v5 criteria.
Timepoint [4] 351893 0
At each 3-monthly follow up visit, which will occur from the end of treatment for a total period of 24 months.
Secondary outcome [5] 351894 0
To document the first site of tumour progression/recurrence using 68Ga-PSMA-I&T scan at biochemical/PSA relapse
Timepoint [5] 351894 0
At each 3-monthly follow up visit, which will occur from the end of treatment for a total period of 24 months
Secondary outcome [6] 351895 0
To determine the delay to initiation of ADT; from the time the patient completes the treatment to the time of initiating ADT when the patient developed polymetastases or symptomatic progression.
Timepoint [6] 351895 0
At each 3-monthly follow up visit, which will occur from the end of treatment for a total period of 24 months

Eligibility
Key inclusion criteria
• Written informed consent

• Male, aged 45 years or more

• Estimated life expectancy of at least 6 months

• Eastern Cooperative Oncology Group (ECOG) score 0 or 1

• Previous radical prostatectomy (RP) with curative intent

• Biopsy proven prostate adenocarcinoma

• Biochemical relapse (any serum PSA level)

• Significant avidity (SUVmax of at least 9) on 68Ga-PSMA-ligand PET/CT, with visualised disease confined to the pelvis and outside the prostatic bed

• Metastatic lymph nodes not beyond the aortic bifurcation

• Androgen deprivation therapy (ADT) naïve

• Chemotherapy naïve

• Adequate renal function: Cr Cl greater than or equal to 40 mL/min (determined by Cockcroft-Gault formula)

• Adequate bone marrow function: platelets greater than or equal to 100 x 109/L (within normal limits); Hb greater than or equal to 90 g/L (within normal limits); neutrophils greater than or equal to 1.5 x 109/L

• Adequate liver function: bilirubin < 1.5 x upper limit of normal (ULN); AST, ALT, AP < 2 x ULN; albumin > 30 g/L

• Willing and able to comply with all study requirements, including all treatments and pre- and post-treatment assessments

• Able to commence treatment within 28 days of randomisation

Minimum age
45 Years
Maximum age
No limit
Gender
Males
Can healthy volunteers participate?
No
Key exclusion criteria
• Previous external beam radiotherapy to prostatic bed

• Bone or visceral metastases

• Lymph node metastases above the aortic bifurcation

• Presence of > 5 metastatic lymph nodes

• Contraindications to pelvic irradiation (e.g., chronic inflammatory bowel disease, previous radiotherapy to pelvic malignancy)

• Known hypersensitivity to any isotope of Lu in any chemical form, or any isotope of Ga in any chemical form, or any of the PSMA-targeting ligands

• Evidence of urinary tract stricture, or significant urinary incontinence

• Presence of active infection at time of screening, or history of serious infection within the previous 4 weeks

• Any uncontrolled significant medical, psychiatric or surgical condition (eg. active infection, unstable angina pectoris, cardiac arrhythmia, poorly controlled type 2 diabetes, uncontrolled congestive heart disease, pulmonary disease, etc.), or laboratory findings that, in the opinion of the investigator, might jeopardise the patient’s safety or that would limit compliance with the treatment and assessment requirements of this study

• History of any malignancy other than prostate cancer within five years of enrolment (excluding localised non-melanoma skin cancers)

• Any mental condition or cognitive impairment that may render the patient unable to adequately understand the requirements, nature and possible consequences of the study


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 concealed. An automated, computerised randomisation will be conducted
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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)
Safety/efficacy
Statistical methods / analysis
All primary analyses will be based on intent-to-treat (ITT) principles using all randomized subjects. Baseline factors across groups will be compared using mean (standard deviation) and median (25th and 75th percentiles) summary measures. Due to clinical interest in departures from both sides of the null hypothesis, all test statistics will be 2-sided.

Assume the proportion of participants in EBRT only group (A) with a 50% decline in pre-treatment PSA is 60% and in EBRT + 177Lu-PSMA group (B) is 80%. Potential dropout is a key factor in the proposed study. The drop-out process assumed 20% lost to follow-up in total. Only 80% of subjects were assumed to be followed for the entire period. Assume during the research, 1 planned interim analysis will be carried out for efficacy. Power calculations were performed using a PASS 11.0 Group-Sequential Tests for Two Proportions. Thus, Sample sizes of 117 (93/0.8) and 117 (93/0.8) achieve 81% power to detect a difference of 0.20 between the group proportions of 0.60 and 0.80 at a significance level (alpha) of 0.05 using a two-sided z-test with continuity correction. These results assume that two sequential tests are made using the O'Brien-Fleming spending function to determine the test boundaries. Details is as follows when Spending = O'Brien-Fleming, N1 = 93, N2 =93, P1 = 0.60, P2 = 0.80, Continuity Correction.

Recruitment
Recruitment status
Not yet 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)
WA
Recruitment hospital [1] 11796 0
Hollywood Private Hospital - Nedlands
Recruitment postcode(s) [1] 23922 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 300599 0
Commercial sector/Industry
Name [1] 300599 0
GenesisCare
Address [1] 300599 0
Building 1 The Mill, Huntley Street Alexandria, Sydney, NSW 2015, Australia
Country [1] 300599 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
GenesisCare
Address
GenesisCare,
Building 1 The Mill, Huntley Street Alexandria, Sydney, NSW 2015, Australia
Country
Australia
Secondary sponsor category [1] 300108 0
None
Name [1] 300108 0
Address [1] 300108 0
Country [1] 300108 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 301387 0
Bellberry
Ethics committee address [1] 301387 0
129 Glen Osmond Road Eastwood South Australia 5063
Ethics committee country [1] 301387 0
Australia
Date submitted for ethics approval [1] 301387 0
01/11/2018
Approval date [1] 301387 0
Ethics approval number [1] 301387 0

Summary
Brief summary
This study will evaluate the safety and efficacy of External Beam Radiation Therapy (EBRT) in combination with 177 Lu-prostate-specific membrane antigen (Lu-PSMA) theranostic against EBRT alone in patients with recurrent prostate cancer.

Who is it for?
You may be eligible to join this study if you are a male aged 45 years or above and have a confirmed diagnosis of recurrent prostate cancer following previous radical prostatectomy (RP) with curative intent.

Study details
Participants will be randomly allocated (by chance) to one of two groups. Participants in one group will undergo external beam radiation therapy (EBRT) in combination with 177Lu-PSMA theranostic treatment. EBRT will be administered daily (on weekdays) over 6.5-7 weeks. 177Lu-PSMA will be administered intravenously in three treatment cycles of once every 8 weeks.

Participants in the other group will receive EBRT alone.

All participants will be asked to attend 3-monthly follow up visits from the end of treatment for a total period of 24 months, in order to assess treatment response, safety, and health-related quality of life. It is hoped that EBRT delivered together with 177Lu-PSMA will enable the delivery of higher radiation doses to the tumour, resulting in a greater treatment response and improved survival.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 86834 0
A/Prof Nat Lenzo
Address 86834 0
GenesisCare,
Building 1 The Mill, Huntley Street Alexandria, Sydney, NSW 2015, Australia
Country 86834 0
Australia
Phone 86834 0
+61 402 345 665
Fax 86834 0
Email 86834 0
Nat.Lenzo@genesiscare.com
Contact person for public queries
Name 86835 0
A/Prof Nat Lenzo
Address 86835 0
GenesisCare,
Building 1 The Mill, Huntley Street Alexandria, Sydney, NSW 2015, Australia
Country 86835 0
Australia
Phone 86835 0
+61 402 345 665
Fax 86835 0
Email 86835 0
Nat.Lenzo@genesiscare.com
Contact person for scientific queries
Name 86836 0
Dr Danielle Meyrick
Address 86836 0
GenesisCare,
Building 1 The Mill, Huntley Street Alexandria, Sydney, NSW 2015, Australia
Country 86836 0
Australia
Phone 86836 0
+61 419 610 137
Fax 86836 0
Email 86836 0
Danielle.Meyrick@genesiscare.com

No information has been provided regarding IPD availability
Summary results
No Results