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To decide Recommended dose of XELIRI and bevacizumab in patients with metastatic colorectal cancer who have oxlplatin based first-line chemotherapy including treatment failure or refractory, and To evaluate the safety and efficacy -PhaseI/II Study

ABSTRACT: Interventions: XELIRI+ bevacizumab Primary outcome(s): Phase I part: To decide Recommended dose Phase II part: Progression Free Survival Study Design: Single arm Non-randomized

DISEASE(S): Colorectal Cancer

PROVIDER: 2619389 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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A Phase I /II Study of Bi-weekly XELIRI with Bevacizumab for patient with Metastatic Colorectal Cancer as second-line chemotherapy.

Project description:Interventions: XELIRI+ bevacizumab Capecitabine:2000mg/m2/day d1-8 Irinotecan:180mg/m2 d1 Bevacizumab:5mg/kg d1 Q2w Primary outcome(s): Phase I part To determine Safety in 1st cycle by Bi-weekly XELIRI+bevacizumab. Phase II part Progression Free Survival Study Design: Single arm Non-randomized

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A Phase I /II Study of Tri-weekly XELIRI with Bevacizumab for patient with Metastatic Colorectal Cancer as second-line chemotherapy.

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Loading Dose of Ceftazidime Needs to Be Increased in Critically Ill Patients: A Retrospective Study to Evaluate Recommended Loading Dose with Pharmacokinetic Modelling.

Project description:To rapidly achieve ceftazidime target concentrations, a 2 g loading dose (LD) is recommended before continuous infusion, but its adequacy in critically ill patients, given their unique pharmacokinetics, needs investigation. This study included patients from six ICUs in Saint-Etienne and Paris, France, who received continuous ceftazidime infusion with plasma concentration measurements. Using MONOLIX and R, a pharmacokinetic (PK) model was developed, and the literature on ICU patient PK models was reviewed. Simulations calculated the LD needed to reach a 60 mg/L target concentration and assessed ceftazidime exposure for various regimens. Among 86 patients with 223 samples, ceftazidime PK was best described by a one-compartment model with glomerular filtration rate explaining clearance variability. Typical clearance and volume of distribution were 4.45 L/h and 88 L, respectively. The literature median volume of distribution was 37.2 L. Simulations indicated that an LD higher than 2 g was needed to achieve 60 mg/L in 80% of patients, with a median LD of 4.9 g. Our model showed a 4 g LD followed by 6 g/day infusion reached effective concentrations within 1 h, while a 2 g LD caused an 18 h delay in achieving target steady state.

| S-EPMC11350857 | biostudies-literature

Phase II study of XELIRI and High-dose bevacizumab as second-line therapy in patients with metastatic colorectal cancer

Project description:Interventions: XELIRI plus bevacizumab therapy Bevacizumab 10mg/kg day1 Irinotecan 150mg/m2 day1 Capecitabin 2,000mg/m2/day day1-8 Primary outcome(s): Progression Free Survival Study Design: Single arm Non-randomized

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Trial of XELIRI/FOLFIRI + Simvastatin Followed by Simvastatin Maintenance in Metastatic Colorectal Cancer

Project description:The purpose of this study is to compare 2nd line XELIRI/FOLFIRI + simvastatin vs XELIRI/FOLFIRI + placebo.

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Randomized Phase III Study of Folfiri+Avastin Versus Xeliri+Avastin as 1st Line Treatment of CRC

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Using transcriptomics to evaluate thresholds in genotoxicity dose-response

Project description:Several genotoxic chemicals have been reported to produce threshold-shaped dose-response curves for mutation and genotoxicity assays, both in vivo and in vitro. These data challenge the current default practice for risk assessment of genotoxic chemicals, which assumes a linear dose-response below the lowest tested dose. Due to the inherent challenges in data collection and analysis, statistical methods cannot determine whether a biological threshold exists with sufficient confidence to overturn this assumption of linearity. Indeed, to truly define the shape of the dose-response curves, we must look to the underlying biology and develop targeted experiments to identify and measure the key processes governing cellular response at low doses. This chapter describes a series of studies aimed at defining the transcriptional responses to DNA damage in an effort to identify the key processes regulating low-dose DNA damage response.

2016-12-31 | GSE74725 | GEO

Estimation of Maximum Recommended Therapeutic Dose Using Predicted Promiscuity and Potency.

Project description:We report a simple model that predicts the maximum recommended therapeutic dose (MRTD) of small molecule drugs based on an assessment of likely protein-drug interactions. Previously, we reported methods for computational estimation of drug promiscuity and potency. We used these concepts to build a linear model derived from 238 small molecular drugs to predict MRTD. We applied this model successfully to predict MRTDs for 16 nonsteroidal antiinflammatory drugs (NSAIDs) and 14 antiretroviral drugs. Of note, based on the estimated promiscuity of low-dose drugs (and active chemicals), we identified 83 proteins as "high-risk off-targets" (HROTs) that are often associated with low doses; the evaluation of interactions with HROTs may be useful during early phases of drug discovery. Our model helps explain the MRTD for drugs with severe adverse reactions caused by interactions with HROTs.

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XPO1 target occupancy measurements confirm the selinexor recommended phase 2 dose.

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Determining the recommended dose of pacritinib: results from the PAC203 dose-finding trial in advanced myelofibrosis.

Project description:PAC203 is a randomized dose-finding study of pacritinib, an oral JAK2/IRAK1 inhibitor, in patients with advanced myelofibrosis who are intolerant of or resistant to ruxolitinib. Patients were randomized 1:1:1 to pacritinib 100 mg once per day, 100 mg twice per day, or 200 mg twice per day. Enhanced eligibility criteria, monitoring, and dose modifications were implemented to mitigate risk of cardiac and hemorrhagic events. Efficacy was based on ≥35% spleen volume response (SVR) and ≥50% reduction in the 7-component total symptom score (TSS) through week 24. Of 161 patients, 73% were intolerant of and 76% had become resistant to ruxolitinib; 50% met criteria for both. Severe thrombocytopenia (platelet count <50 × 103/μL) was present in 44%. SVR rates were highest with 200 mg twice per day (100 mg once per day, 0%; 100 mg twice per day, 1.8%; 200 mg twice per day, 9.3%), particularly among patients with baseline platelet counts <50 × 103/μL (17%; 4 of 24). Although TSS response rate was similar across doses (100 mg once per day, 7.7%; 100 mg twice per day, 7.3%; 200 mg twice per day, 7.4%), median percent reduction in TSS suggested a dose-response relationship (-3%, -16%, and -27%, respectively). Pharmacokinetic and pharmacodynamic modeling based on all available data showed greatest SVR and TSS reduction at 200 mg twice per day compared with lower doses. Common adverse events were gastrointestinal events, thrombocytopenia, and anemia. There was no excess of grade ≥3 hemorrhagic or cardiac events at 200 mg twice per day. Pacritinib 200 mg twice per day demonstrated clinical activity and an acceptable safety profile and was selected as the recommended dose for a pivotal phase 3 study in patients with myelofibrosis and severe thrombocytopenia. This trial was registered at www.clinicaltrials.gov as #NCT03165734.

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