Clinical Trial · NCT03658447

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

Overview

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.

Sponsor

Peter MacCallum Cancer Centre

Phase

Phase 1/2

Contacts

Shahneen Sandhu (PRINCIPAL_INVESTIGATOR)

ClinicalTrials.gov

NCT03658447

Drug / Compound

PSMA-617

Isotope(s):

Target(s):

PSMA

Ligand Class: Small Molecules

Chelator: DOTA

Eligibility

Inclusion

Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 (see Appendix 1).
Imaging evidence of metastatic disease documented with either bone scan or CT scan (Appendix 2).
Patients must meet the following criteria for study entry:
Patients must have a life expectancy ≥ 24 weeks.
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.
Absolute neutrophil count ≥1.5x109/L
Patients must have adequate bone marrow, hepatic and renal function documented within 28 days of registration, defined as:
Total bilirubin ≤1.5 x upper limit of normal (ULN) except for patients with known Gilbert's syndrome.
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).
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:
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.
Soft tissue or visceral disease progression as per modified RECIST 1.1 criteria (see Appendix 2)
Patients who are deemed by PSMA imaging to have readily accessible disease will be required to consent to 3 serial tumour biopsies - at screening, post combination treatment (at any time between weeks 2-4) and on progression
Serum creatinine ≤1.5 x ULN or a calculated creatinine clearance \> 50mL/min (Chronic Kidney Disease Epidemiology (CKD-EPI) equation for patients with creatinine levels above institutional normal.
Patients must be willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled assessments.
International normalized ratio (INR), prothrombin time (PT), activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants.
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.
Patients must agree to use a highly effective form of contraception for the entire duration of the study plus an additional 120 days (a spermatogenesis cycle) after the last dose of study treatment and refrain from donating sperm during this period (see section 10.3.3).
Serum testosterone levels ≤ 50ng/dL. (≤ 1.75nmol/L) within 28 days before registration.
Patients must have progressed on prior enzalutamide, abiraterone and/or apalutamide for treatment of prostate cancer.
Histologically confirmed adenocarcinoma of the prostate without neuroendocrine or small cell differentiation.
White blood cells \>3x109/L
Platelets ≥100 x109/L
Albumin \>30 g/dl
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.
Haemoglobin ≥90 g/L independent of transfusions (no red blood cell transfusion in last 4 weeks)
Aspartate transaminase (AST) (SGOT) and alanine transaminase (ALT) (SGPT) ≤2.5 × ULN or ≤5 × ULN for participants with liver metastases.

Exclusion

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.
Any prior treatment with cabazitaxel.
Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤ Grade 2 neuropathy may be eligible.
Recent administration of a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
Recent administration of the influenza vaccine (within 30 days of registration).
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.
Previous history of interstitial lung disease or non-infectious pneumonitis.
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).
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.
Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
Patients with symptomatic or impending cord compression unless appropriately treated beforehand and clinically stable for ≥ 4 weeks.
Site(s) of disease that are FDG positive with low PSMA expression defined by PSMA SUVmax \< 10.
Any prior exposure to 177Lu-PSMA.
Previous history or presence of brain metastases or leptomeningeal metastases.
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.