PRINCE (PSMA-lutetium Radionuclide Therapy and ImmuNotherapy in Prostate CancEr)

NCT03658447 | Completed Phase 1 DMC

• 1 other identifier: PeterMac project no. 18/114
• Study Type: interventional
• Target: 37
• Locations: 1 country
• Sites: 4

Brief Summary

This investigator driven study will examine the safety, tolerability and efficacy of the combination of 177Lutetium-PSMA (177Lu-PSMA) and pembrolizumab in patients with metastatic Castration Resistant Prostate Cancer (mCRPC). 177Lu-PSMA is a compound that binds to the extra-cellular domain of the prostate-specific membrane antigen. Pembrolizumab is an antibody targeted against anti-programmed cell death 1 (PD-1).This is a single arm study where all patients will be treated with 177Lu-PSMA for upto 6 doses and pembrolizumab for upto 35 cycles.

Conditions

Metastatic Castration Resistant Prostate Cancer

Outcome Measures

Primary Outcomes (3)

• Prostate Specific Antigen (PSA) response

  PSA response will be defined as a 50% or greater decrease in PSA from baseline to the lowest post-baseline PSA result. A second consecutive value obtained 3 or more weeks later is required to confirm the PSA response.

  Through study completion, up until 24 months after the last patient commences treatment.

• Incidence of Treatment-Emergent Adverse Events [Safety]

  Safety will be measured by serious adverse events (SAEs) and AEs assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0.

  Through treatment completion, maximum of 24 months

• Tolerability

  Tolerability is defined as the time from treatment commencement until treatment discontinuation due to toxicity. Participants who ceased treatment due to reasons other than toxicity will be censored at the time of ceasing protocol treatment and participants who died while on treatment from reasons unrelated to the treatment will be censored at the date of death.

  Through treatment completion, maximum of 24 months

Secondary Outcomes (8)

• Radiographic progression free survival

  Through study completion, up until 24 months after the last patient commences treatment.

• PSA-progression free survival

  Through study completion, up until 24 months after the last patient commences treatment.

• Overall survival

  Through study completion, up until 24 months after the last patient commences treatment

• Overall Response Rate by modified RECIST1.1

  Through study completion, up until 24 months after the last patient commences treatment

• Duration of objective tumour response as assessed by modified RECIST 1.1 for soft tissue and PCWG3 for bone lesions

  Through study completion, up until 24 months after the last patient commences treatment

Study Arms (1)

177Lu-PSMA + Pembrolizumab

EXPERIMENTAL

200mg pembrolizumab given 3 weekly for upto 35 cycles and 6-weekly 177Lu-PSMA treatments for upto 6 cycles starting at 8.5GBq with administered radioactivity reduced by 0.5GBq for each cycle.

Drug: Pembrolizumab; Drug: 177Lu-PSMA

Interventions

Pembrolizumab DRUG

200mg Pembrolizumab given 3 weekly for upto 35 cycles

Also known as: Keytruda

177Lu-PSMA + Pembrolizumab

177Lu-PSMA DRUG

6-weekly 177Lu-PSMA treatments for upto 6 cycles starting at 8.5GBq with administered radioactivity reduced by 0.5GBq for each cycle.

177Lu-PSMA + Pembrolizumab

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: Men with mCRPC who are minimally symptomatic and have progressed on at least one line of novel AR targeted agents (e.g. enzalutamide, abiraterone acetate, apalutamide, etc.) will be eligible for the study. Patients may have received docetaxel chemotherapy in the treatment naïve or castrate resistant setting. Patients already receiving anti-bone resorptive therapy for management of SREs are permitted to continue with this treatment.
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must meet the following criteria for study entry:
• Patient who are at least 18 years of age who have provided written informed consent.
• Histologically confirmed adenocarcinoma of the prostate without neuroendocrine or small cell differentiation.
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 (see Appendix 1).
• Patients must have progressed on prior enzalutamide, abiraterone and/or apalutamide for treatment of prostate cancer.
• Determination of disease progression on second generation androgen receptor targeted agent determined by the local investigator. Progressive disease is defined by PCWG3 as any one of the following:
• PSA progression: minimum of two rising PSA values from a baseline measurement with an interval of ≥ 1 week between each measurement. The PSA value at screening should be ≥ 1ng/ml.
• Soft tissue or visceral disease progression as per modified RECIST 1.1 criteria (see Appendix 2)
• Bone progression: ≥ 2 new lesions on bone scan (Appendix 2)
• At least 2 weeks since the completion of surgery or radiotherapy prior to registration. Any clinically relevant sequelae from the surgery or radiotherapy must have improved to grade 1 prior to registration.
• Prior surgical orchiectomy or chemical castration maintained on luteinizing hormone-releasing hormone (LHRH) analog (agonist or antagonist). Patients without prior surgical castration must be currently taking and willing to continue luteinizing hormone-releasing hormone (LHRH) analog (agonist or antagonist) therapy throughout the duration of study treatment.
• Serum testosterone levels ≤ 50ng/dL. (≤ 1.75nmol/L) within 28 days before registration.
• Imaging evidence of metastatic disease documented with either bone scan or CT scan (Appendix 2).
• Prior prostate cancer vaccine therapy, radiation therapy, systemic therapies, diethylstilboestrol (DES) or other estrogens are allowed up to 28 days prior to trial registration. Note: bicalutamide flutamide or nilutamide must be discontinued within 4 weeks of registration.
• Significant PSMA avidity on 68Ga/18F-PSMA PET/CT, defined as a minimum uptake of SUVmax 20 at a site of disease, and SUVmax \> 10 at other sites of disease ≥10mm (unless subject to factors explaining a lower uptake, e.g. respiratory motion, reconstruction artefact).

You may not qualify if:

• Site(s) of disease that are FDG positive with low PSMA expression defined by PSMA SUVmax \< 10.
• Previous history or presence of brain metastases or leptomeningeal metastases.
• Any prior exposure to anti-PD-1, anti-PD-L1/L2, anti-CTLA-4 antibody or any other antibody or drug specifically targeting T cell co-stimulation or checkpoint pathway.
• Any prior treatment with cabazitaxel.
• Any prior exposure to 177Lu-PSMA.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Patients with active, known or suspected autoimmune disease including Sjogren's syndrome. Patients with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are eligible.
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
• Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤ Grade 2 neuropathy may be eligible.
• Patients with a condition requiring systemic treatment with either corticosteroids (\> 10mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of registration. Inhaled or topical steroids, and adrenal replacement doses ≤ 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Other malignancies within the previous 2-years other than, melanoma in situ, basal cell or squamous cell carcinomas of skin with a \> 30% probability of recurrence within 12 months.
• Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.
• Patient has a known history of Human Immunodeficiency Virus (HIV).
• Patients with symptomatic or impending cord compression unless appropriately treated beforehand and clinically stable for ≥ 4 weeks.
• Previous history of interstitial lung disease or non-infectious pneumonitis.

Sponsors & Collaborators

• Peter MacCallum Cancer Centre, Australia: lead

Study Sites (4)

St Vincent's Hospital Sydney

Sydney, New South Wales, 2010, Australia

Location

Chris O'Brien Lifehouse

Sydney, New South Wales, 2050, Australia

Location

Peter MacCallum Cancer Centre

Melbourne, Victoria, 3000, Australia

Location

Box Hill Hospital

Melbourne, Victoria, 3128, Australia

Location

MeSH Terms

Interventions

pembrolizumab

Study Officials

• Shahneen Sandhu

  Peter MacCallum Cancer Centre, Australia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 23, 2018
• First Posted: September 5, 2018
• Study Start: July 12, 2019
• Primary Completion: December 22, 2022
• Study Completion: December 22, 2022
• Last Updated: July 28, 2023

Record last verified: 2023-07

Data Sharing

• IPD Sharing: Will not share

Locations

AU (4)