title: Radiation dosimetry and first therapy results with a (124)I/ (131)I-labeled small molecule (MIP-1095) targeting PSMA for prostate cancer therapy.
abstract: BACKGROUND
  Since the prostate-specific membrane antigen (PSMA) is frequently over-expressed in prostate cancer (PCa) several PSMA-targeting molecules are under development to detect and treat metastatic castration resistant prostate cancer (mCRPC). We investigated the tissue kinetics of a small molecule inhibitor of PSMA ((S)-2-(3-((S)-1-carboxy-5-(3-(4-[(124)I]iodophenyl)ureido)pentyl)ureido)pentanedioicacid; MIP-1095) using PET/CT to estimate radiation dosimetry for the potential therapeutic use of (131)I-MIP-1095 in men with mCRPC. We also report preliminary safety and efficacy of the first 28 consecutive patients treated under a compassionate-use protocol with a single cycle of (131)I-MIP-1095.
  
  
  METHODS
  Sixteen patients with known prostate cancer underwent PET/CT imaging after i.v. administration of (124)I-MIP-1095 (mean activity: 67.4 MBq). Each patient was scanned using PET/CT up to five times at 1, 4, 24, 48 and 72 h post injection. Volumes of interest were defined for tumor lesions and normal organs at each time point followed by dose calculations using the OLINDA/EXM software. Twenty-eight men with mCRPC were treated with a single cycle of (131)I-MIP-1095 (mean activity: 4.8 GBq, range 2 to 7.2 GBq) and followed for safety and efficacy. Baseline and follow up examinations included a complete blood count, liver and kidney function tests, and measurement of serum PSA.
  
  
  RESULTS
  I-124-MIP-1095 PET/CT images showed excellent tumor uptake and moderate uptake in liver, proximal intestine and within a few hours post-injection also in the kidneys. High uptake values were observed only in salivary and lacrimal glands. Dosimetry estimates for I-131-MIP-1095 revealed that the highest absorbed doses were delivered to the salivary glands (3.8 mSv/MBq, liver (1.7 mSv/MBq) and kidneys (1.4 mSv/MBq). The absorbed dose calculated for the red marrow was 0.37 mSv/MBq. PSA values decreased by >50 % in 60.7 % of the men treated. Of men with bone pain, 84.6 % showed complete or moderate reduction in pain. Hematological toxicities were mild. Of men treated, 25 % had a transient slight to moderate dry mouth. No adverse effects on renal function were observed.
  
  
  CONCLUSIONS
  Based on the biodistribution and dose calculations of the PSMA-targeted small molecule (124)I-MIP-1095 therapy with the authentic analog (131)I-MIP-1095 enables a targeted tumor therapy with unprecedented doses delivered to the tumor lesions. Involved lymph node and bone metastases were exposed to estimated absorbed doses upwards of 300 Gy.
authors.affiliation: Department of Nuclear Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Zechmann
authors.forename: Ali
authors.initials: A
authors.lastname: Afshar-Oromieh
authors.forename: Tom
authors.initials: T
authors.lastname: Armor
authors.forename: James B
authors.initials: JB
authors.lastname: Stubbs
authors.forename: Walter
authors.initials: W
authors.lastname: Mier
authors.forename: Boris
authors.initials: B
authors.lastname: Hadaschik
authors.forename: John
authors.initials: J
authors.lastname: Joyal
authors.forename: Klaus
authors.initials: K
authors.lastname: Kopka
authors.forename: Jürgen
authors.initials: J
authors.lastname: Debus
authors.forename: John W
authors.initials: JW
authors.lastname: Babich
authors.forename: Uwe
authors.initials: U
authors.lastname: Haberkorn
mesh_terms: D000368:Aged; D000954:Antigens, Surface / Q000378:metabolism*; D043425:Glutamate Carboxypeptidase II / Q000378:metabolism*; D005971:Glutamates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D007457:Iodine Radioisotopes / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000009:adverse effects / Q000379:methods*; D009362:Neoplasm Metastasis; D058958:Organs at Risk / Q000528:radiation effects; D049268:Positron-Emission Tomography; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology / Q000532:radiotherapy*; D011874:Radiometry; D019275:Radiopharmaceuticals / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D011879:Radiotherapy Dosage; D012449:Safety; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014508:Urea / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: C544834:2-(3-(1-carboxy-5-(3-(4-iodobphenyl)ureido)pentyl)ureido)pentanedioic acid; D000954:Antigens, Surface; D005971:Glutamates; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D014508:Urea; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II