combination of radium-223 and lutetium-177 psma-i&t in men with metastatic castration-resistant prostate cancer

Conditions: Metastatic Castration-resistant Prostate Cancer; MCRPC; Prostate Cancer

Summary: this clinical trial will evaluate the safety of radium-223 in combination with 177lu-psma-i\&t in metastatic castration-resistant prostate cancer: phase i/ii study

this prospective, single-centre, single-arm, open label, phase i/ii trial will assess and establish the maximum tolerated dose (mtd), dose-limiting toxicities (dlts), and recommended phase 2 dose (rp2d) of radium-223 in combination with 177lu-psma-i\&t in patients with mcrpc. 36 men with mcrpc who have progressed on second-generation ar antagonist will be enrolled in this trial in two stages: dose escalation and a dose expansion phase over a period of 24 months.

Eligibility criteria:
inclusion criteria: * patient must be ≥ 18 years of age and must have provided written informed consent. * histologically or cytologically confirmed adenocarcinoma of the prostate, or unequivocal diagnosis of metastatic prostate cancer. (i.e. involving bone or pelvic lymph nodes or para-aortic lymph nodes) with an elevated serum psa. * eastern cooperative oncology group (ecog) performance status of ≤ 2 * patients must have progressed on ≥ 1 second-generation ar-targeted agent (e.g., enzalutamide, abiraterone, apalutamide, or darolutamide). * patients must have progressive disease for study entry. pcwg3 defines this as any one of the following: * psa progression: minimum of two rising psa values from a baseline measurement with an interval of ≥ 1 week between each measurement. * soft tissue progression as per recist 1.1 criteria * bone progression: ≥ 2 new lesions on bone scan * symptomatic progression eg. bone pain * at least three weeks since receiving anti-cancer treatment (other than adt), the completion of surgery or radiotherapy prior to registration. * prior surgical orchiectomy or chemical castration maintained on luteinizing hormone-releasing hormone (lhrh) analogue (agonist or antagonist). * serum testosterone levels ≤ 1.75nmol/l (≤ 50ng/dl) within 28 days before registration. * significant psma avidity on psma pet/ct, defined as a minimum uptake of suvmax 20 at a site of disease, and suvmax \>10 at sites of measurable disease \>10mm (unless subject to factors explaining a lower uptake, e.g. respiratory motion, reconstruction artefact). * ≥ 2 bone metastases must be present on bone scintigraphy which have not been previously treated with radiotherapy. * no contraindication to treatment with a bone antiresorptive agent such as denosumab or zoledronic acid. * patients must have adequate bone marrow, hepatic and renal function documented within 28 days prior to registration, defined as: * haemoglobin ≥ 90 g/l independent of transfusions (no red blood cell transfusion in last four weeks) * absolute neutrophil count ≥ 1.5x10\^9/l * platelets ≥ 150 x10\^9/l * total bilirubin ≤ 1.5 x upper limit of normal (uln) except for patients with known gilbert's syndrome, where this applies for the unconjugated bilirubin component. * aspartate transaminase (ast) and alanine transaminase (alt) ≤ 2.5 x uln if there is no evidence of liver metastasis or ≤ 5 x uln in the presence of liver metastases * albumin ≥ 25 g/l * adequate renal function: patients must have a creatinine clearance estimated of ≥ 40 ml/min using the cockcroft gault equation * sexually active patients are willing to use medically acceptable forms of barrier contraception. * willing to undergo biopsies, if disease is considered accessible and biopsy is feasible. * willing and able to comply with all study requirements, including all treatments and the timing and nature of all required assessments. exclusion criteria: patients who meet any of the following criteria will be excluded from study entry: * superscan on bone scan (wbbs) or diffuse marrow involvement on psma pet/ct * prior treatment with 223ra or 177lu-psma. * has received more than one previous line of chemotherapy for the treatment of metastatic prostate cancer. * sites of discordant fdg-positive disease defined by minimal psma-expression and no uptake on wbbs (for bone metastases). * other malignancies within the previous 2 years other than basal cell or squamous cell carcinomas of skin or other cancers that are unlikely to recur within 24 months. * symptomatic brain metastases or leptomeningeal metastases. * patients with symptomatic or impending cord compression unless appropriately treated beforehand and clinically stable for ≥ four weeks. * concurrent illness, including severe infection that may jeopardise the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety.