First line irinotecan dose escalation study
Ontology highlight
ABSTRACT:
DISEASE(S): Metastatic Colorectal Cancer,Cancer-bowel-back Passage (rectum) Or Large Bowel (colon)
PROVIDER: 2452596 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Interventions: This dose escalation study is designed to assess the safety and efficacy of a single dose of SIR-Spheres when used in combination with irinotecan over a 9 treatment cycle duration. Each 3 week cycle of treatment with irinotecan on days 1 and 8 followed by a rest week on day 15.
Primary outcome(s): Toxicity[Assessed over the duration of treatment and up to 1 month after the conclusion of protocol chemotherapy using UICC criteria];Response Rate[Assessed up until the scan following the completion of protocol chemotherapy]
Study Design: Purpose: Treatment; Allocation: Non-randomised trial; Masking: Open (masking not used);Assignment: Single group;Type of endpoint: Safety/efficacy
| 2452615 | ecrin-mdr-crc
Project description:Interventions: The study is a multi-centre phase I/II dose-escalation study that aims to assess the safety and efficacy of a single implantation of SIR-Spheres when used in combination with systemic chemotherapy with FOLFOX4. Toxicity will be assessed after 3 cycles of treatment, at which stage the oxaliplatin will be escalated to full dose and the patients will go on receive a maximum of 12 cycles of chemotherapy. (The duration of the treatment cycles varies as it is based on the doctor’s discretion. Ideally the treatment cycles would be 1 week of treatment and then 1 week of rest.)
Primary outcome(s): Toxicity[Assessed using standard UICC criteria which will be assessed after patients have completed 12 cycles of chemotherapy.]
Study Design: Purpose: Treatment; Allocation: Non-randomised trial; Masking: Open (masking not used);Assignment: Single group;Type of endpoint: Safety/efficacy
| 2452613 | ecrin-mdr-crc
Project description:Traditional Chinese Medicine (TCM) has been used for thousands of years to treat or prevent diseases, including cancer. Good manufacturing practices (GMP) and sophisticated product analysis (PhytomicsQC) to ensure consistency are now available allowing the assessment of its utility. Polychemical Medicines, like TCM, include chemicals with distinct tissue-dependent pharmacodynamic properties that result in tissue-specific bioactivity. Determining the mode of action of these mixtures was previously unsatisfactory; however, information rich RNA microarray technologies now allow for thorough mechanistic studies about complex mixtures effects. PHY906 is a long used four herb TCM formula employed as adjuvant to relieve side effects associated with chemotherapy. Animal studies documented a decrease in global toxicity and an increase in therapeutic effectiveness of chemotherapy when PHY906 was combined. Using a systems biology approach, we studied tumor tissue to identify reasons for the enhancement of the antitumor effect of Irinotecan by PHY-906 in a well-characterized pre-clinical model; PHY-906 and Irinotecan were administered orally to female BDF-1 mice bearing subcutaneous Colon 38 tumors. We observed that 1) individually PHY-906 and Irinotecan induce distinct alterations in tumor, liver and spleen; 2) PHY-906 alone predominantly induces repression of transcription and immune-suppression in tumors; 3) these effects are reverted in the presence of Irinotecan, with prevalent induction of pro-apoptotic and pro-inflammatory pathways that may favor tumor rejection. Most importantly, PHY-906 together with Irinotecan triggers unique changes not activated by each one alone suggesting that the combination creates a unique tissue-specific response.
2011-10-22 | GSE25192 | GEO
Project description:Traditional Chinese Medicine (TCM) has been used for thousands of years to treat or prevent diseases, including cancer. Good manufacturing practices (GMP) and sophisticated product analysis (PhytomicsQC) to ensure consistency are now available allowing the assessment of its utility. Polychemical Medicines, like TCM, include chemicals with distinct tissue-dependent pharmacodynamic properties that result in tissue-specific bioactivity. Determining the mode of action of these mixtures was previously unsatisfactory; however, information rich RNA microarray technologies now allow for thorough mechanistic studies about complex mixtures effects. PHY906 is a long used four herb TCM formula employed as adjuvant to relieve side effects associated with chemotherapy. Animal studies documented a decrease in global toxicity and an increase in therapeutic effectiveness of chemotherapy when PHY906 was combined. Using a systems biology approach, we studied tumor tissue to identify reasons for the enhancement of the antitumor effect of Irinotecan by PHY-906 in a well-characterized pre-clinical model; PHY-906 and Irinotecan were administered orally to female BDF-1 mice bearing subcutaneous Colon 38 tumors. We observed that 1) individually PHY-906 and Irinotecan induce distinct alterations in tumor, liver and spleen; 2) PHY-906 alone predominantly induces repression of transcription and immune-suppression in tumors; 3) these effects are reverted in the presence of Irinotecan, with prevalent induction of pro-apoptotic and pro-inflammatory pathways that may favor tumor rejection. Most importantly, PHY-906 together with Irinotecan triggers unique changes not activated by each one alone suggesting that the combination creates a unique tissue-specific response. Four groups of BDF-1 mice bearing colon 38 tumors were treated with Phosphate Buffered Saline (PBS) (n=10), PHY-906 (n=10), Irinotecan (CPT-11, Camptosar(TM)) (n=10) or the combination PHY-906 and Irinotecan (n=10). Tumor (38 samples), spleen (38 samples), and liver (35 samples) tissues were removed and frozen for total RNA isolation and subsequent microarray hybridization. There were a total of 111 samples representing 12 treated tissue groups with 8 to 10 biological replicates each. A reference sample was generated from a pool of mixed normal mouse tissue.
2011-10-21 | E-GEOD-25192 | biostudies-arrayexpress
Project description:We evaluated the efficacy and feasibility of pembrolizumab combined with chemotherapy in frontline management of advanced high-grade epithelial ovarian cancer (EOC). Additionally, chemotherapy-induced changes in the tumor microenvironment and biomarkers of response were evaluated. In this single-arm phase II trial, eligible patients received up to 4 cycles of neoadjuvant chemotherapy followed by interval cytoreduction; then, adjuvant intravenous carboplatin/weekly paclitaxel/pembrolizumab was given for 3 cycles and maintenance pembrolizumab until progression or toxicity (maximum 20 cycles). The primary endpoint was progression-free survival (PFS). Secondary endpoints included feasibility, toxicity, and overall survival (OS). PD-L1 staining, multiplex immunofluorescence staining, RNA-sequencing, reverse phase protein array analyses were performed on pre- and post-chemotherapy samples. Thirty-one eligible patients were enrolled. Median PFS was 14.88 months overall (95% CI 12.40 – 23.00). Among those with PD-L1 Combined Positive Score (CPS), the median PFS and OS were not reached compared to those with CPS<10 (10.50 and 30.90 months, respectively). All patients who initiated chemotherapy with pembrolizumab therapy completed their planned adjuvant cycles. Treatment discontinuation due to immune-related toxicity occurred in 6 patients (20%). Chemotherapy resulted in an infiltration of anti-tumor immune cells in the tumor microenvironment. Samples of patients with the best PFS demonstrated increased expression of NF-κB, TGF-β, and β-catenin signaling. In conclusion, pembrolizumab with chemotherapy was feasible and resulted in PFS within the historical range for this EOC population. Patients with CPS≥10 may benefit more from this regimen and future studies should investigate this potential biomarker. Funding for this investigator-initiated trial was provided by Merck. Clinicaltrials.gov: NCT02520154.
2025-01-22 | GSE271757 | GEO
Project description:We investigated the transcriptional responses of fasting against side effects of irinotecan chemotherapy in both tumor and healthy liver tissue
2019-05-03 | GSE72484 | GEO
Project description:We hypothesised that in esophagogastric junction adenocarcinomas combining molecular predictive biomarkers with FDG-PET would optimise response prediction. Changes in FDG uptake in tumours meaured by PET scans after 14 days of chemotherapy define metabolic responders and non-responders. However while <5% of metabolic non-responders will go onto have a response to the full 9-12 week chemotherapy protocol providing a high negative predictive value for FDG-PET, the positive predictive value of metabolic response is more limited. Only 50% of those patients that have a metabolic response determined by FDG PET at day 14 will go on to subsequently have a response to the full 9-12 week chemotherapy protocol . We used global gene expression profiling to identify molecular biomarkers that when combined with FDG-PET would improve predictive accuracy, in particular we aimed to identify molecular biomarkers that could sub-classify FDG PET defined metabolic responders into those that did and did not subsequently go on to have a radiological response and hence clinical benefit from the full chemotherapy protocol. Patients with stage IB-IV esophagogastric junction adenocarcinomas(n=28) received platinum combination chemotherapy .FDG-PET CT scans were performed at baseline and day 14 and expression profiling (Affymetrix ST1.0 Exon Genechips) on baseline tumour biopsies. 14 patients were classified as FDG-PET metabolic responders and gene expression was analysed in these tumour specimens to determine differences between those that did subsequently go on to have a radiological response (n=10) or did not have a radiological response (n=4) to the full 9-12 week chemotherapy protocol. A tissue microarray(n=154 esophagogastric adenocarcinomas who underwent surgery+/-neoadjuvant chemotherapy)was used with immunohistochemistry for qualification of gene expression profiling results. Radiological response was assessed after 3or4 cycles of chemotherapy by RECISTv1.1.
2012-12-01 | E-MEXP-3730 | biostudies-arrayexpress
Project description:Tumor samples were obtained from patients with stage II-III breast cancer before starting neoadjuvant chemotherapy with four cycles of 5-fluorouracil/epirubicin/cyclophosphamide (FEC) followed by four cycles of docetaxel/capecitabine (TX) on US Oncology clinical trial 02-103. Most patients with HER-2-positive cancer also received trastuzumab (H). Pre-treatment FNA from primary tumors were obtained and RNA extracted and hybridized to affymetrix microarrays according to manufacturer protocol.
2012-12-11 | E-GEOD-42822 | biostudies-arrayexpress
Project description:<p>The SUCCESS-A Study (<a href="http://www.success-studie.de">http://www.success-studie.de</a>) is a randomized Phase III study of response to treatment of early primary breast cancer with adjuvant therapy after surgical resection. The primary outcome is disease-free survival and secondary outcomes are overall survival and toxicity. The study design includes comparison of two pairs of treatment regimes performed in sequence. The first randomization contrasts treatment with and without Gemcitabine (3 cycles of Epirubicin-Fluorouracil-Cyclophosphamide(FEC)-chemotherapy, followed by 3 cycles of Docetaxel(D)-chemotherapy versus 3 cycles of Epirubicin-Fluorouracil-Cyclophosphamide(FEC), followed by 3 cycles of Gemcitabine-Docetaxel(DG)-chemotherapy). The second randomization contrasts treatment with Zoledronate for two versus five years. Patients were recruited from 2005 to 2007 and a total of 3754 patients were included from 250 study sites across Germany. Genome-wide SNP microarray data and phenotype outcomes for the first phase of the study (treatment with and without Gemcitabine) are included in the GARNET (Genomics and Randomized Trials Network) pharmacogenomic study in this dbGaP submission. (The Zoledronate treatments are still underway).</p> <p>SUCCESS-A is a an open-label, multicenter, 2x2 factorial design, randomized controlled, Phase III study comparing the disease free survival after randomization in patients treated with 3 cycles of Epirubicin-Fluorouracil-Cyclophosphamide(FEC)-chemotherapy, followed by 3 cycles of Docetaxel(D)-chemotherapy versus 3 cycles of Epirubicin-Fluorouracil-Cyclophosphamide(FEC), followed by 3 cycles of Gemcitabine-Docetaxel(DG)-chemotherapy, and to compare the disease free survival after randomization in patients treated with 2 years of Zoledronate versus 5 years of Zoledronate in patients with early primary breast cancer. Patients were required to have histopathological proof of axillary lymph node metastases (pN1-3) or high risk node negative, defined as: pT>2 or histopathological grade 3, or age , ≤ 35 or negative hormone receptor, but were not allowed to have evidence of distant disease. Patients were entered into the study no later than 6 weeks after complete resection of the primary tumor. No antineoplastic treatment other than surgical treatment, the defined cytotoxic and endocrine treatment, and radiotherapy was allowed prior to study entry and during the course of the study. After surgery, leading to complete resection of the invasive and intraductal components of the primary tumor, patients were randomized to one of the following two treatments for the first phase of the project (which is included in this GARNET pharmacogenomics study):</p> <p><b>AA</b>: 3 cycles of 5-Fluorouracil 500 mg/m² i.v. body surface area and Epirubicin 100 mg/m² i.v. and Cyclophosphamide 500 mg/m² i.v., (FEC100), each administered on day 1, repeated on day 22, subsequently followed by 3 cycles of Docetaxel 75 mg/m² body surface area i.v. (D), and Gemcitabine 1000 mg/m² i.v. (30 min infusion) (G), administered on day 1, followed by Gemcitabine 1000 mg/m² i.v. (30 min infusion) on day 8, repeated on day22</p> <p><b>AB</b>: 3 cycles of 5-Fluorouracil 500 mg/m² i.v. body surface area and Epirubicin 100 mg/m² i.v. and Cyclophosphamide 500 mg/m² i.v., (FEC100), each administered on day 1, repeated on day 22, subsequently followed by 3 cycles of Docetaxel 100 mg/m² body surface area i.v. (D), administered on day 1, repeated on day 22</p> <p>A second randomization was made for assigning patients to one of the following two subsequent treatments for the second phase of the project (NOT included in the pharmacogenetic study in this dbGaP submission):</p> <p><b>BA</b>: Zoledronic acid 4 mg i.v., every 3 months for the duration of two years, subsequently followed by zoledronic acid 4 mg i.v., every 6 months for the duration of additional three years</p> <p><b>BB</b>: Zoledronic acid 4 mg i.v., every 3 months for the duration of two years</p> <p>Patients with positive hormone receptor status (≥10% positively stained cells for estrogen and/or progesterone) of the primary tumor were recommended to receive Tamoxifen treatment 20 mg p.o. per day for 2 years, after the end of chemotherapy . Subsequent to chemotherapy, postmenopausal patients with positive hormone receptor status were recommended to be treated with Anastrozole (Arimidex®) 1 mg p.o. for additional 3 years, premenopausal patients will continue Tamoxifen treatment for those additional 3 years. In addition to tamoxifen, all patients with positive hormone receptor status of the primary tumor and under the age of 40 or restart of menstrual bleeding within 6 months after the completion of cytostatic treatment or with premenopausal hormone levels as defined below were recommended to receive Goserelin (Zoladex®) 3.6 mg subcutaneously every 4 weeks over a period of 2 years following chemotherapy. Premenopausal endocrine status will be assumed, if the following serum levels are met: LH < 20 mIE/ml, FSH < 20 mIE/ml and E2 > 20 pg/ml. Endocrine therapy will start after the end of chemotherapy.</p> <p>All patients with breast conserving therapy or more than 3 axillary lymph node metastases or in the following cases after mastectomy will receive adjuvant radiotherapy: T3/T4-carcinoma, T2-carcinoma > 3 cm, multicentric tumor growth, lymphangiosis carcinomatosa or vessel involvement, involvement of the pectoralis fascia or a safety margin < 5 mm. Radiotherapy was usually performed after the chemotherapy and parallel to the beginning of the zoledronic acid therapy.</p> <p>Initially, DNA was extracted for performing SNP microarray assays using blood collected at baseline prior to the first randomization. However, the first set of SNP microarray results indicated a quality problem with approximately 50% of the DNA samples. A majority of the problematic samples were replaced with DNA extracted from redrawn blood. The remaining problematic samples were 'restored' using an Illumina FFPE Restoration procedure. A total of 3322 subjects (1638 from arm AA and 1684 from arm AB) were successfully genotyped. Among those, 1771 were from original blood samples, 1092 from redrawn blood samples and 459 from restored blood samples.</p> <p>The SUCCESS-A study is part of the Genomics and Randomized Trials Network (GARNET, <a href="http://www.garnetstudy.org">http://www.garnetstudy.org</a>) funded by the National Human Genome Research Institute (NHGRI). The overarching goal is to identify novel genetic factors that contribute to disease-free survival for breast cancer patients using different forms of chemotherapy through large-scale genome-wide association studies of treatment response in randomized clinical trials. The study was conducted at the University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Germany. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were performed at the GARNET Coordinating Center at the University of Washington.</p>
| phs000547 | dbGaP
Project description:Purpose: This open-label, investigator-initiated, phase II study was conducted to evaluate the safety, survival and neoadjuvant outcomes of NAC combined with dual immune checkpoint inhibitors in advanced-stage EOC. Patients and methods: Between June 2019 and July 2021, 45 patients with unresectable stage III-IV EOC were enrolled. The patients received three cycles of NAC combined with durvalumab and tremelimumab. All patients underwent interval debulking surgery and received three cycles of durvalumab and adjuvant chemotherapy, followed by 12 cycles of durvalumab as maintenance therapy. The primary endpoint was the 12-month progression-free survival (PFS) rate; the secondary endpoints were the objective response rate (ORR) after NAC, a chemotherapy response score (CRS), pathologic complete response (pCR), overall survival (OS), and safety. The pre-planned exploratory analyses assessed the lymphocyte infiltration, PD-L1 expression, and genomic profiles of pre-treatment tumors.
2025-01-15 | GSE284400 | GEO