A Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Dosimetry of [177Lu]Lu-PSMA-617 in Chinese Adult Male Patients With Progressive PSMA-Positive mCRPC

A Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Dosimetry of [177Lu]Lu-PSMA-617 in Chinese Adult Male Patients With Progressive PSMA-Positive mCRPC

A Prospective, Open-label, Multi-center, Single-arm, Phase II Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Dosimetry of [177Lu]Lu-PSMA-617 in Chinese Adult Male Patients With Progressive PSMA-Positive Metastatic Castration-Resistant Prostate Cancer (mCRPC)

The purpose of this study is to assess the efficacy, safety, tolerability, Pharmacokinetic(s) (PK) and dosimetry of [177Lu]Lu-PSMA-617 when administered in addition to Best Supportive/Best Standard of Care (BSC/BSoC) in Chinese participants with progressive PSMA-positive mCRPC who received at least 1 novel androgen receptor pathway inhibitor (ARPI) and were previously treated with 1 to 2 taxane regimens. Furthermore, the safety, PK, and dosimetry of [68Ga]Ga-PSMA-11 are assessed. Data from this study will be used to bridge global pivotal phase III study (VISION, AAA617A12301) and to support China registration of [177Lu]Lu-PSMA-617 as a novel anticancer modality, namely radioligand therapy, in mCRPC.

This is a 2-part study: Main part: Approximately 30 participants with at least 1 measurable lesion by PCWG3-modified RECIST v1.1 criteria will be enrolled in the main part. The primary endpoint of confirmed ORR will be analyzed with participants in this part, and will be assessed via independent centralized review of radiographic images provided by the Investigator and as outlined in PCWG3-modified RECIST v1.1 criteria. Extension part: The extension part will enroll additional 30 participants with or without measurable lesions following the main part. The secondary endpoints will be analyzed with all participants in both main part and extension part. Screening and enrollment period: Written informed consent form (ICF) must be obtained prior to any screening procedures. All screening procedures described in the Assessment Schedule must be completed within 28 days prior to enrollment, except for radiographic imaging assessment, which must be done within 21 days prior to enrollment. The participants will be assessed for eligibility and will undergo a mandatory [68Ga]Ga-PSMA-11 Positron Emission Tomography (PET)/Computed Tomography (CT) scan to evaluate Prostate-specific Membrane Antigen (PSMA) positivity for eligibility as assessed by central readers. Only participants with PSMA positive cancer and confirmed eligibility criteria will be enrolled. Following completion of all required screening procedures and verifying participant eligibility, the participant will be enrolled. [177Lu]Lu-PSMA-617 will be ordered in parallel with interactive response technology (IRT) enrollment registration to allow at least 2 weeks to order and deliver [177Lu]Lu-PSMA-617. Treatment period: In principle, all participants should begin [177Lu]Lu-PSMA-617 dosing within 14 days after enrollment registration. However, Cycle 1 Day 1 (C1D1) can be delayed by up to an additional 3 days only for unexpected scheduling delays. Participants will receive 7.4 Gigabecquerel (GBq) (200 Millicuries (mCi)) +/- 10% [177Lu]Lu-PSMA-617 once every 6 weeks for a planned 6 cycles. BSC/BSoC may be used, including available care for the eligible participants according to best institutional practice. ARPIs (e.,g., abiraterone, etc.) are allowed. BSC/BSoC for each participant will be selected at the discretion of the Investigator prior to [177Lu]Lu-PSMA-617 administration, and can be modified over time as needed. BSC/BSoC will be administered per the physician's orders according to clinical best practice. Radiographic imaging (CT with contrast/Magnetic Resonance Imaging (MRI) and bone scan) will be done at every 8 weeks (± 4 days) after first dose of [177Lu]Lu-PSMA-617 for the first 24 weeks (independent of dose delays), then every 12 weeks (± 4 days) thereafter and at End of Treatment (EOT) Visit (if not done within 28 days of EOT) until radiographic disease progression confirmed by central reader, death, withdrawal of consent, loss to follow-up, or subject/guardian's decision. After the last day of study treatment period of [177Lu]Lu-PSMA-617 (i.e. after completion of 6 cycles of treatment OR treatment discontinuation for any reason) [e.g. upon radiographic progression as confirmed by blinded independent centralized review]), the participants must have an EOT visit performed ≤ 7 days and enter into the Post-treatment Follow-up period. If a participant withdraws consent for the treatment period of the study, an EOT must be done and the participant will enter into the Post-treatment Follow-up unless he specifically withdraws consent for post-treatment Follow-up. Post-treatment Follow-up period: 30-day Safety Follow-up. All treated participants should have a safety follow-up conducted approximately 30 days after EOT visit. Long term Follow-up. The long-term follow-up starts after the 30-day Safety follow-up and lasts until study completion. If a participant in the long term follow-up period discontinues treatment for reasons other than BICR-determined radiographic progression, his tumor assessments must be performed every 8 weeks after first dose of study treatment for the first 24 weeks (week 9, 17, 25) and then every 12 weeks (week 37, 49, etc) until confirmation of radiographic progression by BICR. The long-term follow-up period will also include the collection of survival and treatment updates, patient reported outcomes (PROs), serious adverse events (suspected to be related to study treatment), as well as blood sampling for hematology, chemistry testing, coagulation, and PSA. The visits will be carried out every 12 weeks (± 4 weeks) until death, lost to follow-up, withdrawal of consent, opposition to use data/biological samples or study completion, whichever occurs first. This follow-up will allow the data collection on medically significant long-term toxicities, such as long-term radiotoxicity. If the participant withdraws consent for the collection of blood samples, PROs, and imaging assessments during the long-term follow-up, the information on survival, serious adverse events (SAEs) related to study treatment and post-treatment antineoplastic therapy will be collected. PK/dosimetry assessments: Both PK and dosimetry of [68Ga]Ga-PSMA-11 will be evaluated in at least 10 and up to 12 participants (at least 6 participants in main part). PK and dosimetry of [68Ga]Ga-PSMA-11 can be evaluated in any participant regardless of his PSMA status. Both PK and dosimetry of [177Lu]Lu-PSMA-617 will be evaluated in at least 10 and up to 12 participants (at least 6 participants in main part). Participants who take part in PK and dosimetry evaluation of [177Lu]Lu-PSMA-617 will also take part in the efficacy and safety evaluation together with the other participants. The treatment and assessment procedure follow the same as above.

Chinese adult male population, therapeutic agent lutetium (177Lu) vipivotide tetraxetan, [177Lu]Lu-PSMA-617, radiolabeled compound gallium (68Ga) gozetotide, [68Ga]Ga-PSMA-11, Progressive PSMA-Positive Metastatic Castration-Resistant Prostate Cancer, Overall Response Rate, ORR, Prostate-specific Membrane Antigen, PSMA, Taxane, Androgen Receptor Pathway Inhibitor, ARPI

Patients will receive the investigational product 7.4 GBq (+/- 10%) 177Lu-PSMA-617 intravenously every 6 weeks (+/- 1 week) for a maximum of 6 cycles. Best supportive/best standard of care (BS/BSOC) may be used

single intravenous dose of approximately 150 MBq. Administered dose must not be lower than 111 MBq or higher than 259 MBq (3 - 7 mCi).

Confirmed Overall Response Rate (ORR) is defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR). ORR is based on PCWG3-modified RECIST v1.1 response for patients with measurable disease at baseline.

From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 49 months

Radiographic progression free survival (rPFS) is defined as the time of radiographic progression by Prostate Cancer Working Group 3 (PCWG3)-modified RECIST V1.1 as assessed by blinded independent central review, or death

From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 57 months (estimated final OS analysis)

Overall survival (OS) is defined as the time from the date of enrollment to the date of death due to any cause. If a participant is not known to have died, then OS will be censored at the latest date the participant was known to be alive (on or before the cut-off date).

From date of randomization until date of death from any cause, assessed up to 57 months (estimated final OS analysis)

Overall response rate (ORR)is defined as the proportion of participants with best overall response of complete response or partial response in soft tissue as per BIRC and according to PCWG3 modified RECIST 1.1

From date of randomization till 30 day safety follow-up or at the end of long term FU for patients prematurely discontinued, assessed up to 57 months (estimated final OS analysis)

Disease control rate (DCR) is defined as the proportion of participants with best overall response of complete response or partial response or Stable disease in soft tissue as per BIRC and according to PCWG3 modified RECIST 1.1

From date of randomization till 30 day safety follow-up or at the end of long term FU for patients prematurely discontinued, assessed up to 57 months (estimated final OS analysis)

Duration of response (DOR) is defined as the duration of time between the date of first documented response (CR or PR) in soft tissue as per BIRC and according to PCWG3 modified RECIST 1.1, and the date of first documented progression or death due to any cause.

From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to 57 months (estimated final OS analysis)

Time to a first symptomatic skeletal event (TTSSE) is defined as date of randomization to the date of first new symptomatic pathological bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention, requirement for radiation therapy to relieve bone pain or death from any cause, whichever occurs first.

From date of randomization till date of death from any cause, assessed up to 57 months (estimated final OS analysis)

PSA response rate is the proportion of PSA responders, defined as a participant who has achieved PSA decrease of >= 50% from baseline that is confirmed by a second consecutive PSA measurement >= 4 weeks later. Determination of response status will be based on PCWG3 recommendations.

From date of randomization till 30 days safety fup, assessed up to 57 months (estimated final OS analysis)

Progression Free Survival (PFS) is defined as the time from date of randomization to the date of first documented progression by investigator assessment (radiographic progression, clinical progression, PSA progression) or death from any cause, whichever occurs first.

From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to 57 months (estimated final OS analysis)

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.

From date of randomization till 30 day safety follow-up or at the end of long term FU for patients prematurely discontinued, assessed up to 57 months (estimated final OS analysis)

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 FACTGeneral (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.

From date of randomization till 30 day safety follow-up or at the end of long term FU for patients prematurely discontinued, assessed up to 57 months (estimated final OS analysis)

The BPI-SF is a publicly available instrument to assess the pain and includes severity and interference scores. BPI-SF is an 11-item selfreport 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.

From date of randomization till 30 day safety follow-up or at the end of long term FU for patients prematurely discontinued, assessed up to 57 months (estimated final OS analysis)

The distribution of adverse events will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs) and Serious Adverse Event (TESAEs), through the monitoring of relevant clinical and laboratory safety parameters.

From date of randomization till 30 days safety fup, assessed up to 57 months (estimated final OS analysis)

Main & extension parts: Area under the blood concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of [177Lu]Lu-PSMA-617

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization of [177Lu]Lu-PSMA-617 in at least 10 and up to 14 patients. AUClast will be listed and summarized using descriptive statistics.

Cycle 1 Week 1(Day 1) and Cycle 1 Week 2(Day 8): Pre dose, 0(End of infusion), 20 & 60 mins(+/- 5 mins), 2 & 4 hours(+/-30 mins), 24 hours(+/- 2 hr), 48 hours(+/- 4 hr), 72 hours(+/- 6 hr), 168 hours(+/- 12 hr) from the end of infusion (1 cycle=42 days)

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization of [177Lu]Lu-PSMA-617 in at least 10 and up to 14 patients. Cmax will be listed and summarized using descriptive statistics.

Cycle 1 Week 1(Day 1) and Cycle 1 Week 2(Day 8): Pre dose, 0(End of infusion), 20 & 60 mins(+/- 5 mins), 2 & 4 hours(+/-30 mins), 24 hours(+/- 2 hr), 48 hours(+/- 4 hr), 72 hours(+/- 6 hr), 168 hours(+/- 12 hr) from the end of infusion (1 cycle=42 days)

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization of [177Lu]Lu-PSMA-617 in at least 10 and up to 14 patients. Blood concentration of [177Lu]Lu-PSMA-617 will be summarized with descriptive statistics.

Cycle 1 Week 1(Day 1) and Cycle 1 Week 2(Day 8): Pre dose, 0(End of infusion), 20 & 60 mins(+/- 5 mins), 2 & 4 hours(+/-30 mins), 24 hours(+/- 2 hr), 48 hours(+/- 4 hr), 72 hours(+/- 6 hr), 168 hours(+/- 12 hr) from the end of infusion (1 cycle=42 days)

The quantity of ionizing radiation absorbed by organs and tissues will be summarized with descriptive statistics.

Cycle 1 Week 1(Day 1) and Cycle 1 Week 2(Day 8): Pre dose, 0(End of infusion), 20 & 60 mins(+/- 5 mins), 2 & 4 hours(+/-30 mins), 24 hours(+/- 2 hr), 48 hours(+/- 4 hr), 72 hours(+/- 6 hr), 168 hours(+/- 12 hr) from the end of infusion (1 cycle=42 days)

Main & extension parts: Area under the blood concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of [68Ga]Ga-PSMA-11

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization of [68Ga]Ga-PSMA-11 in at least 10 and up to 14 patients. AUClast will be listed and summarized using descriptive statistics.

Screening (Day -42 to Day -14) : 5 mins (+/- 3 mins), 15 & 30 & 45 mins (+/- 5 mins), 85 mins (+/- 10 mins), 175 & 245 mins (+/- 30 mins) from the end of infusion

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization of [68Ga]Ga-PSMA-11 in at least 10 and up to 14 patients. Cmax will be listed and summarized using descriptive statistics.

Screening (Day -42 to Day -14) : 5 mins (+/- 3 mins), 15 & 30 & 45 mins (+/- 5 mins), 85 mins (+/- 10 mins), 175 & 245 mins (+/- 30 mins) from the end of infusion

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization of [68Ga]Ga-PSMA-11 in at least 10 and up to 14 patients. Blood concentration of [68Ga]Ga-PSMA-11 will be summarized with descriptive statistics.

Screening (Day -42 to Day -14) : 5 mins (+/- 3 mins), 15 & 30 & 45 mins (+/- 5 mins), 85 mins (+/- 10 mins), 175 & 245 mins (+/- 30 mins) from the end of infusion

The quantity of ionizing radiation absorbed by organs and tissues will be summarized with descriptive statistics.

Screening (Day -42 to Day -14): 30 mins (+/- 5 mins), 60 mins (+/- 10 mins), 120 mins (+/- 20 mins) and 255 mins (+/- 30 mins) from the end of infusion

Inclusion Criteria: Written informed consent must be obtained before any assessment is performed. Participants must be Chinese male adults >= 18 years of age. Participants must have histological, pathological, and/or cytological confirmation of prostate cancer. Participants must be [68Ga]Ga-PSMA-11 PET/CT scan positive, and eligible as determined by the sponsor's central reader according to the VISION read rules. Participants must have a castrate level of serum/plasma testosterone (< 50 ng/dl, or < 1.7 nmol/L). Participants must have received at least one ARPI (such as enzalutamide and/orabiraterone). Participants must have been previously treated with at least 1, but no more than 2 previous taxane regimens. A taxane regimen is defined as a minimum exposure of 2 cycles of a taxane. If a participant has received only 1 taxane regimen, the participant is eligible if: the participants' physician deems him unsuitable to receive a second taxane regimen (e.g., frailty assessed by geriatric or health status evaluation or intolerance, etc.) Documented progressive mCRPC, based on at least 1 of the following criteria: Serum/plasma PSA progression defined as 2 consecutive increases in PSA measured at least 1 week apart, the minimal start value is 2.0 ng/ml Soft-tissue progression defined based on PCWG3-modified RECIST v1.1 (Eisenhauer et al 2009, Scher et al 2016) Progression of bone disease: two new lesions; only positivity on the bone scan defines metastatic disease to bone (PCWG3 criteria (Scher et al 2016) Participants must have >= 1 metastatic lesion that is present on baseline CT, MRI or bone scan imaging obtained =< 21 days prior to enrollment via central reading. In main part: participant must have at least one measurable lesion by PCWG3-modified RECIST v1.1 via central reading Participants must have adequate organ function: Bone marrow reserve: White blood cell (WBC) count >= 2.5 × 109/L OR absolute neutrophil count (ANC) >= 1.5 × 109/L Platelets >=100 × 109/L Hemoglobin >= 9 g/dL Hepatic: Total bilirubin =< 1.5 x the institutional upper limit of normal (ULN). For participants with known Gilbert's Syndrome =< 3 × ULN is permitted Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) =< 3.0 × ULN OR =< 5.0 × ULN for participants with liver metastases Renal: eGFR >= 50 mL/min/1.73m2 using the Modification of Diet in Renal Disease (MDRD) equation Albumin >3.0 g/dL. Exclusion Criteria: Previous treatment with Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223 or hemi-body irradiation. Previous PSMA-targeted radioligand therapy. Any systemic anti-cancer therapy (e.g. chemotherapy, immunotherapy or biological therapy [including monoclonal antibodies], APRI is not included) within 28 days prior to day of enrollment. Any investigational agents (e.g. poly adenosine diphosphate-ribosyl polymerase inhibitors [PARPi]) within 28 days prior to day of enrollment. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar chemical classes. Other concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, or investigational therapy. Transfusion for the sole purpose of making a subject eligible for study inclusion. Participants with a history of central nervous system (CNS) metastases who are neurologically unstable, symptomatic, or receiving corticosteroids for the purpose of maintaining neurologic integrity. Participants with CNS metastases are eligible if received therapy (surgery, radiotherapy, gamma knife), asymptomatic and neurologically stable without corticosteroids. Participants with epidural disease, canal disease and prior cord involvement are eligible if those areas have been treated, are stable, and not neurologically impaired. Symptomatic spinal cord compression, or clinical or radiologic findings indicative of impending cord compression.

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