Phase I study of onapristone, a type I antiprogestin, in female patients with previously treated recurrent or metastatic progesterone receptor-expressing cancers.

Introduction: Onapristone is a type I progesterone receptor (PR) antagonist, which prevents PR- mediated DNA transcription. Onapristone is active in multiple preclinical models and two prior studies demonstrated promising activity in patients with breast cancer. We conducted a study of extended release (ER) Onapristone to determine a recommended dose and explore the role of transcriptionally-activated PR (APR), detected as an aggregated subnuclear distribution pattern, as a predictive biomarker.

Validation of an ergonomic method to withdraw [Tc] radiopharmaceuticals.

The main objective of the present work was to ensure quality of radiopharmaceuticals syringes withdrawn with a "Spinal needle/obturator In-Stopper" system. Visual examinations and physicochemical tests are performed at T0 and T+4h for [Tc]albumin nanocolloid and T+7h for [Tc]eluate, [Tc] HydroxyMethylene DiPhosphonate and [Tc]Human Serum Albumin. Microbiological validation was performed according to European pharmacopoeia.

PIKHER2: A phase IB study evaluating buparlisib in combination with lapatinib in trastuzumab-resistant HER2-positive advanced breast cancer.

Background: Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin pathway is frequently activated in HER2-positive breast cancer and may play a major role in resistance to trastuzumab. Buparlisib is a pan-class-I PI3K inhibitor with potent and selective activity against wild-type and mutant PI3K p110 isoforms.

Patients And Methods: PIKHER2 phase IB study aimed primarily to determine a maximum tolerated dose (MTD) and propose a recommended phase II dose (RP2D) for buparlisib in combination with lapatinib in HER2-positive, trastuzumab-resistant, advanced breast cancer.

OTX015 (MK-8628), a novel BET inhibitor, displays in vitro and in vivo antitumor effects alone and in combination with conventional therapies in glioblastoma models.

Bromodomain and extraterminal (BET) bromodomain (BRD) proteins are epigenetic readers that bind to acetylated lysine residues on chromatin, acting as co-activators or co-repressors of gene expression. BRD2 and BRD4, members of the BET family, are significantly increased in glioblastoma multiforme (GBM), the most common primary adult brain cancer. OTX015 (MK-8628), a novel BRD2/3/4 inhibitor, is under evaluation in dose-finding studies in solid tumors, including GBM.

Bromodomain inhibitor OTX015 in patients with lymphoma or multiple myeloma: a dose-escalation, open-label, pharmacokinetic, phase 1 study.

Background: The first-in-class small molecule inhibitor OTX015 (MK-8628) specifically binds to bromodomain motifs BRD2, BRD3, and BRD4 of bromodomain and extraterminal (BET) proteins, inhibiting them from binding to acetylated histones, which occurs preferentially at super-enhancer regions that control oncogene expression. OTX015 is active in haematological preclinical entities including leukaemia, lymphoma, and myeloma. We aimed to establish the recommended dose of OTX015 in patients with haematological malignancies.

Bromodomain inhibitor OTX015 in patients with acute leukaemia: a dose-escalation, phase 1 study.

Background: Bromodomain and extraterminal (BET) proteins are chromatin readers that preferentially affect the transcription of genes with super-enhancers, including oncogenes. BET proteins bind acetylated histone tails via their bromodomain, bringing the elongation complex to the promoter region. OTX015 (MK-8628) specifically binds to BRD2, BRD3, and BRD4, preventing BET proteins from binding to the chromatin, thus inhibiting gene transcription.

Influence of tumour burden on trastuzumab pharmacokinetics in HER2 positive non-metastatic breast cancer.

Aims: Trastuzumab, an antibody binding to epidermal growth factor receptor-2 (HER2), has been approved to treat HER2-positive breast cancer in different settings. This study aimed at evaluating the influence of tumour size on trastuzumab pharmacokinetics (PK) in non-metastatic breast cancer patients treated with short term pre-operative trastuzumab.

Methods: Trastuzumab PK data were obtained from a multicentre, randomized and comparative study.

A Phase I Trial of High-Dose Chemotherapy Combining Topotecan plus Cyclophosphamide with Hematopoietic Stem Cell Transplantation for Ovarian Cancer: The ITOV 01bis Study.

Background: Dose-intensive chemotherapy with hematopoietic stem cell transplantation has been evaluated as a salvage treatment for recurrent ovarian cancer, but its benefit has not yet been demonstrated. In a previous phase I trial, we reported the feasibility of administering topotecan as a salvage regimen.

Methods: Twenty-one patients were treated with escalating doses of topotecan associated with a fixed dose of cyclophosphamide.

Phase I Population Pharmacokinetic Assessment of the Oral Bromodomain Inhibitor OTX015 in Patients with Haematologic Malignancies.

Background And Objectives: OTX015 (MK-8628) is a novel inhibitor of the bromodomain and extraterminal (BET)-bromodomain (BRD) protein family, binding specifically to bromodomains BRD2/3/4 and impacting the epigenetic regulation of several oncogenes. We characterized the pharmacokinetics of this first-in-class BET-BRD inhibitor administered as a single agent, including population pharmacokinetic modelling.

Methods: A dose-escalation, phase Ib study was performed with oral OTX015 in patients with haematologic malignancies, at doses starting from 10 mg once daily (QD) with continuous or discontinuous schedules.

A single-dose PK study of onapristone including the effect of food on absorption.

Purpose: Onapristone is an antiprogestin with activity in breast cancer and is under investigation for use in endometrial, ovarian and prostate cancers. Megestrol acetate and abiraterone generally show variability in absorption and, depending on the formulation, food effect. This study was conducted to determine the effect of food on 10 mg oral immediate-release (IR) onapristone and to help identify a formulation to minimize variability.

Acute and delayed toxicity of gemcitabine administered during isolated lung perfusion: a preclinical dose-escalation study in pigs.

Objectives: Colorectal cancer is the third most commonly diagnosed cancer worldwide, with up to 25% of patients presenting with metastases at the time of diagnosis. Despite pulmonary metastasectomy many patients go on to develop pulmonary recurrence, which might be linked to the presence of lung micrometastases. In this setting, the adjuvant administration of high-dose chemotherapy by isolated lung perfusion (ILP) has shown encouraging results.

A phase I pharmacokinetics study of lapatinib and tamoxifen in metastatic breast cancer (EORTC 10053 Lapatam study).

Objective: This phase I study assessed the pharmacokinetic (PK), tolerability, safety and preliminary clinical activity of tamoxifen (T) and lapatinib (L) in patients with metastatic breast cancer (MBC).

Methods: Patients (pts) with hormone receptor positive MBC, irrespective of HER-2 status, were randomly assigned to T → T + L group, tamoxifen in cycle 1 for 28 days then adding lapatinib on day 1 of cycle 2; or L → T + L group, lapatinib in cycle 1 for 14 days, then adding tamoxifen on day 1 of cycle 2 to evaluate the potential drug-drug PK interaction at steady-state. The dose of tamoxifen was 20 mg/day and lapatinib 1500 mg/day.

Extracellular adenosine triphosphate affects the response of human macrophages infected with Mycobacterium tuberculosis.

Granulomas are the hallmark of Mycobacterium tuberculosis infection. As the host fails to control the bacteria, the center of the granuloma exhibits necrosis resulting from the dying of infected macrophages. The release of the intracellular pool of nucleotides into the surrounding medium may modulate the response of newly infected macrophages, although this has never been investigated.

Influence of ABCB1 polymorphisms and docetaxel pharmacokinetics on pathological response to neoadjuvant chemotherapy in breast cancer patients.

We have previously reported an association between ABCB1 C3435T polymorphism and docetaxel pharmacokinetics in breast cancer patients. We therefore investigated whether these parameters could account for variations in pathological response. Five ABCB1 polymorphisms including C3435T polymorphism were analyzed in breast cancer patients receiving neoadjuvant chemotherapy with doxorubicin and docetaxel (n = 101).

Phase I dose-escalation study of EZN-2208 (PEG-SN38), a novel conjugate of poly(ethylene) glycol and SN38, administered weekly in patients with advanced cancer.

Purpose: This study evaluated the tolerability, pharmacokinetics, and preliminary antitumor activity of EZN-2208, a water-soluble poly(ethylene) glycol conjugate of SN38.

Methods: Patients with advanced malignancies were enrolled in dose-escalating cohorts (3 + 3 design). EZN-2208 was administered as a 1-h intravenous infusion given weekly for 3 weeks per each 4-week cycle.

A comparative analysis of paediatric dose-finding trials of molecularly targeted agent with adults' trials.

Background: Dose-finding phase I trials in children are usually carried out once clinical data have already been accumulated in the adult population. The objectives, place and role of paediatric dose-finding trials are investigated in the era of molecularly targeted agents (MTAs).

Methods: Phase I paediatric oncology trials of MTAs approved in adults before June 15th, 2012 were reviewed.

Isolated lung perfusion as an adjuvant treatment of colorectal cancer lung metastases: a preclinical study in a pig model.

Background: The lung is a frequent site of colorectal cancer (CRC) metastases. After surgical resection, lung metastases recurrences have been related to the presence of micrometastases, potentially accessible to a high dose chemotherapy administered via adjuvant isolated lung perfusion (ILP). We sought to determine in vitro the most efficient drug when administered to CRC cell lines during a short exposure and in vivo its immediate and delayed tolerance when administered via ILP.

mTOR inhibitors in advanced renal cell carcinomas: from biology to clinical practice.

To date, oral everolimus is indicated for the treatment of patients with advanced renal cell carcinoma, whose disease has progressed on or after treatment with vascular endothelial growth factor-targeted therapy, and intravenous temsirolimus for the first-line treatment of patients with poor prognosis metastatic renal cell carcinoma. However, some factors could guide the treatment choice aiming to individualize a treatment plan. Besides the crucial issue of treatment efficacy, other factors are to be considered such as disease status, histological subtype, extent of the disease, patient-specific factors, and agent-specific factors.

Pharmacokinetics and Toxicity in Rats and Monkeys of coDbait: A Therapeutic Double-stranded DNA Oligonucleotide Conjugated to Cholesterol.

Increased DNA repair activity in cancer cells is one of their primary mechanisms of resistance to current radio- and chemotherapies. The molecule coDbait is the first candidate in a new class of drugs that target the double-strand DNA break repair pathways with the aim of overcoming these resistances. coDbait is a 32-base pair (bp) double-stranded DNA molecule with a cholesterol moiety covalently attached to its 5'-end to facilitate its cellular uptake.

Safety, pharmacokinetics, and activity of EZN-2208, a novel conjugate of polyethylene glycol and SN38, in patients with advanced malignancies.

Background: EZN-2208 is a water-soluble, polyethylene glycol drug conjugate of SN38, which is the active moiety of irinotecan. In this study, the authors evaluated the tolerability, pharmacokinetics (PK), and activity of EZN-2208 in adult patients with advanced solid tumors.

Methods: Patients in sequential cohorts (3 + 3 design) received intravenous EZN-2208 at doses between 1.

[Adaptation of methotrexate determination in serum with Unicel DxC600(®)].

High-dose methotrexate treatment requires pharmacological monitoring in order to tailor administration of folinic acid to reduce side effects. The aim of the study was to validate the adaptation of the EMIT reagent on the l'Unicel DxC 600® Beckman Coulter. The establishment of two assays was necessary to obtain a quantification limit as low as possible (0.

Doxorubicin and ifosfamide for high-grade sarcoma during pregnancy.

Purpose: Doxorubicin and ifosfamide are highly active drugs for the treatment of high-grade sarcomas, but little is known on the optimal management of young patients who develop such malignancies during pregnancy.

Methods: We report on a single-institution series of patients (n = 9) with high-grade sarcoma diagnosed during the third trimester of pregnancy. Neoadjuvant chemotherapy combining doxorubicin (50 mg/m(2) day 1) and ifosfamide (2.

A phase I trial combining oral cisplatin (CP Ethypharm) with radiotherapy in patients with locally advanced head and neck squamous cell carcinoma.

Purpose: To determine the maximum tolerated dose (MTD) of oral cisplatin (CP Ethypharm®) in combination with radiotherapy in head and neck squamous cell carcinoma (HNSCC) and the recommended dose for phase II trials.

Patients And Methods: Phase I, multicenter, open-labelled, non-comparative and dose escalating trial. CP Ethypharm® was administered on five consecutive days every other week for 7 weeks (4 treatment cycles) in combination with radiotherapy.