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Prostatic Neoplasms, Castration-ResistantPhase 1NCT04597411

Study of 225Ac-PSMA-617 in Men With PSMA-positive Prostate Cancer

A Phase 1 study testing 225^Ac-PSMA-617 and 68^Ga-PSMA-11 in people with Prostatic Neoplasms, Castration-Resistant, run by Endocyte at 2 sites in 2 countries.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial summary

This is a Phase 1, open-label, international, dose escalation study to evaluate the safety of [225Ac]Ac-PSMA-617 (225Ac-PSMA-617) in men with PSMA-positive prostate cancer who have and have not had prior exposure to [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) or [177Lu]Lu-PSMA I\&T (177Lu-PSMA I\&T). Read more about this study

Who is it for?
Ages 18 years and older, men only
What is being tested?
225^Ac-PSMA-617 and 68^Ga-PSMA-11
Could I receive a placebo?
No, everyone receives an active treatment
How many people
101 participants
Where
2 sitesin 2 countries
Study dates
1 Apr 2021to 1 Jan 2027
Phase
Phase 1
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • Men only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients must have the ability to understand and sign an approved ICF.
  • Patients must have the ability to understand and comply with all protocol requirements.
  • Patients must be >=18 years of age.
  • Patients must have an ECOG performance status of 0 to 2.
  • Patients must have had histological, pathological, and/or cytological confirmation of prostate cancer.
  • Patients must have a positive 68Ga-PSMA-11 PET/CT scan performed within 28 days of study entry. If a patient also has soft tissue or visceral disease, it must be PSMA-positive on 68Ga-PSMA-11 PET/CT scan.
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  • Patients may not participate in the study if their baseline scan shows PSMA-negative disease (defined as disease that expresses PSMA at a level equal to or less than liver by visual assessment) in any of the following regions:
  • One or more PSMA negative lymph nodes >2.5 cm on short axis B) Bone metastasis with PSMA-negative soft tissues component > 1 cm in short axis
  • Note that PSMA-negative osseous metastases without a soft tissue component >1 cm does not exclude the subject C) PSMA-negative solid organ metastases (i.e. lung, liver, adrenal glands, etc) that are PSMA-negative and ≥ 1cm in short axis
  • Patients must have recovered or stabilized to =< Grade 2 or baseline from all clinically significant toxicities related to prior prostate cancer therapy.
  • Determination of disease progression on treatment prior to enrollment. Progressive disease for study entry is defined as any one or more of the following:
  • PSA progression: minimum of two rising PSA values from a baseline measurement with an interval of >= 1 week between each measurement. 2.0 ng/mL is the minimal starting value if PSA rise is only indication of progression.
  • Soft tissue or visceral disease progression as per RECIST 1.1 criteria: 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.
  • Bone progression: >= 2 new lesions on bone scan.
  • Patients must have adequate organ function (bone morrow reserve, hepatic function and renal function).
  • Known HIV-positive patients who are healthy and have a low risk of AIDS-related outcomes are eligible. HIV testing is required.
  • For patients who have partners of childbearing potential, patient must use a method of birth control with adequate barrier protection, deemed acceptable by the principal investigator during the study and for 6 months after last study drug administration.
  • Group A Subjects: Patients must have prior orchiectomy and/or ongoing androgen-deprivation therapy, a castrate level of serum testosterone (< 50 ng/dL or < 1.7 nmol/L) and must have received prior cytotoxic chemotherapy and a novel androgen axis drug (e.g., abiraterone or enzalutamide). Patients must also be naïve to prior 177Lu-PSMA radioligand therapy (177Lu-PSMA-617 or 177Lu-PSMA I\&T)
  • Group B Subjects (South-Africa only): Patients must have ongoing androgen deprivation therapy (ADT) and either prior orchiectomy or be medically castrate using LHRH agonists/antagonists in order to achieve adequate suppression of serum testosterone (< 50 ng/dL) but must not have received prior cytotoxic chemotherapy or novel androgen axis drugs (e.g., abiraterone or enzalutamide). These patients are naïve to 177Lu-PSMA radioligand therapy (177Lu-PSMA-617 or 177Lu-PSMA I\&T).
  • Group C Subjects: Patients must have ongoing androgen deprivation therapy (ADT) and either prior orchiectomy or be medically castrate using LHRH agonists/antagonists in order to achieve adequate suppression of serum testosterone (< 50 ng/dL). Patients must have been treated with prior 177Lu-PSMA radioligand therapy (177Lu-PSMA-617 or 177Lu-PSMA I\&T) for at least one cycle administered greater than 6 weeks from study enrollment, and been evaluated for biochemical and radiological response to therapy. Prior exposure to ARPI and/or chemotherapy is not required.

Who cannot join

  • Previous treatment with Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223 or hemi-body irradiation.
  • Any investigational agents within 28 days of study enrollment.
  • Known hypersensitivity to the components of the study therapy or its analogues.
  • Other concurrent cytotoxic chemotherapy, targeted therapy, biologic agents, immunotherapy, radioligand therapy, or investigational therapy.
  • Transfusion for the sole purpose of eligibility into the study.
  • Patients with a history of CNS metastases must have received therapy (surgery, radiotherapy, gamma knife) and be neurologically stable, asymptomatic, 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, are stable, and not neurologically impaired.
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  • Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression.
  • Concurrent serious (as determined by the Principal Investigator) medical conditions, including, but not limited to, uncontrolled infection, active hepatitis B or C, or other significant co-morbid conditions that in the opinion of the investigator would impair study participation or cooperation.
  • Diagnosed with other malignancies that are expected to alter life expectancy or may interfere with disease assessment. Patients with a prior history of malignancy who have been disease free for more than 3 years are eligible.
  • Participants with an active documented COVID-19 infection (any grade of disease severity) at the time of informed consent may be included only when completely recovered (in accordance with local guidance).

Trial locations and contacts

2 sites in 2 countries.

2 sites in 2 countries

Australia1 site

  • St. Vincent's Hospital Research Office-Translational Research Center

    Darlinghurst

Other trials in Australia

South Africa1 site

  • Steve Biko Hospital-Department of Nuclear Medicine

    Pretoria

Other trials in South Africa

About this study

Official title: AcTION: A Phase I Study of [225Ac]Ac-PSMA-617 in Men With PSMA-positive Prostate Cancer With or Without Prior [177Lu]Lu-PSMA-617 Radioligand Therapy

This is a Phase 1, open-label, international, dose escalation study to evaluate the safety of [225Ac]Ac-PSMA-617 (225Ac-PSMA-617) in men with PSMA-positive prostate cancer who have and have not had prior exposure to [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) or [177Lu]Lu-PSMA I\&T (177Lu-PSMA I\&T).

Read the detailed description

Total duration of study participation of each participant is approximately 18-24 months (12 months from enrollment to end of each treatment (EOT) plus 12 months of long-term follow up (LTFU). The total duration of the study, from first patient in (FPI) to last LTFU will be approximately 48 months.

A minimum of 3 patients will be treated in each patient group at each dose level and evaluated for the occurrence of dose-limiting toxicity (DLT) during the first 6 weeks of treatment before consideration will be given to enrolling patients into the next dose level. Dose modifications for toxicity are allowed and defined per protocol.

No more than 6 cycles of 225Ac-PSMA-617 will be administered. Patients may receive less than 6 cycles if they have disease progression, intolerable toxicity, started other anticancer therapy, or have withdrawn from treatment per participant or physician decision.

Participants may also receive supportive care therapy, as determined by the study physician, however, participants cannot receive concurrent investigational agents, cytotoxic chemotherapy, biological agents, targeted therapy, immunotherapy, other systemic radioisotopes, and hemi-body radiotherapy until completion of treatment with 225Ac-PSMA-617.

Being tested
225^Ac-PSMA-617, 68^Ga-PSMA-11
Keywords
Androgen-Resistant Prostatic Neoplasms, Castration-Resistant Prostatic Cancer, Castration-Resistant Prostatic Neoplasms, Prostatic Cancer, Castration-Resistant, Prostatic Neoplasms, Genital Neoplasms, Male, Urogenital Neoplasms, Neoplasms by Site, Neoplasms, Genital Diseases, Male, Prostatic Diseases, [225Ac]Ac-PSMA-617, 225Ac-PSMA-617, [68Ga]Ga-PSMA-11, 68Ga-PSMA-11, [177Lu]Lu-PSMA-617, 177Lu-PSMA-617, [177Lu]Lu-PSMA I&T, 177Lu-PSMA I&T
Medical subject headings
Prostatic Neoplasms, Castration-Resistant, Prostatic Neoplasms, Genital Neoplasms, Male, Urogenital Neoplasms, Neoplasms by Site, Neoplasms, Genital Diseases, Male, Prostatic Diseases

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • 225^Ac-PSMA-617Radiation

    administered intravenously under the dose escalation schedule

  • 68^Ga-PSMA-11Radiation

    administered intravenously at a dose of 111 - 185 MBq (3 - 5 mCi)

Study groups in NCT04597411
Study groupRoleWhat they receive
Group A (mCRPC who have received prior ARPI and chemotherapy, but are PSMA RLT naïve)ExperimentalMen that have received prior cytotoxic chemotherapy and ARPI (e.g., abiraterone or enzalutamide), who HAVE NOT been previously treated with 177Lu-PSMA-617 radioligand therapy or 177Lu-PSMA I\&T will receive a dose of 225^Ac-PSMA-617 via intravenous injection every 8 weeks (+/- 1 week) for a maximum of 6 cycles.
Receives: Radiation: 225^Ac-PSMA-617; Radiation: 68^Ga-PSMA-11
Group B (mCRPC who have not had prior ARPI or chemotherapy, and are PSMA RLT naïve)ExperimentalMen previously treated with luteinizing hormone-releasing hormone (LHRH) agonists or orchiectomy and primary anti-androgen therapy that have not received prior cytotoxic chemotherapy or novel androgen axis drugs (e.g., abiraterone or enzalutamide) will receive a dose of 225Ac-PSMA-617 via intravenous injection every 8 weeks (+/- 1 week) for a maximum of 6 cycles.
Receives: Radiation: 225^Ac-PSMA-617; Radiation: 68^Ga-PSMA-11
Group C (mCRPC who have received prior PSMA RLT)ExperimentalMen with progressive metastatic castration resistant prostate cancer (mCRPC) who HAVE been previously treated with 177Lu-PSMA-617 radioligand therapy or 177Lu-PSMA I\&T will receive a dose of 225Ac-PSMA-617 via intravenous injection every 8 weeks (+/- 1 week) for a maximum of 6 cycles. Prior chemotherapy and/or novel androgen axis drugs not required.
Receives: Radiation: 225^Ac-PSMA-617; Radiation: 68^Ga-PSMA-11

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Recommended Phase 2 Dose (RP2D)

    The RP2D for each group (Group A, B and C) is defined as the dose level that is well tolerated (i.e., at or below the MTD) and for which there may be additional findings (e.g., longer term tolerability) effecting the RP2D decision. In the case where an MTD is not identified, even at the highest dose level tested, the RP2D may be determined on the basis of data indicating adequate tolerability and therapeutic effectiveness.

    Measured: 6 weeks post Cycle 1 Day 1 (C1D1) of each dosing cohort through enrollment completion, an average of 1.5 years to determine RP2D

Secondary outcomes (13)

  1. Percentage of Participants with treatment emergent adverse events

    Safety measured by the percentage of participants with treatment emergent adverse events (events started after the first dose of study medication or events present prior to start of treatment but increased in severity based on preferred term).

    Measured: Day 1/Infusion Day up to 60 days post infusion

  2. Overall Response Rate (ORR)

    Overall Response Rate (ORR) is defined as the proportion of participants with best overall response of Complete Response (CR) or Partial Response (PR) as measured by RECIST v1.1.

    Measured: Every 8 weeks after first dose of 225Ac-PSMA-617 for the first 24 weeks, then every 12 weeks through the end of treatment visit, on average 2.5 years

  3. Duration of Response (DOR)

    Duration of Response (DOR) is the time from the date of the first documented response (CR or PR) to the date of the first radiologically documented disease progression or death due to disease according to RECIST v1.1.

    Measured: Every 8 weeks after first dose of 225Ac-PSMA-617 for the first 24 weeks, then every 12 weeks through the end of treatment visit, on average 2.5 years

  4. Disease Control Rate (DCR)

    Disease Control Rate (DCR) is the percentage of participants with a best overall response of Complete Response (CR), Partial Response (PR) or Stable Disease (SD) according to RECIST v1.1.

    Measured: Every 8 weeks after first dose of 225Ac-PSMA-617 for the first 24 weeks, then every 12 weeks through the end of treatment visit, on average 2.5 years

  5. Progression Free Survival (PFS)

    Progression Free Survival (PFS) is defined as the time from Cycle 1 Day 1 (C1D1) to the first of radiographic, clinical, or prostate-specific antigen [PSA] progression-free survival, or censorship with events defined as follows:

    1. Radiographic disease progression as determined from bone scans and contrast CT/MRI as outlined in Prostate Cancer Working Group 3 (PCWG3) and RECIST 1.1
    2. Unequivocal clinical progression
    3. PSA progression, defined as the date that a ≥ 25% increase in PSA and an absolute increase of 2 ng/mL or more from the nadir is documented and confirmed by a second consecutive value obtained 3 or more weeks later. Rises in PSA within the first 12 weeks will be ignored. Where no decline from baseline is documented, baseline PSA is the nadir. The date of progression is date of first occurrence, not date of confirmation (PCWG3 Guidance).

    Measured: Every 8 weeks after first dose of 225Ac-PSMA-617 for the first 24 weeks, then every 12 weeks through the end of treatment visit, on average 2.5 years

  6. Percentage of Participants with Biochemical Response as measured by Prostate Specific Antigen (PSA)

    Prostate-specific antigen is a glycoprotein considered as a biomarker for the response to therapy in men with prostate cancer. A 50 percent (%) decline in PSA from Baseline to the PSA level at End of Study was considered as a PSA response.

    Measured: Baseline, Days 1, 15, 29 and 43 of each Cycle (1 cycle = 8 weeks +/- 1 week), End of Treatment and every 3 months during the 12-month follow-up period

  7. Notable Changes in Alkaline phosphatase (ALP) levels

    Safety measured by the notable post-baseline changes in Alkaline phosphatase (ALP) levels compared to baseline.

    Measured: Baseline, Cycle 1 and Cycle 2 (Weekly), Cycle 3 to Cycle 6 (Bi-weekly) (1 cycle = 8 weeks +/- 1 week)

  8. Notable Changes in Lactate dehydrogenase (LDH) levels

    Safety measured by the notable post-baseline changes in Lactate dehydrogenase (LDH) levels compared to baseline.

    Measured: Baseline, Cycle 1 and Cycle 2 (Weekly), Cycle 3 to Cycle 6 (Bi-weekly) (1 cycle = 8 weeks +/- 1 week)

  9. Change from Baseline in European Quality of Life (EuroQol) - 5 Domain 5 Level scale (EQ-5D-5L)

    EQ-5D-5L is a standardized participant completed questionnaire that measures health-related quality of life and translates that score into an index value or utility score. EQ-5D-5L consists of two components: a health state profile and an optional visual analogue scale (VAS). EQ-5D health state profile is comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1= no problems, 2= slight problems, 3= moderate problems, 4= severe problems, and 5= extreme problems. Higher scores indicated greater levels of problems across each of the five dimensions.

    Measured: Baseline, Day 1 of each Cycle (1 cycle = 8 weeks +/- week), End of Treatment, on average 2.5 years

  10. Change from Baseline in Functional Assessment of Cancer Therapy - Prostate (FACT-P) Questionnaire

    FACT-P assesses symptoms/problems related to prostate carcinoma and its treatment. It is a combination of the FACT- General + the Prostate Cancer Subscale (PCS). The FACT-General (FACT-G) is a 27 item Quality of Life (QoL) measure that provides a total score as well as subscale scores: Physical (0-28), Functional (0-28), Social (0-28), and Emotional Well-being (0-24). The total score range is between 1-108, higher scores indicates better for total score and subscale scores. PCS is a 12-item prostate cancer subscale that asks about symptoms and problems specific to prostate cancer (Range 0-48, higher scores better). The FACT-P total score is the sum of all 5 subscale scores of the FACT-P questionnaire and ranges from 0-156. Higher scores indicate higher degree of functioning and better quality of life.

    Measured: Baseline, Day 1 of each Cycle (1 cycle = 8 weeks +/- week), End of Treatment, on average 2.5 years

  11. Change from Baseline in Brief Pain Inventory - Short Form (BPI-SF) Questionnaire: Pain Severity Score

    The BPI-SF is a publicly available instrument to assess the pain and includes severity and interference scores. BPI-SF is an 11-item self-report questionnaire that is designed to assess the severity and impact of pain on daily functions of a participant. Pain severity score is a mean value for BPI-SF questions 3, 4, 5 and 6 (questions inquiring about the extent of pain, where the extent is ranked from 0 [no pain] to 10 [pain as bad as you can imagine]). Pain severity progression is defined as an increase in score of 30% or greater from baseline without decrease in analgesic use.

    Measured: Baseline, Day 1 of each Cycle (1 cycle = 8 weeks +/- week), End of Treatment, on average 2.5 years

  12. Change from Baseline in Brief Pain Inventory - Short Form (BPI-SF) Questionnaire: Pain Interference Score

    The BPI-SF is a publicly available instrument to assess the pain and includes severity and interference scores. BPI-SF is an 11-item self-report questionnaire that is designed to assess the severity and impact of pain on daily functions of a participant. Pain interference score is mean value for the 7 BPI-SF questions (questions inquiring about the extent of interference with activities by pain) where the extent is ranked from 0 (does not interfere) to 10 (completely interferes). Pain interference progression is defined as an increase in score of 50% or greater from baseline without decrease in analgesic use.

    Measured: Baseline, Day 1 of each Cycle (1 cycle = 8 weeks +/- week), End of Treatment, on average 2.5 years

  13. Change from Baseline in Xerostomia-Related Quality of Life Scale (XeQOLS)

    The XeQOLS is a validated patient reported 15-item assessment scale with 4 domains: physical functioning, pain/discomfort, personal/psychologic functioning, and social functioning. The score is the average of all responses of all domains and can range from 0 to 4, with higher scores indicating increased xerostomia burden. A negative change from Baseline indicates an improvement of the xerostomia burden.

    Measured: Baseline, Day 1 of each Cycle (1 cycle = 8 weeks +/- 1 week), End of Treatment and every 3 months during the 12-month follow-up period

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted22 Oct 2020
  2. Study start1 Apr 2021
  3. Primary completion1 Jan 2027 (estimated)
  4. Study completion1 Jan 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Model description
Study-eligible participants with PSMA-positive, metastatic, castration resistant (mCRPC) prostate cancer will be assigned to one of three groups, A, B, and C based on their prior prostate cancer treatment history: 1. Group A: Men that have received prior cytotoxic chemotherapy and an ARPI, who Have Not been previously treated with prior 177Lu-PSMA-617 radioligand therapy or 177Lu-PSMA I\&T. 2. Group B: Men that Have Not received cytotoxic chemotherapies, ARPIs, and 177Lu-PSMA radioligand therapy or 177Lu-PSMA I\&T. Due to geographical differences in disease presentation/aggressiveness and access to treatment of mCRPC, group B participants will be enrolled only in South Africa, after medical review determines the need for therapy as part of a clinical study. 3. Group C: Men who HAVE been previously treated with 177Lu-PSMA-617 radioligand therapy or 177Lu-PSMA I\&T. Prior chemotherapy or ARPI is not required.
Masking
None (open label)
Enrolment
101 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04597411
Sponsor's protocol ID
PSMA-617-100
Other IDs
CAAA817A12101
Status last verified
Apr 2026
First submitted
29 Sep 2020
Last updated
30 Apr 2026
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing 225^Ac-PSMA-617 and 68^Ga-PSMA-11 in people with Prostatic Neoplasms, Castration-Resistant, run by Endocyte at 2 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 20 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 30 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Australia, South Africa. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Recommended Phase 2 Dose (RP2D) (time frame: 6 weeks post Cycle 1 Day 1 (C1D1) of each dosing cohort through enrollment completion, an average of 1.5 years to determine RP2D). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04597411.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Apr 2026.

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