Lutetium-177-PSMA-617 in Low Volume Metastatic Prostate Cancer

Study Overview
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Brief Summary
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Radioligand therapy (RLT) using Lu-177 labelled PSMA is a promising new therapeutic approach to treat metastatic prostate cancer. This tumor-specific treatment is directed against prostate-specific membrane antigen (PSMA), which is overexpressed in prostate cancer cells. In the last few years, several lutetium-177 (177Lu, β emitter) labeled PSMA ligands have been developed and are currently applied to treat metastatic castrate resistant prostate cancer (mCRPC) patients. However, there are no prospective studies published so far using this treatment approach in hormone sensitive setting. In this pilot study patients with hormone sensitive prostate cancer who did not undergo hormonal treatment will be treated with Lu-177 PSMA-617.

Detailed Description
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Radioligand therapy (RLT) is a promising new therapeutic approach to treat metastatic prostate cancer. This tumor-specific treatment is directed against prostate-specific membrane antigen (PSMA), which is overexpressed in prostate cancer cells. In the last few years, several lutetium-177 (177Lu, β emitter) labeled PSMA ligands have been developed and are currently applied in nuclear medicine departments world-wide to treat metastatic castrate resistant prostate cancer (mCRPC) patients. A large retrospective study reported an overall biochemical response rate of 45% following multiple 177Lu-PSMA RLT cycles in mCRPC patients, while 40% of patients already responded after a single cycle. RLT with PSMA ligand PSMA-617 was generally well tolerated and 12% of the patients suffered grade 3 to 4 hematological toxicity. In addition, mild and often transient xerostomia occurred in 8%. These results were confirmed in a smaller scale prospective study published recently. Although these results are very promising, it is noteworthy that all currently Lu-177-PSMA-617 RLT only has been evaluated in end stage prostate cancer patients to date. In theory, RLT could be more effective in low volume disease because of the very high tumor uptake of radioligands in small lesions. There are no published data so far evaluating the therapeutic effect of Lu-177-PSMA-617 RLT in an earlier stage of the disease. Because of the difference in tumor load between mCRPC patients and patients with low volume metastatic disease, dosimetry and toxicity in these patients need evaluation. Here a clinical trial to investigate the efficacy of Lu-177-PSMA-617 RLT in patients with low volume metastatic prostate cancer, prior to the hormone insensitive state is proposed. Objective: The aim of this study is to evaluate the dosimetry and toxicity of Lu-177-PSMA-617 RLT, in patients with low volume, hormone sensitive metastatic prostate cancer under treatment condition. Ultimately, the goal of this study is to stabilize previously progressive disease in these patients and to improve the quality of life by postponing the need for androgen deprivation therapy (ADT).

Official Title
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Pilot Study: Lutetium-177-PSMA-617 in Low Volume Metastatic Prostate Cancer

Conditions
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Prostate Neoplasm

Intervention / Treatment
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* Drug: Lu-177 PSMA-617


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological proven adenocarcinoma of the prostate Prior local therapy for prostate cancer Biochemical recurrence or clinical progression after local therapy (PSA > 0.2 µg/l), PSA-DT < 6 months Gallium-68 (68Ga)-PSMA-PET-CT positive metastases in bones and/or lymph nodes (N1/M1ab): ≥1, maximally 10 metastases (at least 1 lesion with a lesion size of ≥1 cm to enable adequate dosimetry studies) Local treatment for oligo-metastases with radiotherapy or surgery appears to be no option anymore (due to prior treatment or the location of the metastatic lesions) No prior hormonal therapy or chemotherapy; testosteron > 1.7 nmol/l. Exception: local prostate cancer treated with local radiotherapy plus adjuvant ADT; these patients need to be stopped with ADT at least 3 months No visceral metastases Laboratory values: White blood cells > 3.5 x 109/l Platelet count > 150 x 109/l Hemoglobin > 6 mmol/l Alanine transaminase, aspartate aminotransferase < 3 x upper limit of normal Modification of Diet in Renal Disease Study glomerular filtration rate ≥ 60 ml/min Signed informed consent Exclusion Criteria: No detectable lesions on the Ga-68 PSMA PET/CT with an uptake level below the liver uptake. A known subtype other than prostate adenocarcinoma Any medical condition present that in the opinion of the investigator will affect patients' clinical status when participating in this trial. Prior hip replacement surgery potentially influencing performance of PSMA PET/CT and nano Magnet Resonance Tomography (nMRI) Contra-indication for MRI imaging (claustrophobia, implanted electric and electronic devices (heart pacemakers, insulin pumps, implanted hearing aids, neurostimulators), intracranial metal clips, metallic bodies in the eye) Contra-indication for Buscopan (allergy to hyoscine or any other ingredients of this medication, allergy to to other atropines (e.g. atropine, scopolamine), myasthenia gravis, enlarged colon, glaucoma or obstructive prostatic hypertrophy) Additional contra-indications for the intravenous injection form of Buscopan (taking blood thinning medication (e.g. warfarin, heparin), narrowing of the gastrointestinal tract, fast heartbeat, angina or heart failure) Contra-indication to glucagon (pheochromocytoma)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lu-177 PSMA-617<br>Two cycles with 3 and 3-6 GBq Lu-177 PSMA-617 (including 3D-dosimetry) | Drug: Lu-177 PSMA-617<br>* Two cycles of Lu-177 PSMA (3GBq and 3-6 GBq)<br>* Other names: Lutetium-177 Prostate Specific Membrane Antigen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Doses delivered to the tumors | Calculation of the doses given in Gray per gigabequerel (Gy/GBq) delivered to the tumors | For cycle 1 (duration of one cycle is 56 days) | 
| Doses delivered to the tumors | Calculation of the doses given in Gray per gigabequerel (Gy/GBq) delivered to the tumors | For cycle 2 (duration of one cycle is 56 days) | 
| Doses delivered to organs at risk | Calculation of the doses given in Gray per gigabequerel (Gy/GBq) delivered to all organs at risk | For cycle 1 (duration of one cycle is 56 days) | 
| Doses delivered to organs at risk | Calculation of the doses given in Gray per gigabequerel (Gy/GBq) delivered to all organs at risk | For cycle 2 (duration of one cycle is 56 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PSA progression free survival | PSA progression free survival, defined as the time from baseline to PSA progression, assessed using PCWG3 criteria on blood test results. | Baseline, at the end of cycle 1 and 2 (each cycle is 28 days) and 3 and 6 months after last cycle | 
| Uptake on prostate specific membrane antigen (PSMA) positron emission tomography (PET) | Comparing the changes on baseline PSMA PET and after each cycle (defined according to EORTC PET response criteria) | Baseline, at the end of cycle 1 and 2 (each cycle is 28 days) and 3 and 6 months after last cycle | 
| Radiographic progression free survival | Radiographic progression free survival - defined as the time from baseline to radiographic progression (assessed using Prostate Cancer Working Group 3 (PCWG3) criteria for bone lesions and RECIST 1.1 for soft tissue lesions) | Baseline, at the end of cycle 1 and 2 (each cycle is 28 days) and 3 and 6 months after last cycle | 
| Health-related quality of life | Health-related quality of life, assessed using a composite of the European Organisation of Research and Treatment of Cancer (EORTC) core quality of life questionnaire (QLQ C-30) | Baseline, at the end of cycle 1 and 2 (each cycle is 28 days) and 3 and 6 months after last cycle |