An Open-Label, Dose-Escalation and Expansion, Phase I Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Clinical Activity of IMC-002 in Patients with Advanced Cancer Failed to Standard Therapy

This is an Open-Label, Dose-Escalation and Expansion, Phase I Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Clinical Activity of IMC-002 in Patients with Advanced Cancer Failed to Standard Therapy

开始日期2022-05-10

申办/合作机构

Immuneoncia Therapeutics, Inc.初创企业

NCT04306224 / Completed临床1期

A First-in-Human, Open-Label, Multiple-Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of IMC-002 in Subjects With Metastatic or Locally Advanced Solid Tumors and Relapsed or Refractory Lymphomas

This is the first-in-human, Phase I, open-label, multiple-ascending dose study to investigate the safety, tolerability, PK, PharmDyn, and clinical activity of IMC-002 in subjects with metastatic or locally advanced solid tumors and relapsed or refractory lymphomas.
Male or female subjects 18 years and older with metastatic or locally advanced solid tumors and relapsed or refractory lymphomas will be included in the study if they meet all the inclusion criteria and none of the exclusion criteria.
The study will consist of 2 parts:
Part 1: Dose Escalation Part 2: Expansion Cohorts

开始日期2020-06-05

申办/合作机构

Immuneoncia Therapeutics, Inc.初创企业

CTR20220544 / Not yet recruiting临床1期

一项评价3D-197单药在局部晚期或转移性实体瘤和复发或难治性血液肿瘤受试者中的安全性、耐受性、药代动力学、药效动力学特征以及有效性的单臂、开放、多中心的 I 期临床研究

评估3D-197单药在局部晚期或转移性实体瘤和复发或难治性血液肿瘤受试者中的安全性和耐受性；确定 3D-197 的 II 期推荐剂量（RP2D）

开始日期-

申办/合作机构

思路迪生物医药（上海）有限公司

[+2]

100 项与 3D-197 相关的临床结果

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100 项与 3D-197 相关的转化医学

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100 项与 3D-197 相关的专利（医药）

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项与 3D-197 相关的文献（医药）

2024-12-31·Human Vaccines & Immunotherapeutics

A novel anti-CD47 antibody with therapeutic potential for NK/T-cell lymphoma

Article

作者: Qin, Liping ; Zhou, Hui ; Xiao, Ling ; Li, Yajun ; Zeng, Ruolan ; He, Yizi ; Chen, Xiaoyan

NK/T-cell lymphoma (NKTCL) is a rare type of non-Hodgkin lymphoma (NHL). Although L-asparaginase-based chemotherapy has significantly improved survival in early-stage patients, the prognosis is poor in advanced and relapsed or refractory patients. CD47 is a promising target for cancer immunotherapy. However, the expression of CD47 in NKTCL and the antitumor effect and mechanism of the anti-CD47 monoclonal antibody (mAb) AK117 in NKTCL remain unclear. Firstly, the expression level of CD47 protein in NKTCL cells was detected by immunoblot and flow cytometry. Secondly, in order to validate the role of CD47 downregulation in the proliferation, apoptosis, and cell cycle of NKTCL cells, we used shRNA transfection to knock down CD47 expression. We determined the effect of knocking down CD47 and the novel anti-CD47 antibody AK117 on the phagocytosis of NKYS and YTS cells by M2 macrophages in vitro. Finally, we assessed the ability of AK117 to inhibit tumor growth in an NKTCL xenograft model in which YTS cells were engrafted in SCID mice. The results showed that CD47 is relatively highly expressed in NKTCL cells. CD47 knockdown in NKTCL promoted phagocytosis by M2 macrophages in an in vitro coculture assay. The study also demonstrated that anti-CD47 mAb AK117 promoted phagocytosis of NKTCL cells by M2 macrophages. In addition, in vivo experiments showed that the anti-CD47 mAb AK117 significantly inhibited the growth of subcutaneous xenograft tumors in SCID mice compared to the control antibody IgG. Our results indicate that targeting CD47 monoclonal antibodies is a potential therapeutic strategy for NKTCL.

2024-12-31·OncoImmunology

CD20 expression regulates CD37 levels in B-cell lymphoma – implications for immunotherapies

Article

作者: Domagala, Joanna ; Gehlert, Carina Lynn ; Firczuk, Malgorzata ; Majchrzak, Martyna ; Graczyk-Jarzynka, Agnieszka ; Inderberg, Else Marit ; Winiarska, Magdalena ; Prochorec-Sobieszek, Monika ; Barankiewicz, Joanna ; Bobrowicz, Malgorzata ; Wälchli, Sébastien ; Marhelava, Katsiaryna ; Dostalova, Lenka ; Kusowska, Aleksandra ; Zhylko, Andriy ; Forcados, Christopher ; Poreba, Marcin ; Szumera-Cieckiewicz, Anna ; Kubacz, Matylda ; Pepek, Monika ; Krawczyk, Marta ; Fidyt, Klaudyna ; Peipp, Matthias ; Šmída, Michal ; Baranowska, Iwona ; Granica, Monika ; Slusarczyk, Aleksander

Rituximab (RTX) plus chemotherapy (R-CHOP) applied as a first-line therapy for lymphoma leads to a relapse in approximately 40% of the patients. Therefore, novel approaches to treat aggressive lymphomas are being intensively investigated. Several RTX-resistant (RR) cell lines have been established as surrogate models to study resistance to R-CHOP. Our study reveals that RR cells are characterized by a major downregulation of CD37, a molecule currently explored as a target for immunotherapy. Using CD20 knockout (KO) cell lines, we demonstrate that CD20 and CD37 form a complex, and hypothesize that the presence of CD20 stabilizes CD37 in the cell membrane. Consequently, we observe a diminished cytotoxicity of anti-CD37 monoclonal antibody (mAb) in complement-dependent cytotoxicity in both RR and CD20 KO cells that can be partially restored upon lysosome inhibition. On the other hand, the internalization rate of anti-CD37 mAb in CD20 KO cells is increased when compared to controls, suggesting unhampered efficacy of antibody drug conjugates (ADCs). Importantly, even a major downregulation in CD37 levels does not hamper the efficacy of CD37-directed chimeric antigen receptor (CAR) T cells. In summary, we present here a novel mechanism of CD37 regulation with further implications for the use of anti-CD37 immunotherapies.

2024-06-03·Clinical cancer research : an official journal of the American Association for Cancer Research

KLRG1 Cell Depletion as a Novel Therapeutic Strategy in Patients with Mature T-Cell Lymphoma Subtypes

Article

作者: Yang, Lei ; Crabbe, Andrew ; Cotton, Matthew J. ; Huuhtanen, Jani ; Powers, Foster ; Park, Sung Rye ; Brain, Ian ; Chopra, Kusha ; Jain, Salvia ; Kariya, Khyati Maulik ; Haskett, Garrett ; McCabe, Sean M. ; Loughran, Thomas P. ; Tolstorukov, Michael Yevgeniy ; Pinckney, Brandy ; Ford, Josie Germain ; Kim, Won Seog ; Putteman, Tom ; Morgan, Elizabeth A. ; Greenberg, Steven A. ; Trevisani, Christopher ; Nemec, Ronald ; Johnson, P. Connor ; Mustjoki, Satu ; Taghon, Tom ; Louissaint, Abner ; Heavican-Foral, Tayla B. ; Duffy, Jessica ; Boehme, Lena ; Koh, Min Jung ; Iqbal, Javeed ; Roels, Juliette ; Feith, David J. ; Rider, Anna Baird ; Bhattacharya, Dipabarna ; Barnes, Jeffrey A. ; Weinstock, David M. ; Koh, Min Ji ; Ziemba, Jessica Beth ; Choi, Jaehyuk ; Assatova, Bimarzhan ; Willim, Robert ; Jacobsen, Eric D. ; Scanlan, Nora

Abstract:

Purpose::

Develop a novel therapeutic strategy for patients with subtypes of mature T-cell and NK-cell neoplasms.

Experimental Design::

Primary specimens, cell lines, patient-derived xenograft models, commercially available, and proprietary anti-KLRG1 antibodies were used for screening, target, and functional validation.

Results::

Here we demonstrate that surface KLRG1 is highly expressed on tumor cells in subsets of patients with extranodal NK/T-cell lymphoma (ENKTCL), T-prolymphocytic leukemia (T-PLL), and gamma/delta T-cell lymphoma (G/D TCL). The majority of the CD8+/CD57+ or CD3−/CD56+ leukemic cells derived from patients with T- and NK-large granular lymphocytic leukemia (T-LGLL and NK-LGLL), respectively, expressed surface KLRG1. The humanized afucosylated anti-KLRG1 monoclonal antibody (mAb208) optimized for mouse in vivo use depleted KLRG1+ TCL cells by mechanisms of ADCC, ADCP, and CDC rather than apoptosis. mAb208 induced ADCC and ADCP of T-LGLL patient-derived CD8+/CD57+ cells ex vivo. mAb208 effected ADCC of subsets of healthy donor-derived KLRG1+ NK, CD4+, CD8+ Tem, and TemRA cells while sparing KLRG1− naïve and CD8+ Tcm cells. Treatment of cell line and TCL patient-derived xenografts with mAb208 or anti-CD47 mAb alone and in combination with the PI3K-δ/γ inhibitor duvelisib extended survival. The depletion of macrophages in vivo antagonized mAb208 efficacy.

Conclusions::

Our findings suggest the potential benefit of a broader treatment strategy combining therapeutic antibodies with PI3Ki for the treatment of patients with mature T-cell and NK-cell neoplasms.See related commentary by Varma and Diefenbach, p. 2300

项与 3D-197 相关的新闻（医药）

2024-09-12

·Business Wire

Global CD47 Inhibitor Drug Clinical Trials Insight & Market Opportunity Outlook to 2028 - ResearchAndMarkets.com

DUBLIN--( BUSINESS WIRE )--The "Global CD47 Inhibitor Drug Clinical Trials Insight & Market Opportunity Outlook 2028" report has been added to ResearchAndMarkets.com's offering. Inhibition of the cell surface protein CD47 has emerged as a novel cancer immunotherapy approach that has piqued the interest of both academia and industry in the recent years. Cancer cells often overexpress CD47, which triggers the "don't eat me" signal pathway, thereby helping malignant cells to escape immune surveillance. CD47 inhibitors seek to uncover cancer cells by inhibiting this protein, leaving them open to immune system attack, specifically through increased macrophage phagocytosis. Although no CD47 inhibitor is currently approved for therapeutic usage, the availability of candidates in phase 3 trials suggests that one may be approved in the coming years. With multiple candidates at varying stages of development, the field of CD47 inhibitor research and development is rapidly evolving. Developed by Forty Seven, which is now a part of Gilead, magrolimab is among the most advanced CD47 inhibitors. In early stage clinical trials for hematological tumors, it has demonstrated encouraging outcomes, especially when combined with other cancer treatments. Furthermore, late stage clinical trials evaluating Magrolimab in solid cancer alongside conventional cancer treatments such as docetaxel, Nivolumab, Pembrolizumab, Azacitidine, and Venetoclax are now under progress. Another significant candidate is Evorpacept (ALX148) from ALX Oncology, a high affinity SIRP? fusion protein that inhibits CD47. Currently, evorpacept is being assessed as a monotherapy and in combination with widely used anticancer drugs in a number of early phase clinical trials for a variety of solid and hematological tumors. Furthermore, a late-phase trial evaluating Evorpacept in combination with Trastuzumab, Ramucirumab, and Paclitaxel for the treatment of HER2+ gastric cancer is also under progress. A number of other CD47 inhibitors, including as TQB 2928 (Chia Tai Tianqing Pharmaceutical), MP 0621 (Molecular Partners), IMC-002 (ImmuneOncia Therapeutics), and CC 90002 (Celgene), are in the early phases of clinical research. The emphasis on combination therapies is undoubtedly one of the key trends in clinical development. Combining CD47 inhibitors with other immunotherapies, targeted treatments, and chemotherapy is being studied in an effort to overcome resistance mechanisms and provide synergistic benefits. Anticipated growth in the global market for CD47 inhibitors is attributed to the rising cancer incidence and increased use of immunotherapies in the upcoming years. The potential of CD47 inhibitors has been acknowledged by a number of prominent pharmaceutical companies, which has resulted in notable partnerships and acquisitions. The commercial interest in this field is demonstrated by Gilead Science's US$ 4.9 billion acquisition of Forty Seven in 2020 and Pfizer's US$ 2.26 billion acquisition of Trillium Therapeutics in 2021. Although Chinese and American companies presently dominate the market, there is increasing participation from South Korea, Australia, Canada, and Japan. Through clinical research, companies such as Shaperon, InnobationBio, Bitterroot Bio, and ImmuneOncia Therapeutics are making strides with their CD47 inhibitors. The market is becoming increasingly competitive, with several firms striving for market share. Therefore, for commercial success, differentiation based on safety profile, efficacy, and possible combination strategies will be essential. The market for CD47 inhibitors has both opportunities and challenges. Strong commercial interest and encouraging clinical evidence point to substantial development potential. However, there are challenges to address, such managing toxicity profiles, coming up with the best combination plans, and demonstrating distinct therapeutic advantages over current treatments. As the field develops, biomarker development for response prediction and patient selection will probably become more crucial for clinical development as well as marketing tactics. In conclusion, the market for CD47 inhibitors globally is an active rapidly expanding area of cancer immunotherapy. In the years to come, CD47 inhibitors could have a big impact on cancer therapy paradigms because there are several candidates in clinical development and a lot of commercial interest. Global CD47 Inhibitor Drug Clinical Trials Insight & Market Opportunity Outlook 2028 Report Highlights Global & Regional Market Opportunity Outlook Insight On More Than 100 CD47 Inhibitor Drugs In Clinical Trials Global CD47 Inhibitors Clinical Trials Insight By Company, Country, Indication & Phase Orphan, Fast Track, Breakthrough Therapy Designation Insight Key Drugs Initiation & Completion Year CD47 Clinical Application & Development Outlook By Indication CD47 Inhibitor Drugs Clinical Developments & Trends By Country Global CD47 Inhibitor Drug Market Dynamics Key Topics Covered: 1. CD 47 As Novel Cancer Immunotherapy Target 2. Global CD47 Inhibitors Drug Clinical Pipeline Overview 2.1 By Country 2.2 By Company 2.3 By Indication 2.4 By Patient Segment 2.5 By Phase 2.6 By Priority Status 3. CD47 Inhibitors Clinical Trials Insight By Company, Country, Indication & Phase 3.1 Research 3.2 Preclinical 3.3 Phase I 3.4 Phase I/II 3.5 Phase II 3.6 Phase II/III 3.7 Phase III 4. Global CD47 Inhibitor Drug Market Opportunity Outlook 4.1 Current Market Overview 4.2 Future Outlook & Opportunities 5. CD47 Clinical Application & Development Outlook by Indication 5.1 Solid Cancers 5.1.1 Breast Cancer 5.1.2 Colorectal Cancer 5.1.3 Lung Cancer 5.1.4 Urogenital Cancer 5.1.5 Gastrointestinal Cancer 5.2 Hematological Malignancies 5.2.1 Lymphoma 5.2.2 Leukemia 5.2.3 Multiple Myeloma 5.2.4 Myelodysplastic Syndrome 5.3 Microbial Infections 6. CD47 Inhibitor Drugs Clinical Developments & Trends By Country 6.1 China 6.2 US 6.3 South Korea 6.4 Australia 6.5 Canada 7. Global CD47 Inhibitors Market Dynamics 7.1 Favorable Parameters 7.2 Market Restraints 8. Competitive Landscape Adagene ALX Oncology ImmuneOncia Therapeutics ImmuneOnco Biopharma Light Chain Bioscience Phanes Therapeutics Virtuoso Therapeutics For more information about this report visit https://www.researchandmarkets.com/r/qs8ua0 About ResearchAndMarkets.com ResearchAndMarkets.com is the world's leading source for international market research reports and market data. We provide you with the latest data on international and regional markets, key industries, the top companies, new products and the latest trends.

免疫疗法临床3期快速通道并购临床研究

2024-06-03

·BioSpace

ImmuneOncia Announces Biomarker Results from Phase 1 Clinical Trial of CD47 Antibody at ASCO

SEOUL, South Korea--(BUSINESS WIRE)-- ImmuneOncia (CEO Heung Tae Kim) announced the results of its solid tumour Phase 1a clinical trial of IMC-002, an anti-CD47 mAb, presented at the American Society of Clinical Oncology (ASCO) Annual Meeting held in Chicago, USA on June 1, 2024 (local time). These results include updates on the Phase 1a clinical trial outcomes, along with biomarker findings achieved through collaboration with Lunit (CEO; Brandon Suh), a leading provider of AI-powered solutions for cancer diagnostics and therapeutics. This press release features multimedia. View the full release here: ImmuneOncia Announces Biomarker Results from Phase 1 Clinical Trial of CD47 Antibody at ASCO (Graphic: ImmuneOncia Therapeutics, Inc.) The study, a dose escalation part of Phase 1, enrolled a total of 12 patients across four dose cohorts starting from May 2022. Each patient received IMC-002 at doses of 5, 10, 20, or 30 mg/kg every two weeks. Treatment outcomes revealed stable disease (SD) in 6 out of 12 evaluable patients, demonstrating a disease control rate (DCR) of 50%. Among these, 5 patients had hepatocellular carcinoma, and 1 had breast cancer. Furthermore, 4 patients maintained stable disease for over 6 months, resulting in a clinical benefit rate (CBR) of 33.3%. AI-powered biomarker analysis, utilizing Lunit SCOPE IO, revealed that the density of CD47-positive macrophages was numerically higher in the CBR group compared to the non-CBR group (71.0/mm² vs. 44.3/mm²), while the density of CD47-positive tumour cells was similar between the two groups. These findings suggest a correlation between the density of CD47-positive macrophages and treatment response, underscoring the potential significance of targeting CD47 in future therapeutic strategies. Principal investigator Dr. Ho Yeong Lim of Samsung Medical Center stated, "No dose-limiting toxicities (DLTs) were observed across all cohorts, and common adverse events associated with anti-CD47 therapy such as infusion-related reactions, haemolytic anaemia, thrombocytopenia, and neutropenia were not reported, confirming the high safety pro IMC-002." He added, "Particularly noteworthy is the absence of long-term toxicity in a patient with hepatocellular carcinoma who has been on single-agent IMC-002 treatment for 15 months, demonstrating a favourable prognosis with stable disease and a 20% reduction in tumour size." CEO Heung Tae Kim of ImmuneOncia commented, "We previously disclosed the high safety and tolerability of IMC-002, along with the recommended Phase 2 dose (RP2D) of 20 mg/kg every 3 weeks, based on interim results presented at the European Society for Medical Oncology (ESMO) in October 2023." He further stated, "With the Phase 1b trial for IMC-002 initiated last November, we anticipate additional efficacy confirmation for IMC-002 in specific solid tumours with high unmet needs." About IMC-002 IMC-002 is an immune-checkpoint-inhibitor targeting the CD47 of macrophages, blocking the 'don't eat me' signal of CD47/SIRPα interaction between cancer cells and macrophages to enhance phagocytosis of cancer cells. IMC-002 is a potential first-in-class and second-generation anti-CD47 mAb demonstrating high safety with no commonly associated adverse events (hemagglutination, thrombocytopenia, neutrophilia, etc.) due to minimal binding to normal cells such as red blood cells. About ImmuneOncia Therapeutics, Inc. ImmuneOncia is a South Korean clinical-stage biotech company focused on immuno-oncology, established in 2016. Leveraging expertise in drug development and antibody engineering, ImmuneOncia is dedicated to delivering safe, effective, and novel immunotherapies to oncology patients worldwide. Its portfolio includes a variety of immune checkpoint antibodies such as PD-L1, CD47, LAG3, Bi-specifics, and ADC/AIC.

临床1期免疫疗法临床结果ASCO会议临床2期

2023-10-23

·BioSpace

ImmuneOncia Announces Phase 1 Results of CD47 Antibody at ESMO 2023

SEOUL, South Korea--(BUSINESS WIRE)-- ImmuneOncia (CEO Heung Tae Kim) announced the results of its Phase 1a solid tumour clinical trial (IMC-002-K102 Study) of IMC-002, a CD47 monoclonal antibody, at the European Society for Medical Oncology (ESMO 2023) held in Madrid, Spain on October 23rd, 2023. The dose-escalation study aimed to assess the safety and tolerability, and to establish the recommended Phase 2 dose (RP2D) of IMC-002. From May 2022 to October 2023, a total of 12 patients were enrolled in four dose cohorts, each receiving IMC-002 at doses of 5, 10, 20, or 30 mg/kg every 2 weeks (Q2W). The clinical data showed no dose-limiting toxicities (DLT). 92% of treatment-related adverse events (TRAE) were of Grade 1-2, with 94% occurring during the first treatment cycle. Common side effects associated with anti-CD47 therapy, such as infusion-related reactions, thrombocytopenia, and neutropenia, were not reported. The recommended Phase 2 dose of 20 mg/kg every 3 weeks (Q3W) was established. 6 out of 11 evaluable patients with measurable lesions also demonstrated stable disease (SD). 5 of the patients had liver cancer, and 1 had breast cancer. Professor Ho Young Lim of Samsung Medical Center, the Principal Investigator (PI) of IMC-002, commented, "CD47 is a promising immune checkpoint inhibitor for activating the anticancer function of macrophages, but it is also expressed on normal cells, raising concerns about hemolytic anemia and thrombocytopenia. However, most of the side effects of IMC-002 were mild, and 4 out of 6 SD patients received long-term treatment for over 6 months. This clinical trial has confirmed the safety of IMC-002." Heung Tae Kim, CEO of ImmuneOncia, said, "The recommended dose of every 3 weeks (Q3W) enhances patient convenience and opens up combination treatment opportunities with immune checkpoint inhibitors such as PD-(L)1 or other cytotoxic agents. Observing disease control for over 6 months in 4 SD patients, we expect to further confirm efficacy in Phase 1b, which is set to commence in November this year. We hope to further advance towards our goal of providing patients with a best-in-class anti-CD47 therapy." IMC-002 is an anti-CD47 antibody that functions as an immune checkpoint inhibitor against macrophages, allowing them to attack cancer cells by blocking the 'don't eat me' signal between CD47 on cancer cells and SIRPα on macrophages. IMC-002 is expected to have a good safety pro minimising binding to normal cells, including red blood cells. ImmuneOncia is a biotechnology company specialising in immuno-oncology drug development. In addition to the CD47 antibody IMC-002, ImmuneOncia also has a wide range of pipeline that includes the Phase 2 clinical-stage PD-L1 antibody IMC-001, and the preclinical-stage bispecific antibody IMC-201.

免疫疗法临床1期临床结果临床2期

100 项与 3D-197 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
晚期癌症	临床1期	韩国	Immuneoncia Therapeutics, Inc.初创企业	2022-05-10
血液肿瘤	临床1期	中国	思路迪生物医药（上海）有限公司	2022-03-09
血液肿瘤	临床1期	中国	3D Medicines, Inc. (United States)	2022-03-09
实体瘤	临床1期	中国	思路迪生物医药（上海）有限公司	2022-03-09
实体瘤	临床1期	中国	3D Medicines, Inc. (United States)	2022-03-09
局部晚期恶性实体瘤	临床1期	美国	Immuneoncia Therapeutics, Inc.初创企业	2020-06-05
局部晚期恶性实体瘤	临床1期	韩国	Immuneoncia Therapeutics, Inc.初创企业	2020-06-05
淋巴瘤	临床1期	美国	Immuneoncia Therapeutics, Inc.初创企业	2020-06-05
淋巴瘤	临床1期	韩国	Immuneoncia Therapeutics, Inc.初创企业	2020-06-05

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT05276310 (ASCO2024) 人工标引	临床1期	晚期恶性实体瘤 CD47 positive	12	IMC-002	衊膚衊願糧憲鹽餘鹽顧(範製淵鬱積築製膚遞鏇) = 選鏇獵廠鹽夢範艱積衊鹹鏇願鏇襯鬱夢簾蓋廠 (壓窪齋鹹襯觸構鏇餘淵 ) 更多	积极	2024-05-24
NCT05276310 (ESMO2023) 人工标引	临床1期	晚期恶性实体瘤二线	12	IMC-002	築顧構獵壓齋選醖鹽憲(顧膚鬱繭糧艱膚鏇艱餘) = 餘鹽壓鏇蓋糧廠範憲構蓋鹹淵觸餘願餘鏇繭築 (網憲鬱蓋鬱築壓鹽餘鏇 ) 更多	积极	2023-10-23