Immunogenic Priming With PSMA-Targeted Radioligand Therapy in Advanced Prostate Cancer: A Phase 1b Study of 177Lu-PSMA-617 in Combination With Pembrolizumab
Overview
- Phase
- Phase 1
- Intervention
- Lutetium Lu 177-PSMA-617
- Conditions
- Castration Levels of Testosterone
- Sponsor
- University of California, San Francisco
- Enrollment
- 43
- Locations
- 1
- Primary Endpoint
- Number of Reported Dose Limiting Toxicities (DLT) (Part A Only)
- Status
- Completed
- Last Updated
- last year
Overview
Brief 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. 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: 1. 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) 2. To determine the objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. (Part B (Dose Expansion)) SECONDARY OBJECTIVES: 1. To characterize the safety profile of the combination. 2. To determine the median duration of response by RECIST 1.1 criteria. 3. To determine the proportion of participants who experience \>= 50% decline from baseline in serum prostate-specific antigen (PSA). 4. To determine the median PSA progression-free survival. 5. To determine the median time to symptomatic skeletal related event. 6. To determine the 6 month radiographic progression-free survival rate and median radiographic progression-free survival. 7. To determine the median overall survival. CORRELATIVE OBJECTIVES: 1. 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). 2. 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). 3. 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. 4. To descriptively characterize the patterns of uptake on 68Ga-PSMA-11 PET at the time of disease progression. 5. To explore relationship between tumor genomic profile with clinical outcomes including response rate and progression-free survival. 6. 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.
Investigators
Rahul Aggarwal
Associate Clinical Professor
University of California, San Francisco
Eligibility Criteria
Inclusion Criteria
- •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
- •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
Exclusion Criteria
- •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
- •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
Arms & Interventions
Part A: Dosing Schedule 1 (lutetium Lu 177-PSMA-617, pembrolizumab)
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.
Intervention: Lutetium Lu 177-PSMA-617
Part A: Dosing Schedule 1 (lutetium Lu 177-PSMA-617, pembrolizumab)
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.
Intervention: Pembrolizumab
Part A: Dosing Schedule 2 (lutetium Lu 177-PSMA-617, pembrolizumab)
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.
Intervention: Lutetium Lu 177-PSMA-617
Part A: Dosing Schedule 2 (lutetium Lu 177-PSMA-617, pembrolizumab)
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.
Intervention: Pembrolizumab
Part A: Dosing Schedule 3 (lutetium Lu 177-PSMA-617, pembrolizumab)
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.
Intervention: Lutetium Lu 177-PSMA-617
Part A: Dosing Schedule 3 (lutetium Lu 177-PSMA-617, pembrolizumab)
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.
Intervention: Pembrolizumab
Part B: Recommended Phase 2 Dosing Schedule (RP2DS) (lutetium Lu 177-PSMA-617, pembrolizumab)
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.
Intervention: Lutetium Lu 177-PSMA-617
Part B: Recommended Phase 2 Dosing Schedule (RP2DS) (lutetium Lu 177-PSMA-617, pembrolizumab)
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.
Intervention: Pembrolizumab
Outcomes
Primary Outcomes
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.
Secondary Outcomes
- Number of Participants With Treatment-related Adverse Events(Up to 2 years)
- Median Duration of Response(Up to 3 years)
- Prostate-specific Antigen (PSA) Response Rate (PSA50)(Up to 3 years)
- Radiographic Progression-Free Survival Rate (rPFS) at 6 Months(Up to 6 months)
- Median PSA Progression-free Survival(Up to 3 years)
- Median Overall Survival (OS)(Up to 3 years)
- Median Time to Symptomatic Skeletal Related Event (SSRE)(Up to 3 years)