Clinical trial NCT05383079: Combination of Radium-223 and Lutetium-177 PSMA-I&T in Men with Metastatic Castration-Resistant Prostate Cancer
Official title: Combination of Radium-223 and Lutetium-177 PSMA-I&T in Men with Metastatic Castration-Resistant Prostate Cancer
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Metastatic Castration-resistant Prostate Cancer
MCRPC
Prostate Cancer
Lead sponsor: Peter MacCallum Cancer Centre, Australia
Sponsor class: OTHER
First posted: 2022-05-19
Enrollment: 36
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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

Detailed 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.

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.

Primary outcomes:
measure: Dose Limiting toxicities (DLTs)
timeFrame: Dose escalation phase is expected to be completed 6 months from the time the first patient is recruited.
measure: Maximum Tolerated dose (MTD)
timeFrame: Dose escalation phase is expected to be completed 6 months from the time the first patient is recruited.
measure: Recommended Phase 2 Dose (RP2D)
timeFrame: Up to 30 months from the time the first patient is recruited.
measure: 50% Prostate-Specific Antigen Response Rate (PSA-RR)
timeFrame: Through study completion, up until 12 months after the last patient commences treatment
Secondary outcomes:
measure: Adverse Events and Serious Adverse Events measured using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0
timeFrame: Through study completion, up until 12 months after the last patient commences treatment
measure: Radiographic Progression-Free Survival (rPFS)
timeFrame: Through study completion, up until 12 months after the last patient commences treatment
measure: PSA progression free survival (PSA-PFS)
timeFrame: Through study completion, up until 12 months after the last patient commences treatment
measure: Overall survival (OS)
timeFrame: Through study completion, up until 12 months after the last patient commences treatment
measure: Objective response rate (ORR) by RECIST1.1 in patients with measurable disease
timeFrame: Through study completion, up until 12 months after the last patient commences treatment
measure: Progression Free Survival (PFS)
timeFrame: Through study completion, up until 12 months after the last patient commences treatment
measure: Describe pain within 12 months of treatment commencement
timeFrame: Through completion of 12 months after treatment commencement of last patient
measure: Describe health-related QoL within 12 months of treatment commencement
timeFrame: Through completion of 12 months after treatment commencement of last patient
Other outcomes:
Locations:
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
Study officials:
affiliation: Peter MacCallum Cancer Centre, Australia
name: Prof Michael Hofman
role: PRINCIPAL_INVESTIGATOR
References: