Dataset Information

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.

SUBMITTER: Zechmann CM

PROVIDER: S-EPMC4052014 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:PurposeProstate-specific membrane antigen (PSMA) continues to be the hallmark biomarker for prostate cancer as it is expressed on nearly all prostatic tumors. In addition, increased PSMA expression correlates with castration resistance and progression to the metastatic stage of the disease. Recently, we combined both an albumin-binding motif and an irreversible PSMA inhibitor to develop the novel PSMA-targeted radiotherapeutic agent, CTT1403. This molecule was novel in the field of PSMA-targeted agents as its key motifs resulted in extended blood circulation time and tumor uptake, rapid and extensive internalization into PSMA+ cells, and promising therapeutic efficacy. The objective of this study was to perform IND-enabling translational studies on CTT1403 in rodent models.ProceduresA dose optimization study was performed in PC3-PIP (PSMA+) tumor-bearing mice. Treatment groups were randomly selected to receive one to three 14-MBq injections of CTT1403. Control groups included (1) saline, (2) non-radioactive [175Lu]CTT1403, or (3) two injections of 14 MBq CTT1751, a Lu-177-labeled non-targeted albumin-binding moiety. Tumor growth was monitored up to 120 days. Small-animal single photon emission tomography/X-ray computed tomography imaging was performed with CTT1403 and CTT1751 in PC3-PIP tumor-bearing mice to visualize infiltration of the Lu-177-labeled agent into the tumor. In preparation for a first-in-human study, human absorbed doses were estimated based on rat biodistribution out to 5 weeks to determine a safe CTT1403 therapy dose in humans.ResultsTwo to 3 injections of 14 MBq CTT1403 yielded significant tumor growth inhibition and increased survival compared with all control groups and mice receiving 1 injection of 14 MBq CTT1403. Five of 12 mice receiving 2 or 3 injections of CTT1403 survived to the 120-day post-treatment study endpoint. Dosimetry identified the kidneys as the dose-limiting organ, with an equivalent dose of 5.18 mSv/MBq, resulting in a planned maximum dose of 4.4 GBq for phase 1 clinical trials.ConclusionsThe preclinical efficacy and dosimetry of CTT1403 suggest that this agent has significant potential to be safe and effective in humans.

Project description:IntroductionCLR1404 is a theranostic molecular agent that can be radiolabeled with 124I (CLR 124) for positron emission tomography (PET) imaging, or 131I (CLR 131) for single-photon emission computed tomography (SPECT) imaging and targeted radionuclide therapy. This pilot study evaluated a pretreatment dosimetry methodology in a triple-negative breast cancer patient who was uniquely enrolled in both a CLR 124 PET imaging clinical trial and a CLR 131 therapeutic dose escalation clinical trial.Materials and methodsThree-dimensional PET/CT images were acquired at 1, 3, 24, 48, and 120 h postinjection of 178 MBq CLR 124. One month later, pretherapy 2D whole-body planar images were acquired at 0.25, 5, 24, 48, and 144 h postinjection of 370 MBq CLR 131. Following the therapeutic administration of 1990 MBq CLR 131, 3D SPECT/CT images were acquired at 74, 147, 334, and 505 h postinjection. The therapeutic CLR 131 voxel-level absorbed dose was estimated from PET (RAPID PET) and SPECT (RAPID SPECT) images using a Geant4-based Monte Carlo dosimetry platform called RAPID (Radiopharmaceutical Assessment Platform for Internal Dosimetry), and region of interest (ROI) mean doses were also estimated using the OLINDA/EXM software based on PET (OLINDA PET), SPECT (OLINDA SPECT), and planar (OLINDA planar) images.ResultsThe RAPID PET and OLINDA PET tracer-predicted ROI mean doses correlated well (m ≥ 0.631, R2 ≥ 0.694, p ≤ 0.01) with both the RAPID SPECT and OLINDA SPECT therapeutic mean doses. The 2D planar images did not have any significant correlations. The ROI mean doses differed by -4% to -43% between RAPID and OLINDA/EXM, and by -19% to 29% between PET and SPECT. The 3D dose distributions and dose volume histograms calculated with RAPID were similar for the PET/CT and SPECT/CT.ConclusionsThis pilot study demonstrated that CLR 124 pretreatment PET images can be used to predict CLR 131 3D therapeutic dosimetry better than CLR 131 2D planar images. In addition, unlike OLINDA/EXM, Monte Carlo dosimetry methods were capable of accurately predicting dose heterogeneity, which is important for predicting dose-response relationships and clinical outcomes.

Project description:Background68Ga-labeled Glu-NH-CO-NH-Lys(Ahx)-HBED-CC ([68Ga]PSMA-11) has been increasingly used to image prostate cancer using positron emission tomography (PET)/computed tomography (CT) both during diagnosis and treatment planning. It has been shown to be of clinical value for patients both in the primary and secondary stages of prostate cancer. The aim of this study was to determine the effective dose and organ doses from injection of [68Ga]PSMA-11 in a cohort of low-risk prostate cancer patients.MethodsSix low-risk prostate cancer patients were injected with 133-178 MBq [68Ga]PSMA-11 and examined with four PET/CT acquisitions from injection to 255 min post-injection. Urine was collected up to 4 h post-injection, and venous blood samples were drawn at 45 min, 85 min, 175 min, and 245 min post-injection. Kidneys, liver, lungs, spleen, salivary and lacrimal glands, and total body where delineated, and cumulated activities and absorbed organ doses calculated. The software IDAC-Dose 2.1 was used to calculate absorbed organ doses according to the International Commission on Radiological Protection (ICRP) publication 107 using specific absorbed fractions published in ICRP 133 and effective dose according to ICRP Publication 103. We also estimated the absorbed dose to the eye lenses using Monte Carlo methods.Results[68Ga]PSMA-11 was rapidly cleared from the blood and accumulated preferentially in the kidneys and the liver. The substance has a biological half-life in blood of 6.5 min (91%) and 4.4 h (9%). The effective dose was calculated to 0.022 mSv/MBq. The kidneys received approximately 40 mGy after an injection with 160 MBq [68Ga]PSMA-11 while the lacrimal glands obtained an absorbed dose of 0.12 mGy per administered MBq. Regarding the eye lenses, the absorbed dose was low (0.0051 mGy/MBq).ConclusionThe effective dose for [68Ga]PSMA-11 is 0.022 mSv/MBq, where the kidneys and lacrimal glands receiving the highest organ dose.

Project description:Patients with metastatic differentiated thyroid cancer (DTC) may be prepared using either thyroid-stimulating hormone withdrawal (THW) or recombinant human thyroid-stimulating hormone (rhTSH) injections before 131I administration for treatment. The objective of this study was to compare the absorbed dose to the critical organs and tumors determined by 124I PET/CT-based dosimetry for 131I therapy of metastatic DTC when the same patient was prepared with and imaged after both THW and rhTSH injections. Methods: Four DTC patients at MedStar Washington Hospital Center were first prepared using the rhTSH method and imaged by 124I PET/CT at 2, 24, 48, 72, and 96 h after administration of approximately 30-63 MBq of 124I. After 5-8 wk, the same patients were prepared using the THW method and imaged as before. The 124I PET/CT images acquired as part of a prospective study were used to perform retrospective dosimetric calculations for 131I therapy for the normal organs with the dosimetry package 3D-RD. The absorbed doses from 131I for the lungs, liver, heart, kidneys, and bone marrow were obtained for each study (rhTSH and THW). Twenty-two lesions in 3 patients were identified. The contours were drawn on each PET image of each study. Time-integrated activity coefficients were calculated and used as input in OLINDA/EXM sphere dose calculator to obtain the absorbed dose to tumors. Results: The THW-to-rhTSH organ absorbed dose ratio averaged over 5 organs for the first 3 patients was 1.5, 2.5, and 0.64, respectively, and averaged over 3 organs for the fourth patient was 1.1. The absorbed dose per unit administered activity to the bone marrow was 0.13, 0.086, 0.33, and 0.068 mGy/MBq after rhTSH and 0.11, 0.14, 0.22, and 0.080 mGy/MBq after THW for each patient, respectively. With the exception of 3 lesions of 1 patient, the absorbed dose per unit administered activity of 131I was higher in the THW study than in the rhTSH study. The ratio of the average tumor absorbed dose after stimulation by THW compared with stimulation by rhTSH injections was 3.9, 27, and 1.4 for patient 1, patient 2, and patient 3, respectively. The ratio of mean tumor to bone marrow absorbed dose per unit administered activity of 131I, after THW and rhTSH, was 232 and 62 (patient 1), 12 and 0.78 (patient 2), and 22 and 11 (patient 3), respectively. Conclusion: The results suggest a high patient variability in the overall absorbed dose to the normal organs per MBq of 131I administered, between the 2 TSH stimulation methods. The tumor-to-dose-limiting-organ (bone marrow) absorbed dose ratio, that is, the therapeutic index, was higher in the THW-aided than rhTSH-aided administrations. Additional comparison for tumor and normal organ absorbed dose in patients prepared using both methods is needed before definitive conclusions may be drawn regarding rhTSH versus THW patient preparation methods for 131I therapy of metastatic DTC.