[Ac-225]-PSMA-62 Trial in Biochemically Recurrent and Metastatic Castration Resistant Prostate Cancer (ACCEL)

[Ac-225]-PSMA-62 Phase I/II Clinical Trial to Characterize Efficacy, Safety, Tolerability, and Dosimetry in Biochemically Recurrent and Metastatic Castration Resistant Prostate Cancer (ACCEL)

ACCEL is a multicenter, open label phase I/II study of [Ac-225]-PSMA-62 in participants with prostate-specific membrane antigen (PSMA)-positive prostate cancer.

Study Overview

• Status: Recruiting
• Conditions: Prostate Cancer; Biochemically Recurrent Prostate Carcinoma; Metastatic Castration-resistant Prostate Cancer
• Intervention / Treatment: Drug: [Ac-225]-PSMA-62 (BCR); Drug: [Ac-225]-PSMA-62 (mCRPC)

Detailed Description

The primary aim of the phase I study is to evaluate the safety and tolerability of [Ac-225]-PSMA-62 to determine recommended phase II doses for patients with mCRPC and BCR prostate cancer. The aim of the phase II study for patients with mCRPC is to evaluate the efficacy of [Ac-225]-PSMA-62.

• Study Type: Interventional
• Enrollment (Estimated): 48
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Richard Cioci; Phone Number: 202 (647) 812-2417; Email: rcioci@pointbiopharma.com

Study Locations

• Canada
  • Quebec
    • Montréal, Quebec, Canada, H3H 2L9
      • Recruiting
      • McGill University Health Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adults aged 18 years or older
2. Histological, pathological, and/or cytological confirmation of adenocarcinoma of the prostate
3. Adequate organ function (bone marrow reserve, liver function, renal function)
4. Patients with human immunodeficiency virus who are healthy and have a low risk of acquired immunodeficiency syndrome-related outcomes are included in this trial.
5. Willing and able to comply with all study requirements and treatments (including [Ac-225]-PSMA-62) as well as the timing and nature of required assessments
6. ECOG performance status 0 to 2
7. Life expectancy of at least 6 months per investigator judgement
8. Patients and their female partner(s) of childbearing potential must agree to use two acceptable forms of contraception, one of which must be a barrier method during the study and for 21 weeks after last study drug administration.
9. The patient has read, understood, and signed the written informed consent form(s)

10. Criteria specific for patients with mCRPC:

    1. Previously received treatment for their underlying disease and have exhausted all satisfactory or available approved treatment options

    2. Progressive mCRPC at the time of consent based on at least 1 of the following criteria:

       • Serum/plasma PSA progression defined as increase in PSA greater than 25% and >2 ng/mL above nadir, with a confirmatory PSA test at least 1 week later
       • Soft-tissue progression defined as an increase ≥20% in the sum of the diameter (SOD) (short axis for nodal lesions and long axis for non-nodal lesions) of all target lesions based on the smallest SOD since treatment started or the appearance of one or more new lesions
       • Progression of bone disease defined as the appearance of one or more new lesions by bone scan
    3. Positive PSMA-PET within 90 days of enrolment; note that either [Ga-68] or [F-18] PSMA targeted agents, approved for commercial use, may be used as per diagnostic standard of care
    4. Castrate circulating testosterone levels (<1.74 nmol/L or <50 ng/dL)

11. Criteria specific for patients with BCR:

    1. The patient's primary tumor must have been previously treated with surgery and/or definitive radiation. Prior salvage treatments (radiation or surgery) to the prostate bed or pelvis are allowed

    2. Biochemical recurrence after primary therapy. Patients without any prior ADT, or those with prior ADT having recovered testosterone to within the normal range - defined as ≥5.2 nmol/L (≥150 ng/dL) - must meet the following thresholds for BCR:

       • Patients with prior radical prostatectomy, with or without definitive radiation treatment must have a prostate specific antigen (PSA) ≥ 0.2ng/mL OR,
       • Patients who received only definitive radiation for treatment of their primary tumor must have a PSA of ≥ 2 ng/mL above nadir
    3. Positive PSMA-PET within 90 days of enrolment. Either [Ga-68] or [F-18] PSMA targeted agents, which are approved by the respective health authority, may be used as per standard of care (diagnostic protocols) for each institution
    4. No indication for urgent or emergent radiation
    5. Patient has not received any form of prostate-cancer directed therapy since undergoing screening PSMA scan

Exclusion Criteria:

1. Patients with neuroendocrine or small cell carcinoma of the prostate
2. Major surgery ≤30 days prior to start of study treatment
3. Patient has received any other investigational therapeutic agents within 4 weeks or 5 halflives (whichever is shorter) of starting the study treatment
4. Evidence of ongoing and untreated urinary tract obstruction
5. History of grade 4 myelosuppression lasting > 7 days, or grade 3 myelosuppression requiring more than 6 weeks recovery
6. Patients receiving medications which are known to cause xerostomia or xerophthalmia (e.g. Darafenicin) are excluded if they are not on stable doses for at least 4 weeks prior to screening
7. Existing Grade 1 dry mouth (xerostomia) or symptomatic Grade 1 dry eye (xerophthalmia) for any reason
8. Contraindications to the use of planned [Ac-225]-PSMA-62 therapy, including but not limited to hypersensitivity to [Ac-225]-PSMA-62 excipients
9. Has a known history of other malignancy within the last 5 years. Except: malignancies that were treated curatively and have not recurred within 2 years prior to study treatment; completely resected basal cell and squamous cell skin cancers; any malignancy considered to be indolent and that has never required therapy; and completely resected carcinoma in situ of any type
10. Patient has any concurrent severe and/or uncontrolled medical conditions that could increase the patient's risk for toxicity while on the study or that could confound discrimination between disease- and study treatment-related toxicities
11. Serious psychological, familial, sociological, or geographical condition that might hamper compliance with the study protocol and follow-up schedule.
12. Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression
13. Inability to lie flat during or tolerate PET/CT or MRI
14. History of Torsades de Pointes or congenital prolonged QT syndrome
15. Concurrent serious (as determined by the investigator) medical conditions

16. Criteria specific for patients with mCRPC:

    1. Patient has received any therapeutic systemic radionuclides (e.g., radium-223, rhenium-186, strontium-89), or therapeutic radioligands (e.g., Lu-177-PSMA) within 5 half-lives of starting the study treatment
    2. Patients currently receiving systemic anti-cancer therapy, with the exception of ADT with or without ARPI. However, patients may be included in the study if they stop all prohibited anti-cancer therapy, prior to receiving the first dose of investigational study drug
    3. Patient has initiated therapy with, or switch to, an alternative ARPI since PSMA-PET scan used for eligibility. Patients already receiving an ARPI may continue treatment with the same ARPI during study
    4. Patients with a history of central nervous system (CNS) metastases must have received therapy (surgery, radiotherapy, gamma knife) and be neurologically stable, and not receiving corticosteroids for the purposes of maintaining neurologic integrity. Patients with epidural disease, canal disease, and prior cord involvement are eligible if those areas have been treated and are stable. For patients with parenchymal CNS metastasis (or a history of CNS metastasis), baseline and subsequent radiological imaging must include evaluation of the brain

17. Criteria specific for patients with BCR:

    1. Any prior cytotoxic chemotherapy
    2. Prior treatment with therapeutic systemic radionuclides (e.g., radium-223, rhenium-186, strontium-89), or therapeutic radioligands (e.g. Lu-177-PSMA)
    3. Prior immuno-therapy or adoptive T-Cell Therapy (e.g. CAR-T therapy, TCR therapy, etc.)
    4. Prior poly ADP ribose polymerase (PARP) inhibitor for prostate cancer
    5. Patient has received any systemic anti-cancer therapy for prostate cancer with the exception of limited course of ADT for management of localized disease
    6. Presence of any liver metastases
    7. Use of opioids for cancer-related pain ≤ 30 days prior to screening
    8. Known presence of central nervous system metastases

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BCR; Patients with BCR prostate cancer, after definitive surgery or radiation therapy, who have PSMA-positive disease and have not yet initiated lifelong hormone therapy.	Drug: [Ac-225]-PSMA-62 (BCR); Administered intravenously per dose escalation scheme. Patients will receive a single dose of [Ac-225]-PSMA-62 on Day 1 of each 8-week cycle for up to 2 cycles.
Experimental: mCRPC; Patients with PSMA-positive mCRPC who have exhausted all satisfactory or available approved treatment options.	Drug: [Ac-225]-PSMA-62 (mCRPC); Administered intravenously per dose escalation scheme. Patients will receive a single dose of [Ac-225]-PSMA-62 on Day 1 of each 6-week cycle for up to 4 cycles.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recommended Phase II Dose (RP2D)	Treatment emergent adverse events (TEAEs) and dose limiting toxicities (DLTs) for [Ac-225]-PSMA-62	From first dose of study drug through end of treatment (~16 - 24 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The incidence of treatment emergent adverse events as assessed per CTCAE v5.0	To assess safety and tolerability of [Ac-225]-PSMA-62	From first dose of study drug through end of study (~5 years)
Time to initiation of any life-long ADT or hormonal therapies	BCR only: Preliminary efficacy assessment	From first dose of study drug through end of study (~5 years)
Objective Response Rate (ORR)	mCRPC only: Preliminary efficacy assessment based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) (soft tissue) and the Prostate Cancer Working Group 3 (PCWG3) criteria (bone) per investigator review	From first dose of study drug until disease progression (up to approximately 3 years)
Absorbed dose estimates (Gy) in normal organs	Evaluation of the biodistribution and radiation dosimetry of [Ac-225]-PSMA-62 to normal organs	From first dose of study drug through end of treatment (~16 - 24 weeks)
The proportion of patients with a PSA change from baseline	To determine the effect of [Ac-225]-PSMA-62 on prostate-specific antigen (PSA) kinetics	From first dose of study drug through efficacy follow-up period (up to approximately 3 years)
The change from baseline in Patient-Reported Outcome Common Terminology Criteria (PRO-CTCAE) Questionnaire scores	To determine the effect of [Ac-225]-PSMA-62 on patient reported outcomes (PROs) responses scored from 0 ("never", "none", "not at all") to 5 ("almost constantly", "very severe", "very much") on the frequency, severity and/or interference of symptoms related to adverse events	From first dose of study drug until disease progression (up to approximately 3 years)

Collaborators and Investigators

• Sponsor: POINT Biopharma, a wholly owned subsidiary of Eli Lilly and Company
• Collaborators: Eli Lilly and Company
• Investigators: Study Director: Richard Cioci, POINT Biopharma, a wholly owned subsidiary of Eli Lilly and Company

Study record dates

Study Major Dates

• Study Start (Actual): March 26, 2024
• Primary Completion (Estimated): August 1, 2027
• Study Completion (Estimated): March 1, 2032

Study Registration Dates

• First Submitted: January 3, 2024
• First Submitted That Met QC Criteria: January 19, 2024
• First Posted (Actual): January 29, 2024

Study Record Updates

• Last Update Posted (Actual): April 23, 2024
• Last Update Submitted That Met QC Criteria: April 18, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: mCRPC; Radioligand Therapy; Castration Resistant Prostate Cancer; Prostatic Neoplasms; Genital Neoplasms, Male; BCR; Radiopharmaceuticals; Actinium; Urogenital Neoplasm; Oligometastatic Prostate Cancer; Biochemically Recurrent Prostate Cancer; [225Ac]-PSMA-62; Ac-225-PSMA-62
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Disease Attributes; Genital Neoplasms, Male; Prostatic Diseases; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Prostatic Neoplasms; Recurrence
• Other Study ID Numbers: PSMA-62-01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No