Most of the adverse effects were either hematologic or gastrointestinal toxicity, meaning nausea or vomiting, but usually low grade. One major limitation of chemotherapy is the toxicity associated with higher dose exposure. The emergence of trophoblast cell-surface antigen 2 (TROP-2) as a novel cancer target. This study is being done to see if a drug called disitamab vedotin, alone or with pembrolizumab, works to treat HER2 expressing urothelial cancer. Incidence of pneumonitis/interstitial lung disease induced by HER2-targeting therapy for HER2-positive metastatic breast cancer. Cancer Immunol Immunother. EP: 1. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. Single arm with T-Dxd plus pembrolizumab, HER2-positive BC, HER2-low expressing BC, HER2-expressing NSCLC, and HER2-mutant NSCLC, Occurrence of DLTs (part 1) and ORR (part 2), Phase I/II, single arm; SGN-LIV1A plus pembrolizumab, Phase I dose escalation and dose expansion; different cohorts will receive SGN-LIV1A monotherapy or in combination with trastuzumab, Phase Ib/II, open label, randomizing to several cohorts, including one of atezolizumab plus sacituzumab govitecan, Phase III; open label, randomizing to one of two arms: trastuzumab duocarmazine vs. TPC, HER2-positive, refractory to at least two lines of CT for MBC, Phase I, single arm; trastuzumab duocarmazine plus niraparib, HER2-positive or HER2-low tumors for which no standard therapy exists, Phase I, single arm; trastuzumab duocarmazine plus paclitaxel, HER2-low breast cancer; one to two prior lines of treatment in the advanced setting. Ongoing clinical trials evaluating ADCs are likely to reshape the standard of care for both early and advanced breast cancer. The .gov means its official. This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. Overall, the study showed that the combination has a tolerable toxicity profile and promising efficacy in mTNBC (Table (Table33). Careers. Other HER2-directed therapies, including trastuzumab, trastuzumab emtansine, and topoisomerase I inhibitors, have been associated with pulmonary toxicity; however, trastuzumab deruxtecan has higher rates, including some grade 5 events [27]. 8th Edition. Disitamab Vedotin: First Approval - PubMed Thus, the treatment efficacy was rated as partial response (PR) according to the Response Evaluation Criteria in Solid Tumors version 1.1 (17). The cellular proteases cleave the linker to release cytotoxic drugs that specifically kill the target cancer cells. Finally, the patient received RC48 as the third-line therapy and achieved a durable and effective clinical response. Disitamab Vedotin Shows Efficacy in HER2-Negative Metastatic - OncLive Phase 1 study of the antibodydrug conjugate SGN-LIV1A in patients with heavily pretreated triple-negative metastatic breast cancer [abstract]. The site is secure. NCI CPTC Antibody Characterization Program, Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Toxicities: transaminitis, fatigue, nausea, vomiting, headache [, Preliminary ORR in patients receiving 3 mg/kg = 52.4% (11/21) [. Vidicizumab combined with immunotherapy may be a new adjuvant treatment option for HER-2 low expression breast cancer patients. The most common classes of treatment-emergent adverse events were gastrointestinal and hematological. The presentation of the data from DESTINY-Breast04, TROPiCS-02, and other trials with disitamab vedotin and trastuzumab duocarmazine [will help us understand the roles of these agents going forward]. D0486 and D0487; Dako; Agilent Technologies, Inc.) at 37C for 15 min. Basically, this trial included patients with pretreated HER2-low tumors, both with HR-positive and triple-negative disease. Among these 48 patients, five (10.4%) had adjudicated drug-related ILD, including one fatal case (2.1%). Patients had received at least one dose of trastuzumab deruxtecan, ranging from 1.6 to 8.0 mg/kg. Measurement of the hemoglobin level and platelet count (C) after the first-line treatment and (D) during the second- and third-line therapy. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Modi S, Pusztai L, Forero A, et al. Favourable outcome of patients with breast cancer brain metastases treated with dual HER2 blockade of trastuzumab and pertuzumab. Clinical Development of New Antibody-Drug Conjugates in Breast Cancer (D) Cranial T1 weighted MRI (15 days after initial presentation) revealed nodular lesions in the right cerebellum (marked by the arrow). Disitamab Vedotin Combined With Tislelizumab in Advanced HER2 Positive Disitamab vedotin (DV) also has MMAE as its payload but targets HER2 rather than nectin-4 (as is the case with EV). Data from the central nervous system (CNS) subgroup included in the DESTINY-Breast01 trial demonstrated a consistent safety and efficacy profile when compared with the overall population [25]. Bardia A, Tolaney SM, Loirat D, et al. Huang H, Zhang Y, Chen Z, Zeng X, Hu Z, Yang C. Heliyon. Neoadjuvant therapy with Disitamab vedotin in treating muscle-invasive ADCs are composed of four key components: (1) the target antigen, (2) an antibody construct, (3) a payload (most commonly a cytotoxic agent), and (4) a linker moiety that couples the payload and the antibody. HER2-targeting antibody-drug conjugate RC48 alone or in combination with immunotherapy for locally advanced or metastatic urothelial carcinoma: a multicenter, real-world study. Key secondary endpoints include OS, clinical benefit rate, and quality of life (Table (Table44). TNBC is] also mainly treated with chemotherapy, although some novel options are emerging, such as immunotherapy or other ADCs targeting TROP2. In 2019, the preliminary results of the DESTINY-Breast01 study ({"type":"clinical-trial","attrs":{"text":"NCT03248492","term_id":"NCT03248492"}}NCT03248492) were published [19]. New antibodydrug conjugates in clinical development for treating patients with breast cancer, Phase II window of opportunity, neoadjuvant study, ({"type":"clinical-trial","attrs":{"text":"NCT04610528","term_id":"NCT04610528"}}NCT04610528), ({"type":"clinical-trial","attrs":{"text":"NCT03094169","term_id":"NCT03094169"}}NCT03094169), ({"type":"clinical-trial","attrs":{"text":"NCT02952729","term_id":"NCT02952729"}}NCT02952729), Antibody: humanized mAb with same sequencing as trastuzumab, Phase I dose escalation and dose expansion, ({"type":"clinical-trial","attrs":{"text":"NCT03284723","term_id":"NCT03284723"}}NCT03284723). A 60-year-old postmenopausal female initially presented to Minhang Branch of Zhongshan Hospital, Fudan University (Shanghai, China) in April 2019 with a mass in the right breast, complaining of fatigue and lethargy. (A) PET/CT, Baseline imaging presentation. The .gov means its official. Once the RC48-HER2 complex is internalized, MMAE is generated from Hertuzumab-VC-MMAE, and unites to -tubulin, preventing cellular fission by suppressing microtubule assembly, leading to apoptosis and cell death. Unable to load your collection due to an error, Unable to load your delegates due to an error. ORR, overall response rate; SD, stable disease; PR, partial response; CBR, clinical benefit rate; pts, patients; HER2, human epidermal growth factor receptor 2; ADC, antibody-drug conjugates; RC48, Disitamab Vedotin. Trastuzumab deruxtecan for the treatment of HER2-positive advanced gastric cancer: a clinical perspective. LH and QW contributed to generating the figures and table. It is also important to rule out other possible etiologies, including infection, such as with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; coronavirus disease 2019 [COVID-19]). 1Oncology Center, Hospital Srio-Libans, Braslia, Brazil, 2Breast Oncology Program, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue, Yawkey 1257, Boston, MA 02215 USA. PD-L1 positive (CPS 10 assessed by 22C3 assay). However, both extracranial and intracranial lesions achieved progressive disease (PD), which eventually occurred during 5 sequential cycles of maintenance therapy. Beckwith H, Schwab R, Yau C, et al. The patient was a postmenopausal female and therefore, no further hormonal blood tests were performed. Duocarmycin alkylates the DNA, resulting in DNA damage in both dividing and non-dividing cells and, ultimately, cell death [30]. Trastuzumab deruxtecan has a high DAR: eight molecules of the exatecan derivative per monoclonal antibody, which allows the delivery of high concentrations of the payload [11]. 2021 Nov;81(16):1929-1935. doi: 10.1007/s40265-021-01614-x. The patient initially responded well to 26 cycles of the first-line anti-HER2 targeted therapy plus chemotherapy (trastuzumab+pertuzumab+nab-paclitaxel) combined with whole-brain radiotherapy. Mller P, Kreuzaler M, Khan T, Thommen DS, Martin K, Glatz K, Savic S, Harbeck N, Nitz U, Gluz O, et al. Comparison of MRI prior to (June, 2021) and after (December, 2021) third-line treatment based on the newest evidence. Updated Epidemiology of Gastric Cancer in Asia: Decreased Incidence but Still a Big Challenge. Efficacy of Disitamab Vedotin in Treating HER2 2+/FISH- Gastric Cancer Thus, patients with BMBC may consistently benefit from RC48 with promising efficacy and safety. No patients permanently discontinued treatment because of a decrease in the ejection fraction. Xu B, Wang J, Fang J, et al. Presented at the 2020 San Antonio Breast Cancer Sympsoium. Disitamab vedotin (Aidixi) is an antibody-drug conjugate comprising a monoclonal antibody against human epidermal growth factor receptor 2 (HER2) conjugated via a cleavable linker to the cytotoxic agent monomethyl auristatin E. Disitamab vedotin is being developed by RemeGen for the treatment of solid tumours, including gastric cancer; Seagen h. Prior treatment with anthracyclines, To assess efficacy (PFS) of ADC vs. control arm, Randomized phase II (vs. lapatinib plus capecitabine), HER2-positive breast cancer; prior treatment with trastuzumab; one to two prior lines of treatment in the advanced setting, Phase I/II, single arm; sacituzumab govitecan plus talazoparib, Phase III; open label, randomizing to one of two arms: sacituzumab govitecan vs. TPC, Early-stage TNBC with residual disease following neoadjuvant CT, Phase II, open label; randomizing to one of two arms: sacituzumab govitecan vs. sacituzumab govitecan plus pembrolizumab, Metastatic TNBC. Krop I, Yonemori K, Takahashi S, et al. In 2015, a phase I, first-in-human study accrued heavily pretreated patients with advanced HER2-positive breast, or with gastric or gastro-esophageal cancer, with the primary objective of establishing the recommended dose for study expansion and assessing the safety, tolerability, and activity of trastuzumab deruxtecan [11]. The strategy of using anti-estrogen treatment was considered for the patient of the present study. Sponsored in part by Daiichi Sankyo. Careers, Unable to load your collection due to an error. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Trastuzumab deruxtecan (T-DXd; DS-8201) with nivolumab in patients with HER2-expressing, advanced breast cancer: A 2-part, phase 1b, multicenter, open-label study [abstract]. Bardia A, Mayer IA, Vahdat LT, et al. Breast cancer (BC) with overexpression of human epidermal growth factor receptor 2 (HER2) is closely associated with an elevated risk of multiple distant metastases and unfavorable prognosis. 0.82-0.84 and 0.93-0.98, respectively (29). -. Notably, there were 20 cases (17%) of interstitial lung disease (ILD), pneumonitis, or organizing pneumonia, including one grade 3 event and two treatment-related deaths due to pneumonitis. -, Akbari V, Chou CP, Abedi D. (2020). Of note, in the present case, there was no obvious recurrent myelosuppression during the treatment. Staudacher AH, Brown MP. and transmitted securely. Single-arm, four cohorts (T-Dxd with one of these four regimens: durvalumab, pertuzumab, paclitaxel, pertuzumab plus paclitaxel), HER2-positive MBC; part 1disease progression on or after the last systemic therapy prior to starting study treatment. Seagen and RemeGen Announce Exclusive Worldwide License and Co In order to enhance the patient's ability to tolerate chemotherapy, the patient received transfusion of red blood cells to improve anemia, as well as recombinant human thrombopoietin injection (RHTI; Sansheng Pharmaceutical Co., Ltd.) to elevate the platelet count. Candidate for neoadjuvant therapy, Phase I dose escalation (part 1) and dose expansion (part 2). [33] reported results of a first-in-human, phase I dose-escalation and dose-expansion study ({"type":"clinical-trial","attrs":{"text":"NCT02277717","term_id":"NCT02277717"}}NCT02277717). It is noteworthy that only a number of the bone metastatic lesions were detected with high uptake of 16-[18F] fluoro-17-estradiol (18F-FES) by ER imaging, which demonstrated inter-tumoral and temporal heterogeneity of ER expression levels. (2019). Preclinical safety profile of disitamab vedotina novel anti-HER2 SN-38 is released throughout antibody degradation followed by hydrolysis of the linker at low pH that can be found within lysosomes as well as extracellularly in the tumor microenvironment. sharing sensitive information, make sure youre on a federal 2019;5:66. doi: 10.1038/s41572-019-0111-2. A new HER2-ADC drug, Disitamab Vedotin, entered the market in China on June 9, 2021, which could be used in the treatment of advanced gastric cancer of HER2 2+ and 3+, irrespective of whether a FISH test was positive or not. As per protocol, patients with untreated or progressing brain metastases were not eligible for DESTINY-Breast 01. Such activity in HER2-low-expressing tumors may be due to the already mentioned bystander effect in conjunction with the high DAR of trastuzumab deruxtecan with the high potency of payload [16, 17, 23]. Progression on or within 12 months of adjuvant ET or have progressed on at least one of ET for metastatic disease, Phase II; open label, single arm; sacituzumab govitecan monotherapy, Early-stage TNBC, candidate for neoadjuvant therapy, Phase IIb, single arm; sacituzumab govitecan monotherapy, Metastatic TNBC refractory to at least two lines of CT for MBC, Phase III, open label; randomizing to one of two arms: sacituzumab govitecan vs. TPC, HR-positive/HER2-negative refractory to at least two lines of CT for MBC, Phase Ib/II, open label; randomizing to several cohorts, including one of atezolizumab plus sacituzumab govitecan, Phase Ib/II, open label; with different cohorts including one of sacituzumab govitecan plus rucaparib, Occurrence of AEs, DLT and ORR (phase II), Determine safety/tolerability, MTD, and RDE. Antibody-drug conjugates; disitamab vedotin; human epidermal growth factor receptor 2; trastuzumab deruxtecan; trastuzumab emtansine. Huang L, Wang R, Xie K, Zhang J, Tao F, Pi C, Feng Y, Gu H, Fang J. During the study, the most common grade 3 or higher adverse events were neutropenia (20.7%), anemia (8.7%), and nausea (7.6%). No cases of decreased ejection fraction were reported. Endocrine therapy is tolerable, while it requires a longer time to reach its highest efficacy. An anti-HER2 antibody conjugated with monomethyl auristatin E is highly effective in HER2-positive human gastric cancer. See this image and copyright information in PMC. Table Table55 summarizes the ADC molecule and clinical data [59, 6265]. Basic composition of an antibodydrug conjugate (ADC) and its mechanisms of action. In this review, we discuss the clinical development of ADCs for the treatment of breast cancer, focusing on two recently FDA-approved agents, trastuzumab deruxtecan and sacituzumab govitecan, and discuss the ongoing efforts exploring new agents. (A) H&E staining of breast tissue and axillary lymph nodes suggested grade II invasive ductal carcinoma with the following IHC staining results: HER2 (+++), ER (++), PR () and Ki67 (20%). Xu Z, Guo D, Jiang Z, Tong R, Jiang P, Bai L, Chen L, Zhu Y, Guo C, Shi J, Yu D. Eur J Med Chem. China, E-mail: Received 2022 Apr 27; Accepted 2022 Jul 15. An open-label, dose-escalation phase I study to evaluate RC48-ADC, a novel antibody-drug conjugate, in patients with HER2-positive metastatic breast cancer. The site is secure. A promising ORR of 33% was reported in patients with HER2-positive breast cancer (N = 48) and, among the 47 patients with HER2-low breast cancer, the response rate was 28 and 40% for patients with HR-positive and HR-negative breast cancer, respectively. Detailed Description: Subjects who met the criteria for admission were treated with Disitamab Vedotin2.0mg/kg,iv,q3w combined with Penpulimab (200mg,iv,q3w) as neoadjuvant therapy for 6 cycles before surgery, and DCR and ORR were assessed before surgery. Disitamab vedotin (Aidexi) is an antibody-conjugated drug that contains the human epidermal growth factor receptor-2 (HER2) antibody portion, linker and the cytotoxic drug monomethyl auristatin E (MMAE). Further work is ongoing to evaluate optimal monitoring and management of ILD due to trastuzumab deruxtecan. It is unknown whether trastuzumab deruxtecan is as effective in treating or preventing brain metastasis as has been shown for non-CNS disease. Afterwards, trastuzumab and pertuzumab were recommended as maintenance therapy for intolerable grade III neurotoxicity resulting from nab-paclitaxel. Rudnicka H, Niwiska A, Murawska M. Breast cancer leptomeningeal metastasis-the role of multimodality treatment. Disitamab vedotin, a novel HER2-directed antibody-drug conjugate in gastric cancer and other solid tumors. Our main challenge is that this definition relies on these low categories of IHC, which were not really standardized. Antibodydrug conjugates (ADCs) are designed to deliver antineoplastic medicines precisely and in selectively targeted ways. Of note, patients who progressed within 12 months from the end of (neo)adjuvant therapy were considered as having had a prior line of therapy. Clin Cancer Res 20:443641. Analysis of blood samples indicated markedly low hemoglobin level (48 g/l; normal range: 110150 g/l) and platelet count (39109/l; normal range: 100300109/l) with high levels of carcinoembryonic antigen (CEA; 203.70 ng/ml; normal range: 05 ng/ml), carbohydrate antigen 125 (CA125; 2,267 U/ml; normal range: 035 U/ml) and CA15-3 (4,754 U/ml; normal range: 025 U/ml). von Minckwitz G, Huang CS, Mano MS, et al. (B) CA-125 levels continuously increased with the maintenance and second-line therapies. Contrast-enhanced breast magnetic resonance imaging (MRI) and computed tomography (CT) revealed right-sided breast malignant tumor with breast imaging-reporting and data system score of 5 (15) and the possibility of multiple axillary lymph nodes and multiple systemic bone metastases (Fig. Hamilton EP, Barve MA, Bardia A, et al. This agent has been tested in several trials now. Keywords: Patients may also experience neuropathy with prolonged exposure to the drug. US Food and Drug Administration. Swain SM, Miles D, Kim SB, Im YH, Im SA, Semiglazov V, Ciruelos E, Schneeweiss A, Loi S, Monturus E, et al. Novel antibody drug conjugates containing exatecan derivative-based cytotoxic payloads. 1. . This means that we are learning to better manage [the toxicities with] this agent. Accessibility Thus, RC48 demonstrated consistent efficacy in MBC with high or low expression of HER2. This becomes a problem because there are some studies, such as a study from Yale, showing that there is very little concordance among pathologists when reading slides with very low HER2 expression. This was concerning because there were some fatal effects. Mercogliano MF, Bruni S, Mauro FL, Schillaci R. Cancers (Basel). This study was approved by the Ethics Committee of Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine (Shanghai, China) and the Ethics Committee of Minhang Branch, Zhongshan Hospital Affiliated to Fudan University (Shanghai, China). More recently, the KATHERINE study [5] established T-DM1 as the standard of care in the adjuvant setting for patients with HER2-positive disease treated with neoadjuvant trastuzumab-based therapy who present with residual disease at the time of surgery. Furthermore, treatment-related adverse events (AEs) were commonly grade 12. Drugs. Disitamab vedotin is a novel ADC that selectively delivers the anti-cancer agent monomethyl auristatin E (MMAE) into HER2-expressing tumor cells. The question used to be whether a tumor could be categorized as either 3+ or 2+, and there wasnt a strong need in clinical practice to distinguish the 0 score from the 1+ score. Disitamab vedotin: a novel antibody-drug conjugates for cancer - PubMed Tamura K, Tsurutani J, Takahashi S, et al. Disitamab vedotin (RC48-ADC) HER2: Monomethyl auristatin E: 4: No: Not approved to date: Neutropenia, AST . Thus, in the next few years, we might witness a switch from the standard treatment of cytotoxic chemotherapy to anticancer treatment based on ADCs, given either as monotherapy or in combination with other agents. The ADC was given at 2.5 mg/kg every 3 weeks for four cycles, followed by doxorubicin/cyclophosphamide (AC) every 23 weeks for four cycles. Additionally, most HER2-low tumors also coexpress hormone receptors. Tissue samples derived from core needle and bone marrow biopsy specimens were fixed in 10% formalin at room temperature for 24 h, paraffin embedded and subjected to histological or immunohistochemical analysis. Furthermore, CA-125 levels continued to rise, accompanied by progressively decreased hemoglobin levels, and PET-CT was repeated and indicated enlarged splenic metastases with a higher level of glucose metabolism, again indicating PD. During the dose-expansion part of the study, patients with HER2-low breast cancer were enrolled (Table (Table2).2). Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD1-03. Disitamab vedotin monotherapy continues to be assessed in phase II and phase III trials for gastric cancer in China. Breast cancer (BC) with overexpression of human epidermal growth factor receptor 2 (HER2) is closely associated with an elevated risk of multiple distant metastases and unfavorable prognosis. Disitamab Vedotin (RC48) Combined With Penpulimab (AK105) for To date, the patient has benefited from 12 cycles of RC48 without any severe adverse effects. 1). These patients had received a median of three prior lines of endocrine therapies and two (range 09) prior lines of chemotherapy for MBC. Federal government websites often end in .gov or .mil. government site. For instance, trastuzumab deruxtecan has 8 molecules of payload compared with 3.5 molecules with trastuzumab emtansine. Would you like email updates of new search results? PD-L1 negative (SP142 assay). Bookshelf -, Aoki M, Iwasa S, Boku N. (2021). Before Between 40 and 50% of patients with breast cancer have tumors with low HER2 expression (defined as immunohistochemistry [IHC] 1 + or IHC 2 + with no HER2 amplification) [22]. The study also showed that patients from Japan were more likely to develop ILD after treatment with trastuzumab deruxtecan than were those of non-Japanese ethnicity. A previous study demonstrated that myelosuppression occurred faster and more severe in patients with bone metastasis after chemotherapy or radiotherapy (20). {"type":"clinical-trial","attrs":{"text":"NCT04457596","term_id":"NCT04457596"}}, {"type":"clinical-trial","attrs":{"text":"NCT03975647","term_id":"NCT03975647"}}, {"type":"clinical-trial","attrs":{"text":"NCT03523585","term_id":"NCT03523585"}}, {"type":"clinical-trial","attrs":{"text":"NCT03529110","term_id":"NCT03529110"}}, {"type":"clinical-trial","attrs":{"text":"NCT04539938","term_id":"NCT04539938"}}, {"type":"clinical-trial","attrs":{"text":"NCT04538742","term_id":"NCT04538742"}}, {"type":"clinical-trial","attrs":{"text":"NCT04622319","term_id":"NCT04622319"}}, {"type":"clinical-trial","attrs":{"text":"NCT03734029","term_id":"NCT03734029"}}, {"type":"clinical-trial","attrs":{"text":"NCT04494425","term_id":"NCT04494425"}}, {"type":"clinical-trial","attrs":{"text":"NCT04553770","term_id":"NCT04553770"}}, {"type":"clinical-trial","attrs":{"text":"NCT04556773","term_id":"NCT04556773"}}, {"type":"clinical-trial","attrs":{"text":"NCT03742102","term_id":"NCT03742102"}}, {"type":"clinical-trial","attrs":{"text":"NCT04420598","term_id":"NCT04420598"}}, {"type":"clinical-trial","attrs":{"text":"NCT03523572","term_id":"NCT03523572"}}, {"type":"clinical-trial","attrs":{"text":"NCT04042701","term_id":"NCT04042701"}}, {"type":"clinical-trial","attrs":{"text":"NCT03248492","term_id":"NCT03248492"}}, {"type":"clinical-trial","attrs":{"text":"NCT02564900","term_id":"NCT02564900"}}, {"type":"clinical-trial","attrs":{"text":"NCT02277717","term_id":"NCT02277717"}}, {"type":"clinical-trial","attrs":{"text":"NCT03262935","term_id":"NCT03262935"}}, {"type":"clinical-trial","attrs":{"text":"NCT03310957","term_id":"NCT03310957"}}, {"type":"clinical-trial","attrs":{"text":"NCT01969643","term_id":"NCT01969643"}}, {"type":"clinical-trial","attrs":{"text":"NCT03424005","term_id":"NCT03424005"}}, {"type":"clinical-trial","attrs":{"text":"NCT04235101","term_id":"NCT04235101"}}, {"type":"clinical-trial","attrs":{"text":"NCT04602117","term_id":"NCT04602117"}}, {"type":"clinical-trial","attrs":{"text":"NCT04400695","term_id":"NCT04400695"}}, {"type":"clinical-trial","attrs":{"text":"NCT03500380","term_id":"NCT03500380"}}, {"type":"clinical-trial","attrs":{"text":"NCT01631552","term_id":"NCT01631552"}}, {"type":"clinical-trial","attrs":{"text":"NCT04647916","term_id":"NCT04647916"}}, {"type":"clinical-trial","attrs":{"text":"NCT03901339","term_id":"NCT03901339"}}, {"type":"clinical-trial","attrs":{"text":"NCT04039230","term_id":"NCT04039230"}}, {"type":"clinical-trial","attrs":{"text":"NCT04595565","term_id":"NCT04595565"}}, {"type":"clinical-trial","attrs":{"text":"NCT04468061","term_id":"NCT04468061"}}, {"type":"clinical-trial","attrs":{"text":"NCT04448886","term_id":"NCT04448886"}}, {"type":"clinical-trial","attrs":{"text":"NCT04230109","term_id":"NCT04230109"}}, {"type":"clinical-trial","attrs":{"text":"NCT04454437","term_id":"NCT04454437"}}, {"type":"clinical-trial","attrs":{"text":"NCT03992131","term_id":"NCT03992131"}}, {"type":"clinical-trial","attrs":{"text":"NCT02980341","term_id":"NCT02980341"}}, {"type":"clinical-trial","attrs":{"text":"NCT04610528","term_id":"NCT04610528"}}, {"type":"clinical-trial","attrs":{"text":"NCT03504488","term_id":"NCT03504488"}}, {"type":"clinical-trial","attrs":{"text":"NCT03094169","term_id":"NCT03094169"}}, {"type":"clinical-trial","attrs":{"text":"NCT03401385","term_id":"NCT03401385"}}, {"type":"clinical-trial","attrs":{"text":"NCT02952729","term_id":"NCT02952729"}}, {"type":"clinical-trial","attrs":{"text":"NCT03284723","term_id":"NCT03284723"}}.
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