当前位置： SCI文献检索 > INVESTIGATIONAL NEW DRUGS期刊下所有文献 > A phase 1 dose-escalating study of pegylated recombinant human arginase 1 (Peg-rhArg1) in patients with advanced hepatocellular carcinoma.

A phase 1 dose-escalating study of pegylated recombinant human arginase 1 (Peg-rhArg1) in patients with advanced hepatocellular carcinoma.

Abstract：

BACKGROUND:Hepatocellular carcinoma (HCC) cells are auxotrophic for arginine, depletion of which leads to tumour regression. The current study evaluated safety, pharmacokinetics (PK)/ pharmacodynamics (PD) parameters, and potential anti-tumor activity of pegylated recombinant human arginase 1 (peg-rhArg1) in advanced HCC patients. METHODS:Eligibility criteria included advanced HCC with measurable lesions, Child-Pugh A or B, and adequate organ function. Initial single IV bolus was followed by weekly doses of peg-rhArgI escalated from 500 U/kg to 2500 U/kg in a 3 + 3 design. RESULTS:Fifteen patients were enrolled at weekly doses of 500 U/kg (n = 3), 1000 U/kg (n = 3), 1600 U/kg (n = 3) and 2500 U/kg (n = 6). The median age was 57 years (33-74); 87% were hepatitis B carriers and 47% had prior systemic treatment. The most commonly reported drug-related non-haematological adverse events (AEs) were diarrhea (13.3%), abdominal discomfort (6.7%) and nausea (6.7%). No drug-related haematological AEs were seen. Only 1 of the six patients that received 2500U/kg peg-rhArg1 experienced DLT (grade 4 bilirubin elevation) and thus the maximum tolerated dose was 2500 U/kg. PK and PD analysis indicated that peg-rhArg1 was efficacious in inducing arginine depletion in a dose-dependent manner. Adequate arginine depletion dose was achieved in the 1,600-2,500 U/kg range and therefore the optimal biological dose was at 1600 U/kg, which was chosen as the recommended dose. The best response was stable disease for >8 weeks in 26.7% of the enrolled patients. CONCLUSION:Peg-rhArg1 has manageable safety profile and preliminary evidence of activity in advanced HCC patients.

journal_name

Invest New Drugs

journal_title

Investigational new drugs

authors

Yau T,Cheng PN,Chan P,Chan W,Chen L,Yuen J,Pang R,Fan ST,Poon RT

doi

10.1007/s10637-012-9807-9

subject

Has Abstract

pub_date

2013-02-01 00:00:00

pages

99-107

issue

1

eissn

0167-6997

issn

1573-0646

journal_volume

31

pub_type

杂志文章

相关文献

INVESTIGATIONAL NEW DRUGS文献大全
  • Artemisinin reduces human melanoma cell migration by down-regulating alpha V beta 3 integrin and reducing metalloproteinase 2 production.

    abstract：:Artemisinin and its derivatives are well known antimalarial drugs, particularly useful after resistance to traditional antimalarial pharmaceuticals has started to occur in Plasmodium falciparum. In recent years, anticancer activity of artemisinin has been reported both in vitro and in vivo. Artemisinin has inhibitory ...

    journal_title：Investigational new drugs

    pub_type： 杂志文章

    doi：10.1007/s10637-008-9188-2

    authors： Buommino E,Baroni A,Canozo N,Petrazzuolo M,Nicoletti R,Vozza A,Tufano MA

    更新日期：2009-10-01 00:00:00

  • Clinical pharmacokinetic/pharmacodynamic and physiologically based pharmacokinetic modeling in new drug development: the capecitabine experience.

    abstract：:Preclinical studies, along with Phase I, II, and III clinical trials demonstrate the pharmacokinetics, pharmacodynamics, safety and efficacy of a new drug under well controlled circumstances in relatively homogeneous populations. However, these types of studies generally do not answer important questions about variabi...

    journal_title：Investigational new drugs

    pub_type： 杂志文章,评审

    doi：10.1023/a:1023525513696

    authors： Blesch KS,Gieschke R,Tsukamoto Y,Reigner BG,Burger HU,Steimer JL

    更新日期：2003-05-01 00:00:00

  • A phase II study of tandutinib (MLN518), a selective inhibitor of type III tyrosine receptor kinases, in patients with metastatic renal cell carcinoma.

    abstract：:Therapies which target VEGF and mTOR are now available for patients with metastatic renal cell carcinoma, but there is a continued need to develop agents for patients who become refractory to these initial agents. Tandutinib is a relatively selective inhibitor of type III tyrosine kinase receptor kinases with promisin...

    journal_title：Investigational new drugs

    pub_type： 杂志文章

    doi：10.1007/s10637-010-9516-1

    authors： Shepard DR,Cooney MM,Elson P,Bukowski RM,Dreicer R,Rini BI,Garcia JA

    更新日期：2012-02-01 00:00:00

  • Multicenter, randomized phase II trial of bevacizumab plus folinic acid, fluorouracil, gemcitabine (FFG) versus bevacizumab plus folinic acid, fluorouracil, oxaliplatin (FOLFOX4) as first-line therapy for patients with advanced colorectal cancer.

    abstract：PURPOSE:To assess safety and efficacy of folinic acid, 5-fluorouracil, gemcitabine (FFG) and folinic acid, fluorouracil, oxaliplatin (FOLFOX4) regimens with added bevacizumab as first-line treatment in patients with advanced colorectal cancer (CRC). PATIENTS AND METHODS:Patients with Stage III unresectable or Stage IV...

    journal_title：Investigational new drugs

    pub_type： 杂志文章,多中心研究,随机对照试验

    doi：10.1007/s10637-010-9598-9

    authors： Madajewicz S,Waterhouse DM,Ritch PS,Khan MQ,Higby DJ,Leichman CG,Malik SK,Hentschel P,Gill JF,Zhao L,Nicol SJ

    更新日期：2012-04-01 00:00:00

  • Phase II trial of topotecan in patients with cisplatin-refractory germ cell tumors.

    abstract：:Fifteen patients with advanced, cisplatin-refractory germ cell tumors (GCT) were treated on a phase II trial with topotecan. None of the 14 evaluable patients achieved a complete or partial response. Myelosuppression was the major toxicity. The median nadir leukocyte count was 1.75 cells/mm3, neutrophil count was 1.55...

    journal_title：Investigational new drugs

    pub_type： 临床试验,杂志文章

    doi：10.1007/BF00872866

    authors： Puc HS,Bajorin DF,Bosl GJ,Amsterdam A,Motzer RJ

    更新日期：1995-01-01 00:00:00

  • Phase I study of oral CP-4126, a gemcitabine derivative, in patients with advanced solid tumors.

    abstract：:CP-4126 is a gemcitabine (2',2'-difluorodeoxycytidine; dFdC) 5' elaidic acid ester. The purpose of this dose-escalating study was to assess safety, pharmacokinetics (PK) and preliminary antitumor activity of the oral formulation and to determine the recommended dose (RD) for phase II studies. The study had a two-step ...

    journal_title：Investigational new drugs

    pub_type： 杂志文章,多中心研究,随机对照试验

    doi：10.1007/s10637-013-9925-z

    authors： Stuurman FE,Voest EE,Awada A,Witteveen PO,Bergeland T,Hals PA,Rasch W,Schellens JH,Hendlisz A

    更新日期：2013-08-01 00:00:00

  • A phase I clinical trial of navitoclax, a targeted high-affinity Bcl-2 family inhibitor, in combination with gemcitabine in patients with solid tumors.

    abstract：PURPOSE:To investigate the safety, optimal dosing, pharmacokinetics and clinical activity of a regimen of navitoclax (ABT-263) combined with gemcitabine in patients with solid tumors. EXPERIMENTAL DESIGN:Patients with solid tumors for which gemcitabine was deemed an appropriate therapy were enrolled into one of two di...

    journal_title：Investigational new drugs

    pub_type： 杂志文章

    doi：10.1007/s10637-014-0110-9

    authors： Cleary JM,Lima CM,Hurwitz HI,Montero AJ,Franklin C,Yang J,Graham A,Busman T,Mabry M,Holen K,Shapiro GI,Uronis H

    更新日期：2014-10-01 00:00:00

  • Evaluation of pyrazoloacridine in patients with advanced pancreatic carcinoma.

    abstract：PURPOSE:Pyrazoloacridine (PZA) is an acridine derivative selected for clinical development because of broad pre-clinical antitumor activity and solid tumor selectivity. Phase I evaluations with PZA have demonstrated predictable toxicity and suggested clinical efficacy. A phase II trial in patients with previously untre...

    journal_title：Investigational new drugs

    pub_type： 临床试验,杂志文章

    doi：10.1023/a:1006087114621

    authors： Zalupski MM,Shields AF,Philip PA,Kraut M,LoRusso P,Heilbrun LK,Vaitkevicius V

    更新日期：1998-01-01 00:00:00

  • Determinants of pain in advanced HCC patients recieving hepatic artery infusion chemotherapy.

    abstract：:Purpose Hepatic arterial infusion chemotherapy (HAIC) is one of the options to treat unresectable hepatocellular carcinoma (HCC). The majority of HCC patients suffer great pain in the course of HAIC treatment. To improve the quality of life and the efficacy of HAIC treatment, the causes of pain, the choice of an analg...

    journal_title：Investigational new drugs

    pub_type： 杂志文章

    doi：10.1007/s10637-020-01009-x

    authors： Wu Z,Guo W,Chen S,Zhuang W

    更新日期：2020-10-01 00:00:00

  • The nuclear transport capacity of a human-pancreatic ribonuclease variant is critical for its cytotoxicity.

    abstract：:We have previously described a human pancreatic-ribonuclease variant, named PE5, which carries a non-contiguous extended bipartite nuclear localization signal. This signal comprises residues from at least three regions of the protein. We postulated that the introduction of this signal in the ribonuclease provides it w...

    journal_title：Investigational new drugs

    pub_type： 杂志文章

    doi：10.1007/s10637-010-9426-2

    authors： Tubert P,Rodríguez M,Ribó M,Benito A,Vilanova M

    更新日期：2011-10-01 00:00:00

  • Phase II study of n-methylformamide (NSC 3051) and spirogermanium (NSC 192965) in the treatment of advanced small cell lung cancer.

    abstract：:Fifty-four evaluable patients with SCLC previously treated with chemotherapy received either N-methylformamide or spirogermanium. There was one partial response to N-methylformamide. The median survival times for patients treated with N-MF and spirogermanium were 11.7 and 12.6 weeks respectively. Five patients treated...

    journal_title：Investigational new drugs

    pub_type： 临床试验,杂志文章

    doi：10.1007/BF00177255

    authors： Ettinger DS,Finkelstein DM,Abeloff MD,Chang YC,Smith TJ,Oken MM,Ruckdeschel JC

    更新日期：1990-05-01 00:00:00

  • Oral idarubicin in non-Hodgkin's lymphomas.

    abstract：:Idarubicin (DMDR), a new analogue of daunorubicin, was administered orally once every 3 weeks at the dose of 40 to 45 mg/m2 to 20 evaluable patients with non-Hodgkin's lymphomas (NHL). Eighty-six percent of patients with favorable histology and 54% with unfavorable histology (intermediate and high grade as IWF) achiev...

    journal_title：Investigational new drugs

    pub_type： 杂志文章

    doi：10.1007/BF00179594

    authors： Lopez M,Di Lauro L,Papaldo P

    更新日期：1986-01-01 00:00:00

  • Phase II trial of edatrexate in relapsed or refractory germ cell tumors: a Southwest Oncology Group study (SWOG 9124).

    abstract：:Up to 30% of patients with advanced germ cell tumors will fail induction chemotherapy or will relapse. New agents with activity in this still potentially curable subgroup of patients are needed. Edatrexate (10-ethyl, 10-deaza-aminopterin) is a methotrexate analogue that has preclinical and clinical activity in breast,...

    journal_title：Investigational new drugs

    pub_type： 临床试验,杂志文章

    doi：10.1023/a:1006128024879

    authors： Meyers FJ,Lew D,Lara PN Jr,Williamson S,Marshall E,Balcerzak SP,Rivkin SE,Samlowski W,Crawford ED

    更新日期：1998-01-01 00:00:00

  • Combination treatment of cancer cells with pan-Akt and pan-mTOR inhibitors: effects on cell cycle distribution, p-Akt expression level and radiolabelled-choline incorporation.

    abstract：:Signal transduction pathways, which regulate cell growth and survival, are up-regulated in many cancers and there is considerable interest in their pharmaceutical modulation for cancer treatment. However inhibitors of single pathway components induce feedback mechanisms that overcome the growth moderating effect of th...

    journal_title：Investigational new drugs

    pub_type： 杂志文章

    doi：10.1007/s10637-018-0642-5

    authors： Phyu SM,Smith TAD

    更新日期：2019-06-01 00:00:00

  • Phase II study of iproplatin (CHIP) in patients with cisplatin-refractory germ cell tumors; the need for alternative strategies in the investigation of new agents in GCT.

    abstract：:Fifteen patients with advanced, cisplatin-refractory germ cell tumors (GCT) were treated with iproplatin (CHIP). No objective responses were noted in any of the patients treated. By restricting the entry criteria to heavily pre-treated patients, the identification of new active agents in phase II trials may be hindere...

    journal_title：Investigational new drugs

    pub_type： 临床试验,杂志文章

    doi：10.1007/BF00944190

    authors： Murphy BA,Motzer RJ,Bosl GJ

    更新日期：1992-11-01 00:00:00

  • Inhibitors of cathepsins B and L induce autophagy and cell death in neuroblastoma cells.

    abstract：:This study was designed to test the hypothesis that specific inhibition of cathepsins B and L will cause death of neuroblastoma cells. Five compounds that differ in mode and rate of inhibition of these two enzymes were all shown to cause neuroblastoma cell death. Efficacy of the different compounds was related to thei...

    journal_title：Investigational new drugs

    pub_type： 杂志文章

    doi：10.1007/s10637-012-9826-6

    authors： Cartledge DM,Colella R,Glazewski L,Lu G,Mason RW

    更新日期：2013-02-01 00:00:00

  • Macromolecular DNA-damage in murine and human leukemic and lymphoid cells after in vitro exposure to ASTA Z 7557 (INN mafosfamide).

    abstract：:Cyclophosphamide (CPA) is widely used against leukemic and lymphoproliferative diseases, but in vitro studies on response to this agent so far have been limited to instable derivatives with poor galenic properties. ASTA Z 7557 is a newly synthesized "activated cyclophosphamide" that circumvents the need for hepatic ac...

    journal_title：Investigational new drugs

    pub_type： 杂志文章

    doi：10.1007/BF00232346

    authors： Osieka R,Pannenbäcker R,Schmidt CG

    更新日期：1984-01-01 00:00:00

  • Phase II study of esorubicin (4'-deoxydoxorubicin) in advanced epithelial carcinoma of the ovary: a Gynecologic Oncology Group study.

    abstract：:Twenty-six patients with advanced, measurable epithelial carcinoma of the ovary were treated with 76 courses of esorubicin at doses ranging from 20-30 mg/m2 every 3 weeks. All patients are evaluable for toxicity and response. All patients had received prior therapy including radiation therapy in 9, non-anthracycline c...

    journal_title：Investigational new drugs

    pub_type： 杂志文章

    doi：10.1007/BF00173763

    authors： McGuire WP,Blessing JA,Berman ML

    更新日期：1989-11-01 00:00:00

  • Phase 1b investigation of the MEK inhibitor binimetinib in patients with advanced or metastatic biliary tract cancer.

    abstract：:Background The MAPK pathway plays a central role in regulation of several cellular processes, and its dysregulation is a hallmark of biliary tract cancer (BTC). Binimetinib (MEK162), a potent, selective oral MEK1/2 inhibitor, was assessed in patients with advanced BTC. Patients and Methods An expansion cohort study in...

    journal_title：Investigational new drugs

    pub_type： 杂志文章,多中心研究

    doi：10.1007/s10637-018-0600-2

    authors： Finn RS,Ahn DH,Javle MM,Tan BR Jr,Weekes CD,Bendell JC,Patnaik A,Khan GN,Laheru D,Chavira R,Christy-Bittel J,Barrett E,Sawyer MB,Bekaii-Saab TS

    更新日期：2018-12-01 00:00:00

  • Phase 1b study of the oral gemcitabine 'Pro-drug' LY2334737 in combination with capecitabine in patients with advanced solid tumors.

    abstract：:Background This Phase 1b study aimed to determine the recommended Phase 2 dose of LY2334737, an oral pro-drug of gemcitabine, in combination with capecitabine, an oral pro-drug of 5-fluorouracil, in patients with advanced solid tumors. In addition, pharmacokinetics (PK) and tumor response were evaluated. Patients and ...

    journal_title：Investigational new drugs

    pub_type： 杂志文章

    doi：10.1007/s10637-015-0207-9

    authors： Infante JR,Benhadji KA,Dy GK,Fetterly G,Ma WW,Bendell J,Callies S,Adjei AA

    更新日期：2015-04-01 00:00:00

  • Cytotoxicity of withaferin A in glioblastomas involves induction of an oxidative stress-mediated heat shock response while altering Akt/mTOR and MAPK signaling pathways.

    abstract：:Withaferin A (WA), a steroidal lactone derived from the plant Vassobia breviflora, has been reported to have anti-proliferative, pro-apoptotic, and anti-angiogenic properties against cancer growth. In this study, we identified several key underlying mechanisms of anticancer action of WA in glioblastoma cells. WA was f...

    journal_title：Investigational new drugs

    pub_type： 杂志文章

    doi：10.1007/s10637-012-9888-5

    authors： Grogan PT,Sleder KD,Samadi AK,Zhang H,Timmermann BN,Cohen MS

    更新日期：2013-06-01 00:00:00

  • Cellular pharmacology of fluorinated pyrimidines in vivo in man.

    abstract：:Fluorinated pyrimidines, particularly 5-fluorouracil (FUra), have been the subject of intense and almost continuous basic and clinical study since development in the late 1950's by Dr. Charles Heidelberger. Despite this intensive effort, the most important mechanisms by which FUra influences tumor growth in individual...

    journal_title：Investigational new drugs

    pub_type： 杂志文章,评审

    doi：10.1007/BF00178188

    authors： Kovach JS,Beart RW Jr

    更新日期：1989-04-01 00:00:00

  • Effects of 13-hydroxy SM5887 in combination with other anticancer agents on human tumor cell lines.

    abstract：:A new anthracycline derivative, SM5887, in combination with commonly used anticancer agents was evaluated against T-cell leukemia MOLT-3 and human osteosarcoma MG-63 cell lines in culture. MOLT-3 and MG-63 cells were incubated with various concentrations of 13-hydroxy SM5887 (SM5887-OH, the active metabolite of SM5887...

    journal_title：Investigational new drugs

    pub_type： 杂志文章

    doi：10.1007/BF00180811

    authors： Takagi T,Yazawa Y,Suzuki K,Yamauchi Y,Kano Y

    更新日期：1996-01-01 00:00:00

  • Spirogermanium: a new investigational drug of novel structure and lack of bone marrow toxicity.

    abstract：:Spirogermanium (NSC 192965) is a new metallic investigational anticancer drug of novel heterocyclic structure. Although its mode of action has not been fully elucidated, it appears that spirogermanium is not a phase or cell cycle specific drug and inhibits DNA, RNA and protein synthesis, the protein synthesis being th...

    journal_title：Investigational new drugs

    pub_type： 杂志文章

    doi：10.1007/BF00208894

    authors： Slavik M,Blanc O,Davis J

    更新日期：1983-01-01 00:00:00

  • Irinotecan and DNA-PKcs inhibitors synergize in killing of colon cancer cells.

    abstract：:This study sought to measure the degree of synergy induced by specific small molecule inhibitors of DNA-PK [NU7026 and IC486241 (ICC)], a major component of the non-homologous end-joining (NHEJ) pathway, with SN38 or oxaliplatin. Synergy between the DNA damaging drugs and the DNA-PK inhibitors was assessed using the s...

    journal_title：Investigational new drugs

    pub_type： 杂志文章

    doi：10.1007/s10637-010-9626-9

    authors： Davidson D,Coulombe Y,Martinez-Marignac VL,Amrein L,Grenier J,Hodkinson K,Masson JY,Aloyz R,Panasci L

    更新日期：2012-06-01 00:00:00

  • Phase II study of oral S-1 with irinotecan and bevacizumab (SIRB) as first-line therapy for patients with metastatic colorectal cancer.

    abstract：:Fluorouracil (5-FU) plus irinotecan combined with bevacizumab has significant activity in metastatic colorectal cancer (mCRC), but S-1 has become a substitute for continuous infusion of 5-FU and has a very low incidence of hand-foot syndrome. With the S-1 plus irinotecan regimen (SIR), the response rate was 62.5%, and...

    journal_title：Investigational new drugs

    pub_type： 杂志文章

    doi：10.1007/s10637-011-9743-0

    authors： Yamada Y,Yamaguchi T,Matsumoto H,Ichikawa Y,Goto A,Kato K,Hamaguchi T,Shimada Y

    更新日期：2012-08-01 00:00:00

  • Phase I trial of Adozelesin using the treatment schedule of daily x5 every 3 weeks.

    abstract：:CC-1065 is a unique alkylating agent that preferentially binds in the minor groove of double-stranded DNA at adenine-thymine-rich sites. Although it has broad antitumor activity in preclinical models its development was discontinued because of deaths observed during preclinical toxicology studies. Adozelesin is a pote...

    journal_title：Investigational new drugs

    pub_type： 临床试验,杂志文章

    doi：10.1007/BF00873138

    authors： Foster BJ,LoRusso PM,Poplin E,Zalupski M,Valdivieso M,Wozniak A,Flaherty L,Kasunic DA,Earhart RH,Baker LH

    更新日期：1996-01-01 00:00:00

  • Phase II study of flutamide as second line chemotherapy in patients with advanced pancreatic cancer.

    abstract：:Androgen receptors are present in both pancreatic cancer tissue and cell lines. Flutamide is a potent antiandrogen widely used in clinical practice for patients with metastatic prostate cancer. This Phase II trial was undertaken to evaluate the impact of flutamide in patients with advanced pancreatic adenocarcinoma wh...

    journal_title：Investigational new drugs

    pub_type： 临床试验,杂志文章

    doi：10.1023/a:1005989519350

    authors： Sharma JJ,Razvillas B,Stephens CD,Hilsenbeck SG,Sharma A,Rothenberg ML

    更新日期：1997-01-01 00:00:00

  • The molecular mechanism of anticancer action of novel octahydropyrazino[2,1-a:5,4-a']diisoquinoline derivatives in human gastric cancer cells.

    abstract：:Objective The aim of the current study was to examine the anticancer activity and the detailed mechanism of novel diisoquinoline derivatives in human gastric cancer cells (AGS). Methods The viability of AGS cells was measured by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Cell cycle analy...

    journal_title：Investigational new drugs

    pub_type： 杂志文章

    doi：10.1007/s10637-018-0584-y

    authors： Pawłowska N,Gornowicz A,Bielawska A,Surażyński A,Szymanowska A,Czarnomysy R,Bielawski K

    更新日期：2018-12-01 00:00:00

  • Dual inhibition of MEK1/2 and EGFR synergistically induces caspase-3-dependent apoptosis in EGFR inhibitor-resistant lung cancer cells via BIM upregulation.

    abstract：:Epidermal growth factor receptor (EGFR) gene mutations activate the KRAS-RAF-MEK-ERK pathway in lung cancer cells. EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib induce apoptosis of cancer cells, but prolonged treatment is often associated with acquired resistance. Here, we identified a novel MEK1/2 inhibito...

    journal_title：Investigational new drugs

    pub_type： 杂志文章

    doi：10.1007/s10637-013-0030-0

    authors： Song JY,Kim CS,Lee JH,Jang SJ,Lee SW,Hwang JJ,Lim C,Lee G,Seo J,Cho SY,Choi J

    更新日期：2013-12-01 00:00:00