Combination of Radium-223 and Lutetium-177 PSMA-I&T in Men with Metastatic Castration-Resistant Prostate Cancer (AlphaBet)

Peter MacCallum Cancer Centre, Australia

Status and phase: Active, not recruiting; Phase 2; Phase 1

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

Treatments: Drug: Lutetium-177 PSMA-I&T; Drug: Radium-223

Study type: Interventional

Funder types: Other

Identifiers

NCT05383079

21/029

Details and patient eligibility

About

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

Full description

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.

Enrollment: 36 estimated patients

Sex: Male

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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36 participants in 1 patient group

Radium-223 and Lutetium-177 PSMA-I&T

Experimental group

Description:

In this single-arm study, patients will receive 7.4 GBq of 177Lu-PSMA-I\&T on Day 1 of every 6 week Cycle. Radium-223 will be administered concurrently every 6 weeks. The dose of Radium-223 will vary in dose-escalation. Up to 6 Cycles will be given.

Treatment:

Drug: Radium-223

Drug: Lutetium-177 PSMA-I&T