Lu-177-PSMA-617 Prostate-Specific Membrane Antigen Inhibitor Therapy in Patients with Castration-Resistant Prostate Cancer: Stability, Bio-distribution and Dosimetry

Kabasakal, Levent; Toklu, Türkay; Yeyin, Nami; Demirci, Emre; Abuqbeitah, Mohammad; Ocak, Meltem; Aygün, Aslan; Karayel, Emre; Pehlivanoğlu, Hüseyin

doi:10.4274/mirt.08760

Cited by 58 publications

(53 citation statements)

References 17 publications

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“…Healthy organ dosimetry estimates for the historical control patients used as direct comparators in this study fall very near median values previously reported for other mCRPC patients receiving therapeutic or sub-therapeutic concentrations of 177 Lu-PSMA-617 (9,15,21,(30)(31)(32)(33)(34). Controls in the current report exhibited mean absorbed doses to the salivary glands of 1.44…”

Section: Jhu-2545 Pre-treatment Attenuatedsupporting

confidence: 80%

“…Gy (biological effective dose) above which risk of chronic renal disease significantly increases (35). Reported kidney dose estimates for 177 Lu-PSMA-617 range from 0.53 to 0.99 Gy/GBq (9,15,21,(30)(31)(32)(33)(34) so this threshold is predicted to be passed after cumulative administration of between 28 and 52 GBq. When observed kidney doses in JHU-2545 pre-treated patients are compared to the most conservative kidney doses previously reported, JHU-2545 more than doubles the calculated treatment limit.…”

Section: Discussionmentioning

confidence: 99%

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JHU-2545 Selectively Shields Salivary Glands and Kidneys during PSMA-Targeted Radiotherapy

Nedelcovych

Dash

et al. 2018

Preprint

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PURPOSEProstate-specific membrane antigen (PSMA) radiotherapy is a promising treatment for metastatic castration-resistant prostate cancer (mCRPC) with several beta or alpha particle-emitting radionuclide-conjugated small molecules showing efficacy in late stage patients. However, PSMA is also expressed in kidneys and salivary glands where specific uptake causes dose-limiting xerostomia and potential for nephrotoxicity. The PSMA inhibitor 2- (phosphonomethyl)pentanedioic acid (2-PMPA) can prevent kidney uptake in mice, but also blocks tumor uptake, precluding its clinical utility. Selective delivery of 2-PMPA to non-malignant tissues could improve the therapeutic window of PSMA radiotherapy.EXPERIMENTAL DESIGNA tri-alkoxycarbonyloxy alkyl (TrisPOC) prodrug of 2-PMPA, JHU-2545, was synthesized to enhance 2-PMPA delivery to non-malignant tissues. Preclinical pharmacokinetic and imaging experiments were conducted prior to assessment in 3 mCRPC patients receiving PSMA PET and radiotherapy.RESULTSJHU-2545 resulted in 3- and 53-fold greater exposure of 2-PMPA in rodent salivary glands (18.0 ± 0.97 h*nmol/g) and kidneys (359 ± 4.16 h*nmol/g) versus prostate tumor xenograft (6.79 ± 0.19 h*nmol/g). JHU-2545 also blocked rodent kidneys and salivary glands uptake of the PSMA PET tracers 68Ga-PSMA-11 and 18F-DCFPyL by up to 85% without effect on tumor. In a mCRPC patient, JHU-2545 treatment prior to 68Ga-PSMA-617 administration reduced kidney SUVmax by 76% without effect on metastatic lesions. When administered prior to injection of the beta emitter 177Lu-PSMA-617, JHU-2545 shielded both the salivary glands (72% Gy reduction) and kidneys (45% Gy reduction) without effect on metastases’ dose.CONCLUSIONSJHU-2545 pre-treatment raises the cumulative dose limit and improves the safety and efficacy profile of PSMA radiotherapy.STATEMENT OF TRANSLATIONAL RELEVANCEProstate Specific Membrane Antigen (PSMA) molecular radiotherapy has emerged as a promising treatment for metastatic castration-resistant prostate cancer (mCRPC), but endogenous expression of PSMA in kidneys and salivary glands causes uptake into these organs resulting in dose-limiting toxicities. We describe the discovery of JHU-2545, a PSMA inhibitor prodrug that selectively blocks kidney and salivary gland uptake of PSMA theranostics without altering tumor uptake in both preclinical models and in mCRPC patients. Pretreatment of JHU-2545 thereby improves the safety and efficacy profile of the multiple PSMA radiotherapies in development.

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Section: Jhu-2545 Pre-treatment Attenuatedsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

JHU-2545 Selectively Shields Salivary Glands and Kidneys during PSMA-Targeted Radiotherapy

Nedelcovych

Dash

et al. 2018

Preprint

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“…0.03 Gy/GBq) and kidneys (approx. 0.6 Gy/GBq) should be considered as dose limiting organs (6)(7)(8)18,19). (14) and despite moderate xerostomia there is no evidence of relevant treatment-related toxicity.…”

Section: Responsementioning

confidence: 99%

Repeated ¹⁷⁷Lu-Labeled PSMA-617 Radioligand Therapy Using Treatment Activities of Up to 9.3 GBq

et al. 2017

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Current treatment protocols for 177Lu-PSMA-617 therapies were cautiously derived from dosimetry data, but their practical appropriateness have not yet been proven clinically.We retrospectively report our clinical observations using four different treatment activities. Methods: Forty patients with advanced prostate cancer and positive uptake in PSMA-imaging were treated in fractions of 4 GBq / 80 nmol, 6 GBq / 120 nmol, 7.4 GBq / 150 nmol or 9.3 GBq / 150 nmol 177 Lu-activity / precursor-amount (n=10, respectively) every 2 months. Safety lab was checked every 2 weeks, PSA-response every 4 weeks; other effects were assessed per anamnesis. Results: Initial PSA response presented no correlation to treatment activity. However, 2/10, 4/10, 4/10 and 7/10 patients with doses of 4, 6, 7.4 and 9.3 GBq were in partial remission 8 weeks after completing all 3 cycles;This would be in line with, but due to low patient numbers not proving, a positive doseresponse-relationship. Acute hematological toxicity was also irrespective of treatment activity and no more than one grade-3/4 toxicity was observed in each group.Nevertheless, in contrast to the other groups the mean platelet count in the 9. (8,12). Nevertheless, tolerance limits for normal organs reported in the literature are based on external beam radiotherapy and have only been extrapolated to RLT using radiobiological models, which themselves have manifold limitations as reviewed recently (13). Thus, dosimetry in nuclear medicine can only approximate a guidance level for dosing RLT but the optimal treatment regime has still to be refined clinically.In this retrospective analysis we report our clinical experience with fractions of 4 GBq, 6GBq, 7.4 GBq or 9.3 GBq 177 Lu-PSMA-617 repeated every 2 months.by on May 10, 2018. For personal use only. jnm.snmjournals.org Downloaded from MATERIALS AND METHODS Patients 177Lu-PSMA-RLT was performed under the conditions of the updated declaration of Helsinki, § 37 (Unproven interventions in clinical practice) and in accordance to the German Pharmaceuticals Law §13(2b) as a salvage therapy for patients with mCRPC, which had to be resistant against or ineligible for approved options and presented with progressive disease. Patient selection is outlined in Fig. 1. For patients stratified to 177 Lu-PSMA-617, each dose level was administered to 10 consecutive patients. If toxicities were comparable to the placebo group of the ALSYMPCA-trial (14), individual dose escalations for non-responders were considered ethically justified, resulting in a short learning-phase using heterogeneous dosing regimens between respective dose escalation groups. Data of these heterogeneous interim patients were not suitable for this kind of systematical evaluation, nevertheless some have been made public available within other publications (8,15). The chronology how this dose escalation was embedded into clinical practice is summarized in Fig. 2. Patient characteristics were summarized in (Table 1). All patients were informed about the experime...

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“…It is a widely established therapy option in the entire Europe and Asia, while in USA, the irst multi-center phase II clinical trial of Lu-PSMA-DKFZ-617 RLT safe with minimal absorbed dose to kidney [14][15][16]. Subsequently several clinical studies including our recently published articles have demonstrated excellent response to 177 Lu-PSMA-DKFZ-617 RLT [7,[10][11][12][13][14][15]. The patient in the current report has been followed up in our department since 1 year and attained normalization of sPSA levels with corresponding near complete resolution of disease.…”

Section: The Introduction Of 68mentioning

confidence: 99%

“…177 Lu-PSMA-DKFZ-617 therapy has rapidly gained global importance during last ive years due to its proven effectiveness in the prolonged overall survival and safety with no major toxicities [7,[10][11][12][13][14][15]. It is a widely established therapy option in the entire Europe and Asia, while in USA, the irst multi-center phase II clinical trial of Lu-PSMA-DKFZ-617 RLT safe with minimal absorbed dose to kidney [14][15][16]. Subsequently several clinical studies including our recently published articles have demonstrated excellent response to 177 Lu-PSMA-DKFZ-617 RLT [7,[10][11][12][13][14][15].…”

Section: The Introduction Of 68mentioning

confidence: 99%

Near Complete Response to 177Lu-PSMA-DKFZ-617 Therapy in a Patient with Metastatic Castration Resistant Prostate Cancer

MP¹

2017

J Radiol Oncol

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Lu-177-PSMA-617 Prostate-Specific Membrane Antigen Inhibitor Therapy in Patients with Castration-Resistant Prostate Cancer: Stability, Bio-distribution and Dosimetry

Cited by 58 publications

References 17 publications

JHU-2545 Selectively Shields Salivary Glands and Kidneys during PSMA-Targeted Radiotherapy

JHU-2545 Selectively Shields Salivary Glands and Kidneys during PSMA-Targeted Radiotherapy

Repeated ¹⁷⁷Lu-Labeled PSMA-617 Radioligand Therapy Using Treatment Activities of Up to 9.3 GBq

Near Complete Response to 177Lu-PSMA-DKFZ-617 Therapy in a Patient with Metastatic Castration Resistant Prostate Cancer

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Lu-177-PSMA-617 Prostate-Specific Membrane Antigen Inhibitor Therapy in Patients with Castration-Resistant Prostate Cancer: Stability, Bio-distribution and Dosimetry

Cited by 58 publications

References 17 publications

JHU-2545 Selectively Shields Salivary Glands and Kidneys during PSMA-Targeted Radiotherapy

JHU-2545 Selectively Shields Salivary Glands and Kidneys during PSMA-Targeted Radiotherapy

Repeated 177Lu-Labeled PSMA-617 Radioligand Therapy Using Treatment Activities of Up to 9.3 GBq

Near Complete Response to 177Lu-PSMA-DKFZ-617 Therapy in a Patient with Metastatic Castration Resistant Prostate Cancer

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Repeated ¹⁷⁷Lu-Labeled PSMA-617 Radioligand Therapy Using Treatment Activities of Up to 9.3 GBq