A phase 1 study evaluating the combination of an allosteric AKT inhibitor (MK-2206) and trastuzumab in patients with HER2-positive solid tumors

Introduction

Trastuzumab is effective in human epidermal growth factor receptor 2 (HER2)-over-expressing breast and gastric cancers. However, patients may develop resistance through downstream signaling via the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. This phase 1 trial was conducted to determine the safety and tolerability of the investigational AKT inhibitor MK-2206, to prepare for future studies to determine whether the combination with trastuzumab could inhibit compensatory signaling.

Methods

Patients with HER2+ treatment-refractory breast and gastroesophageal cancer were enrolled. Treatment consisted of standard doses of intravenous trastuzumab and escalating dose levels of oral MK-2206 using either an every-other-day (45 mg and 60 mg QOD) or once-weekly (135 mg and 200 mg QW) schedule.

Results

A total of 34 patients with HER2+ disease were enrolled; 31 received study-drug. The maximum tolerated dose (MTD) for MK-2206 in combination with trastuzumab was 60 mg for the QOD schedule and 135 mg for the QW schedule, although a true MTD was not established due to early termination of the trial. The most common treatment-emergent toxicities included fatigue, hyperglycemia, and dermatologic rash, consistent with prior experience; one death unrelated to treatment was reported. There was one complete response in a patient with metastatic breast cancer, one patient achieved a partial response, and 5 patients had stable disease for at least 4 months, despite progression on multiple prior trastuzumab- and lapatinib-based therapies. Results also indicate that trastuzumab does not affect the pharmacokinetics of MK-2206.

Conclusions

Results suggest the AKT inhibitor MK-2206 can be safely combined with trastuzumab, and is associated with clinical activity, supporting further investigation.

Trial registration

ClinicalTrials.gov; identifier: {"type":"clinical-trial","attrs":{"text":"NCT00963547","term_id":"NCT00963547"}}NCT00963547.     

Molecular typing of antimicrobial-resistant Shiga-toxin-producing Escherichia coli strains (STEC) in Brazil

Antimicrobial resistance patterns and molecular characteristics were determined in thirty-two Shiga-toxin-producing Escherichia coli (STEC) strains previously identified in São Paulo State associated with human infections (n = 21) and in cattle feces (n = 11). The highest resistance rates were identified for tetracycline (100%), streptomycin (78%) and trimethoprim-sulfamethoxazole (56%). Eleven STEC strains showed resistance to ampicillin and carried bla_TEM that was confirmed as bla_TEM-1 in one representative isolate. The class 1 integrase gene (intI1) was detected in seven (22%) strains, and most of them belonged to the O111:H8 serotype. The class 1 integron was located on plasmids in five of the seven STEC strains, and conjugation assays confirmed the plasmid support of those resistant determinants. STEC strains were genetically classified into the B1 group, and PFGE analysis showed that most of the strains in each serogroup were grouped into the same cluster (80-97% similarity). The presence of a class 1 integron and bla_TEM-1 genes is described for the first time among STEC isolates in Brazil and clearly represents a public health concern.     

Effect of sibutramine on 5-hydroxyindole acetic acid levels and selected oxidative biomarkers on brain regions of female rats in the presence of zinc

Abstract: A number of drugs, like sibutramine, which are used clinically in weight control, act on serotonergic metabolism. However, their relation with zinc and free radical (FR) production in central nervous system remains unknown. This study aimed to evaluate the effect of sibutramine and zinc on FR production. Female Wistar rats (about 250 g) were used in this study. The animals received 400 μg/kg of zinc and 10 mg/kg of sibutramine intraperitoneally every 36 hr for 15 days. At the end of the study, the rats were killed and their brains used for the measurement of lipid peroxidation thiobarbituric acid‐reactive substances (TBARS), reduced glutathione (GSH), hydrogen peroxide (H₂O₂), calcium and 5‐hydroxyindole acetic acid (5‐HIAA) levels, all by means of validated methods. Corporal weight and food consumption were found to be decreased in the zinc/sibutramine group. TBARS decreased in cortex, hemispheres and medulla oblongata. GSH decreased in cortex, hemispheres and cerebellum in the sibutramine group. Zinc given alone and in combination with sibutramine decreased H₂O₂ concentration in cortex, hemispheres and cerebellum but increased calcium and 5‐HIAA concentration in all brain regions. Our results suggest that sibutramine and zinc are associated with weight loss, an effect that was more pronounced in the group treated with both drugs. Reduction in oxidative stress may be involved in these effects.     

Simultaneous diffuse reflectance infrared determination of clavulanic acid and amoxicillin using multivariate calibration techniques

A method for simultaneous determination of clavulanic acid (CA) and amoxicillin (AMO) in commercial tablets was developed using diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) and multivariate calibration. Twenty-five samples (10 commercial and 15 synthetic) were used as a calibration set and 15 samples (10 commercial and 5 synthetic) were used for a prediction set. Calibration models were developed using partial least squares (PLS), interval PLS (iPLS), and synergy interval PLS (siPLS) algorithms. The best algorithm for CA determination was siPLS model with spectra divided in 30 intervals and combinations of 2 intervals. This model showed a root mean square error of prediction (RMSEP) of 5.1 mg g(-1). For AMO determination, the best siPLS model was obtained with spectra divided in 10 intervals and combinations of 4 intervals. This model showed a RMSEP of 22.3 mg g(-1). The proposed method was considered as a suitable for the simultaneous determination of CA and AMO in commercial pharmaceuticals products.     

Late onset vanishing white matter disease presenting with learning difficulties

BACKGROUND: Vanishing white matter is an inherited leukoencephalopathy with typical childhood onset. Late onset forms are rare and may present with an extended range of phenotypes. Case report We present a patient born to consanguineous parents who developed learning disabilities by the age of 16 years. At the age of 25 she had a focal motor seizure with subsequent hemiparesis. After an extensive investigation she was diagnosed and treated as multiple sclerosis. There was progressive memory and planning impairment and, six years later, Sj?gren syndrome with central nervous system involvement was diagnosed. For six months she was treated with cyclophosphamide, without any improvement. The next two years she had major clinical deterioration following infections. A homozygous mutation was identified in the EIF2B5 gene at the age of 33, and she died a year later. CONCLUSIONS: VWM leukoencephalopathy is still largely recognized as a pediatric disorder, with many adult neurologists being unfamiliar with the late onset presentations. We wish to draw attention into these forms, avoiding submitting these patients to extensive workup and unnecessary treatments.