This is a Phase 2a, open-label, parallel group, partly randomized dose escalation trial to assess the safety and efficacy of a low dose, an intermediate dose, and high dose MSB0010445 given by intravenous infusion to subjects with advanced (unresectable or metastatic) melanoma in combination with stereotactic body radiation therapy (SBRT).

开始日期2014-01-01

申办/合作机构

EMD Serono, Inc.

NCT00879866 / Completed临床1期

An Open-label, Phase Ib, Dose-escalation Trial on the Safety, Tolerability, Pharmacokinetics, Immunogenicity, Biological Effects and Antitumor Activity of EMD 521873 in Combination With Local Irradiation (20 Gy) of Primary Tumors or Metastases in Subjects With Non-small Cell Lung Cancer Stage IIIb With Malignant Pleural Effusion or Stage IV With Disease Control (Partial Response or Stable Disease) After Application of 4 Cycles of Platinum-based, First-line Chemotherapy

Primary trial objective in this single arm trial is to assess the safety and tolerability of Selectikine (EMD 521873) given in combination with and local tumor irradiation and to determine whether the maximum tolerated dose (MTD) is reached with EMD 521873 doses of up to 0.45 mg/kg.
Secondary objectives are to evaluate PK, immunogenicity, overall response, changes in tumor marker levels and circulating tumor cell numbers, progression-free survival and overall survival. Also, to evaluate biological/immune responses to EMD 521873.
NSCLC patients have to be stable (PR or SD) after first-line chemotherapy in order to be enrolled. A total of 12 to 24 patients are planned. Patients will remain on the dose throughout the trial. It is intended to administer at least 4 cycles (21 d each), or until progression or 2nd line therapy becomes necessary.

开始日期2009-04-01

申办/合作机构

Merck KGaA

NL-OMON34011 / SuspendedN/A

An open-label, phase Ib, dose-escalation trial on the safety, tolerability, pharmacokinetics, immunogenicity, biological effects and antitumor activity of EMD 521873 in combination with local irradiation (20 Gy) of primary tumors or metastases in subjects with non-small cell lung cancer stage IIIb with malignant pleural effusion or stage IV with disease control (partial response or stable disease) after application of 4 cycles of platinum-based, first-line chemotherapy. - EMD 521873 plus Radiotherapy in NSCLC

开始日期2009-03-15

申办/合作机构

Merck KGaA

100 项与 MSB-0010445 相关的临床结果

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100 项与 MSB-0010445 相关的转化医学

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100 项与 MSB-0010445 相关的专利（医药）

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项与 MSB-0010445 相关的文献（医药）

2015-01-01·Journal of translational medicine2区 · 医学

NHS-IL2 combined with radiotherapy: preclinical rationale and phase Ib trial results in metastatic non-small cell lung cancer following first-line chemotherapy

2区 · 医学

ArticleOA

作者: Laurent, Julien ; van den Heuvel, Michel M ; Tighe, Robert ; De Ruysscher, Dirk ; Belderbos, José ; Dingemans, Anne-Marie C ; Quaratino, Sonia ; Boshuizen, Rogier ; Verheij, Marcel ; Haanen, John

BACKGROUND:

NHS-IL2 (selectikine, EMD 521873, MSB0010445) consists of human NHS76 (antibody specific for necrotic DNA) fused to genetically modified human interleukin 2 (IL-2) and selectively activates the high-affinity IL-2 receptor. Based on an evolving investigational concept to prime the tumor microenvironment with ionizing radiation prior to initiating immunotherapy, 2 related studies were conducted and are reported here. The first, a preclinical study, tests the systemic effect of the immunocytokine NHS-IL2 and radiotherapy in a lung carcinoma animal model; the second, a phase Ib trial in patients with metastatic non-small cell lung carcinoma (NSCLC), was designed to determine the safety and tolerability of NHS-IL2 in combination with radiotherapy directly following first-line palliative chemotherapy.

METHODS:

Tumor-bearing C57Bl/6 mice were treated with NHS-IL2 alone (5 mg/kg; days 7-9), fractionated radiotherapy (3.6 Gy; days 0-4) plus cisplatin (4 mg/kg; day 0), or the triple combination. Metastatic NSCLC patients who achieved disease control with first-line palliative chemotherapy were enrolled in the phase Ib trial. Patients received local irradiation (5x 4 Gy) of a single pulmonary nodule. Dose-escalated NHS-IL2 was administered as 1-h intravenous infusion on 3 consecutive days every 3 weeks.

RESULTS:

NHS-IL2 plus radiotherapy induced immune response activation and complete tumor growth regressions in 80%-100% of mice. In patients with metastatic NSCLC treated with NHS-IL2 (3, 3, and 7 patients in the 0.15-mg/kg, 0.30-mg/kg, and 0.45-mg/kg cohorts, respectively), maximum tolerated dose was not reached. Most frequently reported adverse events were fatigue, anorexia, and rash. Transient increases in leukocyte subsets were observed. In 3 patients, thyroid gland dysfunction occurred. No objective responses were reported; long-term survival was observed in 2 patients, including 1 patient with long-term tumor control.

CONCLUSIONS:

Combining NHS-IL2 with radiotherapy achieved synergistic antitumor activity in preclinical studies, supporting the use in lung cancer patients. This combination was well tolerated and 2 of 13 patients achieved long-term survival.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00879866.

2011-06-01·Clinical cancer research : an official journal of the American Association for Cancer Research1区 · 医学

A Low-Toxicity IL-2–Based Immunocytokine Retains Antitumor Activity Despite Its High Degree of IL-2 Receptor Selectivity

1区 · 医学

Article

作者: Brunkhorst, Beatrice ; Lo, Kin-Ming ; Gillies, Stephen D. ; Sun, Yaping ; Lan, Yan ; Hettmann, Thore ; Mueller, Stefan O.

Abstract:

Purpose: The goal of the study was to engineer a form of interleukin 2 (IL-2) that, when delivered as a tumor-specific antibody fusion protein, retains the ability to stimulate an antitumor immune response via interaction with the high-affinity IL-2 receptor but has lower toxicity because of the reduced activation of the intermediate-affinity IL-2 receptor.Experimental Design: We investigated changes in the proposed toxin motif of IL-2 by introducing a D20T mutation that has little effect on the activity of free IL-2. We expressed this IL-2 variant as a fusion protein with an antibody (NHS76) that targets the necrotic core of tumors and characterized this molecule (NHS-IL2LT) in vitro and in vivo.Results: NHS-IL2LT was shown to have near normal biological activity in vitro by using T-cell lines expressing the high-affinity IL-2 receptor, but little or no activity by using cell lines expressing only the intermediate IL-2 receptor. Relative to the control antibody fusion protein containing wild-type IL-2, NHS-IL2LT retained antitumor activity against established neuroblastoma and non–small cell lung cancer metastases in syngeneic mouse tumor models but was much better tolerated in immune-competent mice and in cynomolgus monkeys.Conclusions: The qualities of low toxicity and single-agent efficacy shown suggest that NHS-IL2LT is a good candidate for therapeutic approaches combining standard cytotoxic and immune therapies. In fact, this molecule (also known as Selectikine or EMD 521873) is currently in phase I clinical trial. Clin Cancer Res; 17(11); 3673–85. ©2011 AACR.

100 项与 MSB-0010445 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
黑色素瘤	临床2期	美国	EMD Serono, Inc.	2014-01-01
脑癌	临床1期	荷兰	Merck KGaA	2009-04-01
恶性胸腔积液	临床1期	荷兰	Merck KGaA	2009-04-01
非小细胞肺癌IIIB期	临床1期	荷兰	Merck KGaA	2009-04-01
局部晚期恶性实体瘤	临床1期	德国	Merck KGaA	2006-12-01
局部晚期恶性实体瘤	临床1期	瑞士	Merck KGaA	2006-12-01
非霍奇金淋巴瘤	临床1期	德国	Merck KGaA	2006-12-01
非霍奇金淋巴瘤	临床1期	瑞士	Merck KGaA	2006-12-01

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临床结果

适应症

分期

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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


NCT01973608 (CTgov)	临床2期	黑色素瘤	12	Stereotactic Body Radiation Therapy (SBRT)+MSB0010445 (0.3 milligram per kilogram [mg/kg]) (MSB0010445 Low Dose Cohort 0.3 mg/kg)	廠範夢蓋築鏇齋鹹衊網(獵繭艱築製鹹鏇齋願鬱) = 簾鹽襯鹽選選構鹹遞淵網顧壓構選窪夢鏇齋鏇 (繭選鹹夢選遞製夢遞觸, 廠築淵製窪構壓構積鏇 ~ 願蓋蓋憲廠衊壓製製構) 更多	-	2016-10-31
				Stereotactic Body Radiation Therapy (SBRT)+MSB0010445 (1.0 mg/kg) (MSB0010445 Intermediate Dose Cohort 1.0 mg/kg)	廠範夢蓋築鏇齋鹹衊網(獵繭艱築製鹹鏇齋願鬱) = 鑰鬱襯繭獵艱構鹽網製網顧壓構選窪夢鏇齋鏇 (繭選鹹夢選遞製夢遞觸, 夢遞鹹夢顧顧窪醖蓋鑰 ~ 餘蓋淵蓋遞選艱鬱餘範) 更多