study of re-treatment with [177lu]lu-psma in men with metastatic castration resistance prostate cancer

Conditions: Metastatic Castration-resistant Prostate Cancer

Summary: prostate cancer is the third leading cause of cancer-related death in men in the united states and europe. the treatment of metastatic castration-resistant prostate cancer (mcrpc) has evolved with the arrival of the radioligand \[177lu\]lu-psma-617, which specifically targets psma-expressing cancer cells. the randomized phase iii vision study showed that \[177lu\]lu-psma-617 significantly improved progression-free survival and overall survival with an acceptable toxicity profile. the realup study will evaluate the efficacy of a re-treatment of \[177lu\]lu-psma-617 in mcrpc patients progressing after taxane based therapy and who have been previously treated with \[177lu\]lu-psma without evidence of progression during this first course of treatment. patients will be treated until disease progression, unacceptable toxicity or death, or alternatively up to 9 months after the last dose of treatment. at the end of this follow up period, patients will enter the " long term follow up ", at least for 2 years after the end of the last active follow-up.


Eligibility criteria:
inclusion criteria: * males ≥ 18 years of age * eastern cooperative oncology group (ecog) performance status ≤ 2 assessed within 7 days of study treatment initiation * histologically or cytologically confirmed adenocarcinoma of prostate (patients with small cell carcinoma of the prostate may be included) * metastatic disease documented by at least one lesion on bone scan or abdominal/pelvic/chest computed tomography (ct) or magnetic resonance imaging (mri) scan assessed by investigator. patients without bone metastasis must have measurable lesions in extra-pelvic lymph nodes or in soft-tissues as defined by recist 1.1 criteria * confirmed progression mcrpc despite ongoing androgen deprivation with serum testosterone \< 50ng/dl (1.7nm) within 3 months prior to screening. progression is defined by the presence of at least one of the following criteria : * psa progression using local laboratory values as defined by a minimum of 2 consecutive rising psa levels with an interval of ≥1 week between each assessment where the psa value at screening should be ≥1 ng/ml * radiographic disease progression in bone based on pcwg3 criteria defined as the appearance of 2 or more new bone lesions on bone scan, with or without psa progression * radiographic disease progression in extra-pelvic lymph nodes based or soft-tissues on recist1.1 criteria with or without psa progression * psma positive metastatic lesions on \[68ga\]-psma-pet/ct without psma negative lesion (the presence of psma-positive lesions is defined as \[68ga\]-psma-11 uptake greater than that of liver parenchyma in one or more metastatic lesions of any size in any organ system. the presence of psma-negative lesions is defined as psma uptake equal to or lower than that of liver parenchyma in any lymph node with a short axis of at least 2.5 cm, in any metastatic solid-organ lesions with a short axis of at least 1.0 cm, or in any metastatic bone lesion with a soft-tissue component of at least 1.0 cm in the short axis. patients with any psma negative metastatic lesion meeting these criteria are ineligible). * participants must have been previously treated with at least 4 consecutive cycles of \[177lu\]lu-psma with no evidence of progression during this first course of treatment (including radiological, clinical but also psa progression). (patients with a radiological or clinical progressive disease during the first 120 days after the last cycle of the first course of \[177lu\]lu-psma are not eligible. psa progression is defined by a ≥ 25% increase in psa and an absolute increase of 2 ng/ml or more from the nadir and confirmed by a second consecutive value obtained 3 or more weeks later) * participants must have been previously treated with at least one arsi - androgen receptor signaling inhibitors - (including enzalutamide, apalutamide, abiraterone or darolutamide) initiated for mcspc, nmcrpc or mcrpc. (arsi may be also administered together with \[177lu\]lu-psma-617 provided that the patient has not received an identical arsi in the past and that this arsi was initiated at least 15 days before the first cycle of \[177lu\]lu-psma-617 and less than 2 months ago. the arsi administrated in association with lupsma should not be considered as a prior therapy. a previous arsi treatment is mandatory for patient eligibility) * patients must have been previously treated with at least one taxane based chemotherapy (with docetaxel or cabazitaxel) * patients must have been treated with at least one course of taxane based chemotherapy (docetaxel or cabazitaxel) after the first course of \[177lu\]lu-psma therapy. (patients treated with parp inhibitors, or more than one course of chemotherapy between the first 117lupsma course and screening are also eligible). * be abstinent from heterosexual intercourse or must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary medical cause) until 98 days (14 weeks) post-treatment. * adequate organ functions : * bone marrow reserve : * anc ≥ 1.5 x 109/l * platelets ≥ 100 x 109/l * hemoglobin ≥ 10 g/dl * hepatic : * total bilirubin ≤ 2 x uln. for patients with known gilbert's syndrome ≤ 3 x uln. * alanine aminotransferase (alt) or aspartate aminotransferase (ast) ≤3 x uln * renal : * clearance ≥40 ml/mn * patients must have signed informed consent prior to participating in any study related procedures * willing and able to comply with the protocol, including follow-up visits and examinations * patients have to be affiliated to the french social security system exclusion criteria: * history of a \[177lu\]lu-psma serious adverse event (sae) or ctcae grade 3 or 4 ae during the initial course of \[177lu\]lu-psma that led to the discontinuation of treatment * more than one course of \[177lu\]lu-psma therapy * less than 120 days from the last dose administrated in the initial course of \[177lu\]lu-psma treatment and the radiological or clinical disease progression, or the initiation of a subsequent therapy. * any history of treatment with radium-223 dichloride or other systemic radiotherapy (including strontium-89, samarium-153, actinium-psma...) * transfusion of red blood cells within 30 days prior to the first injection of the re-treatment of \[177lu\]lu-psma-617 * current central nervous system (cns) metastases * hypersensitivity to the active substance (lutetium \[177lu\] vipivotide tetraxetan or gallium \[68ga\] gozetotide) or to any of the excipients * prior \> hemibody external radiotherapy * imminent or established spinal cord compression based on clinical findings and / or mri that has not yet been treated * other malignancy treated within the last 3 years (except non-melanoma skin cancer or low-grade superficial bladder cancer) * chronic conditions associated with non-malignant abnormal bone growth (e.g., confirmed paget's disease of bone) * ongoing participation in any other clinical trial who may interfere with the present study in the judgment of the investigator * concurrent serious (as determined by the principal investigator) medical conditions, including, but not limited to, uncontrolled infection, known active hepatitis b or c, or other significant co-morbid conditions that in the opinion of the investigator would impair study participation or cooperation. * active clinically significant cardiac disease * history of somatic or psychiatric disease/condition that may interfere with the objectives and assessments of the study * patients under tutorship or guardianship

Keywords: metastatic castration resistance prostate cancer internal vectorized radiotherapy [177lu]lu-psma rechallenge