ACTinium in Castrate-RESistant Prostate Cancer After LUTEtium

A Multi-site, Prospective, Open-label Phase I/II Trial of Actinium (225Ac) rhPSMA 10.1 to Evaluate Safety and Anti-tumour Activity in Men With Metastatic Castrate-resistant Prostate Cancer (mCRPC) Including Those Who Have Previously Responded to Lutetium-PSMA

Advanced metastatic castration-resistant prostate cancer is a medical condition for which additional effective and tolerable treatments are urgently needed in order to improve patient outcomes and quality of life.

The goal of this clinical trial is to learn more about Actinium (225Ac) radiohybrid prostate-specific membrane antigen-10.1 (rhPSMA-10.1) injection in men with prostate cancer that has spread and progressed after previous treatments, particularly after Lutetium-PSMA.

Actinium (225Ac) rhPSMA-10.1 is an injectable radioactive medication that aims to attach to prostate cancer cells in the body and destroy them using ionising radiation. It is a new medication that has not yet been studied in humans.

Participants will receive a dose of Actinium (225Ac) rhPSMA-10.1 every 6 weeks, to a maximum of 6 doses. They will be reviewed regularly by the trial researchers to monitor side effects and safety signals. A range of medication doses will be administered so that researchers can find out what doses of the medication are safe for men with prostate cancer. The trial will also aim to determine how effective this medication is for treating advanced prostate cancer.

This is a multi-site, prospective, open-label Phase I/II trial of Actinium (225Ac) rhPSMA-10.1 for men with metastatic castration-resistant prostate cancer (mCRPC). The novel ligand radiohybrid (rh) PSMA-10.1 has shown favourable properties in early clinical and preclinical studies. As an emitter of alpha-radiation, Actinium-225 is expected to deposit greater energy at a shorter range than beta-emitting Lutetium-177, conferring the potential to overcome prior PSMA-based radioligand therapy failure.

Phase I of this trial will focus on dose-finding and medication safety. It will investigate men with mCRPC who have previously responded to Lutetium-PSMA, however, a small number of participants will be permitted to be Lutetium-PSMA-naïve. Participants will additionally be assessed for early signals of treatment activity and there will also be an exploratory dosimetry component.

Phase II will utilise the dose selected from Phase I and expand the treatment cohort. In Phase II all participants are required to have previously responded to Lutetium-PSMA.

Study participants must all undergo a screening process and meet trial criteria before they begin any treatment. Provided they tolerate treatment well and their prostate cancer does not worsen during treatment, participants will be offered further treatment every six weeks, to a maximum of six doses.

Study participants will be reviewed weekly by a trial doctor to ensure they are tolerating treatment well and that any potential side effects of the treatment are identified and addressed. These reviews will sometimes be done remotely e.g. on the phone. Monitoring blood tests will be done regularly, and in Phase II this will also include collection of blood samples for exploratory genetic analysis. After starting treatment, participants will have a CT and bone scan every 12 weeks in order to assess whether their prostate cancer sites are responding to treatment.

After trial treatment is complete, participants will be asked to remain on follow-up to help build an understanding of any long-term impacts of the treatment.

Phase I 177Lu-PSMA requirement:

The first 3 participants treated at each dose level may be 177Lu-PSMA treatment naïve or may have previously received 177Lu-PSMA treatment. Additional participants recruited at any dose level must have received prior 177Lu-PSMA treatment and had a response to therapy, as judged by the treating physician.

Phase II 177Lu-PSMA requirement:

All participants must have received prior 177Lu-PSMA and had a response to therapy, as judged by the treating physician.

Inclusion Criteria:

1. Age ≥ 18 years at time of providing informed consent.

2. Histologically- or cytologically-confirmed diagnosis of prostate adenocarcinoma, which may include small cell or neuroendocrine features.

3. Castration-resistant prostate cancer, defined as a rising PSA despite surgical castration or ongoing medical castration, with serum testosterone ≤ 0.5ng/mL or <1.7 nmol/L.

4. Progressive mCRPC with rising PSA level, as defined by PCWG3 criteria, or by radiological progression, and must demonstrate a sequence of rising values above baseline at a minimum of 1-week intervals and PSA > 1 ng/mL.

5. PSMA-avid disease on screening PSMA-PET-CT scan

6. Prior treatment with at least one second-generation androgen receptor pathway inhibitor (ARPI)

7. Prior treatment with at least one but no more than two lines of taxane therapy for prostate cancer, or been deemed ineligible or refused taxane therapy on consultation with their treating physician.

8. At least 4 weeks or 5 half-lives (whichever is longer) elapsed between last anti-cancer treatment administration and the initiation of trial treatment. Anti-cancer treatment includes ARPIs and PARP inhibitors but excludes ADT (e.g. luteinising hormone releasing hormone (LHRH) analogue or gonadotropin-releasing hormone treatment), which should be continued. Prednisone up to 10 mg daily (or equivalent) is also permitted.

9. Prior treatment with 177Lu-PSMA-targeted radiopharmaceutical therapy (e.g. 177Lu-PSMA-617, 177Lu PSMA-I&T) up to a maximum of 6 cycles and with response to therapy as judged by the treating physician.

   Exception: in Phase I, the first 3 participants treated at each dose level may be 177Lu-PSMA naïve Note: last treatment with 177Lu-PSMA must be more than 10 weeks prior to study enrolment.

10. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1.

11. Estimated life expectancy > 12 weeks.

12. Grade ≤ 1 xerostomia symptoms at time of trial enrolment.

13. Adequate bone marrow, renal, and hepatic function

14. Resolution of all previous treatment-related toxicities to CTCAE v5.0 Grade ≤ 1, except for chemotherapy-induced alopecia, Grade 2 peripheral neuropathy, and Grade 2 urinary frequency, which are permitted.

15. Adequate contraception for participants and their partners.

16. Willing and able to provide written informed consent.

Exclusion Criteria:

1. Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression.

2. Active metastatic central nervous system (CNS) disease, including leptomeningeal disease.

3. Receipt of 177Lu-PSMA treatment within 10 weeks of trial enrolment.

4. Prior radiotherapeutic treatment for metastatic prostate cancer (e.g. Radium-223) with the exception of 177Lu-PSMA.

   Note: prior radiotherapeutic treatment for other cancers is permitted (e.g. radioactive iodine for thyroid cancer).

5. Receipt of transfused blood products or erythropoietin stimulating agents within 4 weeks of trial enrolment.

6. Major surgery within 12 weeks of trial enrolment.

7. Other current malignancy, or malignancy diagnosed/relapsed within the past 5 years (other than non melanomatous skin cancer, stage 0 melanoma in situ, or non-muscle invasive bladder cancer that has undergone curative intent therapy).

8. Sjogren's disease or any other medical conditions that in the judgement of the investigator puts the participant at increased risk of xerostomia.

9. Single kidney, renal transplant or any nephrotoxic condition or concomitant therapy that in the judgement of the investigator could put the participant at risk of unacceptable renal toxicity during the trial.

10. Severe urinary incontinence or any other conditions that in the judgement of the investigator would preclude safe disposal of radioactive urine.

11. Any structural kidney/renal tract disease that in the judgement of the investigator could affect excretion of the trial agent (e.g. hydronephrosis), unless addressed with intervention (e.g. ureteric stent insertion with normalisation of renal function).

12. Clinically significant abnormalities on a single 12-lead electrocardiogram (ECG) during screening evaluation.

13. Concurrent serious conditions that in the judgement of the investigator would pose a safety risk or impair trial participation.

14. Radiation therapy within 2 weeks before trial enrolment.

15. Hypersensitivity to the investigational product or any of its constituents.

16. Current participation in another trial with ongoing receipt of an investigational agent.

17. Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the trial protocol and follow-up schedule, or that would pose a risk to the participant's safety.