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First-in-human study of 177Lu-EB-PSMA-617 in patients with metastatic castration-resistant prostate cancer.

ABSTRACT: PURPOSE:This translational study is designed to assess the safety, dosimetry and therapeutic response to a single, low-dose of 177Lu-EB-PSMA-617 in comparison to 177Lu-PSMA-617 in patients with mCRPC. METHODS:Following institutional review board approval and informed consent, nine patients with mCRPC were recruited. Four patients accepted intravenous injection of 0.80-1.1 GBq (21.5-30 mCi) of 177Lu-EB-PSMA-617, then underwent serial whole-body planar and SPECT/CT imaging at 2, 24, 72, 120 and 168 h. The other five patients accepted intravenous injection of 1.30-1.42 GBq (35-38.4 mCi) 177Lu-PSMA-617, then underwent the same imaging procedures at 0.5, 2, 24, 48, and 72 h. All patients were evaluated by 68Ga-PSMA-617 PET/CT before and one month after the treatment. Dosimetry evaluation was compared in both patient groups. RESULTS:When the bone metastasis tumors with comparable baseline SUVmax in the range of 10.0-15.0 were selected from the two groups for comparison, the accumulated radioactivity of 177Lu-EB-PSMA-617 was about 3.02-fold higher than that of 177Lu-PSMA-617. Imaging dose of 177Lu-EB-PSMA-617 treatment showed significant decrease of 68Ga-PSMA-617 uptake within a month, which was not observed in patients imaged with 177Lu-PSMA-617 (SUV change: -32.43?±?0.14% vs. 0.21?±?0.37%; P?=?0.002). 177Lu-EB-PSMA-617 also had higher absorbed doses in the red bone marrow and kidneys than 177Lu-PSMA-617 (0.0547?±?0.0062 vs. 0.0084?±?0.0057 mSv/MBq for red bone marrow, P?

SUBMITTER: Zang J

PROVIDER: S-EPMC6250576 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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First-in-human study of <sup>177</sup>Lu-EB-PSMA-617 in patients with metastatic castration-resistant prostate cancer.

Zang Jie J Fan Xinrong X Wang Hao H Liu Qingxing Q Wang Jingnan J Li Hui H Li Fang F Jacobson Orit O Niu Gang G Zhu Zhaohui Z Chen Xiaoyuan X

European journal of nuclear medicine and molecular imaging 20180808 1

<h4>Purpose</h4>This translational study is designed to assess the safety, dosimetry and therapeutic response to a single, low-dose of <sup>177</sup>Lu-EB-PSMA-617 in comparison to <sup>177</sup>Lu-PSMA-617 in patients with mCRPC.<h4>Methods</h4>Following institutional review board approval and informed consent, nine patients with mCRPC were recruited. Four patients accepted intravenous injection of 0.80-1.1 GBq (21.5-30 mCi) of <sup>177</sup>Lu-EB-PSMA-617, then underwent serial whole-body plan ...[more]

PMID: 30090965

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Project description:BackgroundMyelosuppression is a potential dose-limiting factor in radioligand therapy (RLT). This study aims to investigate occurrence, severity and reversibility of hematotoxic adverse events in patients undergoing RLT with 177Lu-PSMA-617 for metastatic castration-resistant prostate cancer (mCRPC). The contribution of pretreatment risk factors and cumulative treatment activity is taken into account specifically.MethodsRLT was performed in 140 patients receiving a total of 497 cycles. A mean activity of 6.9 [Formula: see text] 1.3 GBq 177Lu-PSMA-617 per cycle was administered, and mean cumulative activity was 24.6 [Formula: see text] 15.9 GBq. Hematological parameters were measured at baseline, prior to each treatment course, 2 to 4 weeks thereafter and throughout follow-up. Toxicity was graded based on Common Terminology Criteria for Adverse Events v5.0.ResultsSignificant (grade ≥ 3) hematologic adverse events occurred in 13 (9.3%) patients, with anemia in 10 (7.1%), leukopenia in 5 (3.6%) and thrombocytopenia in 6 (4.3%). Hematotoxicity was reversible to grade ≤ 2 through a median follow-up of 8 (IQR 9) months in all but two patients who died from disease progression within less than 3 months after RLT. Myelosuppression was significantly more frequent in patients with pre-existing grade 2 cytopenia (OR: 3.50, 95%CI 1.08-11.32, p = 0.04) or high bone tumor burden (disseminated or diffuse based on PROMISE miTNM, OR: 5.08, 95%CI 1.08-23.86, p = 0.04). Previous taxane-based chemotherapy was associated with an increased incidence of significant hematotoxicity (OR: 4.62, 95%CI 1.23-17.28, p = 0.02), while treatment with 223Ra-dichloride, cumulative RLT treatment activity and activity per cycle were not significantly correlated (p = 0.93, 0.33, 0.29).ConclusionHematologic adverse events after RLT have an acceptable overall incidence and are frequently reversible. High bone tumor burden, previous taxane-based chemotherapy and pretreatment grade 2 cytopenia may be considered as risk factors for developing clinically relevant myelosuppression, whereas cumulative RLT activity and previous 223Ra-dichloride treatment show no significant contribution to incidence rates.

Project description:BackgroundMetastatic castration-resistant prostate cancer remains fatal despite recent advances. Prostate-specific membrane antigen (PSMA) is highly expressed in metastatic castration-resistant prostate cancer. Lutetium-177 (177Lu)-PSMA-617 is a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the surrounding microenvironment.MethodsWe conducted an international, open-label, phase 3 trial evaluating 177Lu-PSMA-617 in patients who had metastatic castration-resistant prostate cancer previously treated with at least one androgen-receptor-pathway inhibitor and one or two taxane regimens and who had PSMA-positive gallium-68 (68Ga)-labeled PSMA-11 positron-emission tomographic-computed tomographic scans. Patients were randomly assigned in a 2:1 ratio to receive either 177Lu-PSMA-617 (7.4 GBq every 6 weeks for four to six cycles) plus protocol-permitted standard care or standard care alone. Protocol-permitted standard care excluded chemotherapy, immunotherapy, radium-223 (223Ra), and investigational drugs. The alternate primary end points were imaging-based progression-free survival and overall survival, which were powered for hazard ratios of 0.67 and 0.73, respectively. Key secondary end points were objective response, disease control, and time to symptomatic skeletal events. Adverse events during treatment were those occurring no more than 30 days after the last dose and before subsequent anticancer treatment.ResultsFrom June 2018 to mid-October 2019, a total of 831 of 1179 screened patients underwent randomization. The baseline characteristics of the patients were balanced between the groups. The median follow-up was 20.9 months. 177Lu-PSMA-617 plus standard care significantly prolonged, as compared with standard care, both imaging-based progression-free survival (median, 8.7 vs. 3.4 months; hazard ratio for progression or death, 0.40; 99.2% confidence interval [CI], 0.29 to 0.57; P<0.001) and overall survival (median, 15.3 vs. 11.3 months; hazard ratio for death, 0.62; 95% CI, 0.52 to 0.74; P<0.001). All the key secondary end points significantly favored 177Lu-PSMA-617. The incidence of adverse events of grade 3 or above was higher with 177Lu-PSMA-617 than without (52.7% vs. 38.0%), but quality of life was not adversely affected.ConclusionsRadioligand therapy with 177Lu-PSMA-617 prolonged imaging-based progression-free survival and overall survival when added to standard care in patients with advanced PSMA-positive metastatic castration-resistant prostate cancer. (Funded by Endocyte, a Novartis company; VISION ClinicalTrials.gov number, NCT03511664.).

Project description:Rationale: Lu-177-PSMA-617 radioligand therapy (RLT) is currently under approval for treatment of metastatic castration resistant prostate cancer (mCRPC) patients with late stage disease. However, previous studies demonstrated both heterogeneity of prostate specific membrane antigen (PSMA) expression, as well as response to PSMA treatment among mCRPC patients. Thus, there is an unmet need for identifying predictive parametres prior or under PSMA-RLT treatment. We therefore aimed to correlate several clinical and molecular parameters with response to PSMA treatment in a cohort of mCRPC patients undergoing PSMA RLT followed by a detailed analysis of promising candidates. Methods: Nineteen patients, median age 68.8 years (range: 56.9 - 83.3) with mCRPC were included in this study. We performed baseline analysis of clinical parameters based on PSMA PET/CT, (metabolic tumor volume (MTV), total tumor volume (TTV)), serum PSA, ALP, LDH and gene expression analysis of circulating tumor cells (expression of AR full length (AR-FL), AR splice variant 7 (AR-V7), PSA and PSMA) as well as common markers for neuroendocrine differentiation (NED). Results: Patients presented with bone, lymph node, and visceral metastases (89%, 68%, and 21%, respectively). All patients were pretreated with docetaxel, either abiraterone or enzalutamide, or both. Biochemical response in terms of PSA decline ≥50 or ≥30% was observed in 42% and 63%, respectively. There were significant correlations between PSA and PSMA mRNA expression, as well as tumor volumes (both MTV and TTV), AR-FL and AR-V7 mRNA expression. However, there was no correlation with response to PSMA treatment. Furthermore, none of these parameters was significantly correlated with baseline serum PSA values. Common NED markers were shown to be specifically high expressed and revealed impact on OS independent from AR-V7 gene expression. Conclusion: We demonstrate that AR-FL and its splice variant AR-V7 might serve as prognostic biomarkers displaying high tumor burden in mCRPC patient prior to PSMA-RLT. Contrary, PSMA, which has been discussed as a biomarker for PSMA targeted treatment, does not display strong prognostic ability - at least on the mRNA level. Surprisingly, none of these parameters correlates to response to PSMA treatment. In contrast, commom NED markers such as SYP and ENO2 as well as FOXA1 expression level seem to predict OS, but not PFS, more reliably. We admit that a limitation of our study is the focus on mRNA expression of potential biomarkers only. Further investigations analyzing the potential role of protein expression of these markers are therefore warranted.

Project description:IntroductionThe impact of prior therapies, especially chemotherapy, on overall survival (OS) in patients with castration-resistant prostate cancer (CRPC) receiving [177Lu]Lu-PSMA-617 therapy has been the subject of controversy. Therefore, WARMTH decided to plan a multicenter retrospective analysis (the "617 trial") to evaluate response rate and OS as well as the impact of prior therapies on OS in more than 300 patients treated with 177Lu-PSMA-617.Materials and methodsThe data of 631 metastatic CRPC (mCRPC) patients from 11 different clinics were evaluated. According to the inclusion and exclusion criteria, all patients had to have received at least abiraterone or enzalutamide prior to [177Lu]Lu-PSMA-617 therapy. The patients were divided into three groups: patients who had received prior chemotherapy, patients who avoided chemotherapy, and patients for whom a chemotherapy was contraindicated.ResultsThe analysis included the data of 416 patients, with a median age of 71.9 years. At the time of analysis, 87 patients (20,9%) were still alive. A total of 53.6% of patients had received both abiraterone and enzalutamide; 75.5% and 26.4% had a history of chemotherapy with docetaxel and cabazitaxel, respectively. A total of 20.4% had had Ra-223. The median OS was 11.1 months. Prior chemotherapy, the existence of bone and liver metastases, as well as Eastern Cooperative Oncology Group (ECOG) status, were significant prognosticators of worse overall survival in both univariate and multivariate analyses. Patients without any prior chemotherapy showed a significantly longer OS (14.6 months). The median OS in patients who received one or two lines of chemotherapy with docetaxel or docetaxel followed by cabazitaxel, respectively, was 10.9 months and 8.9 months. There was no difference in OS between patients who had not received chemotherapy and patients for whom chemotherapy was contraindicated. The other prior therapies did not have any significant impact on OS.ConclusionIn the present multicenter analysis, chemotherapy-naïve mCRPC patients receiving [177Lu]Lu-PSMA-617 therapy had a significantly longer OS than patients with a history of chemotherapy. This remained independent in the multivariate analysis besides presence of bone and liver metastases as negative prognosticators for survival, whereas an ECOG of 0-1 is associated with a longer OS.

Project description:In the VISION trial, [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) plus protocol-permitted standard of care significantly improved overall survival and radiographic progression-free survival compared with standard of care alone in patients with prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer. This VISION dosimetry substudy quantified absorbed doses of 177Lu-PSMA-617 in the kidneys and other organs. Methods: Participants were a separate cohort of 30 nonrandomized patients receiving standard of care plus 177Lu-PSMA-617 at 7.4 GBq per cycle for up to 6 cycles. Blood samples, whole-body conjugate planar image scintigraphy, and abdominal SPECT/CT images were collected. SPECT/CT images were collected at 2, 24, 48, and 168 h after administration in cycle 1 and at a single time point 48 h after administration in cycles 2-6. Outcomes were absorbed dose per unit activity per cycle and cumulative absorbed dose over all cycles. Cumulative absorbed doses were predicted by extrapolation from cycle 1, and calculation of observed values was based on measurements of cycle 1 and cycles 2-6. Safety was also assessed. Results: Mean (±SD) absorbed doses per cycle in the kidneys were 0.43 ± 0.16 Gy/GBq in cycle 1 and 0.44 ± 0.21 Gy/GBq in cycles 2-6. The observed and predicted 6-cycle cumulative absorbed doses in the kidneys were 15 ± 6 and 19 ± 7 Gy, respectively. Observed and predicted cumulative absorbed doses were similar in other at-risk organs. Safety findings were consistent with those in the VISION study; no patients experienced renal treatment-emergent adverse events of a grade higher than 3. Conclusion: The renal cumulative absorbed 177Lu-PSMA-617 dose was below the established limit. 177Lu-PSMA-617 had a good overall safety profile, and low renal radiotoxicity was not a safety concern. Cumulative absorbed doses in at-risk organs over multiple cycles can be predicted by extrapolation from cycle 1 data in patients with metastatic castration-resistant prostate cancer receiving 177Lu-PSMA-617.

Project description:PurposeLutetium-177 prostate-specific membrane antigen-617 (177Lu-PSMA-617) in end-stage metastatic castration-resistant prostate cancer (mCRPC) has reported favourable outcomes. In this study, we aimed to prospectively compare the efficacy and safety of 177Lu-PSMA-617 and docetaxel in chemotherapy-naïve mCRPC patients.MethodsThis was a randomized, parallel-group, open-label, phase 2, and non-inferiority trial. Chemotherapy-naïve patients with mCRPC and high PSMA-expressing lesions on 68 Ga-PSMA-11 PET/CT were randomly assigned in 1:1 ratio to 177Lu-PSMA-617 (6.0-7.4 GBq/cycle, every 8 weeks, up to 4 cycles) or docetaxel (75 mg/m2/cycle, every 3 weeks, up to 10 cycles). The primary end-point was best prostate-specific antigen response rate (PSA-RR), defined according to Prostate Cancer Clinical Trials Working Group-3 as proportion of patients achieving ≥ 50% decline in PSA from baseline. Non-inferiority margin of - 15% was pre-specified for PSA-RR.ResultsBetween December 2019 and March 2021, 40 of the 45 patients assessed for eligibility underwent randomization. Fifteen of 20 patients in 177Lu-PSMA-617 arm and 20/20 patients in docetaxel arm received treatment per protocol. Of these, best PSA-RR in the 177Lu-PSMA-617 arm was 60% (9/15) versus 40% (8/20) in the docetaxel arm. The difference in the PSA-RRs between the two arms was 20% (95% confidence interval, CI: - 12-47, P = 0.25), meeting the pre-specified criterion for non-inferiority in per-protocol analysis. Further, progression-free survival rates at 6 months were 30% and 20% in the 177Lu-PSMA-617 and docetaxel arms respectively (difference 10%, 95% CI: - 18-38, P = 0.50). Overall, treatment-emergent grade ≥ 3 adverse events occurred less frequently with 177Lu-PSMA-617 than with docetaxel (6/20, 30% versus 10/20, 50%, respectively, P = 0.20). Quality-of-life outcomes improved significantly in 177Lu-PSMA-617 arm compared to docetaxel arm (P < 0.01).Conclusion177Lu-PSMA-617 was demonstrated to be safe and non-inferior to docetaxel in the treatment of mCRPC and could, thus, be potentially employed earlier in the disease course rather than being solely reserved for advanced end-stage disease.Clinical trial registrationClinical Trials Registry-India, CTRI/2019/12/022282.

Project description:Radiohybrid prostate-specific membrane antigen (rhPSMA) ligands allow for labeling with 18F and radiometals for endoradiotherapy. rhPSMA-7.3 has been designated as a lead compound with promising preclinical data for 177Lu-rhPSMA-7.3, which has shown higher tumor uptake than 177Lu-PSMA I&T. In this retrospective analysis, we compared pretherapeutic clinical dosimetry data of both PSMA ligands. Methods: Six patients with metastatic castration-resistant prostate cancer underwent both 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T pretherapeutic dosimetry. Whole-body scintigraphy was performed at 1 h, 4 h, 24 h, 48 h, and 7 d after injection. Regions of interest covering the whole body, organs, bone marrow, and tumor lesions were drawn for each patient. Absorbed doses for individual patients and pretherapeutic applications were calculated using OLINDA/EXM. To facilitate the comparison of both ligands, we introduced the therapeutic index (TI), defined as the ratio of mean pretherapeutic doses to tumor lesions over relevant organs at risk. Results: Mean whole-body pretherapeutic effective doses for 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T were 0.12 ± 0.07 and 0.05 ± 0.03 Sv/GBq, respectively. Mean absorbed organ doses for 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T were, for example, 1.65 ± 0.28 and 0.73 ± 0.18 Gy/GBq for the kidneys, 0.19 ± 0.09 and 0.07 ± 0.03 Gy/GBq for the liver, 2.35 ± 0.78 and 0.80 ± 0.41 Gy/GBq for the parotid gland, and 0.67 ± 0.62 and 0.30 ± 0.27 Gy/GBq for the bone marrow, respectively. Tumor lesions received mean absorbed doses of 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T of 6.44 ± 6.44 and 2.64 ± 2.24 Gy/GBq, respectively. The mean TIs for the kidneys were 3.7 ± 2.2 and 3.6 ± 2.2 for 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T, respectively, and those for the bone marrow were 15.2 ± 10.2 and 15.1 ± 10.2 for 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T, respectively. Conclusion: Pretherapeutic clinical dosimetry confirmed preclinical results of mean absorbed doses for tumors that were 2-3 times higher for 177Lu-rhPSMA-7.3 than for 177Lu-PSMA I&T. Absorbed doses to normal organs also tended to be higher for 177Lu-rhPSMA-7.3, resulting overall in similar average TIs for both radiopharmaceuticals with considerable interpatient variability. 177Lu-rhPSMA-7.3 has promise for a therapeutic efficacy similar to that of 177Lu-PSMA I&T at smaller amounts of injected activity, simplifying radiation safety measurements (especially for large patient numbers or dose escalation regimens).

Dataset Information

First-in-human study of 177Lu-EB-PSMA-617 in patients with metastatic castration-resistant prostate cancer.

Publications

First-in-human study of <sup>177</sup>Lu-EB-PSMA-617 in patients with metastatic castration-resistant prostate cancer.

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