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
ACTRN12615001183572
Ethics application status
Approved
Date submitted
16/09/2015
Date registered
3/11/2015
Date last updated
20/02/2017
Type of registration
Retrospectively registered

Titles & IDs
Public title
A study to investigate whether a combined Positron emission tomography (PET) and computerised tomography (CT) scan which utilises a tracer called Prostate Specific Membrane Antigen (PSMA) - a substance expressed by prostate cancer cells - can be used to better identify locally recurrent prostate cancer in men with a rising Prostate Specific Antigen (PSA) following radical prostatectomy. The study will then measure the impact of early salvage radiation therapy using advanced localisation techniques on patient survival, clinical toxicity, health related quality of life and prostate cancer-specific quality of life.
Scientific title
Phase II trial in men with rising PSA post-prostatectomy, harnessing PSMA-PET to identify local recurrence only and implanted Calypso real-time tracking beacons to measure the impact of early salvage radiation therapy using advanced localisation techniques on patient survival, clinical toxicity, health related quality of life and prostate cancer-specific quality of life.
Secondary ID [1] 287398 0
Nil known
Universal Trial Number (UTN)
Trial acronym
PINPOINT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Recurrent prostate cancer 296104 0
Condition category
Condition code
Cancer 296358 296358 0 0
Prostate

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Screening intervention: Patients presenting with elevated levels of circulating PSA between 0.1-2.5 ng/mL following post-prostatectomy, and fulfilling all other inclusion criteria as outlined in section 5.2.1, will undergo [68Ga] Gallium-labelled PSMA PET/CT imaging. For the PET scan the 68Ga-PSMA ligand will be administered intravenously, and a 68Ga-PSMA PET/CT will be performed 90 minutes post injection (scanning takes approximately 30-40 minutes). A low dose whole-body computed tomography (CT) scan will be performed during the PET scan as this helps to interpret the PET scan. A contrast enhanced CT Chest/Abdo/Pelvis will be performed following the PSMA PET/CT. This is standard care. However, if the imaging centre does not have the ability to perform the contrast enhanced CT Chest/Abdo/Pelvis, the low dose CT will be acceptable.

Study participants who report a positive PSMA PET scan for metastatic disease will be screened out and receive appropriate treatment for their metastatic disease off-trial, whilst those who are PSMA PET positive for locally recurrent disease only (macroscopic disease), or those with a negative PSMA (microscopic disease), will be offered a course of salvage radiotherapy utilising implanted Calypso (Registered Trademark) radiofrequency beacons to track movement of the prostate bed in ‘real-time’. Participants who are ineligible for Calypso beacons will be enrolled as a control group receiving the standard radiotherapy treatment described above, but without Calypso beacons.

Treatment Intervention: Curative salvage radiotherapy will be undertaken using a series of electromagnetic (EM) transponders (or beacons) that are implanted into the prostate bed then tracked in ‘real-time’ by the Calypso (Registered Trademark) 4D Localisation System (Varian Medical Systems, Palo Alto, CA) during the entire radiation treatment schedule.
1) Prior to treatment, three tiny electromagnetic transponders or beacons — about the size of a grain of rice — will be permanently implanted during a routine day hospital procedure, similar but less invasive than a prostate biopsy.
2) During treatment, an electromagnetic array will be positioned above the treatment site. The array sends a signal that excites the transponders, which then communicates the location of the target.
3) Using harmless non-ionizing electromagnetic waves, the system detects even slight tumour movement in real time and if required, the radiation therapist can pause treatment to make adjustments, so that radiation delivery is once again focused on the tumour.
4) The Varian Calypso (Registered Trademark) system links with our treatment linear accelerators, which produces and delivers the X-rays used to treat cancer.

Following beacon insertion, a CT scan will be acquired in order to demarcate the prostate bed region to be ablated with radiotherapy. This is standard practice. The radiation oncologist will then combine clinical judgment with established radiotherapy protocols to define the clinical tumour volume (CTV). Clinical target volumes will be expanded by 3-5mm to create the planning target volume (PTV) and will be treated to 70Gray (Gy) in 35 fractions at 5 fractions per week if they have a negative PSMA. Participantss with a PSMA that is positive for local recurrence only will receive an additional 4Gy in 2 fractions as a boost dose (therefore total dose = 74Gy in 37 fractions at 5 fractions per week). Radiotherapy plans must meet pre-specified dose constraints to normal tissue and relevant organs at risk. Radiotherapy treatment will be delivered using the existing linear accelerators at Epworth Richmond and Freemasons Hospital. The treatments will be adjusted as required based on the biofeedback of the Calypso (Registered Trademark) system to ensure accurate treatment of the clinical target volumes.
Intervention code [1] 292750 0
Early detection / Screening
Intervention code [2] 292751 0
Treatment: Devices
Intervention code [3] 292946 0
Treatment: Other
Comparator / control treatment
A control group will only be used for the second phase of the trial. Participants who are ineligible for tracking beacons will have standard treatment - salvage radiotherapy to the prostate bed. Standard radiographic imaging for salvage radiotherapy will be followed as per department protocol.

The dose/fractionation will be identical to that given to participants eligible for beacons.

The total radiation dose for the PSMA-PET negative is 70 Gy in 35 fractions over 7 weeks and 74 Gy in 37 fractions over 7.5 weeks for the positive cohort. Fractional dose will be 2 Gy delivered once a day, 5 days a week. All patients will be planned using an IMRT or VMAT technique.
Control group
Active

Outcomes
Primary outcome [1] 296008 0
Biochemical relapse (FFBR) as measured by the serum prostate specific antigen (PSA) level. Biochemical relapse is defined as a rise in serum PSA level by greater than 0.2 ng/mL from a nadir serum PSA after radiotherapy .
Timepoint [1] 296008 0
6 weeks following completion of radiotherapy, then 3 monthly up until 2 years, then 6 monthly up until 5 years, then annually up until 10 years post radiotherapy.
Primary outcome [2] 296009 0
Treatment-related toxicity as measured by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE v4.03).

Acute toxicity (up to 90 days post treatment) will also be measured using the Radiation Therapy Oncology Group (RTOG) scoring measure.

Late toxicity (>90 days after starting radiation therapy) will be classified and rated according to the RTOG/EORTC Late Radiation Morbidity Scoring Schema.
Timepoint [2] 296009 0
Acute toxicity will be assessed weekly during radiation therapy, at 6 weeks and 4.5 months following radiotherapy.

Late toxicity will be assessed from the 7.5 month visit, every 3 months until 2 years, every 6 months until 5 years and at 6 years.
Secondary outcome [1] 317221 0
Metastasis-free survival defined as the time from study enrolment to first evidence of metastases or death due to any cause
Timepoint [1] 317221 0
Assessed at 6 weeks from completion of radiotherapy, then 3 monthly up until 2 years, then 6 monthly up until 5 years, then annually up until 10 years post radiotherapy.
Secondary outcome [2] 317222 0
Prostate cancer specific survival defined as the time from study enrolment to date from last known follow-up alive, or the date of death from undetermined cause, but at last contact was known to have metastatic prostate cancer
Timepoint [2] 317222 0
Assessed at 6 weeks from completion of radiotherapy, then 3 monthly up until 2 years, then 6 monthly up until 5 years, then annually up until 10 years post radiotherapy.
Secondary outcome [3] 317223 0
Overall survival defined as the time from study enrolment to date of death resulting from any cause, or the date last known alive.
Timepoint [3] 317223 0
Assessed at 6 weeks from completion of radiotherapy, then 3 monthly up until 2 years, then 6 monthly up until 5 years, then annually up until 10 years post radiotherapy.
Secondary outcome [4] 317224 0
Generic health and disease-specific quality of life (HRQoL) as measured by the SF-12(R) Short Form Health Survey, version 2 (SF-12(R) (Optum, Eden Prairie, MN, USA, www.optum.com)) and Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP).
Timepoint [4] 317224 0
Assessed at baseline, week two and week 7 of radiotherapy, and then at 6 weeks, 3 monthly up until 2 years, 6 monthly up until 5 years, then annually up until 10 years post radiotherapy.
Secondary outcome [5] 317225 0
Proportions of participants with positive/negative PSMA-PET results.
Timepoint [5] 317225 0
Assessed once PSMA-PET results are obtained for each participant.

Eligibility
Key inclusion criteria
Phase I (PSMA PET/CT)
- Males age 18 years or older.
- Patients who have undergone radical prostatectomy for histologically confirmed clinical stage T1- T3 invasive prostate adenocarcinoma.
- Post-operative PSA 0.1-2.5ng/ml.
- No contraindications to undergoing 68Ga-PSMA-ligand PET/CT (including severe claustrophobia).
- ECOG Status 0-2
- Able to undergo intensity modulated radiotherapy.
- Patients or their legal representatives must have the ability to read, understand and provide written informed consent.
- Able to participate in the stipulated follow-up (either telephone follow-up or on-site visits acceptable, but one follow-up annually should be in person).
- Participants capable of child-bearing are using adequate contraception.

Phase II (radiotherapy)
- No evidence of metastatic disease on PSMA-PET
or
- localized recurrence on PSMA-PET

Inclusion criteria for Calypso beacons
- Body habitus enabling Calypso (Registered Trademark) localisation and tracking (as per Calypso (Registered Trademark) Determining a Patient’s Localisation Designation & Orientation before implantation).
- Able to undergo Calypso (Registered Trademark) beacon insertion.


Minimum age
18 Years
Maximum age
No limit
Gender
Males
Can healthy volunteers participate?
No
Key exclusion criteria
- Prostate cancer with significant sarcomatoid, ductal, spindle cell or neuroendocrine small cell components.
- Evidence of secondary disease outside the prostate bed.
- Previous radiotherapy treatment to the pelvis.
- Any other active malignancy (untreated, progressive or recurrent), except for non-melanoma skin cancer.
- Any inactive malignancy diagnosed within 5 years of entry, except for non-melanoma skin cancer.
- Inflammatory bowel disease (active) such as Crohn’s disease and ulcerative colitis.
- Haemorrhagic cystitis.
- Known hypersensitivity to 68Ga, PSMA or any of the excipients of 68Ga-PSMA.
- Insufficient renal function (eGFR < 30 mL/min/1.73 m2).
- Androgen Deprivation Therapy within 6 months prior to enrolment.
- Unable to lie flat and/or still during PET-CT.
- Patients unable or unwilling to comply with study requirements.
- Patients with a history of psychological illness or condition such as to interfere with the patient’s ability to understand the requirements of the study.

Exclusion criteria for Calypso beacon insertion:
- Any urogenital anatomic abnormality that would interfere with the ability to access the Calypso (Registered Trademark) beacon insertion site.
- Pacemaker or implanted defibrillator.
- Presence of hip prosthesis.


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
Other
Other design features
All patients enrolled into Phase I will undergo PSMA PET/CT. Those who are PSMA PET positive for locally recurrent disease only, or those with a negative PSMA will be offered salvage radiotherapy with or without Calypso (Registered Trademark) beacons. Participants who are ineligible for Calypso beacons will be enrolled as a control group receiving the same radiotherapy treatment plan, but without Calypso beacons.
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
All participants who would have undergone radiotherapy will be included in the analysis of efficacy endpoints . Statistical methods for the different endpoints have been defined in in the protocol and comprise appropriate regression models, such as generalized estimating equations or mixed models and Cox proportional hazards regression. All statistical analyses will be conducted by, or under the direct supervision of Epworth HealthCare Biostatistician(s), using standard professional statistical software packages such as Stata (Stata Corporation, College Station, Texas). A detailed Statistical Analysis Plan will be prepared in consultation with Epworth HealthCare Biostatistician(s).
All treatment-related toxicity outcomes, as defined in the protocol, will be reported as frequencies and percentages.

Sample Size Calculation
Sample size calculation was carried out by Epworth HealthCare Biostatistician Stella Gwini, using Stata 14 (Stata Corporation, College Station, Texas, 2015). In regard to the prior literature, a study reported by Siegmann et al. (2011) found biochemical relapse following radiotherapy of recurrent prostate cancer to be observed in 27% of all patients within two years of follow-up. In a separate study, Ceci et al. (2015) found PSMA-PET detection rates in patients with recurrent prostate cancer to be 73%. Due to the slight differences between the clinical group presented in this protocol and those presented in the two studies, a slightly higher proportion of patients with biochemical relapse within two years is expected and the PSMA-PET detection rate is expected to be lower. Therefore, assuming 30% of patients experience biochemical relapse, 81 patients would be needed to achieve a 95% confidence interval with width of 20% (e.g., 30% plus or minus 10%, where 10% is the half-width or precision, Cumming 2012) Accounting for 60% of patients from Phase I meeting the inclusion criteria for treatment at Phase II, a minimum sample size of 135 patients (i.e., 60% of 135 = 81)will be required at Phase I. For a lower PSMA-PET detection rate of 50%, 162 patients will be required at Phase I.

Level of Significance
The level of significance will be set at 0.05, 2-tailed, in all analyses, except in analyses in which adjustment for multiple comparisons applies, as described in section 12.5 below. 95% confidence intervals will be calculated.

Recruitment
Recruitment status
Active, not 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)
VIC
Recruitment hospital [1] 4296 0
Epworth Richmond - Richmond
Recruitment hospital [2] 4297 0
Epworth Freemasons - Melbourne
Recruitment postcode(s) [1] 10233 0
3121 - Richmond
Recruitment postcode(s) [2] 10234 0
3002 - East Melbourne

Funding & Sponsors
Funding source category [1] 291965 0
Charities/Societies/Foundations
Name [1] 291965 0
Epworth Medical Foundation
Address [1] 291965 0
89 Bridge Road
Richmond
Victoria 3121
Country [1] 291965 0
Australia
Primary sponsor type
Hospital
Name
Epworth Healthcare
Address
89 Bridge Road
Richmond
Victoria 3121
Country
Australia
Secondary sponsor category [1] 290633 0
Individual
Name [1] 290633 0
Dr Patrick Bowden
Address [1] 290633 0
Epworth Radiation Oncology
Level 4
Epworth Centre
32 Erin Street
Richmond
Victoria 3121
Country [1] 290633 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293462 0
Epworth Healthcare Human Research Ethics Committee
Ethics committee address [1] 293462 0
Pelaco Building One
21–31 Goodwood Street
Richmond VIC 3121
Ethics committee country [1] 293462 0
Australia
Date submitted for ethics approval [1] 293462 0
24/03/2015
Approval date [1] 293462 0
06/05/2015
Ethics approval number [1] 293462 0
675-15

Summary
Brief summary
The purpose of this study is to assess the use of Prostate-Specific Membrane Antigen (PSMA) PET/CT scans to identify if men with increased Prostate Specific Antigen (PSA) in the blood have prostate cancer cells in the prostate bed alone, elsewhere in the body, or both. The second phase of the study will evaluate the effectiveness of using the Calypso (Registered Trademark) tracking system for radiation therapy.
Who is it for? You may be eligible to join this study if you are a male aged 18 years or above, and have undergone radical prostatectomy. To be eligible for the second phase, the PSMA PET scan result must show localised recurrence or be negative for disease. There should be no evidence of metastatic disease on the PSMA-PET.
Study details: The study will be divided into two phases. During the first phase all participants will undergo 68Ga-PSMA PET/CT test. This test uses a medical imaging technology called Positron Emission Tomography (PET), a highly sensitive technique using specialised ‘tracer’ particles to detect PSMA. The tracers are given by injection, usually into a vein in the arm. A PET/CT scanner is used to obtain an image showing distribution of the tracer within the body. The PET scan routinely involves a low level CT scan performed at the same time.

There is no preparation for a PSMA PET scan. The scan can take 2-3 hours. Before the test, a needle will be inserted into a vein in your arm or hand. A small amount of radioactive tracer will be injected. You will be asked to rest quietly (45-90 minutes). You will then be taken to the PET/CT scanner bed and asked to lie still on the bed while the PET/CT images are taken. This will take about 30 minutes. You will not feel anything while the images are taken. Some people benefit from a sedative if they suffer from a fear of enclosed spaces (claustrophobia). This must be arranged before the scan. Should you need any form of sedation, you will need to fast for 6 hours (nothing to eat or drink) before scan. The amount of radioactivity used for the scan is small and there are no known side effects to the injection. For the second phase of the study, only participants that show no evidence of metastatic disease will receive radiotherapy. Participants with a negative PSMA will be treated to 70Gray (Gy) in 35 fractions at 5 fractions per week with the Calypso tracking system. Participants with a PSMA that is positive for local recurrence only will receive an additional 4Gy in 2 fractions (total dose = 74Gy in 37 fractions at 5 fractions per week). This therapy will use the Calypso tracking system. It uses radiofrequency emitting beacons implanted within the area being treated, allowing tracking of any movement during delivery of radiation. This means that we can make the margins around the cancer smaller thus reducing the side effects of radiation therapy. Participants who are ineligible for Calypso beacons will receive standard radiotherapy (described above), but without Calypso beacons.
Trial website
Trial related presentations / publications
Public notes
The screening phase of the study Phase I (PSMA PET/CT) will aim to enrol 135 participants. The second Phase (Salvage RT +/-beacons) will aim to enrol 81 participants.

Contacts
Principal investigator
Name 59070 0
Dr Patrick Bowden
Address 59070 0
Epworth Radiation Oncology
Level 4
32 Erin Street
Richmond
Victoria 3121
Country 59070 0
Australia
Phone 59070 0
+61399368277
Fax 59070 0
Email 59070 0
patrick.bowden@epworth.org.au
Contact person for public queries
Name 59071 0
Dr Pat Bowden
Address 59071 0
Epworth Radiation Oncology Research Centre
Level 4
32 Erin Street
Richmond
Victoria 3121
Country 59071 0
Australia
Phone 59071 0
+61399368277
Fax 59071 0
Email 59071 0
patrick.bowden@epworth.org.au
Contact person for scientific queries
Name 59072 0
Dr Patrick Bowden
Address 59072 0
Epworth Radiation Oncology
Level 4
32 Erin Street
Richmond
Victoria 3121
Country 59072 0
Australia
Phone 59072 0
+61399368277
Fax 59072 0
Email 59072 0
patrick.bowden@epworth.org.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary