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A phase lb/ll, open label, single arm study to assess efficacy and safety of alpelisib and capecitabine in patients with PIK3CA mutant metastatic colorectal cancer who failed two prior standard chemotherapies

ABSTRACT: Interventions: Drug : Alpelisib: oral administration In Phase lb, 200mg and 300mg once daily will be tested. In Phase ll, the recommended phase ll dose (RP2D) in phase lb will be used. Capecitabine: oral administration, In Phase lb, 850mg, 1000mg, 1250mg twice daily will be tested. In Phase ll, the recommended phase ll dose (RP2D) in phase lb twice daily on day 1 to 14 followed by 7 days off Primary outcome(s): PFS, Progression Free Survival

DISEASE(S): Neoplasms

PROVIDER: 2513615 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Phase Ib of olaparib and capivasertib

Project description:Background: Combining poly(ADP-ribose) polymerase (PARP) with phosphatidylinositol-3-kinase (PI3K) pathway inhibitors is supported by strong preclinical rationale. We sought to assess safety and a recommended phase 2 dose (RP2D) for the PARPi olaparib combined with the AKT inhibitor, capivasertib, and evaluate molecular markers of response and resistance. Methods: As part of a larger phase 1b trial, we performed a safety lead in of olaparib and capivasertib followed by expansion (n=24) in endometrial, triple negative breast, ovarian, fallopian tube, or peritoneal cancer. Olaparib 300mg orally twice daily and capivasertib orally twice daily on a 4 day on/3 day off schedule were evaluated. Two dose levels (DL) were planned: capivasertib 400mg (DL1); capivasertib 320mg (DL-1). Patients underwent biopsies at baseline and after 28 days.

| EGAS00001004930 | EGA

Differences in the self proteome of human feaces with different dietary protein.

Project description:19 men were split into two groups. 10 were provided with a diet of twice the recommended daily intake of protein and 9 were provided meals with the recommended dietary intake of protein. Faecal samples were collected after 10 weeks on the diet. This project looked at determining any qualitative differences present in the self-proteins from each group.

2021-09-09 | PXD021424 | Pride

A Phase I Study of Oral LGX818 in Adult Patients With Advanced or Metastatic BRAF Mutant Melanoma

Project description:CLGX818X2101 is a first-time in-human, phase I study to establish the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of daily administered LGX818 (daily, twice daily and/or every-other-day), a RAF kinase inhibitor. Patients with locally advanced or metastatic melanoma harboring the BRAF V600 mutation (during dose escalation phase and expansion phase) and patients with metastatic colorectal cancer harboring the BRAF V600 mutation (during the expansion phase) will be enrolled. The study consists of a dose escalation part were cohorts of patients will receive escalating oral doses of LGX818, followed by a safety dose expansion part were patients will be treated with oral dose of LGX818 given at the MTD or RP2D.

| 2113000 | ecrin-mdr-crc

Preclinical and phase I clinical studies of KW-2450, a dual IGF-1R/IR tyrosine kinase inhibitor, in combination with lapatinib and letrozole.

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

A Phase 2 Randomized Sequence Open Label Expanded Safety and Acceptability Study of Oral Emtricitabine/Tenofovir Disoproxil Fumarate Tablet and Rectally-Applied Tenofovir Reduced-Glycerin 1% Gel

Project description:Human immunodeficiency virus (HIV) disproportionately affects men who have sex with men (MSM) and transgender women (TGW). Safe and acceptable topical HIV prevention methods that target the rectum are needed. MTN-017 was a phase 2, 3-period, randomized sequence, open-label, expanded safety and acceptability crossover study comparing rectally applied reduced-glycerin (RG) 1% tenofovir (TFV) and oral emtricitabine/TFV disoproxil fumarate (FTC/TDF). In each 8-week study period participants were randomized to RG-TFV rectal gel daily, or RG-TFV rectal gel before and after receptive anal intercourse (RAI; or at least twice weekly in the event of no RAI), or daily oral FTC/TDF. MSM and TGW (n = 195) were enrolled from 8 sites in the United States, Thailand, Peru, and South Africa with mean age of 31.1 years (range 18-64). The clinical results were reported here https://www.ncbi.nlm.nih.gov/pubmed/27986684. For the gene expression study, rectal biopsies were obtained from a subset of participants (n = 36) in the United States (Pittsburgh) and Thailand (Bangkok). Biopsies were provided at baseline and after each study period.

2020-07-07 | GSE138723 | GEO

Clinical and biological implications of target occupancy in chronic lymphocytic leukemia treated with acalabrutinib

Project description:Inhibition of the B-cell receptor pathway, and specifically of Bruton tyrosine kinase (BTK), is a leading therapeutic strategy in chronic lymphocytic leukemia (CLL). Target occupancy has been measured as a pharmacodynamic parameter in clinical studies of covalent BTK inhibitors. However, the kinetics of BTK turnover, which determines occupancy, and the relationship between occupancy, pathway inhibition and clinical outcomes remains undefined. This randomized phase 2 study investigated the safety, efficacy, and pharmacodynamics of a selective BTK inhibitor acalabrutinib at 100 mg twice daily or 200 mg once daily in 48 patients with relapsed/refractory or high-risk treatment naïve CLL. Acalabrutinib was well tolerated and yielded an overall response rate (ORR) of partial response or better of 95.8% (95% CI 78.9%, 99.9%) and an estimated progression-free survival (PFS) rate at 24 months of 91.5% (95% CI 70.0%, 97.8%) with twice daily dosing and an ORR of 79.2% (95% CI 57.9%, 92.9%) and an estimated PFS rate at 24 months of 87.2% (95% CI 57.2%, 96.7%) with once daily dosing. BTK resynthesis was faster in CLL than in healthy volunteers. Twice daily dosing maintained higher BTK occupancy and achieved more potent pathway inhibition compared to once daily dosing. Additional follow-up is required to address the impact of dosing schedule and BTK occupancy on long-term clinical outcomes.

2020-04-07 | GSE136634 | GEO

The effect pregnane receptor X (PXR) agonist PCN on hepatic gene expression in mouse liver with and without glucose

Project description:The mice were treated i.p. with pregnenolone-16-α-carbonitrile (PCN, 50mg/kg dissolved in DMSO-corn oil 1:3) or vehicle (DMSO-corn oil 1:3) once daily for four days. The mice were fasted for four hours and then administered glucose (2g/kg) by oral gavage or further kept on fasting. The mice were sacrificed 1 hour after glucose administration.

2019-11-25 | GSE125695 | GEO

Gene expression in aortic roots of Apoe KO mice with Nod1 stimulation

Project description:To explore the mechanisms underlying progression of atherosclerosis provoked by Nod1 ligand stimulation, we performed microarray gene expression profiling of aortic roots of 6- and 9-week-old Apoe KO mice with or without oral FK565 administration. A gene ontology analysis of the genes up-regulated in FK565-administrated group at both time points showed that a number of biological process terms were associated with immune response. Among chemokine/cytokine genes, we observed that only 3 genes such as Ccl5, Ccl8 and Cxcl16 elevated more than 2-fold in response to oral administration of FK565 at both time points. An eight chip study using total RNA recovered from aortic roots in Apoe KO mice with or without FK565 administration, at the age of 6 and 9 weeks. Two independent experiments were performed in each group. In FK565-administrated groups, mice were orally administrated FK565 (50 µg) twice a week for 1 or 4 weeks from 5 weeks of age.

2014-11-06 | E-GEOD-48947 | biostudies-arrayexpress

A phase I/II study of Cetuximab combined with irinotecan and S-1 as first line therapy in metastatic colorectal cancer patients with KRAS wild type

Project description:Interventions: Cetuximab; bi-weekly administration 500mg/m2. Irinitecan is administered as an intravenous infusion at a dose of 120mg/m2 on day 1 and 15. And TS-1 is orally administered on days 1-14 of a 28-day cycle. Administration dose of TS-1 is based BSA : BSA<1.25m2, 40mg twice daily; 1.25-1.5m2, 50mg twice daily; >1.5m2, 60mg twice daily. Primary outcome(s): Phase I study To evaluate feasibility Phase II study Response rate Study Design: Single arm Non-randomized

| 2619853 | ecrin-mdr-crc

A Clinical Trial Evaluating the Efficacy and Safety of METi-101 in Patients with Refractory Metastatic Colorectal Cancer

Project description:Interventions: Drug : One cycle is composed of a duration of 4 weeks (28 days), during which METi-101 is orally administered continuously without any interruptions. [Phase 1b clinical trial] Upon completing cycle 1, dose limiting toxicity (DLT) assessment will be conducted. Following the 3+3 traditional dose escalation rules, the dose will be increased to determine the recommended phase 2 dose (RP2D). In the absence of DLT, if the principal investigator determines that the administration of the investigational drug is appropriate, the clinical trial drug will be continued in subsequent cycles until disease progression is confirmed according to RECIST v1.1 and iRECIST, or until unacceptable toxicity occurs. •Dose escalation steps: 500 mg/day (Cohort 1), 1000 mg/day (Cohort 2), 2000 mg/day (Cohort 3) •Administration method - Cohort 1: Take 500 mg once daily at the same time every day (e.g., at 9 AM). - Cohort 2: Take 500 mg twice a day at the same time every day (e.g., at 9 AM and 9 PM). - Cohort 3: Take 1,000 mg twice a day at the same time every day (e.g., at 9 AM and 9 PM). [Phase 2a clinical trial] The RP2D as determined in the Phase 1 clinical trial will be administered. After completion of cycle 2 (56 days), if the principal investigator determines that the administration of the investigational drug is appropriate, the clinical trial drug will be continued in subsequent cycles until disease progression is confirmed according to RECIST v1.1 and iRECIST, or until unacceptable toxicity occurs. Primary outcome(s): [Phase 2a Clinical Trial] Progression-Free Survival (PFS);[Phase 2a Clinical Trial] Overall Survival (OS);[Phase 1b Clinical Trial] Safety and tolerability (Maximum Tolerated Dose and Recommended Phase 2 Dose)

| 74700 | ecrin-mdr-crc

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