This is a phase I study of an agonistic CD40 antibody (mitazalimab) injected intratumorally at the time of surgical IRE in patients with locally advanced pancreatic cancer. Intratumoral delivery has potential to be more effective than systemic (intravenous) delivery while decreasing the systemic side effects of immunotherapy. We hypothesize that local delivery of mitazalimab at the time of IRE in patients with locally advanced pancreatic cancer will be safe, augment the immune effects of IRE, and decrease the risk of recurrence.

开始日期2024-06-25

申办/合作机构

University of California San Diego

[+2]

NCT04888312 / Active, not recruiting临床1/2期

An Open-label Phase 1b/2 Study Assessing the Safety and Efficacy of Mitazalimab in Combination With Chemotherapy in Patients With Metastatic Pancreatic Ductal Adenocarcinoma

Phase 1b/2 study to assess the safety and efficacy of mitazalimab in combination with chemotherapy in patients with metastatic pancreatic ductal adenocarcinoma.

开始日期2021-09-17

申办/合作机构

Alligator Bioscience AB

[+2]

NL-OMON52234 / CompletedN/A

Dendritic Cells loaded with allogeneic tumor lysate (MesoPher) in combination with a CD40 agonist (Mitazalimab) in metastatic pancreatic disease (REACtiVe-2 Trial) - REACtiVe-2

开始日期2021-08-30

申办/合作机构

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

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100 项与米佐利单抗相关的转化医学

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100 项与米佐利单抗相关的专利（医药）

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项与米佐利单抗相关的文献（医药）

2024-07-01·LANCET ONCOLOGY

Combining CD40 agonist mitazalimab with mFOLFIRINOX in previously untreated metastatic pancreatic ductal adenocarcinoma (OPTIMIZE-1): a single-arm, multicentre phase 1b/2 study

Article

作者: Batlle, Jaime Feliu ; Prenen, Hans ; Gallego, Inmaculada ; Cassier, Philippe Alexandre ; Pilla, Lorenzo ; Pazo-Cid, Roberto Antonio ; Blanc, Jean-Frédéric ; Garrote, Mercedes Rodriguez ; Van Laethem, Jean-Luc ; Borbath, Ivan ; Pico de Coaña, Yago ; Smith, Karin Enell ; Ellmark, Peter ; Mitry, Emmanuel ; Ambarkhane, Sumeet Vijay ; Macarulla, Teresa ; Geboes, Karen Paula ; Lambert, Aurélien

BACKGROUND:

Current systemic therapies for metastatic pancreatic ductal adenocarcinoma are associated with poor outcomes with a 5-year overall survival rate under 5%. We aimed to assess the safety and antitumour activity of mitazalimab, a human CD40 agonistic IgG1 antibody, with modified FOLFIRINOX (mFOLFIRINOX; fluorouracil, leucovorin, oxaliplatin, and irinotecan), in chemotherapy-naive patients with metastatic pancreatic ductal adenocarcinoma.

METHODS:

OPTIMIZE-1 was a single-arm, multicentre, phase 1b/2 study which enrolled adults with histologically-confirmed metastatic pancreatic ductal adenocarcinoma and European Cooperative Oncology Group performance status 0 or 1 in 14 university hospitals in Belgium, France, and Spain. The primary endpoint of phase 1b was to determine the recommended phase 2 dose of intravenous mitazalimab (450 μg/kg or 900 μg/kg) when combined with intravenous mFOLFIRINOX (oxaliplatin 85 mg/m², leucovorin 400 mg/m², irinotecan 150 mg/m², fluorouracil 2400 mg/m²). In the first 21-day treatment cycle, mitazalimab was administered on days 1 and 10, and mFOLFIRINOX on day 8. In subsequent 14-day cycles mitazalimab was administered 2 days after mFOLFIRINOX. The phase 2 primary endpoint was objective response rate. Activity and safety analyses were conducted on the full analysis set (all patients who received the combination of mitazalimab at the recommended phase 2 dose and mFOLFIRINOX for at least two treatment cycles) and safety set (all patients who received any study treatment), respectively. Enrolment is complete, and data represents a primary analysis of the ongoing trial. The trial is registered at Clinicaltrials.gov (NCT04888312).

FINDINGS:

Between Sept 29, 2021, and March 28, 2023, 88 patients were screened and 70 patients were enrolled (40 [57%] were female and 30 [43%] were male). In phase 1b, 900 μg/kg mitazalimab was determined as the recommended phase 2 dose. Overall, five patients received 450 μg/kg mitazalimab; 65 received 900 μg/kg mitazalimab. No dose-limiting toxicities were observed at 450 μg/kg, and one dose-limiting toxicity was observed at 900 μg/kg. 57 patients were evaluated for activity, and all 70 patients were included in the safety set. At data cutoff on Nov 14, 2023, median follow-up was 12·7 months (95% CI 11·1-15·7). Of the 57 patients, 29 (51%) remained on study and 18 (32%) remained on treatment. The primary endpoint (objective response rate >30%) was met (objective response rates in 23 [40%]; one-sided 90% CI ≥32 of 57 patients). The most common grade 3 or worse adverse events were neutropenia (18 [26%] of 70 patients), hypokalaemia (11 patients [16%]), and anaemia and thrombocytopenia (eight patients [11%]). Serious adverse events were reported in 29 (41%) of 70 patients, the most common being vomiting (five [7%] of 70 patients), decreased appetite (four [6%]), and diarrhoea and cholangitis (three [4%] of 70 patients for each), none considered related to mitazalimab. No treatment-related deaths were reported.

INTERPRETATION:

Mitazalimab with mFOLFIRINOX demonstrated manageable safety and encouraging activity, warranting continued development in a phase 3, randomised, controlled trial. The results from OPTIMIZE-1 pave the way for further exploration and confirmation of a novel immunotherapy treatment regimen for metastatic pancreatic ductal adenocarcinoma, which is a complex and aggressive cancer with very low survival rates and restricted treatment options.

FUNDING:

Alligator Bioscience.

2024-02-01·Cytokine & growth factor reviews

Harnessing the potential of CD40 agonism in cancer therapy

Review

作者: Richmond, Ann ; Zhou, Yang ; Yan, Chi

CD40 is a member of the tumor necrosis factor (TNF) receptor superfamily of receptors expressed on a variety of cell types. The CD40-CD40L interaction gives rise to many immune events, including the licensing of dendritic cells to activate CD8⁺ effector T cells, as well as the facilitation of B cell activation, proliferation, and differentiation. In malignant cells, the expression of CD40 varies among cancer types, mediating cellular proliferation, apoptosis, survival and the secretion of cytokines and chemokines. Agonistic human anti-CD40 antibodies are emerging as an option for cancer treatment, and early-phase clinical trials explored its monotherapy or combination with radiotherapy, chemotherapy, immune checkpoint blockade, and other immunomodulatory approaches. In this review, we present the current understanding of the mechanism of action for CD40, along with results from the clinical development of agonistic human CD40 antibodies in cancer treatment (selicrelumab, CDX-1140, APX005M, mitazalimab, 2141-V11, SEA-CD40, LVGN7409, and bispecific antibodies). This review also examines the safety profile of CD40 agonists in both preclinical and clinical settings, highlighting optimized dosage levels, potential adverse effects, and strategies to mitigate them.

2023-09-27·Cells

Early Pharmacodynamic Changes Measured Using RNA Sequencing of Peripheral Blood from Patients in a Phase I Study with Mitazalimab, a Potent CD40 Agonistic Monoclonal Antibody.

Article

作者: de Coaña, Yago Pico ; Sobti, Aastha ; Jimenez, David Gomez ; Hägerbrand, Karin ; Ellmark, Peter ; Ambarkhane, Sumeet Vijay ; Andersson, Hampus ; Smith, Karin Enell ; Lindstedt, Malin

CD40-targeting therapies can enhance the dendritic cell priming of tumor-specific T cells and repolarize intratumoral macrophages to alleviate the tumoral immunosuppressive environment and remodel the extracellular matrix. Mitazalimab is a potent agonistic CD40 monoclonal IgG1 antibody currently under clinical development. This study used RNA sequencing of blood samples from a subset of patients from a Phase I trial with mitazalimab (NCT02829099) to assess peripheral pharmacodynamic activity. We found that mitazalimab induced transient peripheral transcriptomic alterations (at 600 µg/kg and 900 µg/kg dose administered intravenously), which mainly were attributed to immune activation. In particular, the transcriptomic alterations showed a reduction in effector cells (e.g., CD8⁺ T cells and natural killer cells) and B cells peripherally with the remaining cells (e.g., dendritic cells, monocytes, B cells, and natural killer cells) showing transcription profiles consistent with activation. Lastly, distinct patient subgroups based on the pattern of transcriptomic alterations could be identified. In summary, the data presented herein reinforce the anticipated mode of action of mitazalimab and support its ongoing clinical development.

项与米佐利单抗相关的新闻（医药）

2024-09-16

·PipelineReview

Alligator Bioscience and Aptevo Therapeutics Announce Data from Phase 1 ALG.APV-527 Monotherapy Trial Showing 60% of Evaluable Patients Achieved Stable Disease in Solid Tumor Study

LUND, Sweden I September 16, 2024 I Alligator Bioscience AB (“Alligator”) (Nasdaq Stockholm:ATORX) and Aptevo Therapeutics (“Aptevo”) (Nasdaq: APVO) today announced positive interim data from the dose escalation phase of their Phase 1 trial evaluating ALG.APV-527 for the treatment of solid tumors likely to express the tumor antigen 5T4. The results, which include clinical activity, safety, tolerability outcomes, pharmacokinetics and pharmacodynamics were presented in a poster session on Saturday, September 14, 2024, at the European Society for Medical Oncology (ESMO) Annual Congress in Barcelona, Spain. ALG.APV-527 is a first-in-class bispecific antibody that targets 4-1BB and the tumor antigen 5T4. The compound is being evaluated in a multi-center, dose escalation trial that has 18 patients included in the safety analysis. These patients received multiple prior rounds of therapy for the treatment of solid tumor types. The trial is approaching full enrollment and interim results include: Clinical Activity/Efficacy Safety and Tolerability Evidence of favorable pharmacokinetics and biological activity of ALG.APV-527 “4-1BB has been a target of interest-though with excess toxicity-for decades, and novel bispecific approaches like this will enable us to maximize anti-tumor immunity while limiting the systemic toxicity concerns that have plagued this key immune costimulatory receptor. With this backdrop, these Phase 1 interim results are very encouraging, with ALG.APV-527 showing a positive safety profile with 60% of evaluable patients achieving stable disease, meaning not progressing for variable time frames including one breast cancer patient being treated with monotherapy on study with SD for more than 11 months. We are excited to see signs of clinical activity, underscoring the potential of the drug to benefit patients with solid tumors in the clinical setting, supported by a positive safety and tolerability profile,” stated Thomas Marron, MD, PhD, Professor in Immunology & Immunotherapy and in Medicine, Hematology and Medical Oncology at Icahn School of Medicine at Mount Sinai , participating Investigator of the trial. Trial Overview The ALG.APV-527 Phase 1 trial is a multi-center, multi-cohort, open-label dose-escalation trial that includes administration of ALG.APV-527 in up to six escalating dose levels in a 3+3 design*. The trial is enrolling adult patients with multiple solid tumor types/histologies likely to express the 5T4 antigen. ALG.APV-527 will be given intravenously once every two weeks. The trial is assessing the safety and tolerability, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity of ALG.APV-527. *The 3+3 design proceeds in cohorts of three patients treated at increasing dose levels. Dose escalation stops when at least two out of three or six patients experience dose limiting toxicities (DLTs) at that dose level. About ALG.APV-527 ALG.APV-527 is a bispecific conditional 4-1BB agonist, only active upon simultaneous binding to 4-1BB and 5T4. This has the potential to be clinically important because 4-1BB can stimulate the immune cells (antitumor-specific T cells and NK cells) involved in tumor control, making 4-1BB a particularly compelling target for cancer immunotherapy. 5T4 is an oncofetal tumor associated antigen overexpressed on numerous solid tumors including non-small-cell lung carcinoma (NSCLC), breast, head and neck, cervical, renal, gastric, and colorectal cancer. Preclinical studies, highlighting the differentiated design of the molecule that minimizes systemic immune activation, allowing for highly efficacious tumor-specific responses as demonstrated by potent activity in preclinical models, has been published in the peer-reviewed publication, Molecular Cancer Therapeutics , a journal of the American Association for Cancer Research (AACR). About Alligator Bioscience Alligator Bioscience AB is a clinical-stage biotechnology company developing tumor-directed immuno-oncology antibody drugs. Alligator’s portfolio includes several promising drug candidates, with the CD40 agonist mitazalimab as its key asset. Furthermore, Alligator is co-developing ALG.APV-527 with Aptevo Therapeutics Inc., several undisclosed molecules based on its proprietary technology platform, Neo-X-Prime™, and novel drug candidates based on the RUBY™ bispecific platform with Orion Corporation. Out-licensed programs include AC101/HLX22, in Phase 2 development, by Shanghai Henlius Biotech Inc. and an undisclosed target to Biotheus Inc. Alligator Bioscience’s shares are listed on Nasdaq Stockholm (ATORX) and is headquartered in Lund, Sweden. For more information, please visit alligatorbioscience.com . About Aptevo Therapeutics Aptevo Therapeutics Inc. is a clinical-stage biotechnology company focused on developing novel bispecific immunotherapies for the treatment of cancer. Aptevo is seeking to improve treatment outcomes and transform the lives of cancer patients. For more information, please visit www.aptevotherapeutics.com . SOURCE: Aptevo Therapeutics

临床1期临床结果免疫疗法AACR会议临床2期

2024-06-13

·CPHI制药在线

浅谈胰腺导管癌治疗进展：在研药物多样，诺华放弃，康宁杰瑞惨败

关注并星标CPHI制药在线胰腺癌是一组主要起源于胰腺导管上皮及腺泡细胞的恶性肿瘤，恶性程度极高，起病隐匿，早期诊断困难，进展迅速，生存时间短，是预后最差的恶性肿瘤之一，被称为"癌中之王"。即使在新疗法不断涌现的今天，胰腺癌的治疗也并未取得突破进展。下面笔者将浅谈下胰腺癌的主要类型--胰腺导管腺癌的治疗现状，以及近年该领域药物的研究进展。关于胰腺导管癌胰腺导管腺癌（PDAC）是一种发生于胰腺导管上皮的肿瘤，是胰腺癌中的主要类型，约占90%以上。PDAC起病隐匿，且具有高度侵袭性，大多患者确诊时已处于晚期。由于缺乏有效的治疗手段，PDAC患者总体5年生存率< 12 %。据2024年2月中国国家癌症中心（NCC）发布的2022年中国新发癌症病例数和死亡人数数据：2022年中国胰腺癌新发病例11.87万，死亡人数10.63万。手术和化疗是PDAC的主要治疗手段，但只有15%-20%的患者在诊断时符合手术条件。不过据《Nature》官网发布的相关研究论文数据，即便能手术，近90% 的PDAC患者在治疗平均7~9个月内会面临复发。而晚期PDAC标准治疗是化疗，常采用联合治疗方案，如AG（白蛋白紫杉醇联合吉西他滨）方案、改良FOLFIRINOX（mFOLFIRINOX，奥沙利铂+伊立替康+亚叶酸钙+氟尿嘧啶）方案或S-IROX（替吉奥+伊立替康+奥沙利铂）方案。据2023年6月美国国家综合癌症网络（NCCN）指南发表的2023年第2版胰腺癌诊治指南：（1）对于部分可切除性胰腺癌，指南推荐先行新辅助治疗（NAT）再手术，推荐方案包括FOLFIRINOX或改良FOLFIRINOX方案，以及吉西他滨联合白蛋白结合紫杉醇方案（AG方案），其中FOLFIRINOX或mFOLFIRINOX方案适用于美国东部肿瘤协作组（ECOG）评分0~1分的病人。术后指南建议患者常规开展化疗，化疗首选方案包括FOLFIRINOX/mFOLFIRINOX方案或吉西他滨联合卡培他滨方案；（2）对于晚期或转移性胰腺癌：PS评分良好（0~1分）局部晚期/转移性胰腺癌一线治疗新增NALIRIFOX方案，即脂质体伊立替康+5-氟尿嘧啶+亚叶酸+奥沙利铂，PS评分中等（2分）局部晚期胰腺癌一线治疗首选卡培他滨或吉西他滨单药化疗或AG方案，PS评分中等（2分）转移性胰腺癌首选AG方案，其次卡培他滨或吉西他滨，NALIRIFOX方案在某些情况下也可使用；（3）对于复发的局部进展期/转移性胰腺癌，PS评分良好者，当NTRK融合基因阳性，首选恩曲替尼或拉罗替尼；当存在微卫星高度不稳定（MSI-H）、错配修复缺陷（dMMR）或肿瘤突变负荷（TMB）≥10 mut/Mb者，建议使用帕博丽珠单抗。新版指南建议在其他治疗方案中新增以下内容：对于合并MSI-H、dMMR者，可使用多塔利单抗；若TMB≥10 mut/Mb，也可使用纳武利尤单抗+伊匹木单抗；PS评分中等者，无首选方案。胰腺导管癌药物研究进展上述方案对PDAC治疗效果有限，且有些药物只适用于特定患者。药企对PDAC新疗法的探索从未止步，今年2月FDA批准NALIRIFOX（脂质体伊立替康 (Onivyde)+奥沙利铂+氟尿嘧啶 (5-FU)/亚叶酸）方案一线治疗转移性PDAC。此外，目前全球还有多款在研PDAC新疗法，详见下表。这些在研疗法作用靶点各异，具体适应症有所不同，且药物类型多样，涉及化药、单抗、双抗、CAR-T疗法、疫苗以及溶瘤病毒等。研发进度上，NIS793、KN046等处于3期临床。其中NIS793是一种完全人源的单克隆抗体，通过阻断TGFβ细胞因子而发挥作用，2021年被FDA授予治疗胰腺癌的孤儿药资格，其联合吉西他滨和Nab-紫杉醇一线治疗PDAC的临床试验已进入3期阶段。值得一提的是，诺华曾于2015年从Xoma引进NIS793，但2024年诺华宣布停止研发NIS793，并将其退还给Xoma。 KN046是康宁杰瑞研发的一款PD-L1/CTLA-4靶向双抗。已公布的2期临床研究（NCT04324307）数据显示：对于31例无法切除的晚期胰腺癌患者，KN046联合AG方案的ORR为45.2%，DCR为93.5%。遗憾的是，今年5月，康宁杰瑞宣布KN046联合AG方案一线治疗不可切除局部晚期或转移性PDAC的3期临床试验KN046-303惨遭失败，OS结果未达到统计学终点。索凡替尼治疗胰腺癌方面处于2/3期临床，2024年5月其联合卡瑞利珠单抗和化疗（白蛋白结合型紫杉醇+吉西他滨)一线治疗转移性PDAC的2/3期临床试验启动。该药是和黄医药开发的一种新型的口服酪氨酸激酶抑制剂，已被NMPA批准用于无法手术切除的局部晚期或转移性、进展期非功能性、分化良好（G1、G2）的非胰腺（2020年12月）和胰腺（2021年6月）来源的神经内分泌瘤。已公布的索凡替尼治疗胰腺癌的临床试验结果显示：索凡替尼联合TAS-102三线或后线治疗方案对mPDAC患者有令人鼓舞的抗肿瘤活性，特别是对无肝转移患者。此外，与索凡替尼仅联合化疗相比，索凡替尼联合卡瑞利珠单抗和化疗一线治疗胰腺癌可显著延长患者的OS和PFS。 CAN-2409、Motixafortide等处于2期临床。其中CAN-2409是一种复制缺陷的腺病毒，旨将单纯疱疹病毒胸苷激酶（HSV-tk）基因递送至患者的肿瘤并诱导个体化的全身抗肿瘤免疫反应。HSV-tk是一种酶，可局部将口服伐昔洛韦转化为杀死附近癌细胞的有毒代谢物，从而释放多种癌症抗原。该疗法通过局部注射将免疫应答局部聚焦于肿瘤，能够最大限度地减少与全身静脉给药相关的全身毒性。2024年4月，CAN-2409被FDA授予治疗胰腺癌的孤儿药资格。已公布的CAN-2409联合抗病毒药物与标准护理（SoC）放化疗用作可切除PDAC术前辅助治疗的2期临床试验结果显示：截至2024年3月29日数据，在边缘性可切除PDAC中，CAN-2409组患者的mOS为28.8个月（Vs 对照组的12.5个月）；24个月时，CAN-2409治疗组患者的生存率为71.4%（Vs 对照组的16.7%），；36个月时，CAN-2409治疗组的生存率为47.6%（Vs 对照组的16.7%）。CAN-2409还显示出良好的耐受性，没有显著的额外局部或全身毒性。而且，对切除肿瘤的分析显示，患者在使用CAN-2409联合疗法后，其PDAC组织中出现密集的免疫细胞聚集，包括CD8+细胞、细胞毒性肿瘤浸润淋巴细胞和树突状细胞，这证实该疗法能够激活强大的抗肿瘤免疫反应。安全性方面，在SoC中添加CAN-2409方案显示出良好的耐受性，没有观察到剂量限制性毒性。 Motixafortide是Biokine Therapeutics 研发的一款靶向CXCR4的长效合成多肽拮抗剂，后授权给BioLineRx。2023年9月，该疗法被FDA批准联合filgrastim（G-CSF），以在多发性骨髓瘤患者中动员造血干细胞到外周血进行采集，辅助进行自体干细胞移植。治疗PDAC方面，已公布的临床研究结果显示：Motixafortide联合帕博利珠单抗和化疗在治疗PDAC方面表现出良好的安全性和耐受性，且在预后不良和病情凶险的PDAC人群中显示出疗效。 2023 AACR上公布的Motixafortide联合帕博利珠单抗和AG方案一线治疗转移性胰腺癌的单臂2期临床试验结果显示：可评估患者(11人)的ORR为55%，36%患者出现PR，1例患者的肝转移病灶得到缓解。此外，27%的患者(3例)病情稳定，DCR为82%。 Mitazalimab是一种靶向CD40的单克隆抗体，通过激活树突状细胞、B细胞和巨噬细胞等免疫细胞，使肿瘤对化疗敏感，大幅增强抗肿瘤的能力。今年2月，该药被欧盟授予孤儿药资格，联合与mFOLFIRINOX方案一线治疗转移性PDAC。 2024年1月，Alligator Bioscience宣布Mitazalimab联合mFOLFIRINOX化疗一线治疗胰腺癌的2期临床研究达到主要研究终点。具体数据为：57名可评估患者的ORR为40.4%，DCR为79%，mOS为14.3个月，中位缓解持续时间为12.5个月（优于FOLFIRINOX标准治疗的5.9个月）。 CEND-1是一种由9个氨基酸构成的环肽药物，可与肿瘤中选择性表达的alpha-v整合素结合，然后被肿瘤微环境中表达的蛋白酶切割，释放出被称为CendR片段的肽片段，该片段再与第2个受体neuropilin-1结合，从而激活一种新的摄取途径（CendR途径），使抗癌药物能够穿透实体瘤。CEND-1改变肿瘤微环境以增强联合治疗药物的递送和功效的能力已在一系列实体瘤模型中得到证实。2021年2月，齐鲁制药与Cend Therapeutics签订合作和许可协议，获得CEND-1在大中华区开发和商业化权益。柳叶刀杂志上发表的CEND-1联合标准治疗化疗（吉西他滨和白蛋白紫杉醇）一线治疗转移性PDAC的1期临床研究数据显示：29例疗效可评估患者中的ORR为59%，mOS为13.2个月。 Efineptakin Alfa治疗胰腺癌方面处于1/2期临床。该药是一种长效人类白细胞介素 7，其联合帕博利珠单抗对胰腺癌患者展示出良好的疗效：7.7％的患者肿瘤大幅缩小或消失，34.6％的患者疾病得到有效控制。2024年2月，该疗法被FDA授予治疗晚期胰腺癌的孤儿药资格。 ELI-002、D-1553等处于1期临床。其中ELI-002是一款针对KRAS突变的治疗型疫苗，主要针对KRAS突变阳性实体瘤，尤其是PDAC、结直肠癌。该疫苗由两个关键组件构成，即AMP-CpG（一种特有的免疫激活剂，可刺激免疫系统产生强烈的反应）和AMP-mKRAS-肽。其中AMP-mKRAS-肽是一种经修饰的KRAS突变肽，可特异性地引导机体免疫系统，追踪并摧毁携带KRAS突变的癌细胞。 2024年1月《Nature》杂志上发表的1期临床试验AMPLIFY-201结果显示：ELI-002可显著降低患者肿瘤标志物水平，并产生强烈的T细胞应答，从而降低患者复发及死亡的风险，且总体上被认为是安全可控的。 IBI389是信达生物自主研发的一种抗CLDN18.2/CD3双特异性抗体。2024 ASCO上公布的IBI389治疗晚期不可手术或转移性PDAC的1期临床数据显示：600μg/kg治疗组疗效更佳，在27例至少进行了一次基线后肿瘤评估的受试者中，ORR为29.6% ，确认的客观缓解率（cORR）为25.9%，DCR达70.4%（95%CI：49.8-86.2）。在CLDN18.2 IHC 2/3+≥40%的18例受试者中，cORR达38.9%。此外，截至2024年5月1日，中位随访时间为4个月，mPFS尚未成熟，3个月的PFS率达57.1%。 CT041是一种潜在全球同类首创、靶向CLDN18.2蛋白的自体CAR-T细胞疗法，用于治疗Claudin18.2阳性实体瘤，主要治疗胃癌/食管胃结合部腺癌及胰腺癌。最近公布的CT041治疗难治性转移性胰腺癌的两项多中心、开放标签的1/1b期临床试验数据显示：24例患者中有12例观察到肿瘤靶病灶不同程度缩小，ORR为16.7%，DCR为70.8%，临床获益率为37.5%。mDoR为9.5个月，12个月的DoR率为50%，mPFS为3.3个月，mOS为10.0个月，12个月时OS率为45.8%。 D-1553是益方生物自主开发的一款新型、高效、口服KRAS G12C抑制剂。已公布的D-1553针对KRAS G12C突变晚期胰腺癌的早期临床试验结果显示：D-1553单药治疗在KRAS G12C突变胰腺癌患者中展现出良好的耐受性和临床活性，确认的ORR为35.7%（5/14），DCR为85.7%（12/14），mPFS为8.54个月。今年5月，该药被CDE纳入突破性治疗品种，用于治疗经一线治疗失败的伴KRAS G12C突变局部晚期或转移性PDAC。 IMM-1-104是Immuneering 开发一款高选择性第三代小分子MEK抑制剂，每日口服一次。该药通过深度循环抑制MAPK途径，实现对RAS基因的通用抑制活性。在一项1/2a期研究中，IMM-1-104对包括PDAC、恶性黑色素瘤、NSCLC在内的多种实体瘤展现出良好的初步疗效。2024年2月，该药被FDA授予一线治疗PDAC的快速通道认定。总结整体来看，多款在研PDAC新疗法进入临床试验，且早期临床试验结果积极。监管机构也通过授予突破性疗法、快速通道资格等方式加速PDAC的研发进程。但PDAC的治疗较其他恶性肿瘤，如NSCLC、黑色素瘤，并未取得很大突破。而且，与其他恶性肿瘤在研药物不同，在研PDAC药物作用靶点相当分散，笔者分析这可能与PDAC自身的特性，以及诊断上缺乏特异的生物标志物有关。期待在研究人员的不懈努力下，PDAC治疗可以早日迎来新局面。【企业推荐】【智药研习社直播预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

上市批准

2024-06-04

·Pharmaceutical Technology

ASCO 2024: Alligator shares positive data for pancreatic cancer drug

Alligator Bioscience’s pancreatic cancer therapy compared favourably with standard of care chemotherapies in a recent data readout. Credit: peakSTOCK via Getty Images. Alligator Bioscience released positive data from its Phase Ib/II OPTIMIZE-1 study (NCT04888312) investigating its pancreatic cancer monoclonal antibody therapy, mitazalimab. Recommended Buyer's Guides Buyer's Guide Leading Guide to Packaging Materials, Containers and Containment Services for the Pharmaceutical Industry Buyer's Guide Top Guide for Drug Delivery Systems The Sweden-headquartered company presented the Phase II readout at the American Society of Clinical Oncology Annual Meeting (ASCO 2024), publishing the data in the Lancet Oncology on 3 June. Patients who took mitazalimab in combination with mFOLFIRINOX, demonstrated a confirmed objective response rate (ORR) of 40.4% with a median overall survival (mOS) of 14.3 months. This was an improvement compared to historical data from treatment with mFOLFIRINOX where patients typically achieve a 31.6% ORR and a mOS of 11.1 months. In an exclusive interview with Pharmaceutical Technology , Alligator CEO Dr Søren Bregenholt says: “We believe that adding three months to the overall survival is clinically meaningful. It is definitely meaningful for the patients, and it is also a differential that is approvable in almost all major territories.” Bregenholt explains that for 80% of pancreatic cancer patients, the only option available for frontline and second-line treatment is chemotherapy. He adds that approved therapies are quite “mediocre” in terms of response rate and clinical benefit. The US Food and Drug Administration (FDA) recently approved Ipsen Biopharmaceuticals’ chemotherapy combination, NALIRIFOX, for the first-line treatment of pancreatic cancer in February 2024. NALIRIFOX uses Onivyde (irinotecan liposome) with oxaliplatin, fluorouracil, and leucovorin to treat the diseases The regimen is the second US-approved Onivyde regimen for metastatic pancreatic adenocarcimoma with FOLFIRINOX receiving an approval over a decade ago. Bregenholt adds that treatment with mitazalimab has very few adverse reactions and side effects compared to the many commonly associated with the marketed chemotherapy combinations. See Also: J&J seeks expanded approvals for paediatric HIV-1 therapy FDA fast tracks Quince Therapeutics’ rare ataxia drug EryDex Mitazalimab is a CD40 agonist that treats pancreatic cancer by activating and proliferating memory T cells and enhancing the immune response. Bregenholt says that the company has begun to plan its Phase III trial for mitazalimab. “We expect to start the Phase III trial in the first half of next year,” he says.

临床3期临床结果ASCO会议上市批准临床2期

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适应症	最高研发状态	国家/地区	公司	日期
转移性胰腺导管腺癌	临床2期	比利时	Alligator Bioscience AB	2021-09-17
转移性胰腺导管腺癌	临床2期	法国	Alligator Bioscience AB	2021-09-17
转移性胰腺导管腺癌	临床2期	西班牙	Alligator Bioscience AB	2021-09-17
晚期恶性实体瘤	临床1期	丹麦	Alligator Bioscience AB	2015-04-01
晚期恶性实体瘤	临床1期	瑞典	Alligator Bioscience AB	2015-04-01
晚期恶性实体瘤	临床1期	英国	Alligator Bioscience AB	2015-04-01

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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


NCT04888312 (OPTIMIZE-1, ASCO2024) 人工标引	临床2期	转移性胰腺导管腺癌一线	-	mitazalimab+FOLFIRINOX	蓋壓範壓壓構製淵構齋(構顧醖膚膚選網衊網齋) = associated with an expansion in the frequency of effector CD4 T cells (p < 0.0001) at day 8 after receiving mitazalimab. 顧選選憲襯構築蓋鑰觸 (壓壓膚淵範夢積範構觸 )	积极	2024-05-24
NCT04888312 (OPTIMIZE-1, ASCO2024) 人工标引	临床1/2期	转移性胰腺导管腺癌一线 KRAS G12D \| KRAS G12R \| KRAS G12V	57	Mitazalimab + mFOLFIRINOX	鬱糧構顧顧積糧鑰夢醖(範窪積膚簾鹽膚齋觸壓) = 窪醖築憲願築鬱獵膚膚蓋艱鑰鬱網繭鹹鏇鏇鏇 (鬱簾觸願獵選簾鏇膚構, 29.4 - 52.1) 更多	积极	2024-05-24
OPTIMIZE-1 (PRNewswire) 人工标引	临床2期	胰腺癌一线	57	Mitazalimab	艱襯構簾艱構艱鑰鹹夢(蓋願膚鹹醖鏇鏇憲蓋網) = 鬱簾醖願遞遞遞鬱壓鏇鹹鬱選構築衊襯憲夢襯 (鑰鑰窪廠築襯艱壓夢鑰 ) 更多	积极	2023-07-01
NCT04888312 (OPTIMIZE-1, ASCO2023) 人工标引	临床1/2期	转移性胰腺导管腺癌	43	Mitazalimab + mFOLFIRINOX	壓鬱憲願觸築糧鹹範壓(築獵鏇簾鏇鹽繭顧膚顧) = 簾構願鹹遞鏇製襯積糧餘鹽夢鑰窪範艱醖鹽淵 (淵蓋繭觸遞繭築簾憲選 ) 更多	积极	2023-05-31
NCT04888312 (OPTIMIZE-1, PipelineReview) 人工标引	临床2期	胰腺继发性恶性肿瘤一线	23	mFOLFIRINOX+Mitazalimab	醖艱積鏇繭鑰顧遞觸顧(膚壓膚窪簾築夢築遞鏇) = 淵壓遞淵鹹繭構夢製壓鏇獵選壓繭艱蓋簾獵夢 (衊範簾選選鏇獵淵簾築 ) 更多	积极	2023-01-02
NCT02829099 (Pubmed)	临床1期	HR阳性/HER2低表达实体瘤	95	Mitazalimab	鏇夢襯蓋廠獵憲積網窪(鏇遞選衊顧憲鹽蓋鹹鹹) = 襯醖鹽鏇蓋襯齋膚廠夢選鏇築顧網鑰鑰鑰範壓 (壓糧廠築製艱遞淵獵餘 ) 更多	-	2022-12-20
NCT04888312 (OPTIMIZE-1, AACR2022) 人工标引	临床1/2期	转移性胰腺导管腺癌一线	11	Mitazalimab+mFOLFIRINOX	鏇廠齋範鹽築簾餘醖餘(顧鏇範網窪製壓範糧網) = 夢憲艱衊艱鑰築淵夢遞廠繭構積壓鬱壓遞淵淵 (憲齋齋鏇鏇願壓憲蓋範 ) 更多	积极	2022-11-15
NCT04888312 (OPTIMIZE-1, ASCO2022) 人工标引	临床1期	转移性胰腺导管腺癌	5	mFOLFIRINOX+Mitazalimab	鑰膚壓鏇願鑰製襯憲夢(遞襯選壓觸積壓齋憲鬱) = 鑰糧積鑰憲憲觸願夢衊願範築齋衊簾衊鬱構繭 (鹹壓膚蓋齋淵築憲遞築 ) 更多	积极	2022-06-02
SITC2015	临床1期	-	-	ADC-1013	網窪鬱選餘廠範鬱鹽鑰(醖鏇簾構淵鹽遞衊鹽獵) = 構鬱醖築膚膚糧遞鑰夢鹽膚鏇糧遞繭觸範衊構 (鏇夢壓選繭繭鏇壓願鏇 ) 更多	-	2015-11-04