Abstract：
PURPOSE:Vorinostat (V) at levels >2.5 µM enhances chemotherapy in vitro. Yet the approved oral dose of 400 mg inconsistently achieves this level in patients. We developed an intermittent oral pulse-dose schedule of V to increase serum levels. We combined V with the cyclin dependent kinase inhibitor flavopiridol (F) which increases V-induced apoptosis. EXPERIMENTAL DESIGN:One week before combination treatment, V alone was given daily for 3d (cycle -1). Then V was given on d1-3 and d8-10, and F on d2 and d9, every 21-d. Due to neutropenia, this was modified to V on d1-3 and d15-17, and F on d2 and d16, every 28-d. Bolus and split-dose F schedules were studied. RESULTS:34 patients were treated. On the 21-d schedule, the maximum tolerated dose (MTD) was V 600 mg/d and F 60 mg/m(2) bolus. On the 28-d schedule, the MTD was V 800 mg/d and F 30 mg/m(2) over 30 min and 30 mg/m(2) over 4 h. V C(max) at the 800 mg dose was 4.8 µM (± 2.8). V C(max) ≥ 2.5 µM was achieved in 86% of patients at the MTD. F increased the C(max) of V by 27% (95% CI 11%-43%). F C(max) of ≥ 2 µM was achieved in 90% of patients. 8 patients had stable disease for on average 5.5 m (range 1.6-13.2 m). CONCLUSIONS:Intermittent high dose oral V in combination with F is feasible and achieves target serum levels >2.5 µM. V concentrations higher than previously reported with oral dosing were achieved.
journal_name
Invest New Drugsjournal_title
Investigational new drugsauthors
Dickson MA,Rathkopf DE,Carvajal RD,Grant S,Roberts JD,Reid JM,Ames MM,McGovern RM,Lefkowitz RA,Gonen M,Cane LM,Dials HJ,Schwartz GKdoi
10.1007/s10637-010-9447-xsubject
Has Abstractpub_date
2011-10-01 00:00:00pages
1004-12issue
5eissn
0167-6997issn
1573-0646journal_volume
29pub_type
杂志文章abstract：:alpha-Difluoromethylornithine (DFMO) is a known irreversible inhibitor of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis. Cyclosporine (CsA) has been reported to inhibit ODC activity in vitro. In the present study, we compared the effects of DFMO and CsA on growth, survival, and poly...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/BF00175295
更新日期：1987-01-01 00:00:00
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
更新日期：1986-01-01 00:00:00
abstract：:A series of 96 diarylamidine (and diarylimidazoline) derivatives were evaluated for their inhibitory effects on the growth and DNA synthesis of murine leukemia L1210 cells. The amidino- and imidazolino-substituted aryl moieties of the compounds consisted of phenyl, indole, indene, benzofuran, benzo[b]thiophene or benz...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/BF00172069
更新日期：1983-01-01 00:00:00
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
更新日期：2019-06-01 00:00:00
abstract：:Gemcitabine is a nucleoside analogue with excellent clinical activity against solid tumors. Within the cell, gemcitabine is rapidly phosphorylated to its active di- and triphosphate metabolites. Cytotoxicity with gemcitabine appears to be related to multiple effects on DNA replication, where gemcitabine triphosphate c...
journal_title：Investigational new drugs
pub_type： 杂志文章,评审
doi：10.1007/BF00194528
更新日期：1996-01-01 00:00:00
abstract：:Adrenocortical carcinoma (ACC) is an aggressive endocrine cancer with few molecular predictors of malignancy and survival, especially in paediatric patients. Stathmin 1 (STMN1) regulates microtubule dynamics and has been involved in the malignant phenotype of cancer cells. Recently, it was reported that STMN1 is highl...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/s10637-019-00846-9
更新日期：2020-06-01 00:00:00
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
更新日期：2013-06-01 00:00:00
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
更新日期：2013-12-01 00:00:00
abstract：:Fourteen patients with acute leukemia in relapse were treated with difluoromethylornithine (DFMO) alone or in combination with methylglyoxal-bis(guanylhydrazone) (MGBG) as part of Phase I studies. Five patients included in the trial exhibited morphologic evidence of cellular differentiation during the course of treatm...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/BF00170848
更新日期：1989-07-01 00:00:00
abstract：:The (6-maleimidocaproyl)hydrazone derivative of doxorubicin (INNO-206) is an albumin-binding prodrug of doxorubicin with acid-sensitive properties that is being assessed clinically. The prodrug binds rapidly to circulating serum albumin and releases doxorubicin selectively at the tumor site. This novel mechanism may p...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/s10637-008-9208-2
更新日期：2010-02-01 00:00:00
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
更新日期：1996-01-01 00:00:00
abstract：:Based on the high response rates seen among patients with colon cancer receiving high dose Melphalan with autologous marrow infusion, the Southwest Oncology Group conducted a Phase II trial of the compound at a conventional dose. The initial starting dose of 40 mg/m2 was reduced to 30 mg/m2 after severe myelotoxicity ...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/BF00171991
更新日期：1990-01-01 00:00:00
abstract：:HDAC inhibitors (HDACI) are now emerging as one of the most promising new classes of drugs for the treatment of select forms of non-Hodgkin's lymphoma (NHL). They are particularly active in T-cell lymphomas, possibly hodgkin's lymphoma and indolent B cell lymphomas. Presently, two of these agents, vorinostat and romid...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/s10637-010-9591-3
更新日期：2010-12-01 00:00:00
abstract：PURPOSE:To investigate the hypothesis that a systemic agent designed to inhibit dihydropyrimidine dehydrogenase (DPD), the first enzyme in the fluoropyrimidine degradative pathway, could improve the effective amount of 5-fluorouracil (5-FU) delivered to a tumor resulting in enhanced response. PATIENTS AND METHODS:Elig...
journal_title：Investigational new drugs
pub_type： 临床试验,杂志文章,多中心研究
doi：10.1023/a:1020662113061
更新日期：2002-11-01 00:00:00
abstract：:Twenty-four patients with a variety of solid tumors entered a Phase I trial with 4-demethoxydaunorubicin, a new analogue of daunorubicin. The drug was given as a single oral dose of 10-60 mg/m2 repeated every 3-4 weeks. Leukopenia was the dose-limiting toxicity. Other toxic effects included mild to moderate nausea and...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/BF00175378
更新日期：1984-01-01 00:00:00
abstract：:Apoptin is a nonstructural protein encoded by one of the three open reading frames of the chicken anemia virus genome. It has attracted a great deal of interest due to its ability to induce apoptosis in multiple transformed and malignant mammalian cell lines without affecting primary and non-transformed cells. However...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/s10637-017-0431-6
更新日期：2017-06-01 00:00:00
abstract：:A short-term antimetabolic assay based upon the inhibition of incorporation of nucleic acid precursors was used to compare the cytotoxicity of a new halogenated anthracycline, 4'-iodo-4'-deoxydoxorubicin (IDX), with that of its parent compound doxorubicin (DX) on human colo-rectal carcinoma specimens. IDX showed a mar...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/BF00177248
更新日期：1990-05-01 00:00:00
abstract：:The limiting toxicity of low dose continuous infusion 5-fluorouracil (200-300 mg/m2/day) is often palmar-plantar erythrodysesthesia (PPE). PPE developed in 16/25 patients (exact 95% confidence interval of 42%-82%) with metastatic colon cancer enrolled in a phase II trial. In this trial, 5-FU was given continuously at ...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/BF00216925
更新日期：1990-02-01 00:00:00
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
更新日期：2003-05-01 00:00:00
abstract：BACKGROUND:Gemcitabine is a pro-drug that has to be phosphorylated to gemcitabine-triphosphate in order to exhibit its antineoplastic activity. This reaction involves the enzyme deoxycytidine kinase which is saturated at plasma concentrations following standard 30-min infusions. Pharmacological studies indicate that pr...
journal_title：Investigational new drugs
pub_type： 临床试验,杂志文章
doi：10.1007/s10637-005-5859-4
更新日期：2005-03-01 00:00:00
abstract：:Glioblastoma is a fast-growing primary brain tumor observed in adults with the worst prognosis. Preclinical studies have demonstrated the encouraging anticancer activity of statins. This study evaluated the efficacy of atorvastatin in combination with standard therapy in patients with glioblastoma. In this prospective...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/s10637-020-00992-5
更新日期：2020-08-27 00:00:00
abstract：:Background Older non-small cell lung cancer (NSCLC) patients under erlotinib are reported to experience more acute toxicity. We hypothesized that modifications in erlotinib pharmacokinetics might explain this observation. Methods A monocentric prospective clinico-pharmacological study included stage IIIb/IV NSCLC cons...
journal_title：Investigational new drugs
pub_type： 临床试验,杂志文章
doi：10.1007/s10637-016-0400-5
更新日期：2017-04-01 00:00:00
abstract：BACKGROUND:Although its efficacy is unproven, 5-fluorouracil plus cisplatin (FP) is used to prevent postoperative relapse in gastric cancer. We investigated the safety and feasibility of S-1 plus cisplatin (SP) vs. FP for stage IIIB-IV (M0) gastric cancer. METHODS:Following curative resection, 41 stage IIIB-IV (M0) ga...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/s10637-010-9515-2
更新日期：2012-02-01 00:00:00
abstract：:Background Preclinical evidence has suggested that a subset of pancreatic cancers with the G12R mutational isoform of the KRAS oncogene is more sensitive to MAPK pathway blockade than pancreatic tumors with other KRAS isoforms. We conducted a biomarker-driven trial of selumetinib (KOSELUGO™; ARRY-142886), an orally ac...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/s10637-020-01044-8
更新日期：2021-01-06 00:00:00
abstract：:Radioactive iodine-refractory [(18)F] fluorodeoxy-glucose-positron emission tomography-positive thyroid carcinomas represent especially aggressive tumors. Targeting glucose metabolism by the transketolase isoenzyme transketolase like 1 (TKTL-1) which is over-expressed in various neoplasms, may be effective. The correl...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/s10637-008-9174-8
更新日期：2009-08-01 00:00:00
abstract：BACKGROUND:TAS-102 is a nucleoside antitumor agent consisting of trifluridine (FTD) and tipiracil hydrochloride (TPI). We investigated the recommended dose (RD) of TAS-102 plus irinotecan for metastatic colorectal cancer refractory to 5-fluorouracil (5-FU) and oxaliplatin. METHODS:This study was used a escalated dose ...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/s10637-015-0271-1
更新日期：2015-10-01 00:00:00
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
更新日期：1989-04-01 00:00:00
abstract：AIM:To quantify the effect of food on the systemic exposure of lapatinib at steady state when administered 1 h before and after meals, and to observe the safety and tolerability of lapatinib under these conditions in patients with advanced solid tumours. METHODS:This was a three-treatment, randomised, three-sequence c...
journal_title：Investigational new drugs
pub_type： 杂志文章,随机对照试验
doi：10.1007/s10637-013-0055-4
更新日期：2014-06-01 00:00:00
abstract：:Background High-risk neuroblastoma has poor outcomes with high rates of relapse despite aggressive treatment, and novel therapies are needed to improve these outcomes. Ponatinib is a multi-tyrosine kinase inhibitor that targets many pathways implicated in neuroblastoma pathogenesis. We hypothesized that ponatinib woul...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/s10637-016-0387-y
更新日期：2016-12-01 00:00:00
abstract：:Background It would be useful to have criteria for predicting long-term treatment responses to immune checkpoint inhibitors (ICIs). Maximum depth of response correlates with treatment outcomes among patients receiving programmed death protein 1 axis inhibitors for non-small cell lung cancer (NSCLC). We investigated as...
journal_title：Investigational new drugs
pub_type： 杂志文章
doi：10.1007/s10637-019-00770-y
更新日期：2019-12-01 00:00:00
