Cabazitaxel in Combination With 177Lu-PSMA-617 in Metastatic Castration-resistant Prostate Cancer

This prospective, single-centre, single-arm, open label, phase I/II trial will assess the safety, efficacy and anti-tumour activity of cabazitaxel in combination with 177Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer (mCRPC).

This study aims to assess and establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and recommended phase 2 dose (RP2D) of cabazitaxel in combination with 177Lu-PSMA-617 in patients with mCRPC.

32-44 men with mCRPC who have progressed on prior docetaxel and a second-generation AR antagonist will be enrolled in this trial in two stages: dose escalation and a dose expansion phase over a period of 18 months.

Inclusion criteria

• Male patients aged 18 years or older at the time of informed consent.
• Patient has provided written informed consent.
• Histologically confirmed adenocarcinoma of the prostate without neuroendocrine or small cell differentiation.
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1
• Patients must have had prior treatment with docetaxel.
• Patients must have progressed on a second-generation androgen receptor (AR)-targeted agent (e.g., enzalutamide, abiraterone, or apalutamide) in the castrate-resistant setting.
• Patients must have progressive disease. The Prostate Cancer Clinical Trials Working Group 3 (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 or visceral disease progression as per Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1) criteria
• Bone progression: ≥ 2 new lesions on bone scan
• At least three weeks since the completion of surgery 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 within 28 days prior to registration.
• Imaging evidence of metastatic disease documented with either whole body bone scan (WBBS) or computed tomography (CT) scan performed within 28 days prior to registration.
• Significant prostate-specific membrane antigen (PSMA) avidity on PSMA PET/CT, defined as a minimum uptake of SUVmax 15 at a site of disease.
• Patients must have a life expectancy ≥ 12 weeks.
• Assessed by a medical oncologist as suitable for treatment with cabazitaxel and 177Lu-PSMA-617.
• 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 28 days prior to registration)
• Absolute neutrophil count (ANC) ≥ 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 and able to comply with all study requirements, including all treatments and the timing and nature of all required assessments.

Exclusion criteria

• Superscan on WBBS or diffuse marrow disease on PSMA PET.
• Site(s) of measurable disease that are FDG-positive with low PSMA expression (SUVmax <10).
• Prior treatment with cabazitaxel or 177Lu-PSMA-617.
• Contraindications to the use of corticosteroid treatment.
• 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.
• Presence of untreated 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.
• Persistent toxicities (CTCAE v5.0 >/= Grade 2) caused by previous cancer therapy, excluding alopecia.
• Known HIV or hepatitis B or C infection.
• Radiotherapy or systemic anti-cancer therapies administered within 14 days prior to registration, excluding androgen deprivation therapy (ADT).