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Phase I/II clinical trial of ColoAd1 by sub-acute fractionated IV dosing in cancer patients

ABSTRACT: Primary objectives: Phase I: - To evaluate the safety and tolerability of ColoAd1, when administered by sub-acute fractionated IV injection to patients with advanced or metastatic epithelial solid tumours not responding to standard therapy or for whom no standard treatment exists- To determine the maximally-tolerated dose (MTD) and/or maximum-feasible dose (MFD) of ColoAd1 when administered by sub-acute fractionated intravenous (IV) injection to patients with advanced or metastatic epithelial solid tumours not responding to standard therapy or for whom no standard treatment exists, and to recommend a dose for phase II studies. Phase II:- To evaluate the progression free survival (PFS) in patients with metastatic colorectal cancer, who receive ColoAd1 administered by sub-acute fractionated IV injection as an intensification of first line chemotherapy compared with first line chemotherapy alone. Primary endpoints: Phase 1: Safety and tolerabilityDetermine a maximum tolerated dose (MTD) / maximum feasible dose (MFD) of ColoAd1 when administered by sub-acute fractionated IV injection (phase I Dose Escalation) and a recommended dose for phase II studies Phase 2: Rate of Progression-Free Survival (PFS) at 24 weeks, defined as the rate of patients being free from clinical/radiological progression and alive within the week 24 time window from randomisation as determined by an independent review committee.

DISEASE(S): Metastatic Colorectal Cancer,Cáncer Colorrectal Metastásico

PROVIDER: 2530712 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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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.

Project description:Traumatic brain injury occasionally causes posttraumatic epilepsy. To elucidate the molecular events responsible for posttraumatic epilepsy, we established a rodent model that involved the injection of microliter quantities of FeCl3 solution into the amygdalar nuclear complex. We previously compared hippocampal gene expression profiles in the traumatic epilepsy model and normal rats at 5 days after brain injury (acute phase) and observed the role of inflammation. In this study, we focused on later stages of epileptogenesis. We compared gene expression profiles at 5, 15 (sub-chronic phase), and 30 days (chronic phase) after brain injury to identify temporal changes in molecular networks involved in epileptogenesis. A total of 81 genes was significantly (at least 2-fold) up- or downregulated over the course of disease progression. We found that genes related to lipid metabolism, namely, Apoa1, Gh, Mc4r, Oprk1, and Pdk4, were temporarily upregulated in the sub-chronic phase. Changes in lipid metabolism regulation might be related to seizure propagation during epileptogenesis. This temporal description of hippocampal gene expression profiles throughout epileptogenesis provides clues to potential markers of disease phases and new therapeutic targets. We employed amygdalar FeCl3 injection to induce chronic, recurrent limbic-type partial seizures with spontaneous secondarily generalized seizures in rats . Sixteen male Wistar rats were kept in hanging cages with unlimited access to food and water and 12-h light-dark cycles. Surgical procedures were conducted following anesthesia with intraperitoneal (i.p.) sodium pentobarbital injections (37.5 mg/kg) at 5 weeks of age. Stereotaxic coordinates were determined with the rat brain atlas. The incisor bar was set 3.3 mm below the interaural line. While under anesthesia, a polyethylene tube containing a stylet to serve as an external guide cannula (1.09-mm outer diameter (o.d.), 0.55-mm inner diameter (i.d.), 2.5 cm in length) was stereotaxically implanted and anchored to the skull with miniature screws and dental cement. The cannula was fixed 5.6 mm anterior and 4.8 mm to the right of the lambda and 8.5 mm below the surface of the skull, positioning it at the right amygdaloid body. Randomly selected rats for in vivo microdialysis to estimate redox had guide cannula placed but were prepared without dental cement on the skull where the microdialysis guide cannula was to be placed. Five days later, the stylet was replaced with an internal delivery cannula (0.5 mm o.d., 0.25 mm i.d.). FeCl3 was dissolved in saline solution (100 mM, pH 2.2). FeCl3 solution (1.0 M-NM-<l) was injected through the inner cannula by means of a microinfusion pump (EP-60; Eicom, Tokyo, Japan) set at a rate of 1.0 M-NM-<l/min (Fe group; n = 12). The external guide cannula was used for electroencephalogram (EEG) recording with an electroencephalograph (type 1A63; SAN-EI, Tokyo, Japan). Rats in the control group (n = 4) were each injected with 1.0 M-NM-<l saline (pH 2.2). Both EEG and behavior were observed for at least 6 h after the injection. While we did not measure the rate or frequency of seizures, we did confirm that the animals had recurrent seizures. These observations and the acute recording confirmed the accuracy of the amygdalar injection. No seizure activity was observed in control group rats. Animals in the control group were sacrificed by cervical dislocation 15 days after amygdalar injection. Animals in the Fe group were subdivided into 3 groups and were sacrificed at 5 (acute phase), 15 (sub-chronic phase of injury), and 30 days (chronic phase of injury) after amygdalar injection. The stages of disease development were categorized according to the EEGs of the model rats; within 5 days after amygdalar injection, epileptiform discharges were recorded in the contralateral and ipsilateral amygdalae; by 15 days after injection, interictal spike discharges were more consistently observed in the contralateral uninjected amygdala; at 30 days after injection bilateral interictal spike discharges continued to be observed. After sacrifice, the right hippocampi were immediately removed and placed in ice-cold phosphate-buffered saline and homogenized (Polytron PT 3000; Brinkmann Instruments, Inc., Westbury, NY, USA) for RNA extraction.

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Phase I/II clinical trial of ColoAd1 by sub-acute fractionated IV dosing in cancer patients

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