bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical pharmacokinetics of erlotinib (E) in glioblastoma multiforme (GBM) patients and its implication for dosing
Authors: Lu J. , Eppler S. , Ling J. , Prados M. , Klencke B. , Lum B. 
Published: March 2020

2010 Background: E is an orally active, highly potent and selective inhibitor of the epidermal growth factor receptor (EGFR). Preliminary results from both Phase I and Phase II trials of E in GBM patients have been reported (ASCO 2003, Abs#394 and ASCO 2004, Abs#1555). The purpose of this analysis is to characterize E PK in this patient population when administered with or without CYP3A4 enzyme inducing anti-epileptic drugs (EIAEDs) and to identify a dose to provide equivalent exposure during concomitant therapy in GBM patients. Methods: Intensive PK data were collected in the Phase I study and plasma trough concentration data were collected in the Phase II study at steady-state. A total of 775 E concentrations from 107 patients were available for the analysis. A population PK approach (NONMEM) was used to characterize the clinical PK in this patient population and the effect of EIAEDs on the PK of E. Results: Co-administration of EIAEDs was shown to increase the E clearance (CL/F) by 230% in GBM patients. This effect is similar to that seen in a previous drug-drug interaction study with a CYP3A4 enzyme inducer (rifampicin) in healthy volunteers. For patients with no EIAEDs, population estimates and the %CV of inter-individual variance for CL/F and Vc/F of erlotinib were 5.63 L/hr (44%) and 388 L (40%), respectively. Conclusions: Based on the modeling results, for GBM patients with EIAEDs, an estimate of erlotinib dose of 500 mg/d is needed to achieve an equivalent exposure as patients who receive the dose of 150 mg/d with no EIAEDs. The new population PK model provides an operational tool to predict E exposure during treatment, and simulate alternative dosing regimens for GBM patients. [Table: see text]
Identification of genes involved in endometrial cancer etiopathogenesis by the mean of MacroArray technique
Authors: Kubiatowski T. , Rózynska K. , Futyma K. , Smolen A. , Tarkowski R. , Staroslawska E. , Kotarski J. , Wojcierowski J. 
Published: March 2020

20102 Endometrial cancer is one of the most common neoplasms of reproductive system. According to data accumulated in last decades it has been concluded that microsatellite instability and PTEN, K-ras, β-catenin gene mutations are crucial for endometrial cancer etiopathogenesis. Moreover, it is well known that all genes encoded proteins involved in cell cycle regulation, cell differentiation or surrounding tissues infiltration contribute to tumor and metastases development. It has been stressed that different factors such as VEGF, which play a key role in neoplastic angiogenesis are also very important for tumor growth. Complexity of molecular mechanisms leading to endometrial cancer development implies that only experiments utilizing array technique can collect enough data to understand all relationships between different molecular pathways during tumor development and to identify new clinically usable markers of neoplasm. Using MacroArray technique we analyzed expression profile of neoplastic tissue derived from 40 patients diagnosed with endometrial cancer. After data collection all genes present on chip were assigned to different groups according to their role in oncogenesis and artificial neuronal network analysis were performed in order to individuate genes those expression was significantly different in neoplastic tissue regarding to controls. Such procedure allowed us to give shape to preliminary gene expression profile typical for neoplastic tissue and to estimate protein expression of the most significant predictors of neoplastic transformation. Comparison of obtained data with tumor grade can reveal new markers of endometrial cancer useful in routine diagnostic procedures. No significant financial relationships to disclose.
An analysis and epidemiologic study on new cancer patients admitted to our department between 1999–2003
Authors: Dernek B. O. , Akboru M. H. , Yoney A. , Altin S. , Unsal M. 
Published: March 2020

20108 Background: Cancer is one of the most important health problems existing 10.1 millions of new patients and 6.2 millions dead in 2000. 15 millions of new patients will be supposed to be seen in 2020. Method: In this study; between 1999–2003, 41,564 new patients diagnosed as cancer admitted to our center were analyzed. International Classification Disease of Oncology (ICD-O) was used to classify the patients. Basal cell carcinoma and epidermoid carcinoma of the skin were not included. Rest of 41116 patients were reviewed according to their age, sex, diagnosis and coming region. Results: 55.6% of the patients were male. Top five location of the disease can be listed as follows: respiratory system (25.6%), gastrointestinal system (19.2%), breast (15.1%), genitourinary system (11.3%) and lymphoma (4.7%). Analysis according to gender is illustrated in Table . Most cases have come from Marmara Region. While peak incidence was detected between 60–69 years of age in males, it was 50–59 years of age in females. Least comings were seen below 20 years of ages in both sexes. Conclusions: Admission to our department increases gradually while it was 7,020 patients in 1999, it reached to 10,035 person in 2003. General population and population insured by Social Insurance Institution are mostly living in Marmara Region (48.16% of the population are insured by this institution and 41.72% of them reside in Marmara Region). Our department was unique active center in Social Insurance Institution’s order at that time. According to SEER (U.S. Surveillance Epidemiology and EndResults) data in United States (US); although prostate cancer is mostly seen cancer (15%) and lung cancer is recorded in just 13% of cases it is the leading data in our study (22.4%) and prostate cancer is only seen 3.8% of cases. This difference can be explained by effective screening programs in US and prostatic cancer patients mostly prefer to apply the Urology Department in our country. Smoking and environmental conditions may be the reason of high incidence in lung cancer. [Table: see text] No significant financial relationships to disclose.
BRCA mutations: An Appalachian experience
Authors: Mirza M. A. , Sehbai A. , Nestor T. , Brown V. , Abraham J. 
Published: March 2020

20111 Background: BRCA1 and 2 mutations are rare in general population and women with these mutations confer a significantly increased risk of invasive breast and ovarian cancer (65% to 85%, and 15% to 65% cumulative lifetime risk, respectively). A few of these are variant mutations also known as Variant of unknown significance (VUS). Methods: Observational study of 155 patients who presented to MBRCC, WVU for genetic counseling between November 2001 and March 2005. Patients underwent genetic testing after detailed genetic counseling. Clinical data, such as patient’s age, ethnic origin, follow up period, Myriad risk of mutation, clinical outcome i.e., Mastectomy versus Bilateral Salpingo-oophorectomy versus Surveillance, total numbers of patients screened, tested and reason for not testing, and other data, were available for statistical analysis. Results: In out patient population who underwent genetic counseling, 46% (71 out of 155) underwent genetic testing. A large number of patients (54%; 84 out of 155) who underwent genetic counseling could not undergo the genetic testing. Total number of patients not genetically tested were 84, out of which, 27 were low risk, 35 had insurance denial, 7 were not interested, 14 were awaiting results or insurance approval and 1 was deceased. 27 out of 71 patients (38%) who underwent genetic testing were positive for a mutation. Among these patients (n = 27), 8 had BRCA 1; 3 had BRCA1 VUS; 7 had BRCA 2 and 9 had BRCA2 VUS. The average age for patients who had a genetic mutation was 42 years. The most prevalent genetic mutation in our study population was BRCA2 VUS (33%; 9 out of 27) followed by BRCA 1 mutation (29%; 8 out of 27). 11 out of 27 (40%) who had a mutation underwent mastectomy. 13 out of 27 patients (48%) who had a mutation underwent bilateral salpingo-oophorectomy. 7 out of 27 patients (26%) who had a mutation underwent total abdominal hysterectomy. 4 out of 27 patients (15%) who had a germline mutation were lost to followup. Conclusion: We report the prevalence and the clinical outcomes in patients with BRCA mutations in the state of West Virginia, which is comparable to the national database. High number of patients could not undergo genetic testing because of insurance denial. No significant financial relationships to disclose.
Epidemiologic characteristics of colon cancer in Asian Indian and Pakistani population living in the USA compared to US White population in SEER database from 1988 to 2002
Authors: Sehbai A. S. , Hossain A. , Kurian S. , Abraham J. 
Published: March 2020

20112 Background: About 1.5% of the US population is South East Asian in origin and it is one of the rapidly growing groups. Colon cancer is the second most common in male and third most common cancer in females in Asian Indian and Pakistani population living in the USA. This is the first study examining the epidemiologic characteristics of colon cancer in this group. Methods: SEER cancer incidence public use database have reported cancer incidence in 13 SEER registries from 1973 to 2002. Since 1988, Indian/Pakistani populations were reported separately under race and ethnicity. Frequency sessions were performed and descriptive parameters were calculated regarding age, sex, stage, grade, tumor location and diagnostic methods used. Results: A total of 4,229 cases of cancer were reported from 1988 to 2002 in this group and 352 (9%) were colon cancers. The reported incidence of colon cancer in SEER database is increasing (11 in 1988 vs. 53 in 2002). Table shows the comparative studies of different variables of colon cancer between Indian/Pakistani and US White population reported in SEER database. Conclusions: Our study shows that the incidence of colon cancer in Asian Indian and Pakistani population under age 50 is substantially higher than the US White population and the predilection is towards the male sex. Our results suggest that this ethnic group warrants close screening and risk factor stratification for earlier detection of colon cancer as well as awareness and counseling in high-risk families. [Table: see text] No significant financial relationships to disclose.
Final results of a phase I and pharmacokinetic study of STEALTH liposomal CKD-602 (S-CKD602) in patients with advanced solid tumors
Authors: Zamboni W. C. , Friedland D. M. , Ramalingam S. , Edwards R. P. , Stoller R. G. , Belani C. P. , Strychor S. , Ou Y. C. , Tonda M. E. , Ramanathan R. K. 
Published: March 2020

2013 Background: S-CKD602 is a pegylated STEALTH liposomal formulation of CKD-602, a semi-synthetic analogue of camptothecin (CPT) and topoisomerase I inhibitor. Preclinical studies have shown that prolonged exposure to CPT achieves the greatest antitumor activity. STEALTH liposomes prolong the circulation time in plasma, achieve high and extended drug exposure in tumor, and provide a convenient dosing schedule. Methods: Patients (pts) were administered S-CKD602 IV over 1 h once every 3 wks. Modified Fibonacci escalation was used (3–6 pts/cohort), and dose levels ranged from 0.1–2.5 mg/m2. Serial plasma samples were obtained prior to administration to 96 h after administration, and on days 8 and 15 of cycle 1. Plasma samples were processed to measure concentrations of encapsulated (E), released (R), and sum total (E+R) CKD602 total (lactone + hydroxyl acid) by LC-MS/MS. Area under the plasma conc versus time curve (AUC0-∞) and t1/2 were estimated. Results: 45 pts (21 male) have been treated: median age 62 y (range: 33–79 y); ECOG status: 0 and 1 (43 pts), 2 (2 pts). The majority of reported adverse events were grade (G) 1 and 2. Frequent nonhematological toxicities were asthenia, nausea, diarrhea, vomiting, and anorexia. Dose-limiting toxicities of G3 mucositis occurred in 1/6 pts at 0.3 mg/m2, G3/4 bone marrow suppression in 2/3 pts at 2.5 mg/m2, and G3 febrile neutropenia in 1/6 pts at 2.1 mg/m2. The maximum tolerated dose was 2.1 mg/m2. Stable disease for ≥ 6 cycles occurred in 5 pts (hepatocellular carcinoma (CA), thyroid, prostate, 2 pts sarcoma). Partial responses occurred in 2 pts with ovarian CA (1.7 and 2.1 mg/m2). At 2.1 mg/m2, the mean ± SD AUC and t1/2 of sum total S-CKD602 were 44 ± 33 μg/mL·h and 18 ± 8 h, respectively. In all plasma samples, >90% of drug was encapsulated. Conclusions: S-CKD602 represents a promising new STEALTH liposomal CPT agent with manageable toxicity and promising antitumor activity. Phase II studies of S-CKD602 at 2.1 mg/m2 IV once every 3 wks are planned. Prolonged plasma exposure over 1 to 2 wks is consistent with STEALTH liposomes and provides extended exposure compared with non-liposomal CPT. (Supported by ALZA and NIH/NCCR/GCRC #5M01 RR 00056). [Table: see text]
Phase I and pharmacokinetics (PK) study of sequential paclitaxel and trabectedin every 2 weeks in patients with advanced solid tumors
Authors: Papadopoulos K. P. , Chu Q. , Patnaik A. , Mita M. M. , Cooper J. , Van Maanen R. , Lopez-Lazaro L. , Lebedinsky C. , Rowinsky E. K. , Tolcher A. W. 
Published: March 2020

2029 Background: Trabectedin (ET-743) is a DNA minor-groove intercalating agent that blocks transcription factor activity, elicits G2/M cell cycle arrest, and induces apoptosis. Single agent activity has been demonstrated in soft tissue sarcoma (STS), breast, prostate and ovarian cancer. In preclinical studies sequential exposure of paclitaxel (P) followed by trabectedin (T) 24 hrs later resulted in synergy. The objectives of this phase I study were to determine the maximum tolerated dose (MTD) and recommended phase II dose (RD) of sequential P and T administered every 2 weeks in patients with advanced solid tumors. Methods: Escalating doses of P (80–120 mg/m2) over 1hr iv on day 1 and T ( 525–775 μg/m2) as 3 hrs iv day 2 every 2 weeks were administered. To evaluate drug:drug interactions, P was administered alone on day -7 in course 1 and PK studies performed courses 1 & 2. MTD was defined as ≥ 2/3 pts with dose limiting toxicity (DLT) in the 1st 2 courses. Results: 29 pts were enrolled and 27 were evaluable: median age was 48 yrs (19–82). M/F 16/13. Pts were treated over 5 dose levels: I 80/525 (n = 3), II 80/580 (n = 3), III 120/580 (n = 6), IV 120/650 (n = 11), V 120/775 (n = 4). A total of 213 courses of therapy were given, median number of course was 4 (range 1–28). There were 4 DLTs due to neutropenia delaying therapy > 1 week; one each at 120/580 (Grade 2) and 120/650 (Grade 4) and 2 at the MTD of 120/775 (Grade 4). Most common toxicities observed for P+T were neutropenia (24%), nausea (51%), vomiting (24%), transaminitis (23%), myalgia (24%) and alopecia (20%). One pt with PNET has an ongoing CR 16 months, one breast cancer pt (prior P failure) has PR 12 mo+ and 8 pts (6 STS) had SD > 3 mo (range 4–15 mo). There appear to be no marked drug:drug interactions for P and T. Preliminary non-compartmental PK results [geometric mean (CV%)] for T include t1/2 52.4 hr (43.6%); Cl l/hr/m2 31.6 (57.3%); Vss l/m2 1382 (69%) and for P are t1/2, 29.2 hr (39.1%); Cl l/hr/m2 15.3 (44.1%); Vss 213 l/m2 (72%). Conclusions: The recommended dose for this combination is paclitaxel 120 mg/m2 day 1 and trabectedin 650 μg/m2 day 2 administered every 2 weeks. Antitumor activity in STS and breast cancer, predictable PK parameters, and tolerable toxicity warrants further study of this combination. [Table: see text]
A dose-escalating and pharmacologic study of bortezomib in adult cancer patients with impaired renal function
Authors: Mulkerin D. , Remick S. , Ramanathan R. , Hamilton A. , Takimoto C. , Davies A. , Ivy P. , Karol M. , Kolesar J. , Wright J. 
Published: March 2020

2032 Background: Bortezomib is a highly selective and reversible inhibitor of the proteasome with activity in multiple myeloma and other malignancies. Patients (pts) with renal impairment have been treated in previous trials, but there has not been a systematic investigation into the effects of renal dysfunction on dosing. Study objectives were to characterize the pharmacokinetic (PK) and pharmacodynamic (PD) profile of bortezomib, and to determine the maximum tolerated dose (MTD) in adults with advanced malignancy and renal insufficiency ranging in severity from mild to dialysis dependence. Methods: Fifty-one pts have received intravenous bortezomib at 0.7 mg/m2 up to the approved dose of 1.3 mg/m2 on days 1,4, 8, and 11 every 3 weeks. Pts were stratified by 24-hour creatinine clearance (CrCL) normalized to a body surface area of 1.73 m2 into five cohorts per the table . Doses were escalated in cohorts of three pts in groups B-E. Blood samples were assayed for bortezomib concentration, as well as the PD endpoint of 20S inhibition. Results: Escalation of bortezomib doses to 1.3 mg/m2 was well tolerated in all groups with CrCL ≥ 20 mL/min/1.73 m2. There has been only one instance of dose limiting toxicity (group C at 1.3 mg/m2) which did not prevent successful completion of this cohort. No patients discontinued therapy due to renal deterioration. Doses of 0.7 mg/m2 were tolerable in Group D patients (CrCL< 20 mL/min/1.73 m2 ). Five dialysis pts have been treated; 3 at 0.7 mg/m2, and 2 at 1.0 mg/m2. All tolerated therapy well, and accrual to Groups D and E continues. PK and PD assays are underway and the analysis will be reported in full. Conclusions: This study is the first comprehensive evaluation of bortezomib in pts with various degrees of renal insufficiency including dialysis dependence. Bortezemib at the approved dose of 1.3 mg/m2 on this schedule is well tolerated by pts with CrCL ≥ 20 mL/min/1.73 m2. Results of this trial will allow for dosing recommendations for bortezomib use in pts with renal insufficiency. [Table: see text] [Table: see text]
Final results from a phase I trial of ixabepilone in patients with advanced malignancies and lymphoma
Authors: Aghajanian C. , O’Connor O. , Cohen M. , Peck R. , Burris H. 
Published: March 2020

2039 Background: Ixabepilone is the first analog in a new class of antineoplastic agents, the epothilones, which stabilizes microtubules and induces apoptosis. Ixabepilone has shown clinical activity in a broad range of tumors. Methods: This Phase I trial was designed to establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), efficacy, safety, pharmacokinetics and pharmacodynamics of ixabepilone when administered as a 1-hour infusion every 3 weeks to patients with advanced solid tumors or lymphoma. Eligible patients were aged ≥18 years with histologically/cytologically confirmed non-hematologic cancer, or a pathologic diagnosis of relapsed/primary refractory non-Hodgkin’s lymphoma (NHL) or relapsed/primary refractory mantle cell lymphoma, with ≤CTC Grade 1 neuropathy. Ixabepilone doses ranged from 7.5–65 mg/m2. Response was assessed every 6 weeks using RECIST. DLT was defined as Grade 4 neutropenia and/or febrile neutropenia, thrombocytopenia, ≥Grade 3 nausea/vomiting and non-hematologic toxicity, or treatment delay of >2 weeks due to delayed recovery. Results: Of 61 patients (median age 58, range 18–81), 75% had solid tumors; 25% had lymphoma. 98% and 67% of patients had received one or ≥ two prior chemotherapy regimens, respectively. The MTD of ixabepilone as a 1-hour infusion every 3 weeks was established as 50 mg/m2. The most common DLTs were neutropenia, myalgia, arthralgia and stomatitis/pharyngitis. A total of eight patients (13%) achieved a durable objective response. Complete responses were achieved in two patients with primary peritoneal cancer and NHL. A partial response was seen in six patients. The most common Grade 3/4 treatment-related adverse events (only observed at doses ≥40 mg/m2) were sensory neuropathy (13%), fatigue (13%), myalgia (10%), arthralgia (7%), nausea (5%), febrile neutropenia (5%) and neutropenia (5%). Recovery to baseline or ≤Grade 1 neuropathy occurred in some patients. Conclusions: The recommended dose of ixabepilone for the initiation of Phase II studies based on this study is 50 mg/m2 over 1 hour every 3 weeks. Ixabepilone demonstrates promising safety in patients with solid tumors or lymphoma who have failed standard therapy. Encouraging activity was reported in several tumor types. [Table: see text]
Ixabepilone given weekly in patients with advanced malignancies: Final efficacy and safety results of a phase I trial
Authors: Dickson N. , Peck R. , Wu C. , Burris H. 
Published: March 2020

2040 Background: Ixabepilone is a potent tubulin-targeting agent. The first epothilone analog, ixabepilone, has been developed to optimize the characteristics of the naturally occurring epothilone B. Methods: This open-label, single-arm Phase I dose escalation study was designed to establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety and a recommended dose of ixabepilone when administered as a weekly infusion to patients (pts) with solid tumors who had failed standard therapy. Eligible pts were aged ≥18 years and had histologically/cytologically confirmed solid tumor disease and an ECOG status of 0–2. Ixabepilone was administered weekly as a 30-minute infusion on a 21-day schedule. Due to neurotoxicity, infusion time was increased to 1 hour with a 1-week break allowed. Dosing ranged from 1–30 mg/m2. Tumor evaluations were performed every 6 or 8 weeks (21-day or 28-day schedule, respectively). Toxicity was evaluated continuously. Results: 34 pts were treated on the 21-day schedule (median age 55, range 30–73) and 52 on the 28-day schedule (median age 55, range 33–79). 88% of pts had received prior chemotherapy. Grade 3 fatigue was the DLT in 2 of the 4 pts treated with 30 mg/m2 ixabepilone. No DLTs were seen at doses ≤25 mg/m2 on the 21-day schedule, or at doses of 15, 20 or 25 mg/m2 on the 28-day schedule. The MTD was 25 mg/m2 for the 21-day schedule. Of 12 pts who received this dose and schedule, 7 (58%) experienced Grade 1/2 neuropathy, 1 (8%) developed Grade 3 sensory neuropathy and 3 (25%) experienced Grade 3 fatigue. Of 52 pts who received 20 mg/m2 on the 28-day schedule, 2 (13%) had Grade 3 neutropenia, 1 (7%) had Grade 3/4 sensory neuropathy and 4 (27%) had Grade 3 fatigue. Five pts (two pts [21-day schedule], three pts [28-day schedule]) with breast, colon, ovary, head and neck tumors achieved objective partial responses. Conclusions: The recommended doses of ixabepilone from this study are 25 mg/m2 (30-minute weekly infusion, 21-day schedule) and 20 mg/m2 (1-hour weekly infusion, 28-day schedule). Ixabepilone demonstrated efficacy and an acceptable safety profile in pts with a broad range of tumor types, several of whom had failed a taxane. [Table: see text]