A phase 1b study of the ERK inhibitor MK-8353 plus pembrolizumab in patients with advanced solid tumors.

Combining a checkpoint inhibitor with an inhibitor of extracellular signal-regulated kinase (ERK) may result in synergistic antitumor activity. We evaluated MK-8353, an ERK1 and ERK2 inhibitor, plus pembrolizumab in a phase 1b study in patients with advanced solid tumors. This open-label, nonrandomized, dose-escalation study (NCT02972034) enrolled adults with advanced solid tumors previously treated with 1‒5 prior lines of therapy. MK-8353 was administered orally in combination with pembrolizumab 200 mg every 3 weeks as follows: twice daily (arm A; MK-8353 50‒350 mg), once daily (arm B; MK-8353 50‒600 mg), or once daily every other week (arm C; MK-8353 50‒300 mg). The primary objective was evaluation of safety via occurrence of dose-limiting toxicities (DLTs). A secondary objective was objective response by RECIST v1.1 per investigator assessment. Among 110 evaluable patients (arm A, n = 22; arm B, n = 50; arm C, n = 38), median age was 58.0 (range, 35‒79) years and 50% had received 1 or 2 prior lines of therapy. DLTs occurred in 19 patients (n = 6 [27%], n = 8 [16%], and n = 5 [13%], respectively); the most frequent was grade 3 maculopapular rash (n = 15). Grade 3/4 treatment-related AEs occurred in 35% of patients; the most common were maculopapular rash (13%) and increased lipase (5%); none were grade 5. Eight patients (7%) attained an objective response (arm B, n = 7 [complete response, n = 1; partial response, n = 6]; arm C, n = 1 [complete response]). In conclusion, MK-8353 once daily plus pembrolizumab could be administered with a manageable toxicity profile but had modest antitumor activity in patients with advanced solid tumors.

A phase 1 trial of the MEK inhibitor selumetinib in combination with pembrolizumab for advanced or metastatic solid tumors.

MEK inhibitors have immunomodulatory activity and potential for synergistic activity when combined with PD-1 inhibitors. We evaluated selumetinib (inhibitor of MEK1/2) plus pembrolizumab (anti‒PD-1 antibody) in patients with advanced/metastatic solid tumors. In this phase 1b study, adults with previously treated advanced/metastatic solid tumors received pembrolizumab 200 mg intravenously every 3 weeks plus selumetinib on days 1‒14 per 3-week cycle (2 weeks on/1 week off); selumetinib dosing began at 50 mg orally twice daily with escalation in 25 mg increments for ≤ 35 cycles. Primary endpoints were dose-limiting toxicities (DLTs), adverse events (AEs), and treatment discontinuations due to AEs. Thirty-two patients were enrolled. Dose escalation was completed up to selumetinib 125 mg twice daily. The target DLT rate of 30% was not reached at any dose level. In the selumetinib 100 mg group, 2/11 patients (18.2%) experienced DLTs (n = 1 grade 3 diarrhea, n = 1 grade 3 fatigue). In the selumetinib 125 mg group, 3/14 (21.4%) experienced DLTs (n = 1 grade 2 retinal detachment, n = 1 grade 3 retinopathy, n = 1 grade 3 stomatitis). Dose-related changes in pharmacokinetic exposures were observed for selumetinib and N-desmethyl selumetinib up to 100 mg (saturation at 125 mg). Two patients achieved partial responses (1 each with selumetinib 75 mg and 125 mg) for an objective response rate of 6%. The study was stopped early because of insufficient efficacy. Although the target DLT rate was not reached at any dose level and no new safety signals were identified, selumetinib plus pembrolizumab had limited antitumor activity in this population. Trial registration: ClinicalTrials.gov , NCT03833427.

Results of an open-label phase 1b study of the ERK inhibitor MK-8353 plus the MEK inhibitor selumetinib in patients with advanced or metastatic solid tumors.

AIM: We evaluated MK-8353 (small molecule inhibitor of extracellular signal-regulated kinase 1/2) plus selumetinib (mitogen-activated extracellular signal-regulated kinase 1/2 inhibitor) in patients with advanced solid tumors. METHODS: This phase 1b, open-label, dose-escalation study (NCT03745989) enrolled adults with histologically/cytologically documented, locally advanced/metastatic solid tumors. MK-8353/selumetinib dose combinations were intended to be investigated in sequence: 50/25, 100/50, 150/75, 200/75, 200/100, and 250/100. Each agent was administered orally BID 4 days on/3 days off in repeating cycles every 21 days. Primary objectives were safety and tolerability and to establish preliminary recommended phase 2 doses for combination therapy. RESULTS: Thirty patients were enrolled. Median (range) age was 61.5 (26-78) years and 93% had received previous cancer therapy. Among 28 patients in the dose-limiting toxicities [DLT]-evaluable population, 8 experienced DLTs: 1/11 (9%) in the MK-8353/selumetinib 100/50-mg dose level experienced a grade 3 DLT (urticaria), and 7/14 (50%) in the 150/75-mg dose level experienced grade 2/3 DLTs (n = 2 each of blurred vision, retinal detachment, vomiting; n = 1 each of diarrhea, macular edema, nausea, retinopathy). The DLT rate in the latter dose level exceeded the prespecified target DLT rate (~30%). Twenty-six patients (87%) experienced treatment-related adverse events (grade 3, 30%; no grade 4/5), most commonly diarrhea (67%), nausea (37%), and acneiform dermatitis (33%). Three patients (10%) experienced treatment-related adverse events leading to treatment discontinuation. Best response was stable disease in 14 patients (n = 10 with MK-8353/selumetinib 150/75 mg). CONCLUSION: MK-8353/selumetinib 50/25 mg and 100/50 mg had acceptable safety and tolerability, whereas 150/75 mg was not tolerable. No responses were observed.

Phase I study of daily and weekly regimens of the orally administered MDM2 antagonist idasanutlin in patients with advanced tumors.

Aim The oral MDM2 antagonist idasanutlin inhibits the p53-MDM2 interaction, enabling p53 activation, tumor growth inhibition, and increased survival in xenograft models. Methods We conducted a Phase I study of idasanutlin (microprecipitate bulk powder formulation) to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, food effect, and clinical activity in patients with advanced malignancies. Schedules investigated were once weekly for 3 weeks (QW × 3), once daily for 3 days (QD × 3), or QD × 5 every 28 days. We also analyzed p53 activation and the anti-proliferative effects of idasanutlin. Results The dose-escalation phase included 85 patients (QW × 3, n = 36; QD × 3, n = 15; QD × 5, n = 34). Daily MTD was 3200 mg (QW × 3), 1000 mg (QD × 3), and 500 mg (QD × 5). Most common adverse events were diarrhea, nausea/vomiting, decreased appetite, and thrombocytopenia. Dose-limiting toxicities were nausea/vomiting and myelosuppression; myelosuppression was more frequent with QD dosing and associated with pharmacokinetic exposure. Idasanutlin exposure was approximately dose proportional at low doses, but less than dose proportional at > 600 mg. Although inter-patient variability in exposure was high with all regimens, cumulative idasanutlin exposure over the whole 28-day cycle was greatest with a QD × 5 regimen. No major food effect on pharmacokinetic exposure occurred. MIC-1 levels were higher with QD dosing, increasing in an exposure-dependent manner. Best response was stable disease in 30.6% of patients, prolonged (> 600 days) in 2 patients with sarcoma. Conclusions Idasanutlin demonstrated dose- and schedule-dependent p53 activation with durable disease stabilization in some patients. Based on these findings, the QD × 5 schedule was selected for further development. TRIAL REGISTRATION: NCT01462175 (ClinicalTrials.gov), October 31, 2011.

A phase 1 study of the MDM2 antagonist RO6839921, a pegylated prodrug of idasanutlin, in patients with advanced solid tumors.

Purpose MDM2 is a negative regulator of the tumor suppressor p53. RO6839921 is an inactive pegylated prodrug of idasanutlin, an MDM2 antagonist, developed for intravenous administration. On cleavage by plasma esterases, the active principle (AP = idasanutlin) is released. This phase 1 study investigated the safety, pharmacokinetics, and pharmacodynamics of RO6839921 in patients with advanced solid tumors (NCT02098967). Methods Patients were evaluated on a 5-day dosing schedule every 28 days. Dose escalation used the Bayesian new continual reassessment model. Accelerated dose titration was permitted until grade ≥2 drug-related AEs were observed. The target DLT rate to define the MTD was 16-25%. p53 activation was assessed by measuring macrophage inhibitory cytokine-1 (MIC-1). Results Forty-one patients received 14-120 mg AP; 39 were DLT evaluable. The MTD was 110-mg AP (8% DLT rate), whereas 120-mg AP had a 44% DLT rate. DLTs were neutropenia, thrombocytopenia, and stridor. The most common treatment-related AEs (≥30%) were nausea, fatigue, vomiting, and thrombocytopenia. Pharmacokinetic analyses indicated rapid conversion of prodrug to AP and an approximately linear and dose-proportional dose-exposure relationship, with a 2-fold increase in exposure between Days 1 and 5 of AP. MIC-1 increases were exposure dependent. Stable disease was observed in 14 patients (34%). Conclusions RO6839921 showed reduced pharmacokinetic exposure variability and a safety profile comparable with that of oral idasanutlin. Although this study indicated that RO6839921 could be administered to patients, the results did not provide sufficient differentiation or improvement in the biologic or safety profile compared with oral idasanutlin to support continued development.

Phase 1 study of the MDM2 antagonist RO6839921 in patients with acute myeloid leukemia.

In acute myeloid leukemia (AML), TP53 mutations and dysregulation of wild-type p53 is common and supports an MDM2 antagonist as a therapy. RO6839921 is an inactive pegylated prodrug of the oral MDM2 antagonist idasanutlin (active principle [AP]) that allows for IV administration. This phase 1 monotherapy study evaluated the safety, pharmacokinetics, and pharmacodynamics of RO6839921 in patients with AML. Primary objectives identified dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD). Secondary objectives assessed pharmacokinetic, pharmacodynamic, and antileukemic activity. A total of 26 patients received 120-300 mg AP of idasanutlin. The MTD was 200 mg, with DLTs at 250 (2/8 patients) and 300 mg (2/5). Treatment-related adverse events in >20% of patients were diarrhea, nausea, vomiting, decreased appetite, and fatigue. Six deaths (23.1%) occurred, all unrelated to treatment. Pharmacokinetics showed rapid and near-complete conversion of the prodrug to AP and dose-proportional exposure across doses. Variability ranged from 30%-47% (22%-54% for idasanutlin). TP53 was 21 (87.5%) wild-type and 3 mutant (12.5%). The composite response rate (complete remission [CR], CR with incomplete hematologic recovery/morphological leukemia-free state [CRi/MLFS], or CR without platelet recovery [CRp]) was 7.7%. Antileukemic activity (CR, CRi/MLFS, partial response, hematologic improvement/stable disease) was observed in 11 patients (disease control rate, 42%): 10/11 were TP53 wild-type; 1 had no sample. p53 activation was demonstrated by MIC-1 induction and was associated with AP exposure. There was not sufficient differentiation or improvement in the biologic or safety profile compared with oral idasanutlin to support continued development of RO6839921. NCT02098967.

Frequent and specific immunity to the embryonal stem cell-associated antigen SOX2 in patients with monoclonal gammopathy.

Specific targets of cellular immunity in human premalignancy are largely unknown. Monoclonal gammopathy of undetermined significance (MGUS) represents a precursor lesion to myeloma (MM). We show that antigenic targets of spontaneous immunity in MGUS differ from MM. MGUS patients frequently mount a humoral and cellular immune response against SOX2, a gene critical for self-renewal in embryonal stem cells. Intranuclear expression of SOX2 marks the clonogenic CD138(-) compartment in MGUS. SOX2 expression is also detected in a proportion of CD138(+) cells in MM patients. However, these patients lack anti-SOX2 immunity. Cellular immunity to SOX2 inhibits the clonogenic growth of MGUS cells in vitro. Detection of anti-SOX2 T cells predicts favorable clinical outcome in patients with asymptomatic plasmaproliferative disorders. Harnessing immunity to antigens expressed by tumor progenitor cells may be critical for prevention and therapy of human cancer.

Prussian blue nanoparticles as nanocargoes for delivering DNA drugs to cancer cells.

We studied the use of Prussian blue nanoparticles (PBNPs) as novel nanocarriers for sending DNA drugs into cancer cells. 11-mercaptoundecanoic acid (MUA) was used to functionalize the surfaces of PBNPs (nanocubes with an average dimension of 75 nm) for subsequent covalent grafting of a 33-mer DNA drug with a FAM reporter at the 3' end. The PBNPs synthesis and DNA drug conjugation were characterized by transmission electron microscopy (TEM) and Fourier-transform infrared absorption (FTIR), respectively. The drug was a decoy oligodeoxynucleotide (dODN) that inhibits the signal transducer and activator of transcription 3 (STAT3). The DNA-PBNPs drug (dODN@MUA-PBNPs) was delivered into human prostate carcinoma 22rv1 cells by endocytosis in vitro as confirmed by confocal fluorescence microscopy. MTT cell viability assays were carried out to assess the effect of the DNA-PBNPs drug. The results showed that the dODN molecules were successfully conjugated to the MUA modified PBNPs via amide and/or disulfide bond formation and could thus be successfully delivered into the cancer cells. The control experiments showed that the unconjugated dODN molecules were not able to enter the cancer cells no matter whether non-functionalized PBNPs were present or not. It was also found that the DNA-PBNPs drugs were internalized and then distributed homogeneously throughout the cell, including cytoplasmic and nucleic regions, after endocytosis. The cancer cell-killing ability increased with the amount of dODN conjugated on PBNPs and the dosage of DNA-PBNPs drug internalized.

A novel DNA selection and direct extraction process and its application in DNA recombination.

In the conventional bench-top approach, the DNA recombination process is time- and effort-consuming due to laborious procedures lasting from several hours to a day. A novel DNA selection and direct extraction process has been proposed, integrated and tested on chip. The integrative microfluidic chip can perform the whole procedure of DNA recombination, including DNA digestion, gel electrophoresis, DNA extraction and insert-vector ligation within 1 h. In this high-throughput design, the manual gel cutting was replaced by an automatic processing system that performed high-quality and high-recovery efficiency in DNA extraction process. With no need of gel-dissolving reagents and manipulation, the application of selection and direct extraction process could significantly eliminate the risks from UV and EtBr and also facilitate DNA recombination. Reliable output with high success rate of cloning has been achieved with a significant reduction in operational hazards, required materials, efforts and time.

Murine double minute 2 inhibition alone or with cytarabine in acute myeloid leukemia: Results from an idasanutlin phase 1/1b study⋆.

The prognosis remains poor for patients with relapsed or refractory (r/r) acute myeloid leukemia; thus, novel therapies are needed. We evaluated idasanutlin-a new, potent murine double minute 2 antagonist-alone or with cytarabine in patients with r/r acute myeloid leukemia, de novo untreated acute myeloid leukemia unsuitable for standard treatment or with adverse features, or secondary acute myeloid leukemia in a multicenter, open-label, phase 1/1b trial. Primary objectives were to determine the maximum tolerated dose (MTD) and recommended dose for expansion (RDE) and characterize the safety profile of idasanutlin monotherapy and combination therapy. Clinical activity and pharmacokinetics were secondary objectives. Two idasanutlin formulations were investigated: a microprecipitate bulk powder (MBP) and optimized spray-dried powder (SDP). Following dose escalation, patients (N = 122) received idasanutlin at the RDE in the extension cohorts. No formal MTD was identified. Idasanutlin was tolerable alone and in combination with cytarabine. The RDE was determined as 600 mg twice a day for the MBP formulation and 300 mg twice a day for the SDP formulation. Adverse events were mostly grade 1/2 (76.2 %). The most common any-grade adverse events were gastrointestinal (including diarrhea [90.2 %]). The early death rate across all patients was 14.8 %. Plasma idasanutlin exposure was dose related. In TP53 wild-type patients, composite complete remission rates were 18.9 % with monotherapy and 35.6 % with combination therapy. Based on these results, idasanutlin development continued with further investigation in the treatment of acute myeloid leukemia. ClinicalTrials.gov: NCT01773408.

Enhancement of aptamer microarray sensitivity through spacer optimization and avidity effect.

This work aims for ultrasensitive detection of target proteins in complex biological matrixes based on aptamer microarrays. Two extensively studied aptamers (HTQ and HTDQ) that bind distinct epitopes of thrombin are chosen for the microarray study. Although HTQ and HTDQ have nanomolar to subnanomolar affinities, it is found that either aptamer when applied directly has difficulty in detecting a few nanomoles per liter thrombin in the presence of a 10- or 100-fold (w/w) excess of serum total protein (STP). By investigating dodecyl (12-carbon) and oligodeoxythymidine (oligo(dT)) spacers, we observe both spacers enhance the microarray signal response, but oligo(dT) is strikingly better than dodecyl. Moreover, we discover that a microarray spot coprinted with the two distinct aptamers (HTQ and HTDQ) functions like a bivalent molecular construct and exhibits an avidity effect. With the synergy of oligo(dT) spacers and the avidity effect, detection of picomolar-range thrombin in the presence of either 10% unlabeled serum or a 10,000-fold excess of labeled serum total protein is achieved. It corresponds to a 100-1000-fold sensitivity enhancement as compared to using an individual aptamer without a spacer.

A single-center, open-label study investigating the excretion balance, pharmacokinetics, metabolism, and absolute bioavailability of a single oral dose of [14C]-labeled idasanutlin and an intravenous tracer dose of [13C]-labeled idasanutlin in a single cohort of patients with solid tumors.

PURPOSE: Idasanutlin, a selective small-molecule MDM2 antagonist in phase 3 testing for refractory/relapsed AML, is a non-genotoxic p53 activator with oral administration. To determine the need to conduct dedicated trial(s) for organ impairment on pharmacokinetic (PK) exposure and/or drug-drug interactions, a single dose of [14C]- and [13C]-labeled idasanutlin was evaluated. METHODS: This study was an open-label, non-randomized, single-center trial of idasanutlin to investigate the excretion balance, pharmacokinetics, metabolism, and absolute bioavailability of a single oral dose of [14C]-labeled idasanutlin and an IV tracer dose of [13C]-labeled idasanutlin in a single cohort of patients with solid tumors. After completing cycle 1 assessments, patients could have participated in an optional treatment extension of idasanutlin. Clinical endpoints were PK, and safety/tolerability. RESULTS: Co-administration of an oral dose of idasanutlin with an IV tracer dose revealed low systemic CL, a moderate Vd, and a moderate (40.1%) absolute bioavailability of idasanutlin. Idasanutlin and its major inactive metabolite, M4, were the major circulating moieties in plasma, and excretion of idasanutlin-associated radioactivity was primarily via the fecal route (91.5% of the dose), with negligible amounts recovered in urine, following oral administration. CONCLUSION: The clinical implications of this study support the conclusion that renal impairment is unlikely to significantly impact exposure to idasanutlin and M4 metabolite, whereas a significant hepatic impairment may potentially alter exposure to the parent drug and/or metabolite(s). The potential for drug-drug interactions is low.

Spectral contrast imaging method for mapping transmission surface plasmon images in metallic nanostructures.

We propose a spectral contrast method to map the transmission images of surface plasmon resonance (SPR) in metallic nanostructures. Comparing the intensities between two neighboring wavelength bands near the SPR wavelength, the signal-to-noise ratio for biosensing applications obtained using the proposed method is found to be ten times higher than that obtained by conventional intensity analysis and 1.6 times better than that obtained by peak-wavelength fitting. The dynamic range and linearity of the refractive index are comparable to the peak-wavelength shift measurement. Based on the detection method, a spectral modulation system for the optical microscope is developed, combined with a gold-capped nanowire array, to measure the biointeractions in microfluidic devices. The experimental results show that the proposed method obtained multiple detections with a detection limit of 1.04 × 10-5 refractive index units. Two types of analysis methods for SPR images are used to study the protein-antibody interactions. The region-of-interest analysis supports multiplexing detections in a compact microfluidic sensor. The effective pixel analysis eliminates low-response pixels and enhances the signal-to-noise ratios for sensitive label-free detection.

Confocal epifluorescence sensor with an arc-shaped aperture for slide-based PCR quantification.

The increasing needs of point-of-care diagnostics, quarantine of epidemic pathogens, and prevention of terrorism's bio-attacks have promised the future of portable real-time quantitative polymerase chain reaction (qPCR) sensors. This work aims at developing a highly sensitive and low-cost light emitting diode (LED)-based epifluorescence sensor module for qPCR sensor development and relevant bioassay applications. Inspired by the light stop design and dark-field detection of microscopes, this paper first reports a compact confocal LED epifluorescence sensor using a light stop with an arc-shaped aperture for enhancing the flexibility of quick DNA and PCR detection. The sensor features the advantages of the dichroic mirror-free and confocal (shared-focus) characteristics, which benefits size reduction and minimal optics used. It also allows extension to integrate with in situ real-time PCR thermal cycling since the sample slide is placed apart from the epi-sensing module. The epifluorescence sensor can detect as low as sub-ng/µL standard DNA and 101 copies of Salmonella typhimurium InvA gene sequences (cloned in E. coli and after 30-cycle PCR) with SYBR® Green I from non-purified culture samples, having highly sensitive and specific signal responses comparable with that of a commercial qPCR instrument.

Selection of aptamers for AMACR detection from DNA libraries with different primers.

In this work, we investigated aptamer selection against alpha-methylacyl-CoA racemase (AMACR) with three DNA libraries bearing different primers. Because of increased selection diversity, aptamers with varied structural properties, such as pre-folded, induced-folding, high and low primer-dependent conformations, were discovered. From the selection results, a dimeric aptamer was constructed and capable of detecting over-expression of AMACR in prostate cancer cell lines. In summary, this study demonstrates a library-based approach to obtain aptamers with different binding properties and provides distinct aptamers for flexible design of AMACR detection.

Phase 1 summary of plasma concentration-QTc analysis for idasanutlin, an MDM2 antagonist, in patients with advanced solid tumors and AML.

PURPOSE: Idasanutlin, a selective small-molecule MDM2 antagonist in phase 3 testing for refractory/relapsed AML, is a non-genotoxic oral p53 activator. The aim of this analysis is to examine the potential of idasanutlin to prolong the corrected QT (QTc) interval by evaluating the relationship between plasma idasanutlin concentration and QTc interval. METHOD: Intensive plasma concentration QTc interval data were collected at the same timepoints, from three idasanutlin (RO5503781) phase 1 studies in patients with solid tumors and AML. QTc data in absolute values and changes from baseline (Δ) were analyzed for a potential association with plasma idasanutlin concentrations with a linear mixed effect model. Categorical analysis was also performed. RESULTS: A total of 282 patients were exposed to idasanutlin and had at least one observation of QTc and idasanutlin plasma concentration. There was no apparent increase of QTcF or ΔQTcF in a wide idasanutlin plasma concentration range, even at concentrations exceeding the exposure matching the dose adopted in the ongoing phase 3 study (300-mg BID). Categorical analysis did not detect a potential signal of QT prolongation. CONCLUSION: The concentration-QTc analysis indicates that idasanutlin does not prolong the QT interval within the targeted concentration range currently in consideration for clinical development.

Effects of posaconazole (a strong CYP3A4 inhibitor), two new tablet formulations, and food on the pharmacokinetics of idasanutlin, an MDM2 antagonist, in patients with advanced solid tumors.

PURPOSE: Idasanutlin, a selective small-molecule MDM2 antagonist in phase 3 testing for refractory/relapsed AML, is a non-genotoxic oral p53 activator. To optimize its dosing conditions, a number of clinical pharmacology characteristics were examined in this multi-center trial in patients with advanced solid tumors. METHOD: This was an open-label, single-dose, crossover clinical pharmacology study investigating the effects of strong CYP3A4 inhibition with posaconazole (Part 1), two new oral formulations (Part 2), as well as high-energy/high-fat and low-energy/low-fat meals (Part 3) on the relative bioavailability of idasanutlin. After completing Part 1, 2, or 3, patients could have participated in an optional treatment with idasanutlin. Clinical endpoints were pharmacokinetics (PK), pharmacodynamics (PD) of MIC-1 elevation (Part 1 only), and safety/tolerability. RESULTS: The administration of posaconazole 400 mg BID × 7 days with idasanutlin 800 mg resulted in a slight decrease (7%) in Cmax and a modest increase (31%) in AUC for idasanutlin, a marked reduction in Cmax (~ 60%) and AUC0 (~ 50%) for M4 metabolite, and a minimal increase (~ 24%) in serum MIC-1 levels. Cmax and AUC were both 45% higher for the SDP formulation. While the low-fat meal caused a less than 20% increase in all PK exposure parameters with the 90% CI values just outside the upper end of the equivalence criteria (80-125%), the high-fat meal reached bioequivalence with dosing under fasting. CONCLUSION: In patients with solid tumors, multiple doses of posaconazole, a strong CYP3A4 inhibitor, minimally affected idasanutlin PK and PD without clinical significance. The SDP formulation improved rBA/exposures by ~ 50% without major food effect.

Signal-on Protein Detection via Dye Translocation between Aptamer and Quantum Dot.

A unique interaction between the cyanine dye and negatively charged quantum dot is used to construct a signal-on biaptameric quantum dot (QD) Förster resonance energy transfer (FRET) beacon for protein detection and distinct aptamer characterization. The beacon comprises a pair of aptamers, one intercalated with the cyanine dye (YOYO-3) and the other conjugated to a negatively charged, carboxyl-QD. When the target protein is present, structural folding and sandwich association of the two aptamers take place. As a consequence, YOYO-3 is displaced from the folded aptamer and transferred to the unblocked QD surface to yield a target concentration-dependent FRET signal. As a proof-of-principle, we demonstrate the detection of thrombin ranging from nanomolar to submicromolar concentrations and confirm the dye translocation using cylindrical illumination confocal spectroscopy (CICS). The proposed beacon provides a simple, rapid, signal-on FRET detection for protein as well as a potential platform for distinct aptamer screening.