EValuation of radIOLigand Treatment in mEn With Metastatic Castration-resistant Prostate Cancer With [161Tb]Tb-PSMA-I&T (VIOLET)

• ClinicalTrials.gov Identifier: NCT05521412
• Recruitment Status: Active, not recruiting
• First Posted: August 30, 2022
• Last Update Posted: March 18, 2024
• Sponsor: Peter MacCallum Cancer Centre, Australia
• Information provided by (Responsible Party): Peter MacCallum Cancer Centre, Australia

Tracking Information

• First Submitted Date: August 22, 2022
• First Posted Date: August 30, 2022
• Last Update Posted Date: March 18, 2024
• Actual Study Start Date: September 29, 2022
• Estimated Primary Completion Date: August 3, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 26, 2022)

• Maximum Tolerated dose (MTD) [ Time Frame: Dose escalation phase is expected to be completed 6 months from the time the first patient is recruited. ]
  The MTD is defined as the highest dose level at which the incidence of DLT was less than 1/3 or 2/6.
• Adverse Events (AEs) and Serious Adverse Events (SAEs) measured using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 [ Time Frame: Through study completion, up until 12 months after the last patient commences treatment ]
  Safety of the combination will be measured by AEs and SAEs.
• Dose Limiting toxicities (DLTs) [ Time Frame: Dose escalation phase is expected to be completed 6 months from the time the first patient is recruited. ]
  A DLT is defined as a toxicity that prevents further administration of the trial treatment at that dose level. Each cohort of 3 patients will be assessed for DLTs after 6 weeks from administration of cycle 1.
• Recommended Phase 2 Dose (RP2D) [ Time Frame: Up to 30 months from the time the first patient is recruited. ]
  After the MTD is established, additional patients will be treated at the MTD. Safety and efficacy data from the study will be used to define the RP2D.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 26, 2022)

• Absorbed radiation dose [ Time Frame: On Day 4 of Cycle 1 (each Cycle is 42 days) ]
  Absorbed radiation dose will be determined using the SPECT/CT imaging after administration of the first dose of [161Tb]Tb-PSMA-I&T
• 50% Prostate-Specific Antigen Response Rate (PSA-RR) [ Time Frame: Through study completion, up until 12 months after the last patient commences treatment or until PSA progression ]
  PSA will be assessed at baseline and every 3 weeks from Cycle 1 Day 1 during treatment, and every 6 weeks during follow-up. PSA response will be defined as a 50% or greater decrease in PSA from baseline to the lowest post-baseline PSA result.
• Radiographic Progression-Free Survival (rPFS) [ Time Frame: Through study completion, up until 12 months after the last patient commences treatment ]
  rPFS is defined as the time from registration to the first date of documented radiographic progression using conventional imaging or death due to any cause, whichever occurs first. Radiographic progression will be assessed by the Investigator per RECIST 1.1 for soft tissue and PCWG3 for bone lesions
• PSA progression free survival (PSA-PFS) [ Time Frame: Through study completion, up until 12 months after the last patient commences treatment or until PSA progression ]
  PSA progression is defined as a rise in PSA by more than 25% AND more than 2ng/mL above the nadir (lowest PSA point). This needs to be confirmed by a repeat PSA performed at least 3 weeks later. Early rises in PSA prior to 12 weeks will be disregarded in determining PSA progression.
• Progression free survival (PFS) [ Time Frame: Through study completion, up until 12 months after the last patient commences treatment or until PSA progression ]
  PFS is defined as the time to PSA progression, radiographic progression, or death due to any cause
• Overall survival (OS) [ Time Frame: Through study completion, up until 12 months after the last patient commences treatment ]
  OS is defined as the time from treatment initiation to the date of death due to any cause.
• Objective response rate (ORR) by Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST1.1) in patients with measurable disease [ Time Frame: Through study completion, up until 12 months after the last patient commences treatment ]
  Objective Response (OR) is only applicable for the subset of patients with measurable disease by RECIST1.1. OR is defined as a partial response (PR) or complete response (CR) at any stage from time of commencement of protocol treatment to the time of subsequent systemic anti-cancer treatment. The ORR is calculated as the proportion of patients with a best response of CR or PR.
• Describe worst pain within 24 hours of Brief Pain Inventory-Short Form (BPI-SF) completion [ Time Frame: Pain will be assessed at baseline, then at 6, 12, 24, 36 and 48 weeks ]
  Pain will be assessed using the Brief Pain Inventory-Short Form (BPI-SF).
• Health-related quality of life (HR-QoL) [ Time Frame: Through completion of 12 months after treatment commencement of last patient ]
  HR-QoL will be assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. The endpoint is the trial outcome index (TOI) score from FACT-P

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: EValuation of radIOLigand Treatment in mEn With Metastatic Castration-resistant Prostate Cancer With [161Tb]Tb-PSMA-I&T
• Official Title: EValuation of radIOLigand Treatment in mEn With Metastatic Castration-resistant Prostate Cancer With [161Tb]Tb-PSMA-I&T: Phase I/II Study
• Brief Summary: This clinical trial will evaluate the safety and efficacy of [161Tb]Tb -PSMA-I&T in men with metastatic castration-resistant prostate cancer (mCRPC).

Detailed Description

This prospective, single-centre, single-arm phase I/II trial will assess the safety, efficacy and anti-tumour activity of [161Tb]Tb-PSMA-I&T in patients with mCRPC.

This study aims to assess and establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs) and recommended phase 2 dose (RP2D) of [161Tb]Tb-PSMA-I&T in patients with mCRPC.

30-36 men with mCRPC who have progressed with at least one line of taxane chemotherapy and at least one second-generation androgen receptor (AR)-targeted agent will be enrolled in this trial in two stages: dose escalation and a dose expansion phase over a period of 24 months

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Prostate Cancer
• Metastatic Castration-resistant Prostate Cancer

Intervention

Drug: [ 161 Tb]Tb PSMA I&T

During dose escalation, doses of [161 Tb]Tb PSMA I&T will range between 4.4 GBq to 7.4 GBq. The recommended phase 2 dose of [161 Tb]Tb PSMA I&T will be used during dose expansion. [161Tb]Tb-PSMA-I&T dose will be reduced by 0.4 GBq for each subsequent cycles (2 to 6).

Study Arms

Experimental: Experimental: Treatment Arm

In this single-arm study, patients will receive doses of [161 Tb]Tb PSMA I&T on Day 1 of every 6 week Cycle. The dose of [161 Tb]Tb PSMA I&T will vary in dose-escalation. Up to 6 Cycles will be given.

Intervention: Drug: [ 161 Tb]Tb PSMA I&T

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: March 14, 2024): 30
• Original Estimated Enrollment (submitted: August 26, 2022): 36
• Estimated Study Completion Date: December 2026
• Estimated Primary Completion Date: August 3, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Patient has provided written informed consent.
2. Male patients must be 18 years of age or older at the time of written informed consent.
3. 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 prostate specific antigen (PSA).
4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
5. Patients must have had prior treatment with at least one line of taxane chemotherapy, unless medically unsuitable.
6. Patients must have had prior treatment with at least one second-generation androgen receptor (AR)-targeted agent (e.g., enzalutamide, abiraterone, apalutamide or darolutamide).

7. Patients must have progressive disease defined according to The Prostate Cancer Clinical Trials Working Group 3 (PCWG3) as any one of the following:

   1. PSA progression - minimum of 2 rising PSA values from a baseline measurement with an interval of ≥ 1 week between each measurement
   2. Soft tissue progression as per Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1) criteria
   3. Bone progression: ≥ 2 new lesions on bone scan
8. Prior surgical orchiectomy or chemical castration maintained on luteinizing hormone-releasing hormone (LHRH) analogue (agonist or antagonist).
9. Serum testosterone levels ≤ 1.75nmol/L (≤ 50ng/dL).
10. Significant prostate specific membrane antigen (PSMA) avidity on PSMA positron emission tomography (PET)/computed tomography (CT), defined as a minimum uptake of maximum standardised uptake value (SUVmax) 20 at a site of disease, and SUVmax > 10 at sites of measurable soft tissue disease ≥ 15mm (unless subject to factors explaining a lower uptake, e.g. respiratory motion, reconstruction artefact).
11. Patients must have a life expectancy ≥ 6 months.

12. Patients must have adequate bone marrow, hepatic and renal function, defined as:

    1. Haemoglobin ≥ 100g/L independent of transfusions (no red blood cell transfusion in last 4 weeks)
    2. Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
    3. Platelets ≥ 150 x 10^9/L
    4. Total bilirubin ≤ 1.5x upper limit of normal (ULN) except for patients with known Gilbert's syndrome, where this applies for the unconjugated bilirubin component
    5. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3x ULN if there is no evidence of liver metastasis or ≤ 5x ULN in the presence of liver metastases
    6. Adequate renal function: patients must have a creatinine clearance estimated of ≥ 40mL/min using the Cockcroft Gault equation (Appendix 3)
13. Sexually active patients are willing to use medically acceptable forms of barrier contraception.
14. Willing and able to comply with all study requirements, including all treatments and the timing and nature of all required assessments.
15. At least 3 weeks since the completion of surgery or radiotherapy prior to registration.

Exclusion Criteria:

1. Prior treatment with another radioisotope (i.e. PSMA radioligands, radium-223, strontium-89, samarium-153).
2. Site(s) of discordant disease on PET imaging (Fluorodeoxyglucose [FDG]-positive and minimal PSMA-uptake).
3. Other malignancies (in addition to the prostate cancer being treated on this study) within the previous 2-years prior to registration other than basal cell or squamous cell carcinomas of skin or other cancers that are unlikely to recur within 24 months.
4. Symptomatic brain metastases or leptomeningeal metastases.
5. Patients with symptomatic or impending cord compression unless appropriately treated beforehand and clinically stable for more than 4 weeks.
6. Concurrent illness, including severe infection that may jeopardize the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety.

Sex/Gender

• Sexes Eligible for Study: Male
• Gender Based Eligibility: Yes

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia

Administrative Information

• NCT Number: NCT05521412
• Other Study ID Numbers: 21/028
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Peter MacCallum Cancer Centre, Australia
• Original Responsible Party: Same as current
• Current Study Sponsor: Peter MacCallum Cancer Centre, Australia
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Peter MacCallum Cancer Centre, Australia
• Verification Date: March 2024