A Clinical Trial Evaluating the Efficacy and Safety of METi-101 in Patients with Refractory Metastatic Colorectal Cancer
Ontology highlight
ABSTRACT:
DISEASE(S): Neoplasms
PROVIDER: 74700 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:KW-2450 is an oral dual insulin-like growth factor-1 receptor/insulin receptor tyrosine kinase inhibitor. We investigated the in vitro and in vivo preclinical activity of KW-2450 plus lapatinib and letrozole and conducted a phase I trial of the triple-drug combination in one male and 10 postmenopausal female patients with advanced/metastatic hormone receptorpositive, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. A series of in vitro and in vivo animal studies was undertaken of KW-2450 in combination with lapatinib and hormonal agents. The phase I trial was conducted to establish the safety, tolerability, and recommended phase II dose (RP2D) of KW-2450 administered in combination with lapatinib and letrozole. Preclinical studies showed KW-2450 and lapatinib act synergistically to induce in vitro apoptosis and inhibit growth of HER2-positive MDA-MB-361 and BT-474 breast cancer cell lines. This combined effect was confirmed in vivo using the MDA-MB-361 xenograft model. KW-2450 showed synergistic in vitro growth inhibition with letrozole and 4-hydroxytamoxifen in ER-positive MCF-7 breast cancer cells and MCF-7-Ac1 aromatase-transfected MCF-7 cells. In the phase I study, dose-limiting toxicity (DLT; grade 3 rash and grade 3 hyperglycemia, respectively) occurred in two of three patients at the dose of KW-2450 25 mg/day plus lapatinib 1500 mg/day and letrozole 2.5 mg/day. The RP2D of the triple-drug combination was established as KW-2450 25 mg/day, lapatinib 1250 mg/day, and letrozole 2.5 mg/day with no DLT at this dose level.
2018-08-26 | GSE82161 | GEO
Project description:The NEWEST (Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumours) trial compared the clinical and biological activity of fulvestrant 500 mg vs 250 mg in the neoadjuvant setting. In this multi-centre phase II study, post-menopausal women with operable, locally advanced (T2, 3, 4b; N0-3; M0) ER-positive breast tumours were randomised to receive neoadjuvant treatment with either dose of fulvestrant for 16 weeks before surgery. Tumour core biopsies were obtained at baseline, 4 weeks and at surgery for assessment of changes in biomarker expression. Tumour volumes were measured by 3-D ultrasound at the same timepoints. In this trial, the percentage of patients who showed a reduction in tumour volume or stabilisation of disease (using RECIST criteria) after treatment with fulvestrant 500 mg was 36% (26 out of 69 patients). Therefore, within a population of endocrine-therapy naive patients whose tumours were confirmed as being ER-positive at the time of study entry, there is a subgroup who gained particular clinical benefit from fulvestrant treatment. These clinical response data together with the availability of biological response information and frozen tumour tissue from participants makes the NEWEST trial an attractive setting in which to investigate the potential of new markers of response to fulvestrant.
2014-01-08 | GSE48905 | GEO
Project description:The NEWEST (Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumours) trial compared the clinical and biological activity of fulvestrant 500 mg vs 250 mg in the neoadjuvant setting. In this multi-centre phase II study, post-menopausal women with operable, locally advanced (T2, 3, 4b; N0-3; M0) ER-positive breast tumours were randomised to receive neoadjuvant treatment with either dose of fulvestrant for 16 weeks before surgery. Tumour core biopsies were obtained at baseline, 4 weeks and at surgery for assessment of changes in biomarker expression. Tumour volumes were measured by 3-D ultrasound at the same timepoints. In this trial, the percentage of patients who showed a reduction in tumour volume or stabilisation of disease (using RECIST criteria) after treatment with fulvestrant 500 mg was 36% (26 out of 69 patients). Therefore, within a population of endocrine-therapy naive patients whose tumours were confirmed as being ER-positive at the time of study entry, there is a subgroup who gained particular clinical benefit from fulvestrant treatment. These clinical response data together with the availability of biological response information and frozen tumour tissue from participants makes the NEWEST trial an attractive setting in which to investigate the potential of new markers of response to fulvestrant. 42 samples
2014-01-08 | E-GEOD-48905 | biostudies-arrayexpress
Project description:Prospective, non-comparative Phase II multicenter trial (EXPRESSION EudraCT: 2008-006381-29) where the patients received three 3-week cycles of docetaxel (100 mg/m2) followed by three 3-week cycles of 5-fluorouracil (500 mg/m2), epirubicin (100 mg/m2), and cyclophosphamide (500 mg/m2) (FEC). The primary end point was the identification of a gene expression signature predictive of pathological complete response (pCR). In this trial, pCR was defined as absence of invasive or non-invasive cancer in the breast. External validation of the predictive performance was performed using publicly available data.
2020-11-15 | GSE140494 | GEO
Project description:Many chronic cutaneous diseases associated with microbial antigens demonstrate clinical progression due to T cell hyporesponsiveness. Appropriate antimicrobial therapy restores T cell function, leading to clinical resolution. Due to the association of sarcoidosis with mycobacterial antigens, we compared the efficacy of antimycobacterial therapy with placebo in chronic cutaneous sarcoidosis. We conducted a randomized, placebo-controlled, single-blind trial on chronic cutaneous sarcoidosis subjects. Participants received the oral CLEAR regimen: Levofloxacin 750 mg on day 1, then 500 mg daily, Ethambutol 1200 mg daily, Azithromycin 500 mg on day 1, then 250 mg daily, and Rifampin 300 mg daily, or a comparative placebo regimen, for a total of 8 weeks, with a 180 day follow-up. Participants were monitored for absolute change in lesion diameter and decrease in granulomas burden upon completion of therapy.
2013-07-23 | E-GEOD-39606 | biostudies-arrayexpress
Project description:This phase I/II neoadjuvant trial determined maximally-tolerated doses (MTD), dose-limiting toxicities (DLT), response-to-therapy, and explored the role of new response biomarkers. The combination regimens were delivered with acceptable toxicity, good clinical response, inducing changes in tumor RNA content and integrity. Pre-treatment gene expressions impacted clinical response, including several near 17q12, which with ERBB2, may better identify chemoresponsiveness. The NCIC Clinical Trials Group MA.22 phase I/II clinical trial (ClinicalTrials.gov identifier NCT00066443) sought to determine the optimal dosing regimens for docetaxel/epirubicin combination chemotherapy in women with locally advanced (over 95% of patients) or inflammatory breast cancer. The protocol was approved by Health Canada and local Ethics Review Boards, and patients provided written, informed consent. Various doses of epirubicin and docetaxel were administered to patients in either a standard q3 weekly (Schedule A) or dose dense q2 weekly (Schedule B) regimen. Doses for Schedule A were 75 mg/m2 IV of docetaxel and 75, 90, 105, or 120 mg/m2 IV of epirubicin (with 6 mg of pegfilgrastim per cycle on day 2 to prevent neutropenia). Doses for both docetaxel and epirubicin in Schedule B were 50, 60, and 70 mg/m2 IV (with identical pegfilgrastim support). For each schedule, phase I was dose finding for phase II. Patients were allocated to the various phases and dosing regimens of the trial without randomization. None of the patients received trastuzumab in the initial years of the study and HER2+ patients were not enrolled on study, once trastuzumab funding became available. Six tumor biopsy cores were obtained pre-, mid-, and post-treatment: 3 cores for pathologic assessment; 3 cores for microarray studies. Total RNA was isolated from these cores and RNA integrity was assessed using Agilent Bioanalyzer. One of the RNA samples with the best quality was used for microarray study. One colour microarray of Agilent whole human genome nucleotide arrays was conducted with one array per patient. The current data set represents pre-treatment set. MA.22 clinical trial accrued T3N0, any N2 or N3, and T4 breast cancer patients (according to the classification described at; http://emedicine.medscape.com/article/2007112-overview). However, since the current study does not focus on the tumor grade/stage, the information was not provided in the current records.
2015-11-11 | E-GEOD-66999 | biostudies-arrayexpress
Project description:A phase I trial of a SRC kinase Inhibitor, dasatinib, in combination with paclitaxel and carboplatin in patients with advanced or recurrent ovarian cancer. Background: We conducted a phase I study of dasatinib, an oral SRC tyrosine kinase inhibitor, in combination with paclitaxel and carboplatin in advanced and recurrent epithelial ovarian cancer (EOC). Methods: The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included toxicity, response rate (RR), pharmacokinetics and pharmacodynamics. Based on the 3+3 design, cohorts of 3-6 pts received paclitaxel 175 mg/m2 and carboplatin AUC 6 every three weeks with escalating doses of dasatinib (100, 120, 150 mg daily), followed by an 8 patient expansion cohort. Results: Twenty patients were enrolled between 06/07 and 12/09. The median age was 61 yrs (42-82) with a median of 2 prior regimens (0-6), and 71% had platinum-sensitive disease. There were 3-6 pts in each cohort, and 8 in the expansion cohort. Pharmacokinetics were observed over the first 2 cycles of therapy. One DLT was observed in the 100 mg dasatinib cohort (grade 3 myalgia. Other toxicities in all cycles included neutropenia (95% grade 3-4), thrombocytopenia (35% grade 3-4), and fatigue (10% grade 3). The RR was 45% (complete responses, 3/18(17%); partial responses, 5/18(28%)) and 56% (10/18) had stable disease. The PFS6-month actuarial estimate was 86%. The median PFS and OS were 7.8 and 16.2 months, respectively. Conclusions: Due to the high incidence of myelosuppression with subsequent cycles the recommended phase II dose is 150 mg daily of dasatinib in combination with paclitaxel and carboplatin. The combination was safe with evidence of clinical activity in advanced EOC. Global profiles of expression were characterized using unsupervised clustering methods and gene- and pathway-analyses of differential expression.
2012-04-11 | E-GEOD-37180 | biostudies-arrayexpress
Project description:<p>Individuals with Urea Cycle Disorders (UCD) cannot remove ammonia, a waste product, from the blood. At present there is little information on the use of sodium phenylbutyrate (Buphenyl™) in children with argininosuccinic aciduria (ASA). It is hoped that this drug may help lower ammonia and argininosuccinic acid levels in patients with ASA. Through this study we hope to learn whether the use of sodium phenylbutyrate (Buphenyl™) in patients with ASA, in addition to diet and arginine therapy, will decrease liver damage and the number of periods during which ammonia levels are high.</p> <p>The primary study objective is to determine if the treatment of ASA patients with sodium phenylbutyrate (Buphenyl™) in conjunction with lowered doses of arginine improves liver function as measured by short-term assessment of synthetic activity and the use of stable isotope tracers to assess ureagenesis and nitric oxide production.</p> <p>Twelve patients with ASA will be studied using a randomized, cross-over design. Medical records will be reviewed to confirm the diagnosis prior to enrollment. Patients will be on the each arm of the study for one week each preceded by a three day washout period. Patients will come to the Baylor College of Medicine General Clinical Research Center in Texas Children's Hospital for an inpatient hospitalization. This hospitalization is for diet control, clinical evaluation, and stable isotope infusions for measurement of in vivo rates of ureagenesis and nitric oxide production. During the washout periods Buphenyl™ or other alternative route medications, e.g., benzoate, will be discontinued and arginine will be administered at the standard therapeutic dose of 500 mg/kg/day or 10 grams/m2. </p> <p>Following randomization, subjects will be maintained on either high-dose arginine (500 mg/kg/day or 10 grams/m2) alone, or the alternative of low-dose arginine (100 mg/kg/d or 2 grams/m2) along with sodium phenylbutyrate (500 mg/kg/day or 10 grams/m2). For the second week they will be crossed over to the other arm of the study preceded by another three day washout. Previous medications and dietary protein intake (0.6 g/kg/day or current metabolic diet) will be continued during both arms of the study. The two arms may be performed as separate ten-day admissions.</p> <p>The decision to design the study with two arms, high-dose arginine and low-dose arginine/Buphenyl™, was reached after weighing several considerations. First, the current accepted practice for treatment of ASA is high-dose arginine. Based on metabolic flux studies, we have quantified the effects of this dose of arginine as compared to standard doses of Buphenyl™/phenylacetate on ureagenesis. Since the study is not designed or intended to address the independent effects of Buphenyl™ as compared to arginine alone, Buphenyl™ was added for safety reasons to accommodate loss of clearance of nitrogen by decreasing the arginine dose.</p> <p>Moreover, based on our experience with recruiting for previous versions of this study, most ASA patients with liver dysfunction are on an alternative route ammonia scavenger medication in addition to arginine. We found that this has in fact become an accepted practice.</p> <p>Hence, when considering study design from both a safety and recruitment perspective, it was most reasonable to design the study to investigate specifically the hypothesis that the production and presence of argininosuccinic acid leads to liver dysfunction. Since both low-dose arginine with Buphenyl™ and high-dose arginine alone lead to a decreased production of argininosuccinic acid, and both are currently accepted therapies in ASA and UCDs in general, the need to address their effects distinctly is not being investigated at this time.</p> <p>Sodium phenylbutyrate dosage will be 500 mg/kg/day in patients weighing less than 20kg and 10 g/m2/day in larger patients. Daily dosage will be given in equally divided doses 4 times per day. In order to ensure that the study remains double-blind to investigators, study staff and subjects, the Investigational Pharmacy Service at Texas Children's Hospital will dispense both the Buphenyl™ and arginine in powder form which is compounded into capsules or will be mixed with syrpalta (up to 5 grams will dissolve in 10cc liquid) and administered orally or through nasogastric or gastrostomy tube. No nasogastric tube should be placed or gastrostomy performed solely for the purpose of inclusion in this study. Because the reported adverse effects of sodium phenylbutyrate include gastritis, participants will be started on a standard dose of ranitidine (Zantac™), or comparable drug, during both arms of the study. </p>
| phs001305 | dbGaP
Project description:A phase I trial of a SRC kinase Inhibitor, dasatinib, in combination with paclitaxel and carboplatin in patients with advanced or recurrent ovarian cancer. Background: We conducted a phase I study of dasatinib, an oral SRC tyrosine kinase inhibitor, in combination with paclitaxel and carboplatin in advanced and recurrent epithelial ovarian cancer (EOC). Methods: The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included toxicity, response rate (RR), pharmacokinetics and pharmacodynamics. Based on the 3+3 design, cohorts of 3-6 pts received paclitaxel 175 mg/m2 and carboplatin AUC 6 every three weeks with escalating doses of dasatinib (100, 120, 150 mg daily), followed by an 8 patient expansion cohort. Results: Twenty patients were enrolled between 06/07 and 12/09. The median age was 61 yrs (42-82) with a median of 2 prior regimens (0-6), and 71% had platinum-sensitive disease. There were 3-6 pts in each cohort, and 8 in the expansion cohort. Pharmacokinetics were observed over the first 2 cycles of therapy. One DLT was observed in the 100 mg dasatinib cohort (grade 3 myalgia. Other toxicities in all cycles included neutropenia (95% grade 3-4), thrombocytopenia (35% grade 3-4), and fatigue (10% grade 3). The RR was 45% (complete responses, 3/18(17%); partial responses, 5/18(28%)) and 56% (10/18) had stable disease. The PFS6-month actuarial estimate was 86%. The median PFS and OS were 7.8 and 16.2 months, respectively. Conclusions: Due to the high incidence of myelosuppression with subsequent cycles the recommended phase II dose is 150 mg daily of dasatinib in combination with paclitaxel and carboplatin. The combination was safe with evidence of clinical activity in advanced EOC.
2012-04-12 | GSE37180 | GEO
Project description:Systemic sclerosis is associated with skin fibrosis thought mediated by TGFb. This open label clinical trial examines the effect of TGFb inhibition on skin gene expression. Patients 1-9 received two doses 1 mg/kg dose of fresolimumab at baseline and 3 weeks; patients 10-19 received a single 5 mg/kg dose
2015-06-05 | GSE55036 | GEO