Clarity Pharmaceuticals announced the successful completion of cohort 3 and advancement to cohort 4, the first multi-dose cohort in the SECuRE trial. The SECuRE trial (NCT04868604) is a Phase I/IIa theranostic trial for identification and treatment of Prostate-Specific Membrane Antigen (PSMA) expressing mCRPC using 64Cu/67Cu-SAR-bisPSMA. 64Cu-SAR-bisPSMA is used to visualise PSMA expressing lesions and select candidates for subsequent 67Cu-SAR-bisPSMA therapy.

The trial is a multi-centre, single arm, dose escalation trial with a cohort expansion involving up to 44 patients in the US. The aim of the trial is to determine the safety and efficacy of 67Cu-SAR-bisPSMA for the treatment of prostate cancer. Cohort 3 of the dose escalation phase of the trial, where 6 participants received a single administration of 12GBq of 67Cu-SAR-bisPSMA, has been successfully completed.

No DLTs have been reported in any of the participants dosed in this cohort to date. The SRC, responsible for assessing safety of participants and overseeing the general progress of the trial, has assessed the data and recommended progressing the trial to cohort 4 where participants will be treated with multiple therapy cycles of 67Cu-SAR-bisPSMA at a dose level of 12GBq, the highest dose level in the dose escalation phase of the trial. All participants in the SECuRE trial had advanced prostate cancer (stage IV, mCRPC).

Assessment of the baseline characteristics of these patients showed that they were heavily pre-treated before entering the study, having received multiple therapies for their disease. Those treatments included ADT, ARPI, several investigational agents (targeting different pathways of the cancer), chemotherapy and other radioligand therapies. Most trial participants had received chemotherapy (67%, 10/15) and the median number of lines of therapy prior to receiving 67Cu-SAR-bisPSMA was 4. The median PSA at study entry was 117.1 ng/ml (range 0.11-1,494.2).

Preliminary data shows that despite having high levels of PSA and having received multiple treatments, 60% (9/15) of participants across all cohorts (including the lowest dose cohort of 67Cu-SAR-bisPSMA at 4GBq) showed reductions in PSA levels of greater than 35% from a single therapy cycle of 67Cu-SAR-bisPSMA. PSA reductions of greater than 80% were seen in 27% of all trial participants. In cohorts 2 and 3 (8 and 12GBq, respectively), PSA reductions of greater than 35% were observed in almost 80% (78%, 7/9) of participants and PSA was reduced by greater than 80% in 44% (4/9) of participants so far.

Participants in cohort 3 had the highest median baseline PSA and the highest median number of systemic therapies across all cohorts (median baseline PSA 122.6, 47.2 and 140.3 ng/ml; median lines of therapy 4, 3 and 5.5; cohorts 1, 2 and 3, respectively). Nevertheless, two-thirds (67%) of participants in this cohort so far have shown reductions in PSA greater than 35%, with the last participants in this cohort dosed in January 2024. Importantly, a single dose of 12GBq of 67Cu-SAR-bisPSMA was effective in reducing PSA levels in the majority of these patients despite receiving the most lines of prior therapy.

The overall analysis of all cohorts showed that 67Cu-SAR-bisPSMA administered as a single cycle has a favorable safety profile. AEs were reported as related to 67Cu-SAR-bisPSMA in 8 out of the 15 trial participants (all grades). No AEs were reported as related to 64Cu-SAR-bisPSMA.

Most AEs related to 67Cu-SAR-bisPSMA were grade 1 or 2. The most common grade 3 AE was anaemia, reported in 2/15 participants (13%). Based on the safety profile observed in the first 3 cohorts of the SECuRE trial, a change to the dosing schedule of cohort 4 from "2 doses" to "up to 4 doses" has been approved by the SRC. The amendment to the protocol is currently underway, which will be submitted to the US Food and Drug Administration (FDA) and respective Institutional Review Boards (IRBs) for implementation.

This will allow patients who are benefiting from 67Cu-SAR-bisPSMA to receive 2 additional doses under the SECuRE trial in cohort 4 (up to 4 doses in total). Dosimetry has been incorporated into the SECuRE trial in order to assess the absorbed dose (mGy/MBq) in organs and lesions by 67Cu-SAR-bisPSMA using single-photon emission computed tomography (SPECT) at various timepoints post 67Cu-SAR-bisPSMA injection. Dosimetry images showed prolonged tumour retention of 67Cu-SAR-bisPSMA with kidney clearance.

Dose escalation in the current SECuRE study protocol is based on observed organ toxicity rather than arbitrary organ absorbed dose thresholds derived from external beam radiation therapy. Nevertheless, the dosimetry results show high uptake and retention of 67Cu-SAR-bisPSMA in lesions and good clearance from organs, supporting the administration of multiple doses of 67Cu-SAR-bisPSMA at the highest dose level (12GBq). Some participants in the SECuRE trial who have shown clinical benefit during the dose escalation phase of the study received additional cycles of 67Cu-SAR-bisPSMA under the EAP, as outlined in previous announcements.

The first participant from the SECuRE trial to receive additional doses under EAP had achieved a PSA reduction of 61.7% following the administration of a single dose of 4GBq of 67Cu-SAR-bisPSMA in cohort 1 of the trial (PSA reduction from 15.9 to 6.5 ng/ml 6 months post-injection). The treating clinician requested 3 additional doses under the EAP, and the patient continued to show further decrease in PSA levels, to 1 ng/ml (last follow-up). The overall reduction in PSA after 4 doses of 67Cu-SAR-bisPSMA was 93.7%.

This level of reduction has been recently confirmed at the patient's last follow-up, 13 months after the first dose of 67Cu-SAR-bisPSMA. The PSA reduction has also been accompanied by a decrease in uptake of 67Cu-SAR-bisPSMA, measured by SPECT. No adverse events were reported related to either product, 64Cu-SAR-bisPSMA or 67Cu-SAR-bisPSMA.

Another participant from the SECuRE trial (cohort 2, single dose of 8GBq of 67Cu-SAR-bisPSMA) showed a reduction in PSA level of 99.4%. The treating clinician requested a second dose of 67Cu-SAR-bisPSMA under EAP, which led to a further reduction of the patient's PSA to undetectable levels. A radiographical response was also noted: prostate cancer was undetectable using PET and a near complete response (CR) to treatment at the last assessment was observed using Response Evaluation Criteria In Solid Tumours 1.1 (RECIST) assessment.

The reduction in size of one lymph node missed the CR cut-off by 2 mm (reduction in diameter post 67Cu-SAR-bisPSMA cycles from 27 to 12 mm) at time of imaging.