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)
- Conditions
- metastatic castration-resistant prostate cancerCancer - Prostate
- Registration Number
- ACTRN12623001072606
- Lead Sponsor
- South Metropolitan Health Service (SMHS)
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot yet recruiting
- Sex
- Male
- Target Recruitment
- 45
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
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
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method 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.<br> [ 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 Measures
Name Time Method