Hebron University

About: Hebron University is a education organization based out in Hebron, Palestinian Territory. It is known for research contribution in the topics: Population & Cancer. The organization has 2714 authors who have published 4180 publications receiving 163736 citations.

Abstract 5588: A phase I, open label, dose escalation study of an oral mammalian target of rapamycin inhibitor INK128 administered once daily in patients with advanced malignancies

Abstract: Background: INK128 is an orally bioavailable potent and selective ATP site kinase inhibitor of mammalian target of rapamycin (mTOR) complexes TORC1 and TORC2 that play a crucial role in regulating tumor cell growth, metabolism, and motility. INK128 is structurally and mechanistically distinct from rapamycin and rapalogs. mTOR activity is frequently dysregulated in human cancer by constitutive mitogen stimuli or oncogenic mutations upstream of TORC1 and TORC2. TORC1/2 kinase inhibitors are a promising class of novel anti-cancer agents. Methods: Adult patients (pts) with histologically confirmed advanced solid tumors were enrolled in a typical 3+3 dose escalation Phase I study to determine the safety, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity. PD endpoints were evaluated in surrogate (peripheral blood cells [PBCs] and skin) and tumor tissues for the phosphorylation of TORC1-dependent markers (S6/4EBP1), and TORC2-dependent markers (AKT/PRAS40). Results: A total of 25 pts received daily (QD) doses of INK128 in 4 cohorts at 2 mg (n=3), 4 mg (n=7), 6 mg (n=7), and 7 mg (n=8). Dose-limiting toxicities (DLTs) were Grade (G) 3 hyperglycemia, G3 rash, and G4 anemia. The MTD was 6 mg QD with a DLT of G3 rash in 1 out of 6 pts. All AEs reported to date have been reversible. The most common (>20%, n=25) AEs considered possibly related to INK128 included hyperglycemia (88%), rash (52%), nausea (36%), pruritus (36%), diarrhea (32%), dysgeusia (32%), mucosal inflammation (32%), asthenia (24%), blood creatinine increased (24%), decreased appetite (24%), fatigue (24%), and vomiting (24%). The most common G ≥3 AEs (≥10%; n=25) considered possibly related to INK128 were rash (28%) and hyperglycemia (16%). Hyperglycemia was generally well controlled with metformin. INK128 was rapidly absorbed with Tmax of 1 to 4 h with high oral bioavailability. The mean elimination t1/2 ranged from 7 to 11 h and the mean steady-state plasma concentrations (Cmax, ss) ranged from 52 nM to 210 nM across 4 dose levels. Comparisons of plasma exposures (Cmax and AUC0-24 following oral doses suggest dose-linear plasma PK with limited inter-pt variability. PD biomarker measurements in PBCs, skin, and tumor showed dose-dependent TORC1/2 inhibition as evidenced by decreases in p4EBP1, pS6, and PRAS40. Preliminary anti-tumor activity was seen in 24% and 12% of pts experiencing stable disease for ≥4 and ≥6 cycles, respectively. Conclusions: INK128 dosed QD at its MTD of 6 mg has an acceptable tolerability and safety profile in pts with advanced malignancies. INK128 shows high oral bioavailability and dose-linear PK with exposures in the range of predicted biological activity. PD biomarker changes are consistent with inhibition of TORC1 and TORC2. Preliminary antitumor activity is encouraging in this ongoing study. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5588. doi:1538-7445.AM2012-5588

Phase I/II study of pilaralisib (SAR245408) in combination with trastuzumab or trastuzumab plus paclitaxel in trastuzumab-refractory HER2-positive metastatic breast cancer

Abstract: This phase I/II dose-escalation study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, and efficacy of the pan-class I phosphoinositide 3-kinase inhibitor pilaralisib in combination with trastuzumab (Arm 1) or trastuzumab plus paclitaxel (Arm 2) in patients with HER2-positive metastatic breast cancer. Patients had progressed on prior trastuzumab (Arms 1 and 2) and received prior taxane (Arm 2). The MTD of pilaralisib was determined using a 3 + 3 dose-escalation design (starting dose 200 mg once daily). Forty-two patients were enrolled (21 in each arm). Five patients had a dose-limiting toxicity (DLT; three in Arm 1 and two in Arm 2). Dose-limiting toxicities were rash (three patients) and neutropenia (two patients). The MTD of pilaralisib was determined at 400 mg once daily in both arms. The most frequently reported treatment-related adverse events (AEs) were diarrhea (23.8 % in Arm 1 vs. 66.7 % in Arm 2), fatigue (14.3 vs. 42.9 %), and rash (33.3 vs. 38.1 %). The most frequently reported treatment-related grade ≥3 AEs were erythematous rash (9.5 %) in Arm 1 and diarrhea, peripheral neuropathy, and neutropenia (14.3 % each) in Arm 2. Steady-state pilaralisib exposure was similar to previous studies with pilaralisib monotherapy. No responses occurred in Arm 1; four of 20 evaluable patients (20 %) in Arm 2 had a partial response. Observed PIK3CA mutations in cell-free circulating DNA did not correlate with response. Pilaralisib in combination with trastuzumab with or without paclitaxel had an acceptable safety profile in metastatic HER2-positive breast cancer, with clinical activity in the paclitaxel arm.

Psychiatric comorbidities in opioid-dependent patients undergoing a replacement therapy programme in Spain: The PROTEUS study

Abstract: Opioid-dependent patients show a high rate of psychiatric comorbidities. The prevalence and characteristics of patients with dual diagnosis have not been well established in Spanish opioid agonist treatment (OAT) programmes. Thus, 621 opioid-dependent patients enrolled in OAT programmes were assessed, using the EuropASI questionnaire, for psychiatric comorbidities, which were detected in 67% of patients (anxiety 53%, mood disorders 48%, sleep disorders 41%, substance-related disorders 36%). In addition, compared with patients without a dual diagnosis, patients with dual pathology were significantly older, used benzodiazepines and cannabis in significantly greater percentages, and showed significantly more frequent infectious and non-infectious comorbidities, worse overall working status, a lower proportion of drivers and higher levels of severity regarding medical, employment, alcohol, legal, family and psychological issues. Therefore, the data showed a very high prevalence of psychiatric comorbidity in opioid-dependent patients receiving OAT in Spain and several problems frequently associated with patients with dual diagnosis. Physicians treating opioid-dependent patients should be aware of these facts to correctly identify and manage patients with a dual diagnosis.