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
Overview
- Phase
- Phase 1
- Status
- Not yet recruiting
- Sponsor
- University College, London
- Enrollment
- 60
- Primary Endpoint
- Phase II anti-tumour response
Overview
Brief Summary
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.
Detailed Description
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.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- Male
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •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:
- •Age ≥ 18 years at time of providing informed consent.
- •Histologically- or cytologically-confirmed diagnosis of prostate adenocarcinoma, which may include small cell or neuroendocrine features.
- •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.
- •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.
- •PSMA-avid disease on screening PSMA-PET-CT scan
Exclusion Criteria
- •Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression.
- •Active metastatic central nervous system (CNS) disease, including leptomeningeal disease.
- •Receipt of 177Lu-PSMA treatment within 10 weeks of trial enrolment.
- •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).
- •Receipt of transfused blood products or erythropoietin stimulating agents within 4 weeks of trial enrolment.
- •Major surgery within 12 weeks of trial enrolment.
- •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).
- •Sjogren's disease or any other medical conditions that in the judgement of the investigator puts the participant at increased risk of xerostomia.
- •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.
Arms & Interventions
Phase I dose escalation/de-escalation of Actinium (225Ac) rhPSMA-10.1
Participants with advanced metastatic castration-resistant prostate cancer (mCRPC) will receive Actinium (225Ac) rhPSMA-10.1. The dose received by successive participants will be determined according to a pre-specified dose escalation/de-escalation scheme.
Intervention: Actinium (225Ac) rhPSMA-10.1 (Drug)
Phase II cohort expansion at recommended Phase II dose
Participants with advanced metastatic castration-resistant prostate cancer (mCRPC) will receive Actinium (225Ac) rhPSMA-10.1 at the recommended Phase II dose determined in Phase I.
Intervention: Actinium (225Ac) rhPSMA-10.1 (Drug)
Outcomes
Primary Outcomes
Phase II anti-tumour response
Time Frame: From date of IMP administration until the occurrence of PSA nadir (for PSA50) or best radiographic response (for Objective Radiographic Response), monitored for a maximum of 5 years.
Proportion of patients with response to treatment, defined as either (or both) of: PSA reduction of ≥ 50% from baseline (PSA50), objective radiographic response as assessed by imaging using Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1) with Prostate Cancer Working Group 3 (PCWG3) recommendations
Phase I incidence of dose-limiting toxicities (DLTs)
Time Frame: From time of IMP administration until completion of the dose-limiting toxicity period, which is 6 weeks.
Incidence of DLTs during the DLT observation period
Secondary Outcomes
No secondary outcomes reported