Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Rare Diseases

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Kennedy Disease

Antineoplastic Agents

All Drugs and Chemicals

Pembrolizumab

Antibodies

Gallium 68 PSMA-11

Androgens

Immunoglobulins

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Hormones

Hormone Antagonists

Radiopharmaceuticals

Patients will receive one dose of 225Ac-J591 (single dose, either 65 or 90 Kbq/kg) in combination with pembrolizumab (400mg every 6 weeks) and ARPI (standard dose schedule, examples of ARPI include enzalutamide and apalutamide).

Patients will receive pembrolizumab (400mg every 6 weeks) and ARPI (standard dose schedule) without 225Ac-J591.

Alpha-emitter Actinium-225 conjugated to the anti-PSMA antibody J591.

225Ac-J591

Pembrolizumab will be administered intravenously, 400mg every 6 weeks. Patients may receive maximum 18 cycles of therapy, approximately 2 years.

Patients will receive an oral androgen receptor pathway inhibitor (ARPI). Examples include enzalutamide and apalutamide. Dosing will be the standard dosing, as described by the package insert.

Androgen receptor pathway inhibitor

\[185 ±74 MBq or 5 ±2 mCi\] intravenous during screening and 12 weeks. Imaging agent for PSMA PET/CT.

68Ga-PSMA-11

GUONC Research Team

Himisha Beltran, MD

Peter Gregos, MD

GUOnc Research Team

Scott Tagawa, MD, MS

Mark Stein, MD

This is a phase I/II study investigating the combination of 225Ac-J591 (a drug that can deliver radiation to prostate cancer cells) with pembrolizumab (immunotherapy, a drug that increases the immune system's ability to destroy cancer cells). This study will assess whether 225Ac-J591 + pembrolizumab + androgen receptor pathway inhibitor (ARPI) is more effective against prostate cancer than pembrolizumab + ARPI alone.

This clinical trial is for men with progressive metastatic castration-resistant prostate cancer (mCRPC). The primary objectives of the study are to determine the optimal dose of 225Ac-J591 when combined with pembrolizumab (phase I) and then to assess whether the combination of 225Ac-J591, pembrolizumab, and androgen receptor pathway inhibitor (ARPI) is more effective against prostate cancer than pembrolizumab and ARPI alone. 225Ac-J591 is a radionuclide conjugate involving Actinium-225 linked to J591, an antibody that recognizes prostate-specific membrane antigen (PSMA) on the surface of cancer cells; 225Ac-J591 is able to deliver powerful radiation to cancer cells. Pembrolizumab is a drug that strengthens the body's immune response to cancer cells. In the phase I portion of the study, two cohorts of up to 6 patients each will receive combined therapy: ARPI (standard dosing schedule), pembrolizumab (400 mg every 6 weeks), 225Ac-J591 (single dose, either 65 or 90 KBq/kg). Following a minimum of 12 weeks of safety follow-up, the study team will determine which 225Ac-J591 dose is better. In the phase II portion, patients will be randomized to pembrolizumab + ARPI with or without 225Ac-J591. The primary endpoint for phase II will be response - a composite of PSA, circulating tumor cell (CTC) count, and imaging changes. Patients who achieve at least one of the criteria will be considered responders. Imaging (CT scan, bone scan) will occur every 12 weeks. Additionally, participants will undergo 68Ga-PSMA-11 PET/CT scan prior to therapy and at 12 weeks. Patients are able to receive pembrolizumab every 6 weeks for maximum 18 cycles (approximately 2 years).

In the phase I portion of the study, patients will receive 225Ac-J591 at either 65 or 90 KBq/kg, in addition to pembrolizumab and ARPI. In the subsequent phase II portion of the study, patients will be randomized to receive 225Ac-J591 (at the dose determined in phase I) + ARPI and pembrolizumab or ARPI and pembrolizumab alone in a 1:1 ratio. Randomization will take into account prior receipt of ARPI, baseline PSMA imaging intensity, and presence of visceral metastasis.

Metastatic Castrate Resistant Prostate Cancer

Phase I/II Trial of Pembrolizumab and Androgen-receptor Pathway Inhibitor With or Without 225Ac-J591 for Progressive Metastatic Castration Resistant Prostate Cancer

Primary outcome for phase I; DLTs will be measured by utilizing the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. There will be 12 weeks of safety follow-up following visit 1.

Primary outcome for phase I; following 12 weeks of safety follow-up, the study team will make a determination of the 225Ac-J591 dose for phase II (either 65 or 90 KBq/kg).

The primary outcome for phase II will be response, a composite of: PSA decline greater than 50% of baseline, measurable disease response by imaging criteria, conversion of circulating tumor cell count to favorable or undetectable.

Overall survival will be captured through in-clinic or telephone contact with subjects

PSA progression will be defined as a rise of \> 25% above either the pretreatment level or the nadir PSA level (whichever is lowest). PSA must increase by \> 2 ng/ml to be considered progression.

Response evaluation criteria in solid tumors RECIST (Version 1.1) criteria with prostate cancer working group 3 (PCWG3) modifications will be used.

By imaging (RECIST 1.1 criteria with prostate cancer working group 3 modifications) or biochemical (PSA) criteria

Baseline (pre-treatment) PSA levels will be compared to PSA nadir on study

United States Department of Defense

Merck Sharp & Dohme LLC

Weill Medical College of Cornell University

Taxane

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

Administered intravenously once every 6 weeks (1 cycle) for a maximum of 6 cycles.

[177Lu]Lu-PSMA-617

Best supportive/best standard of care as defined by the local investigator

Best supportive/best standard of care (BS/BSOC)

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

Novartis Pharmaceuticals

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:

1. 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.
2. 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:

1. 30-day Safety Follow-up. All treated participants should have a safety follow-up conducted approximately 30 days after EOT visit.
2. 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.

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)

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data is currently available according to the process described on www.clinicalstudydatarequest.com

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.

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

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).

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

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase I/II Trial of Pembrolizumab and Androgen-receptor Pathway Inhibitor With or Without 225Ac-J591 for Progressive Metastatic Castration Resistant Prostate Cancer	NCT04946370	Prostate Cancer	225Ac-J591 Pembrolizumab Androgen recept... 68Ga-PSMA-11	18 Years - 99 Years	Weill Medical College of Cornell University
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	NCT05670106	Metastatic Cast...	[177Lu]Lu-PSMA-... Best supportive... 68Ga-PSMA-11	18 Years -	Novartis
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	NCT05670106	Metastatic Cast...	[177Lu]Lu-PSMA-... Best supportive... 68Ga-PSMA-11	18 Years -	Novartis
Phase I/II Trial of Pembrolizumab and Androgen-receptor Pathway Inhibitor With or Without 225Ac-J591 for Progressive Metastatic Castration Resistant Prostate Cancer	NCT04946370	Prostate Cancer	225Ac-J591 Pembrolizumab Androgen recept... 68Ga-PSMA-11	18 Years - 99 Years	Weill Medical College of Cornell University

Spots Global Cancer Trial Database for androgen receptor pathway inhibitor