[Translation] A single-center, non-randomized, dose-escalation, single/multiple-dose phase I clinical study of multifunctional apoptosis receptor agonist (DATR)

1考察注射用多功能凋亡受体激动剂（DATR）不同给药剂量在中国晚期恶性肿瘤患者单次/多次给药的安全性，在人体的最大耐受剂量（MTD）及剂量限制性毒性（DLT），为II期临床研究推荐安全剂量。2评价DATR在人体单次和多次静脉给药的药代动力学特征。

[Translation]

1. To investigate the safety of single/multiple administration of different doses of multifunctional apoptosis receptor agonist for injection (DATR) in Chinese patients with advanced malignant tumors, the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) in humans, and to recommend safe doses for Phase II clinical studies. 2. To evaluate the pharmacokinetic characteristics of DATR in humans after single and multiple intravenous administration.

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Sponsor / Collaborator

Chengdu Diao Jiuhong Pharmaceutical Factory

100 Clinical Results associated with Multifunctional apoptotic receptor agonist(Chengdu Diao Jiuhong Pharmaceutical Factory)

100 Translational Medicine associated with Multifunctional apoptotic receptor agonist(Chengdu Diao Jiuhong Pharmaceutical Factory)

100 Patents (Medical) associated with Multifunctional apoptotic receptor agonist(Chengdu Diao Jiuhong Pharmaceutical Factory)

Literatures (Medical) associated with Multifunctional apoptotic receptor agonist(Chengdu Diao Jiuhong Pharmaceutical Factory)

01 Dec 2012·Regulatory Toxicology and PharmacologyQ4 · MEDICINE

Synergetic toxicity of DATR, a recombinant soluble human TRAIL mutant, in combination with traditional chemotherapeutics in rats

Q4 · MEDICINE

Article

Author: Xiaodong Zhang ; Bojun Yuan ; Guocai Lu ; Zhiyong Chu ; Yingxin Zou ; Yu Mao ; Mao Huang

The recombinant soluble human TRAIL mutant (DATR), derived from tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), is a promising agent for cancer therapy. The present study evaluated the synergetic toxicity of DATR in combination with traditional chemotherapeutics, including irinotecan, polyene paclitaxel and oxaliplatin in rats. Rats treated with polyene paclitaxel alone or in combination with DATR showed severe diarrhea, appetite inhibition, increasing sodium (Na(+)), potassium (Cl(-)) and glucose (GLU) and serious disorders in the haematological system. Increasing total bilirubin (TBIL) and blood urea nitrogen (BUN) were detected in the rats treated with oxaliplatin alone or in combination with DATR. Furthermore, except that the BUN and Crea of male rats treated with irinotecan in combination with DATR were higher than those of treated with irinotecan, the addition of DATR does not increase the toxicity induced by irinotecan, polyene paclitaxel and oxaliplatin. In conclusion, DATR probably increases kidney lesions of rat with irinotecan, but does not increase the toxicity induced by polyene paclitaxel and oxaliplatin. This indicated that DATR has promising potential in clinical combination therapies. Furthermore, the toxicity induced by DATR on the liver, kidneys and haematological system should be considered carefully if DATR is used in combination with traditional chemotherapeutics.

01 Nov 2011·Regulatory Toxicology and PharmacologyQ4 · MEDICINE

Preclinical toxicity of DATR, a recombinant soluble human TRAIL mutant, in rats and cynomolgus monkeys

Q4 · MEDICINE

Article

Author: Bojun Yuan ; Yu Mao ; Yingxin Zou ; Guocai Lu ; Xiaodong Zhang ; Mao Huang

The recombinant soluble human TRAIL mutant (DATR), derived from tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), is a promising agent for cancer therapy. The present study evaluated the toxicity of DATR in rats and monkeys. Based on the results, the safety and toxic doses of DATR intravenously injected to rats for 50 days were 60 and 180 mg/kg, respectively, and when delivered intravenously guttae to monkeys for 50 days, these levels were 10 and 30 mg/kg, respectively. The main toxic effects in rats were red blood cell count and haemoglobin decreases; blood urea nitrogen and creatinine increases. The main toxic effects in monkeys included red blood cell count and haemoglobin decreases; alanine aminotransferase and aspartate aminotransferase increases; high proliferation of karyocytes of the erythrocyte series; and regional hydropic degeneration of hepatic parenchymal cells. The TUNEL assay showed both 90 mg/kg DATR- and TRAIL-induced apoptosis of the liver in monkeys, which confirmed the hepatotoxicity of DATR. These findings indicated that the target toxic organs of DATR might be the haematological system. Furthermore, kidney in rats and liver in monkeys are also likely target toxic organs. The toxicity was reversible and did not differ from that associated with TRAIL administered at the same dosage.

01 Aug 2010·Human & Experimental ToxicologyQ4 · MEDICINE

Acute toxicity of a single dose DATR, recombinant soluble human TRAIL mutant, in rodents and crab-eating macaques

Q4 · MEDICINE

Article

Author: Zhang, XD ; Mao, Y. ; Yuan, BJ ; Zou, YX ; Lu, GC ; Huang, M.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been reported to possess activity of inducing apoptosis in variety of tumor cells in preclinical models. Several mutational versions of TRAIL have been studied as promising agents for cancer therapy and the recombinant soluble human TRAIL mutant (DATR) is one of them. The objective of the present study was to provide possible toxic target organs and proposal non-toxic dose level of DATR for clinical usage. Rodents and crab-eating macaques were used to estimate potential adverse effects of DATR following a single dose administration. The median lethal dose (LD50 ) of intravenous injection to rats and mice was determined as 262.0 and 1018.0 mg/kg b.w., respectively. The LD50 of intraperitoneal administration to mice was found to be 1432.1 mg/kg b.w. The main changes in macaques were found in the following aspects. Hematology analysis revealed an obvious decrease of red blood cell count (RBC), hemoglobin (HB) and hematocrit (HCT) after injection. Serum biochemical analysis showed an apparent increase of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), blood urea nitrogen (BUN) and creatinine (Crea). Furthermore, inflammatory cell infiltrate in liver and kidney was found by microscope. All the disorders suggested that liver, renal and hematological systems might be the target effectors of toxic effect induced by DATR. Based on the results of this study, the no observed-adverse-effect level (NOAEL) and the lowest observed-adverse-effect level of DATR in macaques are 90.0 and 135.0 mg/kg b.w., respectively.

100 Deals associated with Multifunctional apoptotic receptor agonist(Chengdu Diao Jiuhong Pharmaceutical Factory)

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced cancer	Phase 1	CN	Chengdu Diao Jiuhong Pharmaceutical Factory	07 May 2015

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