177Lu-PSMA-617 and Pembrolizumab in Treating Patients With Metastatic Castration-Resistant Prostate Cancer

NCT03805594 | Completed Phase 1 Results DMC FDA Drug

• 3 other identifiers: 185511NCI-2018-02993R01CA229354
• Study Type: interventional
• Target: 43
• Locations: 1 country
• Sites: 1

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.

Conditions

Castration Levels of Testosterone; Castration-Resistant Prostate Carcinoma; Metastatic Prostate Carcinoma; Prostate Adenocarcinoma; Stage IV Prostate Cancer; Stage IVA Prostate Cancer; Stage IVB Prostate Cancer

Outcome Measures

Primary Outcomes (2)

• 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.

  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.

  Up to 2 years

Secondary Outcomes (7)

• 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

Study Arms (4)

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.

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.

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.

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.

Drug: Lutetium Lu 177-PSMA-617; Biological: Pembrolizumab

Interventions

Lutetium Lu 177-PSMA-617 DRUG

Given IV

Also known as: 177Lu-PSMA-617, Lu177-PSMA-617

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)

Pembrolizumab BIOLOGICAL

Given IV

Also known as: Keytruda, Lambrolizumab, MK-3475, SCH 900475

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)

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• The subject is able and willing to comply with study procedures and provide signed and dated informed consent
• 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
• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• University of California, San Francisco: lead
• Prostate Cancer Foundation: collaborator
• National Cancer Institute (NCI): collaborator

Study Sites (1)

University of California, San Francisco

San Francisco, California, 94143, United States

Location

Related Publications (1)

• 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.

  PMID: 37922930 RESULT

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

Pluvicto; pembrolizumab

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Limitations and Caveats

The additional efficacy endpoints including median duration of response, PSA50 response rate, rPFS rate at 6 months, median PSA progression-free survival, median OS, and median time to SSRE were planned to be analyzed in the overall study cohort (n = 43). Post-hoc determination of efficacy outcomes for schedules 1,2, 3 analyzed separately is precluded by the limited sample size of patients enrolled on schedules 2 and 3 (n = 6 each).

Results Point of Contact

• Title: Dr. Rahul Aggarwal, MD
• Organization: University of California, San Francisco

Rahul.Aggarwal@ucsf.edu

(415) 353-7171

Study Officials

• Rahul Aggarwal, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Clinical Professor

Study Record Dates

• First Submitted: January 9, 2019
• First Posted: January 15, 2019
• Study Start: May 10, 2019
• Primary Completion: January 10, 2024
• Study Completion: January 10, 2024
• Last Updated: February 25, 2025
• Results First Posted: February 25, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)