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

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

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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

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

Project description:XPO1 (exportin 1) is the main nuclear export protein with over 200 different protein cargos. XPO1 is overexpressed in tumor cells and high levels are correlated with poor prognosis. Selective Inhibitor of Nuclear Export (SINE) compounds block nuclear export by inhibiting XPO1. The first SINE compound, selinexor, shows promising anti-cancer activity across hematological and solid tumors in Phase 2 and 3 clinical trials. The 2nd generation SINE compound KPT-8602 is being evaluated as an anti-cancer agent in a Phase 1 clinical trial. To predict patient response to treatment and confirm the selinexor recommended phase 2 dose (RP2D), an assay based on fluorescence cross correlation spectroscopy that measures XPO1 occupancy in cancer cells was developed. Studies comparing cytotoxicity and XPO1 occupancy in cell lines treated with selinexor or KPT-8602 indicated that XPO1 occupancy by both compounds could reach saturation regardless of drug sensitivity. However, higher levels of XPO1 protein correlated with lower sensitivity to SINE compound cytotoxicity. In vivo mouse studies showed XPO1 occupancy could be measured in tumors and was dose-dependent, with >90% target saturation at 10 mg/kg (?50 mg flat dose in humans). Drug-target occupancy was measured in a dose-response time course and full occupancy occurred by 6 hours at all doses. The duration of occupancy was dose-dependent, where 10-15 mg/kg in mice (? 50-75 mg human flat dose) was necessary to maintain XPO1 occupancy up to 48 hours post-dose. These findings confirm the selinexor RP2D of 60 mg for achieving target occupancy and inhibition up to 48 hours.

| S-EPMC5746399 | biostudies-literature

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.

| S-EPMC5161261 | biostudies-literature

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/?L) 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/?L (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.

| S-EPMC7686901 | biostudies-literature

Reasons for not prescribing guideline-recommended medications to adults with heart failure.

Project description:Little is known about how often contextual factors such as patient preferences and competing priorities impact prescribing of guideline-recommended medications, or about the extent to which these factors are documented in medical records and available to performance measurement systems.Mixed-methods study of 295 veterans aged 50 years and older in 4 VA health care systems who had systolic heart failure and were not prescribed a ?-blocker and/or an angiotensin converting enzyme inhibitor or angiotensin-receptor blocker. Reasons for nontreatment were identified from clinic notes and from interviews with 62 primary care clinicians caring for these patients. These reasons were classified using a published taxonomy.Among 295 patients not receiving guideline-recommended drugs for heart failure, chart review identified biomedical reasons for nonprescribing in 42%-58% of patients and contextual reasons in 11%-17%. Clinician interviews identified twice as many reasons for nonprescribing as chart review (mean 1.6 vs. 0.8 reasons per patient, P<0.001). In these interviews, biomedical reasons for nonprescribing were cited in 50%-70% of patients, and contextual reasons in 64%-70%. The most common contextual reasons were comanagement with other clinicians (32%-35% of patients), patient preferences and nonadherence (15%-24%), and clinician belief that the medication is not indicated in the patient (12%-20%).Contextual reasons for not prescribing angiotensin converting enzyme inhibitor / angiotensin-receptor blockers and ?-blockers are present in two thirds of patients with heart failure who did not receive these medications, yet are poorly documented in medical records. The structure of medical records should be improved to facilitate documentation of contextual reasons for not providing guideline-recommended care.

| S-EPMC3806480 | biostudies-literature

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