None listed
Conditions
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.
Interventions
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 tha
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.
Sponsors
South Metropolitan Health Service (SMHS)
Study design
Allocation
Non-randomised trial
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
Male
Age
18 Years to No maximum
Healthy volunteers
No
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 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 registration. 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
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 > 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 registration 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. 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.
Outcome results
None listed