Preliminary results of a phase I/II dose-escalation study of fractionated dose 177Lu-PSMA-617 for progressive metastatic castration resistant prostate cancer (mCRPC)

Tagawa, Scott T.; Osborne, Joseph R.; Hackett, Amy; Niaz, Muhammad Junaid; Cooley, Victoria; Christos, Paul J.; Vlachostergios, Panagiotis J.; Thomas, Charlene; Gracey, Lauren; Beltran, Himisha; Molina, Ana M.; Nanus, David M.; Babich, Jay P.; Vallabhajosula, Shankar; Ballman, Karla V.; Bander, Neil H.

doi:10.1093/annonc/mdz248.006

Cited by 12 publications

(15 citation statements)

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“…Despite the encouraging clinical response rates for the PSMA-targeting small-molecule ligand 225 Ac-PSMA-617 in noncontrolled trials (4), its clinical use, however, is hindered by severe xerostomia, which becomes a dose-limiting toxicity due to strong uptake of the small molecules into the salivary glands (6). This xerostomia has been observed to be less pronounced when combining PSMA-617 with beta emitters (29) instead of alpha emitters (3,6). Nevertheless, this accumulation is thought to be at least partially nonspecific, given the low-tomoderate PSMA expression in the salivary gland, and also due to the fact that PSMA-targeting antibody formats have shown only low salivary gland uptake (6)(7)(8).…”

Section: Discussionmentioning

confidence: 99%

Preclinical Efficacy of a PSMA-Targeted Thorium-227 Conjugate (PSMA-TTC), a Targeted Alpha Therapy for Prostate Cancer

Hammer¹,

Hagemann²,

Zitzmann-Kolbe³

et al. 2020

Clinical Cancer Research

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◥Purpose: Prostate-specific membrane antigen (PSMA) is an attractive target for radionuclide therapy of metastatic castrationresistant prostate cancer (mCRPC). PSMA-targeted alpha therapy (TAT) has shown early signs of activity in patients with prostate cancer refractory to beta radiation. We describe a novel, antibody-based TAT, the PSMA-targeted thorium-227 conjugate PSMA-TTC (BAY 2315497) consisting of the alpha-particle emitter thorium-227 complexed by a 3,2-HOPO chelator covalently linked to a fully human PSMA-targeting antibody.Experimental Design: PSMA-TTC was characterized for affinity, mode of action, and cytotoxic activity in vitro. Biodistribution, pharmacokinetics, and antitumor efficacy were investigated in vivo using cell line and patient-derived xenograft (PDX) models of prostate cancer.Results: PSMA-TTC was selectively internalized into PSMApositive cells and potently induced DNA damage, cell-cycle arrest, and apoptosis in vitro. Decrease in cell viability was observed dependent on the cellular PSMA expression levels. In vivo, PSMA-TTC showed strong antitumor efficacy with T/C values of 0.01 to 0.31 after a single injection at 300 to 500 kBq/kg in subcutaneous cell line and PDX models, including models resistant to standard-of-care drugs such as enzalutamide. Furthermore, inhibition of both cancer and cancer-induced abnormal bone growth was observed in a model mimicking prostate cancer metastasized to bone. Specific tumor uptake and efficacy were demonstrated using various PSMA-TTC doses and dosing schedules. Induction of DNA double-strand breaks was identified as a key mode of action for PSMA-TTC both in vitro and in vivo.Conclusions: The strong preclinical antitumor activity of PSMA-TTC supports its clinical evaluation, and a phase I trial is ongoing in mCRPC patients (NCT03724747).

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Section: Discussionmentioning

confidence: 99%

Preclinical Efficacy of a PSMA-Targeted Thorium-227 Conjugate (PSMA-TTC), a Targeted Alpha Therapy for Prostate Cancer

Hammer¹,

Hagemann²,

Zitzmann-Kolbe³

et al. 2020

Clinical Cancer Research

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“…85,[92][93][94][95] In contrast, PSMA ligand-based RNT results in on-target, off-tumor radiation exposure to salivary glands and the digestive tract and possible late renal toxicity. [63][64][65]82,[84][85][86][87] Beta particle-emitting 90 Y-and 177 Lu-labeled J591 agents have demonstrated promise as theranostic agents in clinical studies. 85,[92][93][94][95][96][97] In SPECT imaging, 90 Y-(using 111 Indium imaging) and 177 111,112 The FDA has not allowed PSA changes to be considered as an indicator of clinical benefit in prostate cancer trials.…”

Section: Recent Developments In Psma-pet Imagingmentioning

confidence: 99%

“…No dose limiting toxicities were observed and MTD was not achieved 86 . The recommended phase 2 activity dose (RP2D) for the trial was chosen to be 22.2 GBq (600 mCi) per single fractionated cycle and preliminary data from the partially completed combined phase 1/2 trial have been presented 87 . The most common adverse events (AEs) observed were temporary and low‐grade pain flares (82%; 43.2% grade 1, 38.6% grade 2) and xerostomia (61%; 56.8% grade 1, 4.5% grade 2).…”

Section: Clinical Development Of 177lu‐psma‐617mentioning

confidence: 99%

Meeting report from the Prostate Cancer Foundation PSMA theranostics state of the science meeting

et al. 2020

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Introduction The Prostate Cancer Foundation (PCF) convened a PCF prostate‐specific membrane antigen (PSMA) Theranostics State of the Science Meeting on 18 November 2019, at Weill Cornell Medicine, New York, NY. Methods The meeting was attended by 22 basic, translational, and clinical researchers from around the globe, with expertise in PSMA biology, development and use of PSMA theranostics agents, and clinical trials. The goal of this meeting was to discuss the current state of knowledge, the most important biological and clinical questions, and critical next steps for the clinical development of PSMA positron emission tomography (PET) imaging agents and PSMA‐targeted radionuclide agents for patients with prostate cancer. Results Several major topic areas were discussed including the biology of PSMA, the role of PSMA‐targeted PET imaging in prostate cancer, the physics and performance of different PSMA‐targeted PET imaging agents, the current state of clinical development of PSMA‐targeted radionuclide therapy (RNT) agents, the role of dosimetry in PSMA RNT treatment planning, barriers and challenges in PSMA RNT clinical development, optimization of patient selection for PSMA RNT trials, and promising combination treatment approaches with PSMA RNT. Discussion This article summarizes the presentations from the meeting for the purpose of globally disseminating this knowledge to advance the use of PSMA‐targeted theranostic agents for imaging and treatment of patients with prostate cancer.

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“…This dose fractionation concept is also being studied with other radiolabeled therapies for prostate cancer, e.g. 177 Lu-PSMA-617, with favorable results [12].…”

Section: Phase I/ii Fractionated Dose Study With 177 Lu-j591mentioning

confidence: 99%

“…After phase I and II single-dose studies of 177 Lu-J591 demonstrated safety and efficacy with dose-response, and dose fractionation of 177 Lu-J591 permitted higher cumulative dose administration with less myelosuppression per similar cumulative dose in single-dose studies, the idea of the hyperfractionation of 177 Lu-J591 emerged [8][9][11][12][13]. The researchers hypothesized that the hyperfractionation of 177 Lu-J591 will allow the safer administration of a higher cumulative dose with less potential toxicity.…”

Section: Pilot Study Of the Hyperfractionated Dosing Of 177 Lu-j591mentioning

confidence: 99%

Review of Lutetium-177-labeled Anti-prostate-specific Membrane Antigen Monoclonal Antibody J591 for the Treatment of Metastatic Castration-resistant Prostate Cancer

Niaz¹,

Sun²,

Ramírez-Fort³

et al. 2020

Cureus

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Preliminary results of a phase I/II dose-escalation study of fractionated dose 177Lu-PSMA-617 for progressive metastatic castration resistant prostate cancer (mCRPC)

Cited by 12 publications

References 0 publications

Preclinical Efficacy of a PSMA-Targeted Thorium-227 Conjugate (PSMA-TTC), a Targeted Alpha Therapy for Prostate Cancer

Preclinical Efficacy of a PSMA-Targeted Thorium-227 Conjugate (PSMA-TTC), a Targeted Alpha Therapy for Prostate Cancer

Meeting report from the Prostate Cancer Foundation PSMA theranostics state of the science meeting

Review of Lutetium-177-labeled Anti-prostate-specific Membrane Antigen Monoclonal Antibody J591 for the Treatment of Metastatic Castration-resistant Prostate Cancer

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