Radiation dosimetry and first therapy results with a (124)I/ (131)I-labeled small molecule (MIP-1095) targeting PSMA for prostate cancer therapy

Abstract

Introduction: 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.

Conclusion: 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.

Fig. 1

¹²⁴I-MIP-1095 PET images (maximal intensity projection) of patient 01 as a function of time

Fig. 2

Average SUVs for normal organs (a and b) and tumor (c). Mean tumor SUVs are determined from 110 individual lesions in 16 patients

Fig. 3

Anterior and posterior whole body scintigrams of ¹³¹I-MIP-1095 in patient 01 at 7, 10 and 17 days post injection

Fig. 4

Hematological data for all patients prior to and after treatment; leukocytes (a), erythrocytes (b) and platelets (c). Solid red lines indicate range or normal limit

Fig. 5

Renal function tests for all patients prior to and after therapy; GFR, measured with ^99mTc-MAG₃ scintigraphy (a), Serum creatinine (b), Blood urea nitrogen (c). Solid red lines indicate range or normal limit

Fig. 6

Effects of PSMA ligand therapy on PSA values. a Waterfall plot of best PSA response, compared to baseline, after a single cycle of ¹³¹I-MIP-1095; b Relation of change in PSA to the activity given and c Relation of the time to PSA progression to the activity given

Fig. 7

Patient 04. a Pre-therapy ¹²⁴I-MIP-1095 PET scans (top) and CT scan (bottom). b Pre-therapy SUV values for LN metastasis, recurrent tumor, submandibular salivary glands and parotid glands as a function of time. c Serum PSA values as a function of time from treatment. d Post-therapy Glu-NH-CO-NH-Lys(Ahx)-[⁶⁸Ga]-HBED-CC PET scan (top) and CT scan (bottom)

Fig. 8

Two patients (a, b and c, d) prior (a, c) and after (b, d) therapy showing reduced tracer accumulation in their tumor lesions after treatment