bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II study of hydroxyurea for unresectable meningioma (Southwest Oncology Group S9811)
Authors: Swinnen L. J. , Rankin C. , Rushing E. J. , Laura H. F. , Damek D. M. , Barger G. R. 
Published: August 2020

2063 Background: Meningiomas account for 15%-18% of CNS tumors. Although benign, recurrence is seen in 16%-39% of cases, depending on the extent of resection possible. Tumor location may make further resection hazardous. Chronic hydroxyurea (HU) was reported to produce well documented objective responses in a small series of patients, with gradual regression occurring over 6–10 months. Induction of apoptosis was furthermore demonstrated with HU in primary benign meningioma explant cultures. The S9811 phase II trial was undertaken to estimate the objective response rate, if any, of unresectable benign meningioma to this HU regimen. Methods: Eligibility required unresectable, measurable, residual or recurrent, histologically-proven benign meningioma. Progressive tumor or progressive neurologic deficit was required. No prior cytotoxics, no radiation therapy for >1 year. Age > 18, adequate hematologic reserve, PS 0–2. HU 20 mg/kg/day po was given for up to 2 years if there was no progressive disease. Single-stage accrual of 38 pts would have allowed detection of 5% null hypothesis response probability vs. 20% with 90% power; the 28 pts actually accrued provide 81% power. Results: Between November 98 and June 2005, 29 pts were accrued, with study closure due to slow accrual. 1 ineligible. Response assessment showed CR+PR 0% (95% CI 0–12%); SD 71% (95% CI 51–87%); PD 21% (95% CI 8–41%); undetermined 7%. Median PFS was 27 months. (95% CI 12–29 months.); 3-year PFS 43% (95% CI 25–61%). Median OS has not been reached. Seven patients were removed from study for toxicity (5/7 hematological). Toxicity was mainly hematologic: 11/28 (39%) grade 3, 2/28 (11%) grade 4. Grade 3 non-hematologic toxicity was seen in 7/28 (25%). Conclusions: Chronic HU therapy for unresectable benign meningioma resulted in an estimated objective response rate of < 12%. Whether the stable disease rate seen differs in any way from what can be expected from the natural history of meningioma cannot be determined from this phase II study design. No significant financial relationships to disclose.
Short-course irradiation as adjuvant treatment of surgically resected single brain metastases
Authors: Alrefae M. A. , Roberge D. , Souhami L. 
Published: August 2020

2067 Background: Surgical resection followed by whole-brain irradiation is a standard treatment approach for patients with a single brain metastasis from solid tumours. As short-course hypofractionated irradiation has proven equivalent to more protracted schedules for the palliative treatment of brain metastasis, it has been commonly applied in the adjuvant setting. Methods: By reviewing our pathology database, we identified patients having undergone complete neurosurgical resection of a single brain metastasis followed by short-course (4–6 fractions) whole-brain irradiation. Irradiation was delivered using standard lateral-opposed megavoltage radiation portals. Local failure and new brain metastases were identified by chart and imaging study reviews. All outcomes were calculated actuarially. Results: Between March 2000 and August 2005, 50 patients received short-course whole-brain irradiation (20 Gy in 5 fractions in 41 of 50 cases) following complete surgical resection of a single brain metastasis. The most common primary malignancies were lung (66%), breast (14%), and cancer of unknown primary origin (10%). Median age was 60 years. Imaging studies were available for all patients and a preoperative MRI was reviewed in 94% of cases. Median follow-up for living patients was 30.0 months. The median overall survival was 10.92 months (29% at 2 years). Following radiation, failure at the surgical site was seen in 51% and 79% of patients at 1 and 2 years. New metastases elsewhere in the brain developed in 26% and 53% of these patients at 1 and 2 years. Conclusions: When calculated actuarially, local failure and new brain metastases were common following surgery and short-course whole-brain radiation therapy. In part, this may represent inefficacy of the short hypofractionated radiation scheme. Further investigation into the local and systemic treatment of these patients is warranted. No significant financial relationships to disclose.
A retrospective survival analysis of whole brain radiotherapy (WBRT) for brain metastases at Mount Vernon Cancer Centre (MVCC)
Authors: Mulholland P. J. , Assoku M. , Sasieni P. 
Published: August 2020

2068 Background: The primary purpose of this retrospective study was to determine the survival of patients with brain metastases following WBRT with regards to the influence of tumor type, age < 65 versus ≥ 65 (RPA RTOG prognostic factor) and recency of treatment date. Methods: From treatment records we identified 1,926 patients with brain metastases from solid tumors who were treated with WBRT at MVCC between February 1992 and March 2008. Dates of death were sourced from records at MVCC, the Cancer Registry and GP practices. Results: We obtained dates of death for patients with lung (n=804), breast (n=457), colorectal (n=129), skin (n=119), kidney (n=82), and unknown primary (n=124) cancers. 42 patients were excluded from analysis as their tumor types were unspecified. A heterogeneous group of 169 patients with a variety of other primary tumor types were also excluded from our primary analyses. 22% of the patients died within the first month following WBRT and only 2.4% remained alive at 2 years. Log-rank analysis of age < 65 versus ≥ 65 demonstrated improved survival for the former for the colorectal, lung, and skin tumor types (p = 0.0048, 0.0001, and 0.0456 respectively). This relationship did not reach significance for the breast, unknown primary, and renal cancer groups (p = 0.14, 0.13, and 0.06 respectively). With the exception of colorectal cancer, the analysis of the effect of treatment date on survival did not reveal recent improvements in survival for patients with brain metastases. An improvement in survival was experienced by the colorectal subgroup treated after March 2006 (HR= 0.51 95% CI 0.27- 0.96). Conclusions: Our data validate age as an important prognostic factor for many tumor types with notable exceptions for as yet undetermined reasons. Metastasis to the brain is a late stage feature of colorectal malignancy. The survival of the majority of patients undergoing WBRT for brain metastases is poor and with the possible exception of colorectal cancer, has not improved over the last decade. [Table: see text] [Table: see text]
A comprehensive view of the structure and expression of the ependymoma genome at presentation and relapse
Authors: Wright K. D. , Rand V. , Leary S. E. , Mack S. , Coyle B. , Gillespie Y. , Allen J. , Taylor M. D. , Grundy R. , Gilbertson R. J. 
Published: August 2020

2073 Background: Although pediatric and adult ependymomas are associated with significant mortality and morbidity, little is known about the biology of these tumors. To identify underlying genetic alterations and cellular pathways that drive this disease, we conducted a genomic study of 200 adult and pediatric ependymomas. Methods: Using 500k single nucleotide polymorphism arrays, U133 Affymetrix gene and microRNA (miRNA) expression microarrays, and appropriate bioinformatics, we characterized 56 supratentorial (ST), 104 posterior fossa (PF), and 40 spinal (SP) ependymomas. Real-Time polymerase chain reaction and fluorescence in situ hybridization validated observed genetic events. Results: Gene expression profiles segregated tumors by site and identified disease subgroups within each anatomical region (4 ST, 4 PF, 1 SP). miRNA expression profiles identified these same subgroups, indicating that they are biologically distinct. Subgroup-specific gene expression profiles were dictated partly by developmental regulatory genes and partly by large chromosomal gains (eg. 1q, 5p, 16p) and losses (eg. 9p, 22q). Integrated genetic and expression mapping revealed key candidate tumor suppressor (TSG) and onco- genes, likely drivers of these large alterations. While large chromosomal changes occurred more frequently in SP tumors (p < 0.0001), ST tumors averaged more focal changes (n = 13.2) than PF (n = 6.2) or SP tumors (n = 3.0) (p < 0.0001). A total of 29 and 33 non-random focal amplifications and deletions, respectively, encompassing 402 known genes and miRNA clusters, were validated, of which 80 displayed copy number driven expression. These genetic alterations targeted specific cellular functions (e.g., cell adhesion, cell-cycle, neuronal development) and pathways (e.g., NOTCH, EPHRIN, TP53). Our cohort also included five sample sets consisting of primary tumor and at least two corresponding relapses. Genomic analysis of these tumors identified large chromosomal alterations as well as focal gains and losses associated with disease relapse. Conclusions: We present a highly comprehensive view of the ependymoma genome, including 80 previously unrecognized candidate TSG and oncogenes that may afford diagnostic and therapeutic targets. No significant financial relationships to disclose.
Scoring systems predictive of survival and local control of patients irradiated for brain metastases
Authors: Dziggel L. , Veninga T. , Haatanen T. , Lohynska R. , Schild S. E. , Schild S. E. , Rades D. 
Published: August 2020

2075 Background: This study was performed to create and validate scoring systems to estimate survival and intracerebral local control at 6 months of patients irradiated for brain metastases. Methods: Data of 1,797 patients irradiated for brain metastases (1,346 whole-brain radiotherapy [WBRT], 131 radiosurgery [RS], 61 WBRT + RS, 259 resection + WBRT) were retrospectively analyzed. Patients were randomly assigned to the test group (N = 1,198) or the validation group (N = 599). In the test group, multivariate analyses (MVA, Cox proportional hazards model) were performed for survival (OS) and local control (LC). Based on the MVA results, two scoring systems were developed, one for OS and another for LC. The scores included the prognostic factors found significant on MVA. Age, performance status, extracranial metastases, interval from tumor diagnosis to RT, and number of brain metastases were significant for OS. Tumor type, performance status, interval from tumor diagnosis to RT, and number of brain metastases were significant for LC. The score for each factor was determined by dividing the 6-month OS or LC rate (%) by 10. The total score represented the sum of the scores for each factor. For OS, total scores ranged from 15–30 points, and patients were divided into three groups (15–19, 20–25, and 26–30 points). For LC, total scores ranged from 14–27 points, and patients were divided into three groups (14–18, 19–23, and 24–27 points). Results: In the test group, the 6-month OS rates were 9 ± 1% for patients with scores of 15–19 points, 41 ± 2% for those with 20–25 points, and 78 ± 2% for those with 26–30 points (p < 0.0001). The corresponding OS rates in the validation group were 7 ± 2%, 39 ± 3%, and 79 ± 3%, respectively (p < 0.0001).In the test group, the 6-month LC rates were 17 ± 3% for patients with 14–18 points, 49 ± 3% for those with 19–23 points, and 77 ± 2% for those with 24–27 points (p < 0.0001). The corresponding LC rates in the validation group were 19 ± 4%, 52 ± 4%, and 77 ± 3%, respectively (p < 0.0001). Conclusions: Patients irradiated for brain metastases can be grouped with these scores to estimate OS and LC. The OS and LC rates of the validation group were almost identical to the test group, which demonstrates the high validity and reproducibility of both scores. No significant financial relationships to disclose.
A drug interaction study between ketoconazole and panobinostat (LBH589), an orally active histone deacetylase inhibitor, in patients with advanced cancer
Authors: DeJonge M. , Woo M. M. , Van der Biessen D. , Hamberg P. , Sharma S. , Chen L. C. , Myke N. , Zhao L. , Hirawat S. , Verweij J. 
Published: August 2020

2501 Background: The effects of ketoconazole (keto), a potent CYP3A inhibitor, on the pharmacokinetics (PK) of panobinostat (PAN) were investigated in an open-label, multicenter, cross-over, single sequence study. Methods: Patients (pts) with advanced solid tumors or NHL received single-agent PAN at 20 mg on Day 1 and single-agent keto at 400 mg daily on Days 5–9. On Day 8, PAN 20 mg was administered 1 hour after keto. All pts had adequate organ function and ECOG performance status <2. Serial plasma samples were collected for PAN PK evaluations on Days 1 and 8 and pre- and post-dose keto samples on Days 5, 8, and 9. Plasma PAN and keto concentrations were measured by LC-MS-MS. PK parameters were estimated by using non-compartmental analysis. Genotyping analysis of CYP3A4*1B, CYP3A5*2, *3, *6 and *7 were performed by using AmpliChip CYP450. Results: Fourteen Caucasian patients (9M, 5F) were enrolled with a median age of 59. Fourteen pts had homozygous wide-type CYP3A4*1A genotype, 11 pts had homozygous CYP3A5*3, and three pts had heterozygous CYP3A5*1/*3 genotype. No residual PAN concentrations were detected in pre-dose samples on Day 8. PAN PK parameters were calculated as either mean (CV%), median [range] or ratio (see Table). Single-dose PAN did not affect keto concentrations. Co-administration of keto and PAN increased PAN Cmax and AUC by 1.6- and 1.7-fold, respectively, but with no change in Tmax. There was no apparent difference in PAN PK between pts who carried CYP3A5*1 allele and homozygous CYP3A5*3 carriers. Conclusions: The less than 2-fold increase in PAN AUC upon co-administration suggests that CYP3A contribution to the total clearance of PAN is low. The observed interaction is not considered clinically relevant, as PAN doses are at least 2-fold greater than 20 mg (40 and 60 mg) have been safely administered in pts. CYP3A4 inhibitors should have no major impact on the exposure of PAN and may be co-administered when medically necessary. [Table: see text] [Table: see text]
Population pharmacokinetics of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone in cancer patients
Authors: Kolesar J. , Brundage R. , Pomplun M. , Jiang Z. , Schelman W. , Alberti D. , Holen K. , Traynor A. , Ivy P. , Wilding G. 
Published: August 2020

2508 Background: 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3AP) is an inhibitor of ribonucletoide reductatse with activity in hematological malignancies as well as melanoma and prostate cancer. This study describes the population PK of 3AP and the relationship between 3AP disposition and patient covariates. Methods: 40 pts with advanced cancer from two phase 1 studies were included in the PK model building. Pts received 3AP 25–105 mg/m2 IV on day 1. 3AP plasma and erythrocyte levels were sampled at 10 timepoints over a 24-hour period and measured by a validated HPLC method. Data were analyzed by a nonlinear mixed- effects modeling approach with NONMEM system Version V. Xpose10 and S-PLUS were used for goodness-of-fit assessment and model evaluation to obtain clearance (CL), volume of distribution (V) for compartment (C) 1, plasma (V1); V for C2, erythrocytes (V2); and V for C3 (V3). 15 covariates were evaluated, including: weight, BSA, gender, PS, age, ABCB1[C1236T, G2667T, C3436T] genotypes, toxicity, concurrent chemotherapy [irinotecan, doxorubicin], response and number of cycles administered. Normal renal and hepatic function were required for study entry and were not included as covariates. Response was assessed after 2 cycles of therapy. Results: 3AP PK were described as a 3-compartment model with first-order elimination. Estimated paramaters were: V1 =5.68 L/m2 (95%CI 4.3–7.1); V2=18.9 L/m2 (95%CI 14.6–23.2); V3= 40.0 L/m2 (95%CI 23.8–55.4); CL 25.4 L/hr/m2 (95%CI 22.4–28.4). Gender was associated with V; women had a lower V2 (p<0.05). This may be related to a lower hemoglobin in women. The number of cycles administered was associated with decreased CL; those with decreased CL received less than 2 cycles before going off study. Conclusions: Women had a lower V2 than men and pts with decreased CL received less than 2 cycles of therapy, suggesting PK may be helpful in individualizing dosing. ABCB1 genotypes and concurrent irinotecan or doxorubicin do not influence 3AP disposition. Supported by: U01CA062491 “Early Clinical Trials of Anti-Cancer Agents with Phase I Emphasis” NCI; CTEP TRI Funding 24XS090, and 1ULRR025011 Clinical and Translational Science Award of the National Center for Research Resources, NIH. No significant financial relationships to disclose.
Unplanned hospital admissions as an early surrogate indicator of patient (pt) attrition in phase I trials
Authors: Tan D. S. , Brunetto A. T. , Ang J. , Olmos D. , Barriuso J. , Frentzas S. , Arkenau H. , Yap T. A. , de Bono J. S. , Kaye S. B. 
Published: August 2020

2516 Background: We have previously reported a high Royal Marsden Hospital (RMH) prognostic score (RPS) of 2- 3 predicts 90-day mortality and reduced overall survival (Arkenau et al BJC & EJC 2008). In this study, we explored the significance of unplanned hospital admissions (UHA) as a potential surrogate indicator of poor clinical outcome. Methods: All pts admitted to RMH Phase I Unit, UK, during 2-month intervals over 3 consecutive years were included in this analysis (2005–2007). We collated pt baseline characteristics, demographic and laboratory profiles, reasons for hospital admissions and relevant clinical trial data. Results: A total of 172 pts accounting for 310 admissions were seen on the Phase I unit during the stipulated time periods (amounting to 6 months in total). Median age: 61 years (range: 19–84); male to female admissions ratio 1.3:1. Pts were on trials of single-agent targeted therapies (69%), cytotoxic combinations (26%), vaccine/viruses (3%) and hormonal modulation (2%). Reasons for planned admissions (n=246) included treatment commencement, PK/PD sampling, paired pre/post treatment biopsies and insertion of central lines. 20.6% (64/310) of overall admissions were unplanned: 50 (78%) were due to disease-associated symptoms/complications and 14 (22%) treatment-related toxicities (TRT). 71% of pts with TRT were on cytotoxic combination trials. Median duration of UHA was 2 days (range:1–20) and there was no relation between length of stay and predicted outcome. 78% of pts in the UHA cohort had a high RPS of 2–3 (i.e. poor outcome) vs 43% in patients whose admission was planned (p=0.001). Of pts who required UHA, only 27% resumed their trial drug after recovery. The main statistically significant risk factors for UHA include >2 metastatic sites, (RR 2.6 [1.64 - 4.38], p=0.001), poor performance status (RR 2.47 [1.48 - 3.72] p=0.003), low albumin (RR 2.17 [1.36 - 3.52] p=0.001) and cytotoxic combination trials (RR 1.7 [1.09 - 2.86] p=0.025). Conclusions: Unplanned admissions constitute 20.6% of Phase I inpatients, with the majority being disease rather than treatment-related. Regardless of length of stay, UHA portend poor outcomes for patients who are on treatment, with a risk profile underscoring the importance of pt and trial selection. No significant financial relationships to disclose.
Determinants of accrual period of time in dose escalating phase I trials
Authors: Dansin E. , Bonneterre J. , Adenis A. , Clisant S. , Ferté C. , Penel N. 
Published: August 2020

2518 Background: New drug development is a time- and resource-consuming process. Phase 1 trials constitute a major key- step of this development. Shortening the accrual time may improve this process. Methods: 292 published phase-1-trials were retrospectively reviewed to establish the determinants of accrual period of time (APT) using Log-rank test and then Cox Model. Results: Out of 292 trials (1997–2008), only 107 reports (36%) described the accrual time (median: 20 months, 5–72). Phase-2- recommended dose was established in 87 studies (81%). Most of studies investigated regimens included cytotoxic drugs (77%) or molecular targeted therapies (29%). Most of parameters did not significantly affect the APT: nature and number of investigated drugs, duration of treatment cycle, phase 1 dedicated to specific tumoral subtypes, number of centers, method of drug escalation (classical 3+3 vs. accelerated titration design), type of dose increment (modified Fibonacci method vs. others) and presence of expanded cohort at the phase-II-recommended dose. Under univariate analysis, two parameters shortened the APT: studies conducted in USA vs. other place (19 vs. 21 months, p=0.03) and regimen with more than 2 dose-escalated drugs (13 vs. 21 months, p=0.003). One parameter was significantly associated with longer APT: starting dose justified by animal toxicology data (first-in-man studies) vs. previous clinical trials (22 vs. 19 months, p=0.03). Cox model analysis retained only one determinant: starting dose justified by animal toxicology data: HR=4.07 [1.45- 11.42], p=0.047. Conclusions: Few parameters influence the APT in the dose-escalation phase-1 setting. Real first-in-man phase 1 studies based on starting dose estimated from animal toxicological data require longer APT. [Table: see text]
Analysis of phase I pharmacokinetic studies with targeted molecules based on gender and age
Authors: Di Segni S. , Sperduti I. , Cinquina A. , Contestabile M. , Nuvoli B. , Giannarelli D. , Cognetti F. , Gelibter A. J. 
Published: August 2020

2521 Background: Pharmacokinetic parameters are usually not sufficiently correlated with patient characteristics, such as age, gender, or excretory organ function, and with outcome measures. Female sex has been shown to be a risk factor for clinically relevant adverse drug reactions and acting as a predictive/prognostic factor. Methods: We analyzed Phase I/II oncology trials of solid tumors with targeted agents enrolling Male and Female population (age>18yrs), reporting pharmacokinetic analysis, published between 2000 and 2007. We excluded trials involving Radiation therapy alone, Hematological malignancies, and trials of Gender related pathology (ovarian, prostate and breast cancer). Standard descriptive statistics was used. Results: 160 phase I and II trials involving 48 targeted agents has been selected. 44%, 37% and 19% of the population enrolled for PK analysis is respectively male, female or unknown gender. 65% of the trials have male preponderance. Authors did not specified number of male and female if only a group of patients enrolled in the trial was submitted to pharmacokinetic analysis. 95% of the trials enrolled patients > 65years, while 16% of the trials enrolled patients >80years. But only 3% of studies specified individual patient age and less than 6% of papers showed the number of male and female for each dose level, while about 10% of studies considered ethnicity as a characteristic. Conclusions: What emerged from our analysis is the irregularity and the lack of important informations when reported for publication. Knowing the impact of important prognostic/predictive factor of such clinical parameter (age, gender) we believe that more informations should be reported in the trials in order to evaluate if Toxicity and Efficacy could be gender or age related. Definitive data will be presented at the meeting. No significant financial relationships to disclose.