bluuebunny/crossref_metadata_2025_split huggingface dataset:
A randomized, double-blind study comparing corticorelin acetate with dexamethasone in patients with primary malignant glioma who require increased dexamethasone doses to control symptoms of peritumoral brain edema
Authors: Shapiro W. R. , Mechtler L. , Cher L. , Wheeler H. , Hines V. , Milsted R. , O'Connor P. C. , Ryan R. P. , Recht L. 
Published: August 2020

2080 Background: Corticorelin acetate (CrA) is a synthetic peptide of corticotropin-releasing factor, undergoing clinical trials as a treatment for peritumoral edema in patients with cerebral tumors. This study compared CrA therapy vs an increase in dexamethasone (dex) dose (+4 mg) for controlling symptoms in primary glioma patients with a subacute exacerbation. Methods: In addition to their prestudy dex dose, patients were randomized to receive CrA 1 mg bid SC or control (+4 mg dex PO) for 8 weeks. Patients were evaluated at baseline and during weeks 1 and 2 for their neurologic status, Karnofsky Performance Score (KPS), and continuing dex requirements. The primary endpoint was response, defined as no post-baseline increase in dex dose >4 mg for >1 day; stable or improved KPS; and ≥25% improvement in 10-item Neurological Examination Score during weeks 1 and 2. Dex therapy requirements were also evaluated. The study aimed to enroll 120 patients, but was terminated with only 37 patients (20 CrA, 17 control) due to slow recruitment. Results: Formal statistical analyses were not undertaken due to the small sample size. The treatment groups had similar demographic and baseline disease characteristics. Despite the small numbers, the data suggest that CrA treatment had similar efficacy to increased dex: (1) The proportions of responders were similar (CrA 3/20; control 3/17); (2) Comparable proportions of patients completed 8 weeks’ treatment (CrA 16/20; control 12/17); (3) After randomization of blinded study drug (CrA or dex 4 mg), dex dosing remained stable for most patients in each arm (CrA 12/20; control 11/17); (4) The mean daily dex dose was 3 mg in the CrA arm and 7 mg in the control arm. There was a lower incidence of cushingoid symptoms in the CrA arm (CrA 1/20, control 3/17). Patients in the CrA arm reported more injection site erythema and flushing vs. the control arm. CrA was well tolerated and no patient withdrew from the trial because of CrA side effects. Conclusions: CrA may be of value in managing patients with cerebral tumors who have subacute exacerbations of their symptoms, without needing to increase their dex dose. [Table: see text]
Effects of omeprazole on the pharmacokinetics and toxicities of irinotecan in cancer patients: A prospective open-label cross-over drug-interaction study
Authors: van der Bol J. M. , Verweij J. , de Jong F. A. , Loos W. J. , Lam M. H. , van Meerten E. , Mathijssen R. H. 
Published: August 2020

2502 Background: The proton pump inhibitor omeprazole (Losec) is one of the most extensively prescribed medications worldwide and within its class, omeprazole is most frequently associated with drug interactions. In vitro studies have shown that omeprazole can alter the function of metabolic enzymes and efflux transporters that are involved in the metabolism of irinotecan, such as UGT1A1, CYP3A, and ABCC2. In this open-label cross-over study we investigated the effects of omeprazole on the pharmacokinetics and toxicities of irinotecan. Methods: Fourteen patients were treated with one course (C1) of single agent irinotecan (600 mg i.v., 90 min) followed three weeks later by a second course (C2) with concurrent use of omeprazole 40 mg once daily, which was started 2 weeks prior to C2. Plasma samples were obtained up to 55 hours after infusion and analyzed for irinotecan, and its metabolites SN-38, SN-38 glucuronide (SN-38G), NPC, and APC by reversed-phase high-performance liquid chromatography with fluorescence detection. Non-compartmental modelling of pharmacokinetic data was performed with WinNonLin. Toxicities were monitored during both courses and graded according to the CTCAE criteria v3.0. Paired statistical tests were performed with SPSS. Results: The mean AUCs of irinotecan and all metabolites were not significantly different between both courses (p>.151; see table). In addition, no differences were seen in Cmax and clearance of irinotecan and all metabolites between C1 and C2 (p>.072). The nadir ANC and WBC and the percentage decrease in ANC and WBC from baseline were not different between both courses (p>.529). Neither were there significant differences in the severity of neutropenia, febrile neutropenia, diarrhea, nausea, and vomiting. Conclusions: Omeprazole 40 mg did not alter the pharmacokinetics and toxicities of irinotecan. This widely used drug can therefore be safely administered during a 3-weekly single agent irinotecan schedule. [Table: see text] No significant financial relationships to disclose.
Pharmacokinetic and pharmacogenetic study of S-1 in Korean patients with metastatic biliary cancer
Authors: Kim K. , Jang G. D. , Lim H. S. , Kim H. S. , Shin J. G. , Lee J. L. , Ryu M. H. , Chang H. M. , Kang Y. K. , Kim T. W. 
Published: August 2020

2505 Background: S-1 is an oral anticancer agent composed of tegafur (FT), CDHP, and oxonate. CYP2A6 is related to the biotransformation of FT to 5-FU. We evaluated associations of genetic variants of CYP2A6 with PK/PD of S-1 when combined with oxaliplatin in metastatic biliary cancer. Methods: This is a prospective study of patients with histologically confirmed metastatic adenocarcinoma of the biliary tract. S-1 was administered orally at a dose of 40 mg/m2 twice daily for 14 days followed by a 7-day rest period. For PK study, S-1 was given only once at day 1 of cycle 1. From day 2, it was administered twice daily. Oxaliplatin was administered intravenously at a dose of 130 mg/m2 for 2 hours every 3 weeks. CYP2A6 polymorphism (*1, *4, *7, *9 or *10) were genotyped. Results: A total of 49 patients were enrolled. Median age was 52 years (range 23–68) and male accounted for 63%. Thirty patients (61%) had intrahepatic cholangiocarcinoma and 10 (20%) gallbladder cancer. Response rate was observed in 24.5%. The median PFS and OS were 3.7 months and 8.7 months . Grade 3–4 adverse events include vomiting (22%), diarrhea (4%) and neutropenia (14%). The allele frequencies of CYP2A6*4, *7, *9 and *10 were 10.2%, 8.2%, 19.4%, and 4.1%, respectively. AUC0–24hr of 5-FU was 1030±617.3 hr*ng/mL (range 249.5–3969, CV: 59.9%). Log- transformed AUC0–24hr were significantly different for FT and 5-FU in the *1/*1 group; metabolic ratio (AUC0- 24hr of 5-FU/AUC0–24hr of FT) of the *1/*1 group was 1.85-times higher than the other group (90% CI 1.37–2.49). AUC0–24hr of CDHP was not significantly associated with CYP2A6 genotype. Despite differences in exposure, CYP2A6 genotypes were not significantly associated with diarrhea (P=0.0740), neutropenia (P=0.396) and clinical efficacy (response rate: P=0.583, PFS: P=0.916). Conclusions: CYP2A6 genotypes was associated with transformation of FT to 5-FU; however, this association did not translate into different clinical efficacy or toxicity. [Table: see text] No significant financial relationships to disclose.
Validation of toxicity burden score for use in phase I clinical trials
Authors: Lee S. M. , Hershman D. , Martin P. , Leonard J. , Cheung K. 
Published: August 2020

2514 Background: In phase I clinical trials, dose limiting toxicity (DLT) is defined as a binary outcome (DLT Yes/No). Concerns have been raised since this does not account for multiple non-DLTs that have a cumulative effect on drug tolerability and do not differentiate the severity of DLTs. Having a continuous toxicity burden score (TBS) as an outcome may provide more information regarding toxicity. We propose a new method for obtaining TBS. Methods: We illustrate the method using a phase I trial in lymphoma. The two main toxicities related to the experimental drug were low platelets and neuropathy with DLT defined as platelet count < 10,000/mm3 or grade 3 neuropathy. Three oncologists were asked to assign severity scores for the two main toxicities by assigning scores based on their impression of the impact of the toxicity on the patient and keeping in mind that DLT should be assigned a score of 1 and no toxicity should be assigned a score of 0. They were then given data from 25 patients along with their observed toxicities and the respective NCI toxicity grades and were asked to assign TBS to each patient. A mixed effects regression model was fit to the data. To validate the model, two of the oncologists assigned TBS to an additional list of 17 patients. Assuming the estimated TBS to be a rating, the three ratings (two oncologists and the estimated TBS) were compared using a mixed effects regression model. Results: The significant predictors of TBS are listed in the Table . Since no patient in the training data experienced grade 3 low- platelet and grade 4 neuropathy, model coefficients for these were not obtained. In the validation data, the TBS among the oncologists and the estimated TBS obtained using the fitted model were not different (P=0.18). Conclusions: A fitted model can be used to obtain TBS from maximal NCI toxicity grades suggesting the feasibility of using a continuous outcome such as TBS in dose finding studies. [Table: see text] No significant financial relationships to disclose.
Phase I trial of patupilone (P) and RAD001 in patients (pts) with advanced solid tumors
Authors: Stein M. N. , Knox B. , Wesolowsky E. , Levitt M. , Moss R. , Poplin E. , Mehnert J. , Gounder M. , Goodin S. , DiPaola R. 
Published: August 2020

2529 Background: P is an epothilone with activity in solid tumors including docetaxel (D) resistant prostate cancer. R is an oral mTOR inhibitor that demonstrates synergy with P in pre-clinical models, possibly by decreasing resistance to apoptosis. This on-going phase I study is assessing the tolerability of P in combination with R in pts with advanced solid tumors. Methods: Eligible patients with ECOG PS 0–2, adequate organ function and no more than 3 prior chemotherapy treatment received P every 21 days and weekly R using a standard 3+3 dose escalation schema in a 21 day(d) cycle starting at 50% of the phase II dose of P and 60% of the standard weekly dosing of R. Dosing levels are (1) P 5mg/m2 D1, R 30mg D1; (2) P 7.5mg/m2 D1, R 30mg D1 (3) P 7.5mg/m2 D1 R 30mg D1, D8 (3A) P 7.5mg/m2 D1 R 30mg D1, D8, D15 (3B) P 8mg/m2 D1 R 50mg D1, D8 (4) P 10 mg/m2 D1, D8 R 30mg D1, D8 (5) P 10 mg/m2 D1, D8 R 50mg D1, D8. Pharmacokinetic (PK) levels of R were obtained D1, D2 and PBMC were obtained to assess phospho-S6 and to assess markers of apoptosis and autophagy. Results: A total of 24 pts have been enrolled and 23 pts are evaluable for toxicity (tumor types: colon-7, prostate-6, lung-3, ampulla-3, leiomyosarcoma-2, cervical cancer-1). DLTs of grade(g) 3 diarrhea, g3 colitis and g3 fatigue were observed in dose levels 5, 4 and 1 pt in cohort 3A with a colostomy. Cohorts 1–3 were well tolerated with the common AEs of g1 diarrhea, g2 neuropathy after cycle 7, g1/g2 anemia, g1 triglycerides. In pts with prostate cancer (all previously pretreated with D) PSA declines of >50% occurred in 3/5 pts treated with >2 cycles; 1/7 pts with colon cancer had a PR and 3/7 pts with colon cancer had stable disease (SD) > 8 cycles; 1/3 pts with ampullary ca had a PR and a pt with cervical ca had SD x10 cycles. Conclusions: P 7.5mg/m2 and R 30mg D1, D8 is safe and well tolerated. Encouraging evidence of clinical activity is observed in prostate, colon and other tumor types. Enrollment to cohort 3A is ongoing. [Table: see text]
A phase I pharmacokinetic (PK) study of MBP-426, a novel liposome encapsulated oxaliplatin
Authors: Sankhala K. K. , Mita A. C. , Adinin R. , Wood L. , Beeram M. , Bullock S. , Yamagata N. , Matsuno K. , Fujisawa T. , Phan A. 
Published: August 2020

2535 Background: MBP-426 is a novel liposome encapsulated oxaliplatin (L-OHP) formulation bound to human transferrin, developed to improve the safety and efficacy of L -OHP through the prolongation of circulation time and by targeting transferrin receptors on tumor cells. In vitro, MBP-426 is effective against various human cancer cell lines. This study assessed the toxicity and safety of intravenously (IV) administered MBP-426, including defining the maximally tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics (PKs). Methods: Patients (pts) with advanced/ metastatic solid tumors refractory to conventional therapy received MBP-426 as 2–4 hrs IV infusion every 3 weeks in cohorts of 3 to 6 pts. Enrollment required age > 18 yrs, ECOG Performance Status 0–2 and adequate organ functions. Tumor response was assessed by RECIST. Plasma was sampled for PK. Results: 39 pts were dosed, median age 59 (range 27–79), 25 (64%) male. The common tumor types were colorectal 23 (60%), pancreas 3 (8%), and neuroendocrine 3 (8%). Most pts were heavily pretreated with chemotherapy or chemoradiation. 77% pts had received oxaliplatin or cisplatin. Eleven dose levels ranging from 6 to 400 mg/m2 were evaluated. At 400 mg/m2, 2/3 pts had DLT as grade 4 thrombocytopenia and prolonged thrombocytopenia (1 pt each). The recommended phase II dose is 226 mg/m2 where 1/6 pts had grade 4 thrombocytopenia. Grade 3–4 toxicities included fatigue (3 pts), hypercholesterolemia (3 pts), anemia (2 pts) and constipation (1 pt). Common grade 1–2 toxicities were nausea and/or vomiting (59%), fatigue (43%), infusion reaction (15%), thrombocytopenia (15%), anemia (13%) and peripheral neuropathy (13%). 15 pts had stable disease after 2 cycles. 3 pts with colon carcinoma refractory to conventional oxaliplatin had stable disease for 4, 5 and 6 cycles respectively, one of them had 25% decrease in target lesions. PKs of MBP-426 were dose-proportional. Main PK parameters at 226 mg/m2 were AUC 2141+419 μg.hr/ml, and t½ 89+92 hr, comparing favorably with intact L-OHP. Conclusions: MBP-426 has a favorable safety profile with thrombocytopenia as main DLT. The PK target concentration of L-OHP was exceeded at higher doses. Based on PK and toxicity profiles, the recommended dose is 226 mg/m2. [Table: see text]
A phase I trial of sns-314, a novel and selective pan-aurora kinase inhibitor, in advanced solid tumor patients
Authors: Robert F. , Verschraegen C. , Hurwitz H. , Uronis H. , Advani R. , Chen A. , Taverna P. , Wollman M. , Fox J. , Michelson G. 
Published: August 2020

2536 Background: Aurora Kinases are a family of serine/threonine kinases (Aurora Kinases (AK) A, B, and C) critical for mitosis. Elevated AKs expression occurs in a high percentage of melanoma, colon, breast, ovarian, gastric, and pancreatic tumors; in a subset of these tumors the AURKA locus (20q13) is amplified. SNS-314 is a selective pan-AK inhibitor with low nanomolar IC50s. Methods: Study design is 3+3 phase 1 dose escalation by modified Fibonacci. Patients (pts) with advanced solid tumors received SNS-314 by 3 hour infusion qweek X 3 (28 day cycle). Primary endpoints: safety, tolerability, and DLT assessment. Secondary endpoints: MTD, pharmacokinetics (PK), pharmacodynamics, and antitumor activity. Pharmacodynamic endpoint was inhibition of Histone H3 phosphorylation (pHH3) evaluated by immunohistochemistry of skin punch biopsies taken pre- and 2 hours post-infusion. Results: Thirty-two pts (16M/16F; median age = 58.5 years) were enrolled into 8 cohorts: dose range 30–1800 mg/m2. Median cycles received =2. SNS-314 was generally well tolerated with Grade 1–2 toxicities ≥ 15% incidence: nausea (31%), fatigue (28%), vomiting, constipation, and pain (16% each), and no Grade 3+ toxicities of ≥ 15% incidence. A DLT of Grade 3 neutropenia preventing administration of all 3 doses was observed at 1440 mg/m2. Plasma PK were dose proportional for exposure with no accumulation of SNS-314 following weekly administration. Clearance was moderate (5.65 L/hr/m2, CV 39.4%); Vss approximated total body water (21.5 L/m2, CV 78.1%); terminal half-life was 10.4 hours (CV 66.8%). Six patients had stable disease as their best response. Inhibition of pHH3 by SNS-314 was observed in skin biopsies of patients treated at doses of 240 mg/m2 and greater. Conclusions: SNS-314 is a novel inhibitor of AKs A, B, and C. The compound has been generally well tolerated; MTD was not established. No objective responses were observed. Pharmacodynamic activity was demonstrated by inhibition of pHH3. [Table: see text]
A phase I dose escalation safety and pharmacokinetic (PK) study of SSR244738 administered as a one-hour intravenous (IV) infusion twice-weekly during a 3-week cycle in patients (pts) with refractory solid tumors
Authors: Isambert N. , Spitaleri G. , Fumoleau P. , Noberasco C. , Ramazeilles C. , Chadjaa M. , Bolloni L. , De Braud F. 
Published: August 2020

2539 Background: SSR244738 is a new cytotoxic agent (G2-cell cycle inhibitor). In this first in man study the original schedule of administration was an IV infusion once every 3 weeks (Q3W); and due to the high clearance variability, 1300 mg/m2 was considered the maximum administered dose (MAD). The study was amended to test the twice weekly schedule (D1-D4-D8-D11-D15, every 3 weeks). Methods: Standard escalation was used in cohorts of 3–6 pts. PK profiles (up to T48h or T96h) were obtained in each pt after the 1st and the 5th administration (D1 and D15) of Cycle 1. In the Q3W, there was a trend to lower clearance (CL) in CYP2C9 *3/*3 and *1/*3 genotype pts therefore genotype samples were analyzed at baseline to identify poor metabolizers (PM) and adjust-dosing accordingly. Results: 22 heavily pretreated patients received SSR244738 at doses of 200 (3 pts), 280 (4 pts), 400 (3 pts), 560 (3 pts), 780 (3 pt), 1000 (6 pts; one pt was a PM and received 500 mg/m2). 15 females, 7 males, median age: 60 years (29–82), ECOG: (0:12, 1:9, Unk:1). Main tumor types: ovary, lung, breast, colon and prostate. Nb cycles/pts: > 2 cycles/21 (95%), > 4 cycles/9 (41%), > 6 cycles/6 (27%), > 8 cycles/2 (9%). The most common reason for treatment discontinuation was disease progression. DLT was seen in 2 pts at 1000 mg/m2 dose level: one patient had febrile neutropenia associated with Grade 3 mucositis and the second patient had Grade 3 neutropenia, which caused a treatment delay. Both pts showed high SSR244738 plasma exposures on D15. SD was reported in 11 patients. No CRs or PRs were observed. SSR244738 exhibited an overall low plasma CL (mean [range]: 0.9 [0.3–2.1] L/h). CL slightly decreased with repeated administration. The distribution volume was low [Vss mean (CV%): 11.6 L (30%)] and the terminal half life was long [mean (CV%): 15.6 h (58%)]. No deviation from dose proportionality could be observed, despite the moderate-to-high inter-individual variability (CV<64%) in exposure. Conclusions: SSR244738 is well tolerated with PK profile similar to the Q3W schedule; by changing the schedule of administration we were able to reach the MAD dose (5000 mg/m2/cycle). [Table: see text]
Influence of food on the pharmacokinetics (PK) of panobinostat (LBH589), an orally active histone deacetylase inhibitor, in patients with advanced cancer
Authors: Lewis L. , Frank R. , Dandamudi U. B. , Gallagher J. , Zhao L. , Woo M. , Hirawat S. , Shapiro G. I. 
Published: August 2020

2550 Background: The effect of food on the bioavailability and PK of panobinostat (PAN) are of considerable importance in allowing appropriate dosing of chronic oral cancer therapy. Methods: Patients (pts) with advanced cancer received 20 mg PAN twice a week of a 21-day cycle and were randomized to receive 1 of 6 treatment sequences where PAN PK was evaluated weekly under fasting, high fat and normal breakfast. Serial blood samples were collected for PAN PK evaluations on Days 1, 8, and 15. Plasma PAN concentrations were measured by LC-MS-MS. PK parameters were estimated by using non-compartmental analysis. Results: A total of 34 patients were evaluated. PAN was generally well tolerated with no significant lab, ECG, or other safety concerns. No residual PAN concentrations were detected in pre-dose samples on Days 8 and 15. Meal conditions and PAN PK parameters expressed as either mean (CV%) or median [range] or ratio are described in the Table . The overall exposure and inter-patient variability (CV 59%) remained unchanged with or without food, whereas Cmax was transiently reduced (<45%) by food. Although tumor response was not the main objective, a pt with recurrent RCC, following sunitinib and sorafenib treatment, has achieved a PR after ∼6 cycles of PAN and is continued on study. Conclusions: Since the overall extent of absorption and variability was not changed due to food, PAN administration with or without food is unlikely to significantly impact systemic PAN exposure in cancer patients. PAN can be administered without regards to food in future studies. [Table: see text] [Table: see text]
A single-dose, placebo- and moxifloxacin-controlled 3-period study of the effects of temsirolimus on cardiac repolarization in healthy subjects
Authors: Hug B. , Boni J. , Leister C. , Burns J. , Sonnichsen D. 
Published: August 2020

2551 Background: Temsirolimus (CCI-779) is a novel selective inhibitor of the mammalian target of rapamycin (mTOR) approved by the US FDA for the treatment of patients with advanced renal cell carcinoma. This study was designed to assess the effect of a single dose of 25 mg IV temsirolimus on the corrected QT interval (QTc) in healthy subjects. Methods: Fifty-eight (58) healthy subjects were enrolled in this 3-period crossover study. In periods 1 and 2, subjects were administered IV placebo either alone or with open-label oral moxifloxacin. In period 3, subjects were administered 25 mg IV temsirolimus. Serial ECGs were digitally captured in triplicate and manually over read by a central vendor. The primary statistical objective was to estimate the effect of temsirolimus compared with placebo on change from time-matched baseline QTc at the end of infusion (0.5 hour time point). Secondary endpoints and objectives included estimates of effect at 12 additional time points, population PKPD analyses, and categorical summaries of interval data. Assay sensitivity was evaluated by the effect of moxifloxacin on change from time-matched baseline QTc as compared with placebo. Results: Temsirolimus had no effect on the QTc interval in the primary analysis. At 11 of 12 secondary time points, the upper bound for the temsirolimus QTc 90% CIs for the time-matched change from baseline difference from placebo was less than 10 msec without evidence of QTc trends or relationship to temsirolimus or sirolimus whole blood concentrations. Mean concentrations were comparable to those observed in patients with renal cell carcinoma following administration of 25 mg IV temsirolimus. Moxifloxacin produced a statistically significant increase in the QTc interval as compared with placebo. No relevant PKPD relationship was seen using linear or Emax models. No subject in this study had a QTc interval exceeding 450 msec and no subjects had a change from baseline >30 msec. Conclusions: We conclude that therapeutic exposures of temsirolimus are not associated with changes in QTc interval that reach the level of regulatory significance, according to ICH E14 guidance. The findings are consistent with the lack of QTc interval prolongation observed in studies of cancer patients. [Table: see text]