Avelumab or talazoparib in combination with binimetinib in metastatic pancreatic ductal adenocarcinoma: dose-finding results from phase Ib of the JAVELIN PARP MEKi trial.

BACKGROUND: Combinations of avelumab [anti-programmed death-ligand 1 (anti-PD-L1)] or talazoparib [poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor] with binimetinib (MEK inhibitor) were expected to result in additive or synergistic antitumor activity relative to each drug administered alone. Here, we report phase Ib results from JAVELIN PARP MEKi, which investigated avelumab or talazoparib combined with binimetinib in metastatic pancreatic ductal adenocarcinoma (mPDAC). PATIENTS AND METHODS: Patients with mPDAC that had progressed with prior treatment received avelumab 800 mg every 2 weeks plus binimetinib 45 mg or 30 mg two times daily (continuous), or talazoparib 0.75 mg daily plus binimetinib 45 mg or 30 mg two times daily (7 days on/7 days off). The primary endpoint was dose-limiting toxicity (DLT). RESULTS: A total of 22 patients received avelumab plus binimetinib 45 mg (n = 12) or 30 mg (n = 10). Among DLT-evaluable patients, DLT occurred in five of 11 patients (45.5%) at the 45-mg dose, necessitating de-escalation to 30 mg; DLT occurred in three of 10 patients (30.0%) at the 30-mg dose. Among patients treated at the 45-mg dose, one (8.3%) had a best overall response of partial response. Thirteen patients received talazoparib plus binimetinib 45 mg (n = 6) or 30 mg (n = 7). Among DLT-evaluable patients, DLT occurred in two of five patients (40.0%) at the 45-mg dose, necessitating de-escalation to 30 mg; DLT occurred in two of six patients (33.3%) at the 30-mg dose. No objective responses were observed. CONCLUSIONS: Combinations of avelumab or talazoparib plus binimetinib resulted in higher-than-expected DLT rates. However, most DLTs were single occurrences, and the overall safety profiles were generally consistent with those reported for the single agents. CLINICAL TRIAL REGISTRATION: ClinicalTrials.govNCT03637491; https://clinicaltrials.gov/ct2/show/NCT03637491.

Phase II study of treatment of advanced ovarian cancer with folate-receptor-targeted therapeutic (vintafolide) and companion SPECT-based imaging agent (99mTc-etarfolatide).

BACKGROUND: This report examines (99m)Tc-etarfolatide imaging to identify the presence of folate receptor (FR) on tumors of women with recurrent/refractory ovarian or endometrial cancer and correlates expression with response to FR-targeted therapy (vintafolide). PATIENTS AND METHODS: In this phase II, single-arm, multicenter study, patients with advanced ovarian cancer were imaged with (99m)Tc-etarfolatide before vintafolide treatment. Up to 10 target lesions (TLs) were selected based on Response Evaluation Criteria In Solid Tumors criteria using computed tomography scans. Single-photon emission computed tomography images of TLs were assessed for (99m)Tc-etarfolatide uptake as either FR positive or negative. Patients were categorized by percentage of TLs positive and grouped as FR(100%), FR(10%-90%), and FR(0%). Lesion and patient response were correlated with etarfolatide uptake. RESULTS: Forty-nine patients were enrolled; 43 were available for analysis. One hundred thirty-nine lesions were (99m)Tc-etarfolatide evaluable: 110 FR positive and 29 FR negative. Lesion disease control rate (DCR = stable or response) was observed in 56.4% of FR-positive lesions versus 20.7% of FR-negative lesions (P < 0.001). Patient DCR was 57%, 36%, and 33% in FR(100%), FR(10%-90%), and FR(0%) patients, respectively. Median overall survival was 14.6, 9.6, and 3.0 months in FR(100%), FR(10%-90%), and FR(0%) patients, respectively. CONCLUSIONS: Overall response to FR-targeted therapy and DCR correlate with FR positivity demonstrated by (99m)Tc-etarfolatide imaging. CLINICAL TRIAL NUMBER: NCT00507741.

Effect of cucurbitacins on bilirubin-albumin binding in human plasma.

The aim of this study is to investigate the effect of three cucurbitacins (Cuc) E, D and I on the bilirubin-albumin binding, both in human serum albumin (HSA) and in plasma. Bilirubin-HSA solution and plasma free of cucurbitacins were prepared as well as others containing serial concentrations of cucurbitacins. The concentration of unbound bilirubin was determined in bilirubin-HSA solution and the direct and total bilirubin concentrations were measured in plasma (with normal or elevated bilirubinemia) by Jendrassik and Grof method. In the conditions we adopted Cuc E and D (to a lesser extent), decreased the levels of unbound bilirubin in bilirubin-HSA solution and decreased direct bilirubin concentration and total bilirubin concentration in plasma in a dose-dependent manner while Cuc I had no effect. The effect of Cuc is related to the presence of native HSA. Thus, when albumin was absent or has been denatured by heating or by urea, Cuc E did not modify bilirubin levels, suggesting that the native structure of albumin is essential for such activity. The interaction of HSA with Cuc E was investigated by fluorescence spectroscopy. Cuc E increased the intrinsic fluorescence of the protein and the magnitude of fluorescence intensity of bilirubin-albumin complex. We concluded that Cuc E and D produced a rearrangement in the structure of albumin, particularly in the domain-II, resulting in an increase in the binding of bilirubin to albumin regardless to whether it's conjugated to glucuronic acid or unconjugated.

A model for double asymmetric induction in the stereocontrolled reduction of glycosyl alpha-ketoesters with oxazaborolidines.

Experimental diastereoselectivities for the stereocontrolled reduction of glycosyl alpha-ketoesters into the corresponding alpha-hydroxyesters have recently been reported with unexpected results. The process is catalyzed by a chiral oxazaborolidine derivative (the so-called CBS catalyst) and represents the key step in the synthesis of glycosyl alpha-amino acids synthons, a class of compounds that allow preparation of natural glycopeptides analogues exhibiting potential therapeutic relevance. Good to very good diastereomeric excesses have been obtained for a series of reactions with different glucidic derivatives, but surprisingly, the major product obtained does not correspond to that predicted by using Corey's model. In the present work, we carry out a theoretical investigation of these reactions at the density functional level. Separated effects from the catalyst and from the glucidic derivative have been computed to rationalize the observed diastereoselectivities and the double asymmetric induction.

Quantification of phthalocyanine concentration in rat tissue using laser-induced fluorescence spectroscopy.

Quantification of photosensitizer concentration in tissue should improve planning and outcome of photodynamic therapy. Laser-induced fluorescence (LIF) can be used to measure in vivo fluorescence of photosensitizers in tissue. This study was designed to determine if in vivo fluorescence intensity of chloroaluminum phthalocyanine tetrasulfonate correlates with its concentration in different rat tissues. Following LIF measurements, the animals were humanely euthanized and the concentration of phthalocyanine in different tissues was determined using chemical extraction technique. The correlation of phthalocyanine fluorescence intensity and its concentration was determined for each tissue using Pearson product-moment correlation analysis. A strong correlation between in vivo phthalocyanine fluorescence intensity and its concentration was found for spleen, kidney, liver, and chemically induced mammary adenocarcinoma. Low correlation was found for thigh skin and planum of nose. No correlation was found for thigh muscle and tongue.

Experimental allergic encephalomyelitis in mice: presence of myelin basic protein in cerebrospinal fluid.

The concentration of myelin basic protein (MBP) in cerebrospinal fluid (CSF) correlates with the development of experimental allergic encephalomyelitis following intradermal injection with encephalitogen in adjuvant; MBP is absent in controls inoculated with adjuvants only. The presence of MBP is a sensitive indicator of disease inasmuch as CNS-inoculated mice with neurologic signs had an average of 0.29 ng/microliter of MBP in their CSF and controls, including normal or adjuvants only, had an average of 0.03 ng/microliter. The amount present per microliter of CSF, as well as the absolute amount, obtained from an individual mouse do not always reflect the severity of disease as indicated by clinical signs and the pathology observed in a sampling of the neuraxis. The presence of MBP does correlate with demyelination, although the extent of pathology observed by light microscopy in the mouse model is minimal, associated only with the inflammatory response, and does not extend beyond the zone of the perivascular cuff.

Chronic Theiler's virus infection in mice: appearance of myelin basic protein in the cerebrospinal fluid and serum antibody directed against MBP.

Myelin basic protein (MBP) appears frequently in the cerebrospinal fluid (CSF) of mice with chronic demyelination following intracerebral infection with Theiler's murine encephalomyelitis virus (TMEV); antibody to MBP can frequently be found in the sera. The peaks of the immune responses to both MBP and TMEV coincide with the time course of the clinical signs of disease. Adsorption of mouse sera with TMEV or MBP indicate the non-identity of the antigens and the specificity of the antisera as measured by ELISA. Immunoblot analysis of sera confirmed the ELISA findings. The mechanism of induction of antibody directed against MBP and its role in TMEV-associated demyelination remain to be determined.