Castration Levels of TestosteronePhase 1NCT03805594
177Lu-PSMA-617 and Pembrolizumab in Treating Patients With Metastatic Castration-Resistant Prostate Cancer
A Phase 1 study testing Lutetium Lu 177-PSMA-617 and Pembrolizumab in people with Castration Levels of Testosterone and Castration-Resistant Prostate Carcinoma, run by University of California, San Francisco at 1 site in United States.
Trial summary
This phase Ib trial studies the dose and schedule of 177Lu-PSMA-617 and pembrolizumab in treating persons with castration-resistant prostate cancer that has spread to other places in the body. Read more about this study
- Who is it for?
- Ages 18 years and older, men only
- Conditions the study is for
- Castration Levels of Testosterone, Castration-Resistant Prostate Carcinoma, Metastatic Prostate Carcinoma
- What is being tested?
- Lutetium Lu 177-PSMA-617 and Pembrolizumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 43 participants
- Where
- 1 siteUnited States
- Study dates
- 10 May 2019to 10 Jan 2024
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Men only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- The subject is able and willing to comply with study procedures and provide signed and dated informed consent
- Histologically confirmed prostate adenocarcinoma. De novo small cell neuroendocrine prostate cancer will not be allowed due to putative lower PSMA expression in this tumor subtype. Treatment-emergent small cell neuroendocrine prostate cancer detected in metastatic tumor biopsy is not an exclusion
- A minimum of three PSMA-avid lesions on baseline 68Ga-PSMA-11 PET, with positive lesions defined as those with maximum standardized uptake value (SUVmax) values greater than liver.
- Progressive metastatic castration-resistant prostate cancer by Prostate Cancer Working Group (PCWG)3 criteria at the time of study entry
- Castrate level of serum testosterone at study entry (< 50 ng/dL). Participants without prior bilateral orchiectomy are required to remain on luteinizing hormone-releasing hormone (LHRH) analogue treatment for duration of study
- Prior progression on at least one second generation androgen signaling inhibitor including abiraterone, apalutamide, darolutamide, and/or enzalutamide
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- Absolute neutrophil count > 1.5 x 10^9/L
- Hemoglobin > 9.0 g/dL
- Platelet count > 100,000/microliter
- Serum creatinine =< 1.5 x upper limit of normal (ULN) or estimated glomerular filtration rate (GFR) > 50 ml/min by Cockcroft-Gault or 24 hour urine collection
- Total bilirubin =< 1.5 x ULN. In participants with known or suspected Gilbert's disease, direct bilirubin =< ULN
- Aspartate aminotransferase and alanine aminotransferase =< 2.5 x ULN (<= 5 x ULN in participants with liver metastases)
- No other systemic anti-cancer therapies administered other than LHRH analogue within 14 days, or 5 half-lives, whichever is shorter, prior to initiation of study treatment. Adverse events related to prior anti-cancer treatment other than LHRH analog treatment must have recovered to Grade <= 1 with the exception of any grade alopecia and grade <= 2 neuropathy.
- Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Participants must use appropriate methods of contraception during study treatment and for at least 60 days after last study treatment
- Participants who are sexually active should consider their female partner to be of childbearing potential if she has experienced menarche and is not postmenopausal (defined as amenorrhea > 24 consecutive months) or has not undergone successful surgical sterilization. Even women who use contraceptive hormones (oral, implanted, or injected), an intrauterine device, or barrier methods (diaphragms, condoms, spermicide) should be considered to be of childbearing potential
- Participants who have undergone vasectomy themselves should also be considered to be of childbearing potential
- Acceptable methods of contraception include continuous total abstinence, or double-barrier method of birth control (e.g. condoms used with spermicide, or condoms used with oral contraceptives). Periodic abstinence and withdrawal are not acceptable methods of contraception
- Participants must provide consent to comply to recommended radioprotection precautions during study
- Participants willing to undergo tumor biopsy and have at least one lesion safely accessible to tumor biopsy. Bone or soft tissue lesion is allowed
- Measurable disease by RECIST 1.1 criteria
Who cannot join
- Untreated brain metastases at study entry. Participants with previously treated brain metastases are eligible provided the following criteria are all met:
- Last treatment was > 28 days prior to cycle 1 day 1 (C1D1)
- No evidence of new/progressive brain metastases is observed on magnetic resonance imaging (MRI) obtained during screening window
- Patient is clinically stable without requirement of steroid treatment for at least 14 days prior to first dose of study treatment
- Receipt of prior PSMA-directed treatment (e.g. radiotherapy, immunotherapy, or antibody-drug conjugate)
- Prior enrollment on clinical study investigating Lu-PSMA-based radioligand therapy
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- Prior treatment with radium-223 or other radioisotope for the treatment of prostate cancer
- Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (=< 2 weeks of radiotherapy) to non-central nervous system (CNS) disease
- Receipt of prior pembrolizumab or another immune checkpoint inhibitor (e.g. nivolumab, ipilimumab)
- Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment
- Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent
- Receipt of taxane chemotherapy applied in the castration-resistant setting. Prior receipt of taxane chemotherapy in the hormone-sensitive setting is allowed
- Grade > 2 peripheral neuropathy at the time of study entry
- Has severe hypersensitivity (>= grade 3) to pembrolizumab and/or any of its excipients
- Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) or treatment with drugs (e.g. neomercazole, carbimazole, etc.) that function to decrease the generation of thyroid hormone by a hyperfunctioning thyroid gland (e.g. in Graves? disease) is not considered a form of systemic treatment of an autoimmune disease
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy at a prednisone equivalent dose of > 10 mg daily or other form of immunosuppressive therapy within 7 days prior to first dose of study drug
- Has a history of (non-infectious) ≥ grade 2 pneumonitis/interstitial lung disease that required steroids within past 2 years or has current ≥ grade 1 pneumonitis/interstitial lung disease at the time of study enrollment..
- Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed.
- Participants who because of age, general medical or psychiatric condition, or physiologic status cannot give valid informed consent
- Has clinically significant cardiovascular disease including, but not limited to:
- Uncontrolled or any New York Heart Association class 3 or 4 congestive heart failure
- Uncontrolled angina, history of myocardial infarction, unstable angina or stroke within 6 months before study entry
- Clinically significant arrhythmias not controlled by medication. Chronic rate controlled or paroxysmal atrial fibrillation/flutter is not an exclusion to study participation
- Prior external beam radiation involving >= 25% of bone marrow or within 14 days of start of protocol therapy
- Major surgery within 28 days of study treatment
- Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.
- Has an active infection requiring systemic therapy
- Has a known history of human immunodeficiency virus (HIV) (screening not required)
- Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (HCV) (defined as HCV ribonucleic acid [RNA] [qualitative] is detected) infection (screening not required)
- Has a known history of active Bacillus tuberculosis (TB)
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
- Any condition that, in the opinion of the principal investigator, would impair the patient's ability to comply with study procedures
- History of bleeding diathesis and not currently on anti-coagulation therapy that cannot be safely discontinued for the tumor biopsy procedure
Trial locations and contacts
1 site in 1 country.
United States1 site
University of California, San Francisco
San Francisco, California, 94143
About this study
Official title: Immunogenic Priming With PSMA-Targeted Radioligand Therapy in Advanced Prostate Cancer: A Phase 1b Study of 177Lu-PSMA-617 in Combination With Pembrolizumab
This phase Ib trial studies the dose and schedule of 177Lu-PSMA-617 and pembrolizumab in treating persons with castration-resistant prostate cancer that has spread to other places in the body. 177Lu-PSMA-617 carries a radioactive component which attached to the prostate specific membrane antigen (PSMA) receptor found on tumor cells. Its radiation component destroys the tumor cell. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving 177Lu-PSMA-617 and pembrolizumab may work better at treating prostate cancer.
Read the detailed description
PRIMARY OBJECTIVES:
- To determine the recommended phase 2 dose and schedule of lutetium Lu 177-PSMA-617 (177Lu-PSMA-617) in combination with pembrolizumab in participants with metastatic castration-resistant prostate carcinoma (mCRPC). (Part A)
- To determine the objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. (Part B (Dose Expansion))
SECONDARY OBJECTIVES:
- To characterize the safety profile of the combination.
- To determine the median duration of response by RECIST 1.1 criteria.
- To determine the proportion of participants who experience >= 50% decline from baseline in serum prostate-specific antigen (PSA).
- To determine the median PSA progression-free survival.
- To determine the median time to symptomatic skeletal related event.
- To determine the 6 month radiographic progression-free survival rate and median radiographic progression-free survival.
- To determine the median overall survival.
CORRELATIVE OBJECTIVES:
- To assess the lesion-specific response rate by baseline PSMA avidity on gallium Ga 68-labeled PSMA-11 (68Ga-PSMA-11) positron emission tomography (PET).
- To quantify the change from baseline in T cell repertoire, circulating T cell subsets, tumor infiltrating lymphocytes, and tumor programmed death-ligand 1 (PD-L1) expression by immunohistochemistry after one priming dose of Lu-PSMA radioligand therapy (RLT).
- To explore the relationship between timing of the 177Lu-PSMA-617 priming dose with initiation of pembrolizumab with respect to immunologic, safety, and efficacy outcomes.
- To descriptively characterize the patterns of uptake on 68Ga-PSMA-11 PET at the time of disease progression.
- To explore relationship between tumor genomic profile with clinical outcomes including response rate and progression-free survival.
- To explore the relationship between tumor dosimetry with objective response.
OUTLINE: Participants are assigned sequentially to 1 of 3 treatment schedules.
DOSING SCHEDULE 1: Participants receive lutetium Lu 177-PSMA-617 intravenously (IV) over 20-30 minutes on day 1 before beginning pembrolizumab IV over 30 minutes on day 1 in cycle 2
DOSING SCHEDULE 2: Participants receive lutetium Lu 177-PSMA-617 IV over 20-30 minutes concurrently with pembrolizumab IV over 30 minutes on day 1.
DOSING SCHEDULE 3: Starting day -21, participants receive pembrolizumab IV over 30 minutes. Participants then receive lutetium Lu 177-PSMA-617 IV over 20-30 minutes on day 1.
In all dosing schedules, treatment with pembrolizumab repeats every 21 days for up to 35 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Participants who achieve stable disease (SD) or better may receive 17 additional cycles (approximately 1 year) of pembrolizumab.
After completion of study treatment, participants are followed up at 30 days after treatment has been discontinued.
- Conditions
- Castration Levels of Testosterone, Castration-Resistant Prostate Carcinoma, Metastatic Prostate Carcinoma, Prostate Adenocarcinoma, Stage IV Prostate Cancer, Stage IVA Prostate Cancer
- Being tested
- Lutetium Lu 177-PSMA-617, Pembrolizumab
- Medical subject headings
- Prostatic Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Lutetium Lu 177-PSMA-617Drug
Also called 177Lu-PSMA-617, Lu177-PSMA-617
Given IV
PembrolizumabBiological
Also called Keytruda, Lambrolizumab, MK-3475, SCH 900475
Given IV
| Study group | Role | What they receive |
|---|---|---|
| Part A: Dosing Schedule 1 (lutetium Lu 177-PSMA-617, pembrolizumab) | Experimental | Participants receive lutetium Lu 177-PSMA-617 IV over 20-30 minutes on day 1. Beginning in cycle 2, participants receive pembrolizumab IV over 30 minutes on day 1. Treatment with pembrolizumab repeats every 21 days for up to 35 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Participants who achieve stable disease (SD) or better may receive 17 additional cycles (approximately 1 year) of pembrolizumab. Receives: Drug: Lutetium Lu 177-PSMA-617; Biological: Pembrolizumab |
| Part A: Dosing Schedule 2 (lutetium Lu 177-PSMA-617, pembrolizumab) | Experimental | Participants receive lutetium Lu 177-PSMA-617 IV over 20-30 minutes and pembrolizumab IV over 30 minutes on day 1. Treatment with pembrolizumab repeats every 21 days for up to 35 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Participants who achieve SD or better may receive 17 additional cycles (approximately 1 year) of pembrolizumab. Receives: Drug: Lutetium Lu 177-PSMA-617; Biological: Pembrolizumab |
| Part A: Dosing Schedule 3 (lutetium Lu 177-PSMA-617, pembrolizumab) | Experimental | Starting day -21, participants receive pembrolizumab IV over 30 minutes. Participants also receive lutetium Lu 177-PSMA-617 IV over 20-30 minutes on day 1. Treatment with pembrolizumab repeats every 21 days for up to 35 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Participants who achieve SD or better may receive 17 additional cycles (approximately 1 year) of pembrolizumab. Receives: Drug: Lutetium Lu 177-PSMA-617; Biological: Pembrolizumab |
| Part B: Recommended Phase 2 Dosing Schedule (RP2DS) (lutetium Lu 177-PSMA-617, pembrolizumab) | Experimental | Participants will receive the RP2DS determined in Part A. Treatment with pembrolizumab repeats every 21 days for up to 35 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Participants who achieve SD or better may receive 17 additional cycles (approximately 1 year) of pembrolizumab. Receives: Drug: Lutetium Lu 177-PSMA-617; Biological: Pembrolizumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Reported Dose Limiting Toxicities (DLT) (Part A Only)
The Recommended Phase 2 Dosing Schedule (RP2DS) (Schedule 1: a single priming dose of 177Lu-PSMA-617 (7·4 giga-becquerel (GBq) [200 millicurie (mCi)] given 28 days before pembrolizumab; Schedule 2: a single priming dose of 177Lu-PSMA-617 given concomitant with pembrolizumab; or Schedule 3: a single priming dose of 177Lu-PSMA-617 given 21 days after the start of maintenance pembrolizumab (200 mg every 3 weeks)) will be determined from the safety data as classified by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 for dose-limiting toxicities, aggregate safety data and feasibility of administration. The number of dose-limiting toxicities reported by participants in Part A used to determine the RP2DS for participants enrolling under Part B will be reported by arm.
Measured: Up to 1 year
Objective Response Rate (ORR) (Part B Only)
The ORR for participants in Part B is defined as the percentage of participants in Part B who obtained a confirmed diagnosis of complete response (CR) or partial response (PR), using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for the evaluation of radiographic CTs or MRIs performed during the course of the study to assess response. The ORR will be reported with a 95% confidence interval.
Measured: Up to 2 years
Secondary outcomes (7)
Number of Participants With Treatment-related Adverse Events
The number of participants who reported adverse events defined by NCI CTCAE version 5.0 and attributed by the investigator to having been possibly, probably, or definitely related to study treatment will be reported.
Measured: Up to 2 years
Median Duration of Response
The median duration of response in months for all participants who received at least one dose of protocol therapy (i.e., one dose of pembrolizumab or 177Lu-PSMA-617) and who also demonstrated a confirmed response of complete response (CR) or partial response (PR) per RECIST criteria from the time of first response until confirmed disease progression, death or study completion will be reported.
Measured: Up to 3 years
Prostate-specific Antigen (PSA) Response Rate (PSA50)
The percentage of all for all participants who received at least one dose of protocol therapy (i.e., one dose of pembrolizumab or 177Lu-PSMA-617) and who also achieved a greater than 50% decline from the time of the baseline PSA value obtained on cycle 1 day 1 (C1D1) at any point in the treatment course will be reported along with the 95% confidence interval.
Measured: Up to 3 years
Radiographic Progression-Free Survival Rate (rPFS) at 6 Months
rPFS is defined as the percentage all for all participants who received at least one dose of protocol therapy (i.e., one dose of pembrolizumab or 177Lu-PSMA-617) and who are still alive and progression-free per RECIST v1.1 and PCWG3 criteria at 6 months.
Measured: Up to 6 months
Median PSA Progression-free Survival
PSA progression-free survival for all participants who received at least one dose of protocol therapy (i.e., one dose of pembrolizumab or 177Lu-PSMA-617) will be defined using Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria as the duration in months from date of first treatment to date the participant first meets the criteria for PSA progression for clinical progression, death, or study completion, whichever occurs first. The median duration and 95% confidence interval will be reported.
Measured: Up to 3 years
Median Overall Survival (OS)
Median overall survival for all participants who received at least one dose of protocol therapy (i.e., one dose of pembrolizumab or 177Lu-PSMA-617) is defined as the number of months from the first date of therapy until date of death from any cause. The median number of months and 95% confidence interval will be estimated using the Kaplan-Meier method.
Measured: Up to 3 years
Median Time to Symptomatic Skeletal Related Event (SSRE)
Symptomatic skeletal related event is defined as the first occurrence of one or more of the following: symptomatic fracture, surgery or radiation to bone, or spinal cord compression. The median time in months to symptomatic skeletal related event for all participants who received at least one dose of protocol therapy (i.e., one dose of pembrolizumab or 177Lu-PSMA-617) will be reported with the 95% confidence interval.
Measured: Up to 3 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Jan 2019
- Study start10 May 2019
- Primary completion10 Jan 2024
- Study completion10 Jan 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Castration Levels of TestosteroneStudies of the same condition, open and under way.
- More trials run by University of California, San FranciscoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 43 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of California, San Francisco
- Sponsor type
- University, hospital or other
- Collaborators
- Prostate Cancer Foundation, National Cancer Institute (NCI)
- Responsible party
- Principal investigator, Rahul Aggarwal, University of California, San Francisco
- Investigators
- Rahul Aggarwal, MD, Principal investigator, University of California, San Francisco
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03805594
- Sponsor's protocol ID
- 185511
- Other IDs
- NCI-2018-02993, R01CA229354
- Status last verified
- Feb 2025
- First submitted
- 9 Jan 2019
- Last updated
- 25 Feb 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Aggarwal R, Starzinski S, de Kouchkovsky I, Koshkin V, Bose R, Chou J, Desai A, Kwon D, Kaushal S, Trihy L, Rastogi M, Ippisch R, Aslam M, Friedlander T, Feng F, Oh D, Cheung A, Small E, Evans M, Fong L, Hope TA. Single-dose 177Lu-PSMA-617 followed by maintenance pembrolizumab in patients with metastatic castration-resistant prostate cancer: an open-label, dose-expansion, phase 1 trial. Lancet Oncol. 2023 Nov;24(11):1266-1276. doi: 10.1016/S1470-2045(23)00451-5.
PubMed 37922930
Study at a glance
From the registry record, last updated by the sponsor on 25 Feb 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Immunogenic Priming With PSMA-Targeted Radioligand Therapy in Advanced Prostate Cancer: A Phase 1b Study of 177Lu-PSMA-617 in Combination With Pembrolizumab
- ClinicalTrials.gov ID
- NCT03805594
- Acronym / sponsor ID
- 185511
- Conditions
- Castration Levels of Testosterone, Castration-Resistant Prostate Carcinoma, Metastatic Prostate Carcinoma, Prostate Adenocarcinoma, Stage IV Prostate Cancer, Stage IVA Prostate Cancer
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 43 participants (actual)
- Lead sponsor
- University of California, San FranciscoUniversity, hospital or other
- Collaborators
- Prostate Cancer Foundation, National Cancer Institute (NCI)
- Study start
- 10 May 2019 (actual)
- Primary completion
- 10 Jan 2024 (actual)
- Study completion
- 10 Jan 2024 (actual)
- First posted
- 15 Jan 2019 (actual)
- Results
- Posted 25 Feb 2025
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This phase Ib trial studies the dose and schedule of 177Lu-PSMA-617 and pembrolizumab in treating persons with castration-resistant prostate cancer that has spread to other places in the body. 177Lu-PSMA-617 carries a radioactive component which attached to the prostate specific membrane antigen (PSMA) receptor found on tumor cells. Its radiation component destroys the tumor cell. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving 177Lu-PSMA-617 and pembrolizumab may work better at treating prostate cancer.
Detailed description
PRIMARY OBJECTIVES:
- To determine the recommended phase 2 dose and schedule of lutetium Lu 177-PSMA-617 (177Lu-PSMA-617) in combination with pembrolizumab in participants with metastatic castration-resistant prostate carcinoma (mCRPC). (Part A)
- To determine the objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. (Part B (Dose Expansion))
SECONDARY OBJECTIVES:
- To characterize the safety profile of the combination.
- To determine the median duration of response by RECIST 1.1 criteria.
- To determine the proportion of participants who experience >= 50% decline from baseline in serum prostate-specific antigen (PSA).
- To determine the median PSA progression-free survival.
- To determine the median time to symptomatic skeletal related event.
- To determine the 6 month radiographic progression-free survival rate and median radiographic progression-free survival.
- To determine the median overall survival.
CORRELATIVE OBJECTIVES:
- To assess the lesion-specific response rate by baseline PSMA avidity on gallium Ga 68-labeled PSMA-11 (68Ga-PSMA-11) positron emission tomography (PET).
- To quantify the change from baseline in T cell repertoire, circulating T cell subsets, tumor infiltrating lymphocytes, and tumor programmed death-ligand 1 (PD-L1) expression by immunohistochemistry after one priming dose of Lu-PSMA radioligand therapy (RLT).
- To explore the relationship between timing of the 177Lu-PSMA-617 priming dose with initiation of pembrolizumab with respect to immunologic, safety, and efficacy outcomes.
- To descriptively characterize the patterns of uptake on 68Ga-PSMA-11 PET at the time of disease progression.
- To explore relationship between tumor genomic profile with clinical outcomes including response rate and progression-free survival.
- To explore the relationship between tumor dosimetry with objective response.
OUTLINE: Participants are assigned sequentially to 1 of 3 treatment schedules.
DOSING SCHEDULE 1: Participants receive lutetium Lu 177-PSMA-617 intravenously (IV) over 20-30 minutes on day 1 before beginning pembrolizumab IV over 30 minutes on day 1 in cycle 2
DOSING SCHEDULE 2: Participants receive lutetium Lu 177-PSMA-617 IV over 20-30 minutes concurrently with pembrolizumab IV over 30 minutes on day 1.
DOSING SCHEDULE 3: Starting day -21, participants receive pembrolizumab IV over 30 minutes. Participants then receive lutetium Lu 177-PSMA-617 IV over 20-30 minutes on day 1.
In all dosing schedules, treatment with pembrolizumab repeats every 21 days for up to 35 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Participants who achieve stable disease (SD) or better may receive 17 additional cycles (approximately 1 year) of pembrolizumab.
After completion of study treatment, participants are followed up at 30 days after treatment has been discontinued.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Part A: Dosing Schedule 1 (lutetium Lu 177-PSMA-617, pembrolizumab) | Experimental | Drug: Lutetium Lu 177-PSMA-617, Biological: PembrolizumabParticipants receive lutetium Lu 177-PSMA-617 IV over 20-30 minutes on day 1. Beginning in cycle 2, participants receive pembrolizumab IV over 30 minutes on day 1. Treatment with pembrolizumab repeats every 21 days for up to 35 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Participants who achieve stable disease (SD) or better may receive 17 additional cycles (approximately 1 year) of pembrolizumab. |
| Part A: Dosing Schedule 2 (lutetium Lu 177-PSMA-617, pembrolizumab) | Experimental | Drug: Lutetium Lu 177-PSMA-617, Biological: PembrolizumabParticipants receive lutetium Lu 177-PSMA-617 IV over 20-30 minutes and pembrolizumab IV over 30 minutes on day 1. Treatment with pembrolizumab repeats every 21 days for up to 35 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Participants who achieve SD or better may receive 17 additional cycles (approximately 1 year) of pembrolizumab. |
| Part A: Dosing Schedule 3 (lutetium Lu 177-PSMA-617, pembrolizumab) | Experimental | Drug: Lutetium Lu 177-PSMA-617, Biological: PembrolizumabStarting day -21, participants receive pembrolizumab IV over 30 minutes. Participants also receive lutetium Lu 177-PSMA-617 IV over 20-30 minutes on day 1. Treatment with pembrolizumab repeats every 21 days for up to 35 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Participants who achieve SD or better may receive 17 additional cycles (approximately 1 year) of pembrolizumab. |
| Part B: Recommended Phase 2 Dosing Schedule (RP2DS) (lutetium Lu 177-PSMA-617, pembrolizumab) | Experimental | Drug: Lutetium Lu 177-PSMA-617, Biological: PembrolizumabParticipants will receive the RP2DS determined in Part A. Treatment with pembrolizumab repeats every 21 days for up to 35 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Participants who achieve SD or better may receive 17 additional cycles (approximately 1 year) of pembrolizumab. |
Who may qualify
- Ages
- 18 years and older
- Sex
- Male only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (21 listed)
- The subject is able and willing to comply with study procedures and provide signed and dated informed consent
- Histologically confirmed prostate adenocarcinoma. De novo small cell neuroendocrine prostate cancer will not be allowed due to putative lower PSMA expression in this tumor subtype. Treatment-emergent small cell neuroendocrine prostate cancer detected in metastatic tumor biopsy is not an exclusion
- A minimum of three PSMA-avid lesions on baseline 68Ga-PSMA-11 PET, with positive lesions defined as those with maximum standardized uptake value (SUVmax) values greater than liver.
- Progressive metastatic castration-resistant prostate cancer by Prostate Cancer Working Group (PCWG)3 criteria at the time of study entry
- Castrate level of serum testosterone at study entry (< 50 ng/dL). Participants without prior bilateral orchiectomy are required to remain on luteinizing hormone-releasing hormone (LHRH) analogue treatment for duration of study
Key exclusion criteria (33 listed)
- Untreated brain metastases at study entry. Participants with previously treated brain metastases are eligible provided the following criteria are all met:
- Receipt of prior PSMA-directed treatment (e.g. radiotherapy, immunotherapy, or antibody-drug conjugate)
- Prior enrollment on clinical study investigating Lu-PSMA-based radioligand therapy
- Prior treatment with radium-223 or other radioisotope for the treatment of prostate cancer
- Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (=< 2 weeks of radiotherapy) to non-central nervous system (CNS) disease
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Lutetium Lu 177-PSMA-617Also: 177Lu-PSMA-617, Lu177-PSMA-617Given IV | Drug | Part A: Dosing Schedule 1 (lutetium Lu 177-PSMA-617, pembrolizumab), Part A: Dosing Schedule 2 (lutetium Lu 177-PSMA-617, pembrolizumab), Part A: Dosing Schedule 3 (lutetium Lu 177-PSMA-617, pembrolizumab), Part B: Recommended Phase 2 Dosing Schedule (RP2DS) (lutetium Lu 177-PSMA-617, pembrolizumab) |
| PembrolizumabAlso: Keytruda, Lambrolizumab, MK-3475, SCH 900475Given IV | Biological | Part A: Dosing Schedule 1 (lutetium Lu 177-PSMA-617, pembrolizumab), Part A: Dosing Schedule 2 (lutetium Lu 177-PSMA-617, pembrolizumab), Part A: Dosing Schedule 3 (lutetium Lu 177-PSMA-617, pembrolizumab), Part B: Recommended Phase 2 Dosing Schedule (RP2DS) (lutetium Lu 177-PSMA-617, pembrolizumab) |
Primary outcome
Number of Reported Dose Limiting Toxicities (DLT) (Part A Only)
Time frame: Up to 1 year
The Recommended Phase 2 Dosing Schedule (RP2DS) (Schedule 1: a single priming dose of 177Lu-PSMA-617 (7·4 giga-becquerel (GBq) [200 millicurie (mCi)] given 28 days before pembrolizumab; Schedule 2: a single priming dose of 177Lu-PSMA-617 given concomitant with pembrolizumab; or Schedule 3: a single priming dose of 177Lu-PSMA-617 given 21 days after the start of maintenance pembrolizumab (200 mg every 3 weeks)) will be determined from the safety data as classified by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 for dose-limiting toxicities, aggregate safety data and feasibility of administration. The number of dose-limiting toxicities reported by participants in Part A used to determine the RP2DS for participants enrolling under Part B will be reported by arm.
Objective Response Rate (ORR) (Part B Only)
Time frame: Up to 2 years
The ORR for participants in Part B is defined as the percentage of participants in Part B who obtained a confirmed diagnosis of complete response (CR) or partial response (PR), using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for the evaluation of radiographic CTs or MRIs performed during the course of the study to assess response. The ORR will be reported with a 95% confidence interval.
7 secondary outcomes
Number of Participants With Treatment-related Adverse Events
Time frame: Up to 2 years
Median Duration of Response
Time frame: Up to 3 years
Prostate-specific Antigen (PSA) Response Rate (PSA50)
Time frame: Up to 3 years
Radiographic Progression-Free Survival Rate (rPFS) at 6 Months
Time frame: Up to 6 months
Median PSA Progression-free Survival
Time frame: Up to 3 years
Median Overall Survival (OS)
Time frame: Up to 3 years
Median Time to Symptomatic Skeletal Related Event (SSRE)
Time frame: Up to 3 years
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Feb 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 37922930Aggarwal R, Starzinski S, de Kouchkovsky I, Koshkin V, Bose R, Chou J, Desai A, Kwon D, Kaushal S, Trihy L, Rastogi M, Ippisch R, Aslam M, Friedlander T, Feng F, Oh D, Cheung A, Small E, Evans M, Fong L, Hope TA. Single-dose 177Lu-PSMA-617 followed by maintenance pembrolizumab in patients with metastatic castration-resistant prostate cancer: an open-label, dose-expansion, phase 1 trial. Lancet Oncol. 2023 Nov;24(11):1266-1276. doi: 10.1016/S1470-2045(23)00451-5.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Rahul Aggarwal, MD principal investigator
University of California, San Francisco
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Lutetium Lu 177-PSMA-617 and Pembrolizumab in people with Castration Levels of Testosterone and Castration-Resistant Prostate Carcinoma, run by University of California, San Francisco at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 21 inclusion and 33 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 25 Feb 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 25 Feb 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Reported Dose Limiting Toxicities (DLT) (Part A Only) (time frame: Up to 1 year). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03805594, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Feb 2025.