Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623001072606
Ethics application status
Approved
Date submitted
25/08/2023
Date registered
6/10/2023
Date last updated
6/10/2023
Date data sharing statement initially provided
6/10/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A phase 1a/b dose-escalation and dose-expansion study to evaluate
Lutetium-177-PSMA I&T (Lu-PSMA) with radiosensitising Capecitabine in
patients with metastatic castration-resistant prostate cancer (mCRPC)
Scientific title
A phase 1a/b dose-escalation and dose-expansion study to evaluate
Lutetium-177-PSMA I&T (Lu-PSMA) with radiosensitising Capecitabine in
patients with metastatic castration-resistant prostate cancer (mCRPC)
Secondary ID [1] 310462 0
Nil known
Universal Trial Number (UTN)
Trial acronym
LuCape
Linked study record

Health condition
Health condition(s) or problem(s) studied:
metastatic castration-resistant prostate cancer
 331258 0
Condition category
Condition code
Cancer 328013 328013 0 0
Prostate

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients will receive up to six cycles of capecitabine + Lu-PSMA at 42-day intervals. Capecitabine will start on day 1 of each cycle and continue for 14 days.
Lu-PSMA will be given on day 10 of every treatment cycle.
The capecitabine is given as an oral tablet.
The Lu-PSMA dosing is given as an intravenous infusion.
Participants will be assessed in the clinic by a doctor on day 1, day 15 and day 29 of each cycle. Blood tests will be done on these days as well as any possible adverse events that the participant my experience. The doctor will check compliance to the medication when the participant is seen in the clinic.

The study is a single arm phase 1a/1b dose-escalation and dose-expansion
study. During dose-escalation, capecitabine will be administered according to a 3+3 dose-escalation schema, using a modified Fibonacci dose-escalation method with four
fixed dose levels for capecitabine of 275mg/m2 twice daily, 550 mg/m2 twice daily, 825mg/m2 and 1000mg/m2 twice daily. The dose-limiting toxicity (DLT) period will be 42 days. Progression to the expansion phase will be considered possible if the maximum tolerated dose is reached with dose-limiting toxicities occurring in <33% of participants or if 2 DLTs have occurred, in which case the recommended phase II dose (RP2D) will be one dose level below the Maximum Tolerated Dose (MTD).

The administered Lu-PSMA is standardised at 8.0 GBq (± 10%) for each treatment dose. All
participants will receive Lu-PSMA on day 10 of each cycle. Treatment will be administered to a maximum of 6 cycles, at an interval of 6 weeks (42 days), unless there is disease progression, unacceptable toxicity, or withdrawal of consent.
Participants will only be enrolled once in the study (they will be unique participants), so for the dose expansion phase, they will not be the same participant who enrolled in the dose escalation phase.
It is not possible to anticipate the duration of the expansion phase, as participants will continue to receive the combined treatments until they experience unacceptable toxicities or disease progression; participants will receive the maximum tolerated dose for up to a maximum of 6 treatment cycles only..

All participants will receive the same assessment plan.
Participants will be assessed in the clinic by a doctor on day 1, day 15 and day 29 of each cycle. Blood tests will be done on these days as well as any possible adverse events that the participant my experience. The doctor will check compliance to the medication when the participant is seen in the clinic.
Intervention code [1] 326858 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 335965 0
Phase 1 a - dose-escalation. To determine effect of adding radiosensitising capecitabine to Lu-PSMA, on the maximum tolerated dose (MTD) and recommended phase 1b dose, that is the dose level at which dose-limiting toxicities (DLTs) occur in <33% of participants, or one level below dose at which 2 DLTs occur in a single cohort. During dose-escalation, capecitabine will be administered according to a 3+3 dose-escalation schema using a modified Fibonacci dose-escalation method with four fixed dose levels for capecitabine. The Dose Limiting Toxicity (DLT) period will be 42 days, during which time the patient must have received at least 75% of planned doses to be considered evaluable.
Timepoint [1] 335965 0
The MTD will be established by the grade and category of treatment related adverse events. This will be undertaken by Clinic assessments and Blood tests will be done on Day 1, 15 and 29 of each cycle, then every 12-weeks until disease progression.
Secondary outcome [1] 425956 0
Safety profile, including dose-limiting toxicities (frequency, timing and severity of Grade 3+ adverse events, as per CTCAE v5.0).
Timepoint [1] 425956 0
Clinic assessments and Blood tests will be done on Day 1, 15 and 29 of each cycle, then every 12-weeks until disease progression.
Secondary outcome [2] 426280 0
PSA response rate (proportion of participants with PSA reduction of greater than or equal to 50% from baseline). Note that participants have to have completed at least one cycle of treatment
Timepoint [2] 426280 0
Bloods will be taken on Day 1, 15 and 29 of each cycle, while on treatment, then every 12-weeks until disease progression (PD)
Secondary outcome [3] 426281 0
Objective response rate (ORR) (proportion of ORR = Complete Response (CR) + Partial Response (PR) as per RECIST 1.1 for soft tissue lesions and PCWG3 criteria for bone lesions).
Timepoint [3] 426281 0
A CT scan and whole body bone scan will be undertaken every 12 weeks (±7 days) until progression.
A SPECT/CT will be done on Day 11 each cycle
Secondary outcome [4] 426793 0
Duration of radiographic progression-free survival (time from randomisation to progression/death; as per RECIST 1.1 for soft tissue lesions and PCWG3 criteria for bone lesions).
Timepoint [4] 426793 0
CT scans and whole body bone scans will be undertaken every 12 weeks until progression.

Eligibility
Key inclusion criteria
1. At least 18 years of age.
2. Metastatic adenocarcinoma of the prostate defined by:
• Documented histopathology of prostate adenocarcinoma (without any features of
neuroendocrine carcinoma) OR
• A clinical diagnosis based on PSA elevation and typical imaging findings for
metastatic prostate cancer
3. Castration-resistant prostate cancer (defined as disease progressing despite castration
by orchiectomy or ongoing luteinising hormone-releasing hormone agonist or
antagonist).
4. Disease progression with rising PSA defined by PCWG3 criteria (sequence of 2 rising
values at a minimum of 1-week intervals).
5. Disease progression after at least one taxane chemotherapy in the mCRPC setting AND
at least one novel androgen receptor signalling inhibitor (in the setting of either mCSPC
or mCRPC). Patients with prostate cancer that has a known BRCA mutation must have
had at least one PARP inhibitor therapy. If BRCA status is unknown patients will be
eligible for inclusion.
6. Imaging evidence of metastatic disease documented with either bone scan or CT scan.
7. Significant PSMA avidity on 68Ga-PSMA PET/CT, defined as SUVmax >15 at a single
site (regardless of lesion size) and SUV max >10 at sites of disease = 10mm (unless
subject to factors explaining a lower uptake, e.g. respiratory motion, reconstruction
artefact) without FDG discordance. Metastases subject to these criteria are for soft
tissue disease (not bone metastases), and lymph node measurement taken from the
short axis.
8. ECOG performance status:
• Dose-escalation phase: 0-2.
• Dose-expansion phase: 0-1.
9. Adequate renal function:
• Creatinine clearance greater than or equal to 40mL/ min (defined by either Cockcroft-Gault formula or by
nuclear medicine renal scan).
10. Adequate liver function:
• Bilirubin < 1.5 x upper limit of normal (ULN) (or if bilirubin is between 1.5 - 2x ULN,
must have a normal conjugated bilirubin).
• AST or ALT less than or equal to 2.0 x ULN (or less than or equal to 5.0 x ULN in the presence of liver metastases).
11. Adequate bone marrow function:
• Platelets greater than or equal to 100 x109 /L.
• Haemoglobin greater than or equal to 90g/L (no red blood cell transfusion in last 4 weeks).
• Neutrophils > 1.5 x109 /L.
12. Estimated life expectancy > 12 weeks.
13. Study treatment both planned and able to start within 21 days of randomisation.
14. Willing and able to comply with all study requirements (including both treatments:
capecitabine and Lu-PSMA), and all required study assessments.
15. Signed, written, informed consent
Minimum age
18 Years
Maximum age
No limit
Sex
Males
Can healthy volunteers participate?
No
Key exclusion criteria
1. Prostate cancer with known significant sarcomatoid, or spindle cell, or neuroendocrine small cell components, or metastasis of other cancer to the prostate.
2. Site(s) of disease that are FDG-positive with minimal PSMA expression defined as FDG
intensity > 68Ga-PSMA activity OR 68Ga-PSMA SUVmax < 10
3. Prior treatment with any PSMA-targeted radiotherapy.
4. Presence of dihydropyrimidine dehydrogenase (DPD) enzyme deficiency.
5. History of another malignancy within 2 years prior to randomisation except for non-melanomatous carcinoma of the skin; or, adequately treated, non-muscle-invasive urothelial carcinoma of the bladder (i.e. Tis, Ta and low grade T1 tumours); or other cancers that are unlikely to reoccur within 24 months.
6. Untreated brain metastases or leptomeningeal disease. Patients with brain metastases that have been treated, and are asymptomatic, and have been stable for 3 or more months after treatment are allowed. A screening MRI brain is required for patients with a known history of brain metastases, and patient will meet exclusion criterion if disease progression evident. A baseline CT brain or MRI is only required if there is clinical suspicion of central nervous system involvement.
7. Concurrent illness, including severe infection that may jeopardise the ability of the
participant to undergo the procedures outlined in this protocol with reasonable safety.
8. Pre-existing G3+ toxicities not resolved to G2 or lower before day of randomisation.
9. Presence of any psychological, familial, sociological or geographical condition potentially
hampering compliance with the study protocol and follow-up schedule, including alcohol
dependence or drug abuse.
10. Men in sexual relationships with women of reproductive potential who are each not
willing/able to use medically acceptable forms of barrier contraception.
11. History of:
i. Significant cardiovascular disease within the last 3 months: including myocardial
infarction, unstable angina, congestive heart failure (NYHA grade II or greater), ongoing arrhythmias of Grade > 2 (NCI CTCAE, version 4.03), Chronic
stable atrial fibrillation is allowed.

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 design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
The Intent-to-Treat (ITT) population includes all enrolled patients who are confirmed to be
eligible for entry into the study and all treated patients, even if they are later determined to be ineligible (Full Analysis Set).
The Safety population includes all participants in both dose-escalation and dose-expansion phases and include all patients who sign informed consent and receive at least one dose of capecitabine (Safety Set).
The Evaluable-for-Response Population is a subset of the ITT population. Patients will be considered evaluable for purposes of assessing objective response rate and duration of response only if they have completed at least 1 treatment and have undergone at least 1 appropriate tumour response assessment (Per Protocol Set).

The MTD will be determined as defined in by primary objective as follows:
To determine effect of adding radiosensitising capecitabine to Lu-PSMA on the maximum tolerated dose (MTD) and recommended phase 2 dose, that is the dose level at which dose-limiting toxicities (DLTs) occur in <33% of participants, or one level below dose at which 2 DLTs occur in a single cohort.
The tolerability of repeat dosing will be evaluated based on the safety profile.
Safety analyses will be performed on the Safety Set and will include all data available at the time of database lock. After the last database lock, follow-up information on SAEs and newly reported related SAEs will be managed through the CTC. Safety assessments to be summarised are:
• AEs
• DLTs
• Changes in clinical laboratory assessments from pre-treatment to study visits
• Change in vital signs from pre-treatment to study visits
• Changes in physical examination from pre-treatment to study visits
AEs will be categorised and tabulated by treatment allocation and CTCAE v5.0 criteria including system organ class, preferred term, worst grade, and outcome. Additionally, discontinuations due to AEs will be summarised. Information collected prior to capecitabine and Lu-PSMA treatment will be presented separately from treatment-emergent signs and symptoms. If a patient has more than 1 occurrence of an AE for a specific preferred term, the patient will be counted only once for that preferred term. The most intense occurrence of an AE, as well as the most extreme relationship of the AE to the study treatment, will be indicated in cases of multiple occurrences of the same AE.
PSA RR, ORR, and rPFS are all being explored. Patient data will be analysed on the basis of
dose administered. The proportion of all participants with a PSA reduction of greater than or equal to 50% from baseline, the proportion of all participants with an objective response (PCWG3 criteria for bone lesions, and RECIST 1.1 criteria for soft tissue lesions), and the interval from the date of
randomisation to the date of first evidence of radiographic progression on imaging (or the date of last known follow-up without progression) will all be presented, along with the corresponding 90% confidence interval. The results will be examined, and each category result will be estimated using the Kaplan-Meier method.
Abnormal clinical laboratory values will be noted as either high or low based on the normal
ranges for each laboratory parameter. Changes from pre-treatment in laboratory parameters will be summarised. Listings of vital sign and physical examination data will be presented

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
13/10/2023
Actual
Date of last participant enrolment
Anticipated
13/10/2026
Actual
Date of last data collection
Anticipated
24/08/2028
Actual
Sample size
Target
45
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 25450 0
Fiona Stanley Hospital - Murdoch
Recruitment postcode(s) [1] 41200 0
6150 - Murdoch

Funding & Sponsors
Funding source category [1] 314668 0
Hospital
Name [1] 314668 0
Fiona Stanley Hospital
Country [1] 314668 0
Australia
Primary sponsor type
Government body
Name
South Metropolitan Health Service (SMHS)
Address
11 Robin Warren Drive
Murdoch WA 6150
Australia
Country
Australia
Secondary sponsor category [1] 316707 0
None
Name [1] 316707 0
Address [1] 316707 0
Country [1] 316707 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313687 0
South Metropolitan Health Service Human Research Ethics Committee
Ethics committee address [1] 313687 0
South Metropolitan Health Service Human Research Ethics CommitteeLevel 2, Education Building, Fiona Stanley Hospital14 Barry Marshall ParadeMURDOCH Western Australia 6150
Ethics committee country [1] 313687 0
Australia
Date submitted for ethics approval [1] 313687 0
28/02/2023
Approval date [1] 313687 0
15/03/2023
Ethics approval number [1] 313687 0
RGS0000005919

Summary
Brief summary
This study aims to assess the effect of combining two different cancer treatments, Lu-PSMA and capecitabine, for the treatment of castration-resistant metastatic prostate cancer.

Who is it for?
You may be eligible for this study if you are aged 18 years or older, you have been diagnosed with castration-resistant metastatic prostate cancer and you meet additional health criteria that will be determined by a blood test.

Study details
This study will be conducted in two parts. Participants who choose to enrol in the first part - dose escalation - will be allocated into one of four capecitabine dosing groups. Participants will attend their cancer treatment centre and receive twice daily doses of capecitabine for 14 days. On the 10th day, participants will also receive a dose of Lu-PSMA. Treatment will be administered to a maximum of 6 cycles, at an interval of 6 weeks (42 days). Participants will be enrolled firstly into the lowest dose group, if there are no serious side effects noted then enrolment into the higher dosing groups will occur. Once the maximum tolerated dose is determined, the second part will begin enrolling participants.
Participants who choose to enrol in the second part - dose expansion - will all receive the maximum tolerated dose of capecitabine twice daily for 14 days. On the 10th day, participants will also receive a dose of Lu-PSMA. Treatment will be administered to a maximum of 6 cycles, at an interval of 6 weeks (42 days).
Participants who choose to enrol in either the first or second part will be asked to undergo routine blood tests and CT imaging to determine any impact the combined treatments may be having on their cancer. Overall participation is not expected to exceed 12 months..

It is hoped this research will determine the maximum safest dose of capcitabine that can be administered to prostate cancer patients together with Lu-PSMA. Once a safe dose has been determined, a larger trial enrolling more cancer patients may be undertaken to further assess the efficacy of the combined treatments.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 129014 0
Dr Thomas Ferguson
Address 129014 0
Medical Oncology Clinical Trials Centre Fiona Stanley Hospital 11 Robin Warren DriveMurdoch WA 6157 Australia
Country 129014 0
Australia
Phone 129014 0
+61 8 6152 6530
Fax 129014 0
+61 8 6152 0954
Email 129014 0
[email protected]
Contact person for public queries
Name 129015 0
Ms Caroline Stone
Address 129015 0
Medical Oncology Clinical Trials Centre Fiona Stanley Hospital 11 Robin Warren DriveMurdoch WA 6157 Australia
Country 129015 0
Australia
Phone 129015 0
+61 8 6152 6530
Fax 129015 0
+61 8 6152 0954
Email 129015 0
[email protected]
Contact person for scientific queries
Name 129016 0
Dr Thomas Ferguson
Address 129016 0
Medical Oncology Clinical Trials Centre Fiona Stanley Hospital 11 Robin Warren DriveMurdoch WA 6157 Australia
Country 129016 0
Australia
Phone 129016 0
+61 8 6152 6530
Fax 129016 0
+61 8 6152 0954
Email 129016 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Not yet decided


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.