bluuebunny/crossref_metadata_2025 huggingface dataset:
MGMT methylation status as a prognostic factor in anaplastic astrocytomas
Authors: Tosoni A. , Franceschi E. , Ermani M. , Bacci A. , Volpin L. , Lombardo L. , Ravenna G. , Pinna G. , Poggi R. , Brandes A. A.
Published: August 2020

2052

Background: MGMT methylation status has been found to be an important prognostic factor in glioblastoma patients (pts). However, further data on the epigenetic feature are needed before its role in rare diseases such as anaplastic astrocytomas (AA) can be established. Methods: A retrospective analysis was made on a database of 139 AA pts followed prospectively from January 1995 and August 2008. We evaluated only pts who met the following inclusion criteria: age >18 years; PS 0–2; histological diagnosis of AA; postoperative radiotherapy (RT) and chemotherapy (CT). MGMT status was determined with methylation specific PCR. The study aim was to evaluate the role of MGMT methylation status in AA. The log-rank test was employed to evaluate the significance of the prognostic variables. Results: 80 pts (m/f: 46/34, median age: 41 years, range: 18–71 years) were enrolled. MGMT was assessable in 71 of 80 pts (88.8%), being methylated in 30 (42.9%), and unmethylated in 41 (57.7%) pts. Median PFS was 48.6 months (95% CI: 33.7 - 63.5), being 96 months (95% CI: 29–163) and 38 months (95%CI: 18.9–57.2) in MGMT methylated and unmethylated pts, respectively (p = 0.09). At univariate analysis, complete resection (p = 0.02), age (p = 0.002), and KPS (p = 0.003) were significantly correlated with PFS. At multivariate analysis only age remains correlated with PFS (p = 0.01). Median survival (OS) was 93.7 months (95% CI: 63.5–123.8), being not reached and 77 months (95% CI: 20–134.2), in MGMT methylated and unmethylated pts, respectively (p = 0.03). MGMT methylation (p = 0.03), age (p = 0.0003), and KPS (p = 0.03) were significantly correlated with OS at univariate analysis. At multivariate analysis, age (p = 0.0002) and MGMT methylation (p = 0.01) were correlated with a better OS. Conclusions: MGMT methylation status is an independent prognostic factor together with age in AA. This datum should provide the background to improve the therapeutic index with temozolomide concurrent with and adjuvant to RT in AA.

No significant financial relationships to disclose.
Neurocognitive function in patients with glioblastoma multiforme in first or second relapse treated with bevacizumab in the BRAIN study
Authors: Wefel J. S. , Cloughesy T. , Zazzali J. , Yi J. , Friedman H. S.
Published: August 2020

2056

Background: Patients with glioblastoma multiforme (GBM) suffer from neurocognitive decline due to both the disease and its treatment. We analyzed neurocognitive function of patients with recurrent GBM who participated in the BRAIN study, a phase II, multicenter, randomized, noncomparative clinical trial which assessed the efficacy and safety of bevacizumab alone or in combination with irinotecan. Methods: Eighty-five patients who participated in the bevacizumab-only group of the BRAIN study were assessed with the Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test parts A (TMTA) and B (TMTB), and the Controlled Oral Word Association (COWA) test. Assessments were conducted at baseline and then every 6 weeks while patients remained on study drug, up to 52 weeks. Change in neurocognitive function from baseline to Week 6 was categorized as improved, stable, or declined, using the reliable change index. Changes were confirmed at the next assessment, when available. Results were not adjusted for practice effects. Results: Between 93 and 98% of patients completed each test at baseline and 73–78% completed each test at both baseline and Week 6. The majority of patients demonstrated stable performance on each test at Week 6, relative to baseline. With the exception of the COWA test, 18–25% of patients demonstrated improved performance on one or more tests at Week 6. Conclusions: Preliminary results suggest that the majority of patients with recurrent GBM who were treated with bevacizumab alone in the BRAIN study demonstrated stable or improved neurocognitive function during the first 6 weeks of treatment. Changes across tasks and associations with measures of clinical efficacy, patient characteristics, and concomitant medications will be explored.

[Table: see text]

[Table: see text]
Correlation of serum urokinase plasminogen activator (uPA) to progression of recurrent malignant glioma during bevacizumab treatment: A marker of invasive phenotype and a candidate to monitor therapy
Authors: Chinot O. L. , Boudouresque F. , Bequet C. , Barrie M. , Thiebaut A. , Matta M. , Autran D. , Ouafik L.
Published: August 2020

2059

Background: Identification of circulating markers that predict tumor response or reflect progression is of crucial importance when using antiangiogenic agents. However, to date, no such parameters have been identified particularly for bevacizumab, for which, recently, increasing data have supported a role in patient with recurrent malignant glioma. Methods: Serial serum levels of VEGF, VEGFR2, FGF, SDFα, urokinase plasminogen activator (uPA), plasminogen activator inhibitor type I (PAI-1), and metalloprotesase type 9 (MMP9) were determined in a cohort of 32 patients treated with bevacizumab and irinotecan for recurrent malignant glioma. Samples were collected at the start of treatment and then at 4 weeks intervals until progression. Serum levels were measured using an enzyme-linked immunosorbent assay. Progression was defined by MacDonald's criteria, modified by integrating increase of infiltration as measured on MRI by Flair sequence. All subjects were followed for PFS and OS. Cox model analysis is used for correlation between markers and clinical outcome. Results: This preliminary analysis is restricted to pre-treatment (D0; n = 32), day 30 (D30; n = 27), and at progression time (DP; n = 15). None of the pretreatment serum level (n = 32) significantly affect PFS or OS although uPA and MMP9 tend to influence OS. Decrease of median level of all serum markers except PAI1 and VEGFR2 is observed from D0 to D30 under bevacizumab therapy, but only uPA and FGF variations tend to impact clinical outcome. From D30 to DP, increase of uPA is correlated to PFS (p = 0.028) while the observed increased of FGF and SDFα fail to reach significant correlation to PFS and OS. Conclusions: Increase of uPA serum level appear to be correlated to disease progression for patients with recurrent malignant glioma treated with bevacizumab and may reflect the invasive phenotype of glioma progression. Serum uPA may help in assessing treatment response under bevacizumab and warrant further studies.

No significant financial relationships to disclose.
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.
Adjustment of creatinine (Cr) to avoid severe thrombocytopenia of carboplatin (C) plus gemcitabine (G) in non-small cell lung cancer (NSCLC)
Authors: Horiike A. , Miyauchi E. , Motokawa I. , Kudo K. , Ohyanagi F. , Mun M. , Sakao Y. , Okumura S. , Nakagawa K. , Horai T. , Nishio M.
Published: August 2020

2525

Background: Carboplatin plus gemcitabine (CG) is a standard regimen for advanced NSCLC. Although the dose of C is calculated from Cr clearance (CCr) by Calvert‘s formula, severe thrombocytopenia sometimes occurs in the CG regimen. Severe thrombocytopenia might arise from differences in the methods of measuring Cr values. We have used two different techniques, the Jaffé method and the enzymatic method. When the enzymatic method was used, CCr overestimated the glomerular filtration rate and the dose of C calculated by Calvert‘s formula leads to overdosing. The aim of this study was to clarify whether severe thrombocytopenia could be avoided by adjusting the CCr in the CG regimen when Cr is measured by the enzymatic method. Methods: All patients (pts) were treated with CG (C, AUC = 5 on day 1; G, 1,000 mg/m2 on days 1 and 8) every 3 weeks for 4 cycles. Serum Cr values were measured by the enzymatic method and CCr was estimated by the Cockcroft-Gault formula in all patients. In the non-adjusted group, the dose of C was calculated by Calvert‘s formula with no adjustment of CCr. In the adjusted group, the dose of C was calculated by Calvert‘s formula, adjusting Cr as follows: (serum Cr +0.2). We compared the correlations between Cr values and the nadir of thrombocytes, and the frequencies of severe thrombocytopenia in both groups. Results: 32 pts and 28 pts were enrolled in the non-adjusted and the adjusted groups, respectively. Grade 3/4 thrombocytopenia was observed in 19 pts (60%) and these pts had low levels of serum Cr values. On the other hand, significantly fewer cases of grade 3/4 thrombocytopenia were observed in the adjusted group (8 pts; 29%, p < 0.0001). In addition, there was a significant correlation between Cr values and the nadir of thrombocytes in the non-adjusted group (R= 0.442, p= 0.0105), but no significant correlation was observed in the adjusted group (R= -0.196, p= 0.3212). These results suggest that adjustment of CCr can reduce the variable nadir of thrombocytes in the CG regimen when Cr is measured by the enzymatic method. Conclusions: If Cr is measured by the enzymatic method, adjustment of Cr is needed to avoid severe thrombocytopenia in the CG regimen.

No significant financial relationships to disclose.
A universal formula based on cystatin C to perform individual dosing of carboplatin in normal weight, underweight, and obese patients
Authors: Chatelut E. , Schmitt A. , Lansiaux A. , Bobin-Dubigeon C. , Etienne-Grimaldi M. , Boisdron-Celle M. , Pinguet F. , Floquet A. , Billaud E. , Le Guellec C.
Published: August 2020

2527

Background: It has recently been shown that it is possible to improve the prediction of carboplatin clearance by adding plasma cystatin C level (cysC), an endogenous marker of glomerular filtration rate, to the other patient characteristics routinely used for carboplatin individual dosing, namely serum creatinine (Scr), body weight (BW), age, and sex. This multi-center pharmacokinetic study was performed to evaluate prospectively the benefit of using cysC for carboplatin individual dosing. Methods: The 357 patients included in the study were receiving carboplatin as part of established protocols. A population pharmacokinetic analysis was performed using the NONMEM program. Seven covariates were studied: Scr, cysC, age, sex, BW, ideal body weight, and lean body mass. Results: The best covariate equation was: carboplatin clearance (mL/min) = 105. (Scr/75)-0.433. (cysC/1.00)-0.290 . (BW/65)+0.547 . (age/56)-0.351 . 0.855sex, with Scr in μmol/L, cysC in mg/L, BW in kg, age in years, and sex = 0 for male. Using an alternative weight descriptor (ideal body weight or lean body mass) did not improve the prediction. This final covariate model was validated by bootstrap analysis. The bias (mean percentage error) and imprecision (mean absolute percentage error) were +2% and 15% respectively on the total population, and were of a similar magnitude in each of the three subgroups of patients defined according to their body mass index. Conclusions: For the first time, a unique formula is proposed for carboplatin individual dosing to patients which is shown to be equally valid for underweight, normal weight, and obese patients.

No significant financial relationships to disclose.
Effects of novel heparin-derived compounds on tumor uptake of chemotherapeutics and chemoresponse
Authors: Phillips P. , Yalcin M. , Cui H. , Abdel-Nabi H. H. , Sajjad M. , Bernacki R. , Mousa S.
Published: August 2020

2537

Thrombotic complications are the second most common cause of mortality in cancer patients and fibrin deposition in the tumor microenvironment might play a key role in tumor progression and inference with tumor chemotherapeutic uptake. Treatments that target these processes may result in improved uptake of chemotherapeutic agents and subsequent inhibition of tumor growth and metastasis. Tissue Factor (TF) is frequently associated with aggressive behavior and poor outcome in tumors. We have previously demonstrated potent anti-tumor efficacy for various mechanisms that interfere with TF/VIIa. The purpose of this study was to investigate the effects of low molecular weight heparins (LMWH) and sulfated non-anticoagulant LMWH (S-NACH) on tumor chemotherapeutic uptake. Studies: (1) Nude mice xenograft A549 human lung carcinoma: LMWH or S-NACH at 10 mg/kg S.C. daily effectively limited tumor growth. (2) LCC6 human lung tumor xenograft model: Paclitaxel alone or in combination with Tinzaparin or S-NACH on tumor re-growth after discontinuation of treatment: Paclitaxel + S-NACH treatment showed significant (P<0.01) tumor growth suppression and improved survival when compared to Paclitaxel. (3) Biodistribution studies: animals were injected with LMWH S.C. daily for 5 days (10 mg/kg) then injected i.v. with [124-I]-Paclitaxel. LMWH increased [124-I]-Paclitaxel uptake into LCC6 tumors with tumor: muscle ratios several fold greater than that of [124-I]-Paclitaxel alone at 24 hrs post injection. This is a highly significant result in the light of the fact that the FDA criterion for a clinically meaningful effect is a 15% increase in uptake. (4) HPLC studies of tumor uptake of Doxorubicin (DOX in mice treated with 10 mg/kg of LMWH or S-NACH for 10 days followed by Doxorubicin (2.5 mg/kg). Both LMWH and S-NACH significantly (P<0.01) increased the uptake of chemotherapeutic agent DOX in MCF7 DOX resistant tumors by 1.5–2 folds but not in heart or lung tissues, confirming the findings obtained with another agent [124-I]-Paclitaxel. Conclusions: LMWH or S-NACH increased chemotherapeutics uptake and hence chemoresponse. Protocols utilizing adjuvant or neo-adjuvant therapy with LMWH or S-NACH could lead to increase tumor chemo responsiveness and overcoming tumor chemo resistance.

No significant financial relationships to disclose.
Population pharmacokinetics of pegylated liposomal CKD-602 (S-CKD602) in patients with advanced solid tumors
Authors: Wu H. , Ramanathan R. K. , Srychor S. , Zamboni B. A. , Ramalingam S. , Edwards R. P. , Friedland D. M. , Stoller R. G. , Belani C. P. , Zamboni W. C.
Published: August 2020

2545

Background: CKD-602, a semi-synthetic analogue of campothecin, is a potent topoisomerase I inhibitor. S-CKD602, a PEGylated long-circulating liposomal formulation of CKD-602, was developed to achieve a longer intra-tumoral exposure of CKD602 and a higher therapeutic index. Age and body composition were reported to affect the pharmacokinetics (PK) of S- CKD602 (Zamboni, ASCO'07). A population PK model for encapsulated and released CKD-602 following administration of S- CKD602 was developed to assess factors that may influence S-CKD602 PK. Methods: Plasma samples from 45 patients (pts) with solid tumors were collected in a phase I study. S-CKD602 was administered as a 1 h IV infusion with doses ranging from 0.1 to 2.5 mg/m2. Plasma concentrations of encapsulated (n=292) and released (n=268) CKD-602 were measured by LC-MS/MS, and population PK modeling was performed using NONMEM. Results: Pts were classified as linear and nonlinear pts according to the clearance (CL) of encapsulated CKD-602 using a classic two stage PK modeling approach. Mean ± SD ratio of total body weight to ideal body weight of pts with linear and nonlinear CL of encapsulated CKD-602 was 1.13 ± 0.16 and 1.53 ± 0.29, respectively (P = 0.003). PK of encapsulated CKD-602 was described by 1-compartment model with nonlinear CL (Michaelis-Menten kinetics). PK of released CKD-602 was described by a 2- compartment model with linear CL for all pts. The presence of primary or metastatic tumor(s) located in the liver decreased the inter- individual variability (IIV) in the CL of encapsulated CKD-602 by 13%. Typical values of Vmax of encapsulated CKD-602 in pts with and without hepatic tumor(s) were 156 and 103 μg/h, respectively (P < 0.001). The inclusion of age decreased IIV in the release of CKD-602 from S-CKD602 by 22%. Typical values of release of CKD-602 from S-CKD602 in pts < 60 years old (yo) and pts ≥ 60 yo were 0.21 and 0.10 L/h, respectively (P < 0.001). Conclusions: These data suggest that older patients (pts ≥ 60 yo) have a reduced release of CKD-602 from S-CKD602. In addition, pts with tumors in the liver may have an increased clearance of S-CKD602. These observations have potential implications in the optimal dosing of liposomal agents.

[Table: see text]
Phase I and pharmacokinetic (PK) study of IHL-305 (pegylated liposomal irinotecan) in patients with advanced solid tumors
Authors: Jones S. F. , Zamboni W. C. , Burris H. A. , Chan E. , Infante J. R. , Keedy V. , Bendell J. C. , Lee W. , Ikeda S. , Rothenberg M.
Published: August 2020

2547

Background: Irinotecan (CPT-11) is a prodrug of SN-38 that has antitumor activity in a wide range of solid tumors. IHL- 305 is a PEGylated-liposomal formulation of irinotecan designed to increase the therapeutic index by prolonging the duration of exposure in both plasma and tumors. IHL-305 demonstrates superior anti-tumor activity in preclinical models. Methods: Eligible patients (pts) had advanced solid tumors, ECOG ≤2, adequate organ function and no prior exposure to CPT-11. In a standard 3+3 escalation, IHL-305 was infused over 60 minutes q 28 days. UGT1A1*28 genotyping was performed with the homozygous (*28/*28) variants treated at 50% of current dose (subsequent escalation allowed). The area under the plasma concentration- time curve (AUC) of sum total (encapsulated + released) CPT-11, released CPT-11, SN-38, and SN-38 glucuronide (SN-38G) was calculated. The % CPT-11 released was calculated as the ratio of released CPT-11 AUC to sum total CPT-11 AUC x 100. The primary objectives were to determine the dose limiting toxicities (DLTs), phase II recommended dose (P2RD), and clinical pharmacology of IHL- 305. Results: 42 pts treated; homozygous wild-type (wt/wt; n=23), heterozygous (wt/*28; n=13) and homozygous variants (*28/*28; n= 6). 10 dose levels explored; 7, 14, 28, 37, 50, 67, 88, 120, 160 and 210 mg/m2. DLTs included: 1 Gr 3 acute nausea/vomiting at 67 mg/ m2 (subsequent pts received premedication), 1 Gr 3 delayed-onset diarrhea at 160 mg/m2, and 1 Gr 3 delayed nausea/vomiting and one Gr 3 febrile neutropenia at 210mg/m2. Pts received repeated courses of IHL-305 with no delays for myelosuppression or diarrhea. 7 pts had stable disease ≥ 6 cycles. The mean ± SD PK parameters are summarized in the table below. Conclusions: The MTD and P2RD of IHL-305 is 160 mg/m2 IV q 28 days. IHL-305 shows a high and prolonged exposure of sum total and released CPT-11 and SN-38.

[Table: see text]

[Table: see text]
A phase I study of daily oral TRC102 (methoxyamine) to enhance the therapeutic effects of pemetrexed in patients with advanced refractory cancer
Authors: Anthony S. P. , Rosen L. S. , Weiss G. J. , Gordon M. S. , Adams B. J. , Gerson S. L. , Alvarez D. , Theuer C. P. , Leigh B. R.
Published: August 2020

2552

Background: TRC102 (methoxyamine) is a small molecule inhibitor of base-excision repair (BER) that enhances the cytotoxicity of alkylator and antimetabolite chemotherapy and reverses chemotherapy resistance. TRC102 inhibits BER by stabilizing abasic sites produced by glycosylase removal of damaged DNA bases. Methods: A phase 1 trial evaluated the safety, PK, and PD of oral TRC102 combined with intravenous pemetrexed in patients with advanced refractory cancer. Patients were required to have ECOG PS ≤ 1 and adequate organ function. TRC102 was escalated in cohorts of 3–6 patients in combination with standard dose pemetrexed. All patients received TRC102 alone on Days 1–4 of a 2 week cycle followed by the combination of pemetrexed and TRC102 every 3 weeks thereafter. Results: Eight patients were treated with a total of 22 cycles of TRC102 at 15 mg/m2 (n=3) and 30 mg/m2 (n=5). No adverse events were attributed to TRC102 alone, and grade 3–4 neutropenia without fever, grade 3 thrombocytopenia, and grade 1–2 fatigue and asthenia were considered possibly related to the combination of TRC102 and pemetrexed. One patient at 30 mg/kg TRC102 experienced grade 3 anemia during Cycle 2 that was considered a dose-limiting toxicity. He recovered after 2 units PRBCs and a 50% dose-reduction of TRC102, and remained on study through Cycle 5. Clinical PK analyses indicate that TRC102 plasma concentrations required for in vivo activity are achievable with daily oral administration (Cmax = 49–62 ng/mL, half-life = 29–40 hr), and PD studies confirm that TRC102 stabilizes pemetrexed-induced abasic sites in these patients. Conclusions: Daily oral TRC102 is tolerated at doses that potentiate the clinical activity of pemetrexed in patients with advanced refractory cancer. Phase 2 studies are planned in multiple indications.

[Table: see text]
Analysis of a phase I pharmacokinetic (PK)/food effect study of AT-101 in patients with advanced solid tumors
Authors: Pitot H. C. , Mould D. , Maleski J. , Leopold L.
Published: August 2020

2557

Background: AT-101 is an oral, pan-Bcl-2 inhibitor (Bcl-2, Bcl-XL, Bcl-W, Mcl-1). Overexpression of Bcl-2 family proteins is common in human cancers. AT-101 activity as a single agent as well as in combination with docetaxel has been reported. The ongoing Phase 1 study of AT-101 as a single agent was expanded to include a cohort of patients to determine the PK of AT-101 in fed and fasted states. Methods: Twelve patients (pts) were enrolled and randomized into cohorts of six pts each. Cohort A received AT-101 (80 mg) orally on day 1 on an empty stomach (fasted) and again on day 8 with a high fat high calorie breakfast (fed), per FDA guidelines. Cohort B received AT-101 on day 1 fed and on day 8 fasted. Preliminary plasma concentration time data for AT-101 from 10 patients administered 80 mg orally were evaluated using noncompartmental analysis. Log transformed peak concentration (Cmax) and exposure (AUC) were compared the between fed and fasted groups with the fasted group as the reference treatment. Results: Preliminary PK results from the first 10 pts are shown in the Table. For AUC and Cmax, the effect of food resulted in an approximately 42% and 5% increase, respectively. However the confidence intervals were not wholly outside the 80–125% intervals. Conclusions: These data indicate that food may increase AT-101 exposure in terms of AUC and Cmax. Updated results from all 12 pts will be presented at the meeting. Based on our preliminary results, it is recommended that AT-101 be taken at least an hour (or more) before or after food.

[Table: see text]

[Table: see text]
Phase I evaluation of SF1126, a vascular targeted PI3K inhibitor, administered twice weekly IV in patients with refractory solid tumors
Authors: Chiorean E. G. , Mahadevan D. , Harris W. B. , Von Hoff D. D. , Younger A. E. , Rensvold D. M. , Shelton C. F. , Hennessy B. T. , Garlich J. R. , Ramanathan R. K.
Published: August 2020

2558

Background: SF1126 is composed of the pan PI3K inhibitor LY294002 conjugated to an RGD targeting peptide. It is designed to increased solubility and binding to integrins expressed on tumor vasculature. This targeted prodrug enhances tumor delivery of the active inhibitor, improving antitumor efficacy and tolerability in xenograft models. LY294002 inhibits other kinases including mTOR, DNA-PK, PIM1, PLK1, and CK2, and induces oxidative stress in cancer cells independent of its PI3K inhibition. Methods: Pts with advanced solid tumors are enrolled in sequential cohorts in standard 3+3 design. SF1126 is administered days 1, 4 weekly by 90 minute IV infusion in cycles of 4 weeks. Pharmacodynamic (PD) evaluations of PI3K pathways are being measured in PBMC, skin/hair and tumor samples as well as by 18FDG PET scans. Primary objectives are safety, establish MTD and recommended phase 2 dose. Results: 28 pts have been treated with SF1126126 across 7 dose levels of 90, 140, 180, 240, 320, 430, and 630 mg/m2. One dose limiting toxicity (DLT) was seen at the 180 mg/m2 dose, consisting of transient G3 diarrhea. No other grade 3/4 drug related toxicities have been reported. No consistent effects on blood glucose levels noted. Eleven pts showed stable disease for ≥ 8 wks, including durations of 20 wks for one GIST, 1 endometrial, and 1 prostate; 15 wks for 1 pancreatic; 11 wks for 2 GIST, 2 ovarian, and 1 CRC pt. PK: SF1126 is rapidly cleared after infusion termination. PK of active hydrolysis product (LY294002) shows t1/2 ∼1.6–2 hrs; dose proportional Cmax, achieving ∼ 21uM at 630 mg/m2; and AUC(0-t) nearly dose proportional. Mean AUC values at doses ≥ 140 mg/m2 exceed those found effective in mouse xenograft studies. PD: Compared to baseline biopsy, we observed significant inhibition of pS6 by IHC in a tumor biopsy 20 hours after the 8th dose in a pancreatic cancer pt at 240 mg/m2. Conclusions: SF1126 is well tolerated at doses up to 630 mg/m2 given twice weekly. MTD has not been reached; dose escalation continues. Clinical activity includes disease stabilization in multiple pts with refractory tumors. There is early evidence of target pathway inhibition.

[Table: see text]