bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantitative analysis of 06-methylguanine-DNA methyltransferase (MGMT) promoter methylation in patients with low-grade gliomas
Authors: Ochsenbein A. F. , Schubert A. D. , Vassella E. , Mariani L.
Published: August 2020

2069

Background: Loss of heterozygosity (LOH) on the chromosomes 1p and 19q is associated with sensitivity to alkylating agents like temozolomide (TMZ) in patients with low-grade gliomas; whether methylation of the MGMT-promoter, a predictive factor in glioblastoma patients, also correlates with tumor response to TMZ in low-grade gliomas is unclear. Methods: We performed a retrospective analysis of patients with histologically verified low-grade gliomas (WHO Grade II) who were treated with TMZ for tumor progression at our hospital between November 1999 and November 2007. Objective tumor response was assessed by MRI at 6-month intervals. LOH of microsatellite markers on chromosomes 1p and 19q was determined by polymerase chain reaction (PCR) amplification of the matched pairs of blood and tumor DNA. A methylation-specific, primer extension based PCR method was developed to quanitatively assess the MGMT methylation status in the tumour tissue. Results: Twenty-two patients with a median age of 53 years (range 27–72) were included in the study; 59% were male. Seven patients had prior surgical resection of the tumor. Histological classification revealed 10 oligodendrogliomas, 7 oligoastrocytomas, and 5 astrocytomas. All patients were treated with TMZ 200mg/m2 day1–5 in a 4 wk cycle. Grade 3–4 hematological toxicity occurred in 32% of the patients (9% leucopenia, 23% thrombocytopenia). The progression free survival was 32 months. Combined LOH 1p and 19q was found in 14 pts; 1 patient had LOH 1p alone and 1 patient LOH 19q alone. The LOH status could not be determined in two patients and was normal in the remaining four. MGMT promoter methylation was detectable in 20 pts by conventional PCR and quantitative analysis revealed a methylation status between 12%-100%. The volumetric response to chemotherapy analyzed after 6 months by MRI correlated with the level of MGMT promoter methylation (p = 0.012). Conclusions: Quantitative methylation-specific PCR of the MGMT promoter correlates with radiological response to chemotherapy with temozolomide in WHO grade II gliomas.

No significant financial relationships to disclose.
Combination immunochemotherapy followed by reduced dose (rd) whole brain radiation therapy (WBRT) in an expanded cohort of patients with newly diagnosed primary central nervous system lymphoma (PCNSL)
Authors: Abrey L. E. , Correa D. , Yahalom J. , Raizer J. , Grimm S. , Lai R. , Schiff D. , Grant B. , DeAngelis L. M. , Morris P. G.
Published: August 2020

2072

Background: High-dose methotrexate (M)-based chemotherapy combined with WBRT has improved survival in patients with PCNSL. However, disease recurrence and treatment-related neurotoxicity are significant problems. We conducted a prospective trial incorporating rituximab (R) and rdWBRT and previously demonstrated this was feasible. This study was extended to assess the long-term outcome of this approach in an expanded cohort. Methods: Patients were treated with R-MPV (d1 R 500mg/m2; d2 M 3.5gm/m2; vincristine 1.4mg/m2; d1–7 procarbazine 100 mg/m2/d on odd-cycles). Patients with a PR after five cycles received two additional cycles. Patients with a CR received rdWBRT (2340cGy), otherwise patients received standard WBRT (4500cGy). Patients then received two cycles of Ara-C 3gm/m2. Prospective neuropsychological evaluations were performed at baseline, before WBRT, and every 6 months thereafter. Results: From October 2002 to September 2008, 50 patients were enrolled (22 female, 28 male), median age 59.5 years (range 30–79 years). Due to neutropenia in two of the first five patients, all subsequent patients received G-CSF. 42 patients are assessable for response (4 patients died from progressive disease prior to completing the first cycle of treatment, 4 patients - treatment ongoing). 33 patients (79%) had a CR, of whom 29 received rdWBRT (3 refused, 1 died). At median follow-up of 3 years for survivors the median OS has not been reached and the estimated 2-year OS is 68%. Patients treated with rdWBRT have a median follow up of 38 months: 21 (72%) are alive with no evidence of disease, seven (24%) relapsed, and one died of unknown causes. Eight of 21 (38%) who are alive with no evidence of disease were age 60+ at diagnosis. The number of patients treated with rdWBRT alive with no evidence of disease at 3, 4, and 5 years is 12, 8, and 4 respectively. 9 patients have completed neuropsychological evaluations 24 months after rdWBRT with no significant cognitive decline detectable. Conclusions: Prolonged follow-up of an expanded cohort of patients treated with immunochemotherapy followed by rdWBRT for patients with an initial CR continues to support our initial conclusions that this approach results in excellent disease control with no observed treatment-related neurotoxicity.

[Table: see text]
A placebo-controlled study investigating the dexamethasone-sparing effects of corticorelin acetate in patients with primary or metastatic brain tumors and peritumoral edema
Authors: Recht L. D. , Mechtler L. , Phuphanich S. , Hormigo A. , Hines V. , Milsted R. , O'Connor P. C. , Ryan R. P. , Wong E. T.
Published: August 2020

2078

Background: The standard therapy for patients with peritumoral edema (PTE) associated with cerebral tumors is long-term dexamethasone (dex), which is associated with significant short- and long-term adverse events (AEs). Corticorelin acetate (CrA) is a synthetic peptide of corticotropin-releasing factor that may have the potential to allow such patients to reduce or stop dex therapy. This study investigated the steroid-sparing effect of CrA in patients with cerebral tumors and PTE. Methods: Patients were randomized to CrA 1.0 mg bid SC (n = 100) or placebo (PLA) SC (n = 100) for 12 weeks. The primary endpoint was the percentage of responders, defined as patients able to reduce their daily dex dose by ≥50% by week 2 and maintain this reduction until week 5, without deterioration in neurologic or performance status. Secondary endpoints included maximum percent dex dose reduction from baseline and proximal myopathy (Kendall Myopathy Scale). Steroid-specific treatment-emergent AEs (TEAEs) were also evaluated. Results: The groups were comparable at baseline. There were more responders in the CrA arm vs the PLA arm (62/100 vs. 47/100; p = 0.03). A maximum dex dose reduction of ≥75% was achieved by 42% of CrA patients vs 22% of PLA patients (p = 0.01). 15% of CrA patients were able to stop dex vs. 6% PLA (p = 0.04). At week 12 vs. baseline, proximal myopathy was improved in the CrA group vs the PLA group for upper limbs (p = 0.06) and lower limbs (p = 0.02). AE profiles in both groups were dominated by dex-associated side effects. The overall AE profiles of the treatment groups were generally similar. Emergent cushingoid signs were seen in 13 PLA vs 2 CrA patients (p = 0.01); 14 PLA patients reported skin/subcutaneous tissue disorders as TEAEs vs. 7 CrA patients (p = 0.07). Conclusions: CrA may benefit patients with symptoms of PTE associated with primary or metastatic cerebral tumors by allowing them to reduce/stop their dex treatment, so reducing the incidence of the steroid-related AEs of myopathy, cushingoid symptoms, and skin disorders.

[Table: see text]
Interaction between sorafenib and erlotinib
Authors: Kuhn J. G. , Gilbert M. , Wen P. , Cloughesy T. , Cooper J. , Puduvalli V. , DeAngelis L. , Lieberman F. , Lamborn K. , Prados M.
Published: August 2020

2500

Background: The combination of sorafenib plus erlotinib was evaluated in patients with recurrent glioblastoma (GBM). In addition to defining the maximum tolerated dose (MTD), pharmacokinetics (PKs) for single agent and combination were determined. Methods: Adults with recurrent GBM with the usual phase I inclusion/exclusion criteria were eligible. No enzyme inducing anti-epileptic agents were allowed. Starting doses for erlotinib and sorafenib were 100mg PO QD and 200 mg PO BID, respectively, for 28 days (a cycle). For cycle 1 PKs, erlotinib was started on day 1 followed on day 2 by sorafenib. Eight plasma samples were collected over 24hrs on days 1, 15 and 28. Sorafenib and its metabolite (N-oxide) were analyzed by HPLC and erlotinib and OSI-420 by LC/MS. PK parameters were characterized by standard non-compartmental methods. Results: The MTD was sorafenib 200 mg PO BID and erlotinib 100 mg PO QD. The PKs for erlotinib (OSI) are displayed below. Conclusions: The PKs for sorafenib are in agreement with previous reports and not affected by the co-administration of erlotinib. However, there is an apparent affect of sorafenib on the PKs of erlotinib. The expected accumulation of erlotinib's Cmax and AUC at steady-state was not observed. This interaction results in at least a 2+ fold decrease in exposure to erlotinib and its active metabolite. The interaction does not appear to be the classical enzyme induction due to the rapidity of the onset/offset. This same phenomenon has been reported with the co-administration of sorafenib with gefitinib (Clin Cancer Res 13:2684,2007). Increasing the maximal velocity (Vmax) of CYP3A4, not the quantity of enzyme, is suggested as a testable hypothesis (J Pharmacol Exp Ther 290:1.1998). The clinical relevance of this interaction with regard to toxicity and efficacy warrants further evaluation.

[Table: see text]

No significant financial relationships to disclose.
Population pharmacokinetic analysis of S-1 including the CYP2A6 genotype in patients with advanced cancer
Authors: Hirose T. , Nishimura K. , Fujita K. , Adachi M. , Sasaki Y. , Tanigawara Y.
Published: August 2020

2507

Background: S-1 is an oral anticancer agent composed of tegafur, CDHP, and potassium oxonate. Tegafur is a prodrug of fluorouracil (5-FU), and CDHP prevents degradation of 5-FU by inhibiting dihydropyrimidine dehydrogenase and enhances the anticancer activity of 5-FU. The biotransformation of tegafur to 5-FU is demonstrated to be catalyzed by CYP2A6. CYP2A6 polymorphisms are seen more frequently in Japanese people than Caucasian. Therefore, we performed a population pharmacokinetic (PPK) analysis of S-1 including the CYP2A6 genotype in Japanese patients with advanced cancer and developed a model describing the disposition kinetics of tegafur, CDHP, and 5-FU after oral administration of S-1. Methods: Fifty-eight patients with advanced cancer were eligible if they had a performance status of 0 to 3 and had adequate organ function. A dose of 80 mg/m2 of S-1 was given orally twice daily for 28 consecutive days, followed by 14 days of rest. The PPK analysis was performed with plasma concentration data for tegafur, CDHP, and 5-FU. The CYP2A6 genotype was analyzed with the polymerase chain reaction-restriction fragment length polymorphism method or an allele-specific polymerase chain reaction-based method. On the basis of the CYP2A6 genotype, all patients were classified into 1 of 3 groups: wild type, 1 variant allele, and 2 variant alleles. Results: Creatinine clearance correlated with the individual clearance of CDHP. Body surface area correlated with the individual clearance and volumes of CDHP and tegafur. In patients with 2 variant alleles of CYP2A6, tegafur clearance was 58% less than that in patients with wild type or 1 variant allele of CYP2A6. In addition, in patients with a history of gastrectomy, the absorption rate constant of tegafur was 66% higher than that in patients with no history of gastrectomy. The time-varying concentration of CDHP was the most appropriate model component describing the inhibitory effect on 5-FU catabolism. The individual Bayesian predictions of CDHP, tegafur, and 5-FU concentrations based on the present PPK model were in good agreement with the observed data. Conclusions: This is the first PPK model of S-1 including the CYP2A6 genotype.

No significant financial relationships to disclose.
Phase I dose-escalating study of PM02734 in a 24-hour infusion schedule every 21 days in advanced solid tumors
Authors: Evans T. R. , Oaknin A. , Jones R. J. , Vandermeeren A. , Coronado C. , Soto-Matos A. , Germa J. R. , Crawford D. , Frontelo P. , Salazar R.
Published: August 2020

2511

Background: PM02734 is a chemically synthesized depsipeptide with a broad spectrum of activity against solid tumors in vitro (breast, colon, lung, neuroblastoma, prostate, sarcoma and thyroid) and in vivo (breast, prostate, melanoma); as well as an acceptable non-clinical toxicology profile. Methods: Patients (pts) with metastatic or advanced solid tumors were enrolled in a phase I, open-label, dose-escalating study to assess safety, tolerability, pharmacokinetics (PK), and to identify the dose limiting toxicity (DLT) and recommended dose (RD) of PM02734 infused over 24 hours every 21 days (d). The starting dose was 0.48 mg/m2. Cohorts of 1–6 pts were treated at different dose levels. Results: Thirty seven pts were treated in this study. The median age was 55 years (40–75), sex: males/females 20/19. The median PS was 1 (range 0–2). The most frequent cancer types were colon/ gastric/ sarcoma (n=8/5/5). Most patients were heavily pretreated, with a median of prior therapy lines of 4 (1–12). Patients were treated at 8 dose levels (0.48, 0.72, 1.0, 1.6, 2.4, 3.6, 5.4, and 6.8 mg/m2), the MTD was 6.8 mg/m2 and the RD was 5.4 mg/m2 (10 mg flat dose).Common toxicities grade ≤ 2 included asthenia, nausea/emesis, lymphopenia, injection site reactions and asymptomatic elevated transaminases (TAs). DLT were grade 3 asymptomatic, reversible TA elevations at 6.8 mg/m2. Preliminary PK data is characterized by long half life (>100 h), a wide distribution and high inter-patient variability. Clearance was not correlated with dose or body surface area (BSA), therefore, flat dose was implemented and the RD was explored with this schedule. Efficacy data showed one complete response (CR) of +28 months observed in a pt with metastatic large cell esophageal carcinoma, and five more showed stable disease (SD) for more than 3 months in different histologies. Conclusions: PM02734 shows to be safe, well tolerated and with evidence of activity (1 CR and 5 SD > 3 months) in pts with advanced solid tumors. The DLT was grade 3 asymptomatic and reversible TA elevations, and the RD for further phase II studies is 10 mg.

[Table: see text]
Is the maximal tolerated dose still the best primary endpoint? Analysis of 288 dose-seeking phase I trials
Authors: Bonneterre J. , Adenis A. , Dansin E. , Ferté C. , Clisant S. , Penel N.
Published: August 2020

2513

Background: For decades, the phase-2-recommended dose (P2RD) depends on toxicity (especially ‘the maximal tolerated dose', MTD) experienced by patients enrolled in dose-escalating phase 1 trials. Recent studies suggest that this policy is not suitable for modern anti-cancer agents. Methods: We retrospectively studied288 recently (1997–2008) published phase-I-trials using the maximal tolerated dose (MTD) to define the P2RD. We analysed how the P2RD was actually defined and then identified the risk factors for failure to establish the P2RD. Results: Seventeen percent (37/288) of the trials failed to identify the P2RD: 13% of studies investigating cytotoxic agents, 23% of studies investigating molecular targeted therapies and 33% of studies investigating immunostimulant agents. The risk factors for this failure were: trials investigating immunostimulant agents (Relative risk (RR)=2.9 [1.1–8.0]) or molecular targeted therapy (RR=3.1 [1.6–6.0]), single-agent regimen (RR=2.5 [1.3–4.9]), dose increments using of Fibonacci-modified series (RR=3.0 [1.5–5.8]), other method of escalation than ‘classical 3+3’ (RR=4.9 [1.6–14.2]) and almost the absence of clear definition of the MTD (RR=10.7 [3.6–32.2]). Indeed, in 9% of these studies (26/288), the definition of the MTD was not clearly established. Moreover, in 17% of all studies (38/288), the authors had proposed alternative but not standardised definitions of the P2RD (13 different definitions). These alternative definitions of P2DR were used in 18% of studies investigating cytotoxic agents, in 19% of studies investigating immunostimulant agents and in 24% of studies investigating molecular targeted therapies. Conclusions: In studies investigating cytotoxic agents, the definition of the MTD needs to be clarified in its 3 dimensions: severity of toxicity, duration of toxicity and proportion of patients experiencing this toxicity. Nevertheless, this appears less relevant for studies investigating immunostimulant agents and molecular targeted therapies. We have to explore and standardise alternative definitions of the P2DR in the era of modern agents.

[Table: see text]
Comparison between RECIST evaluations and variations in tumor growth dynamics in patients included in phase I trials
Authors: Gomez-Roca C. A. , Koscielny S. , Dromain C. , Marzouk I. , Bidault F. , Bahleda R. , Ferte C. , Massard C. , Soria J.
Published: August 2020

2515

Background: Monitoring of treatment efficacy is mainly based on RECIST post-treatment evaluations. We investigated the impact of pre-treatment tumor growth dynamics on the evaluation of response to treatment in phase I trials. Methods: Response at 12 weeks was evaluated using RECIST criteria in 76 patients treated in phase I trials. All patients had a scannographic evaluation at the start of the experimental treatment (D0), at least 2 evaluations before D0 and one evaluation after D0. The mean time between evaluations was 6 weeks. Tumor growth rate (GR=% change in tumor volume per month) was calculated for the pre-treatment period (from the 1st available evaluation to D0), and the experimental period (after D0). GR was compared to RECIST and to time to progression. Disease control (DC) was defined as stable disease, partial response or complete response. We also classified patients according to the variation in GR. Results: A total of 550 evaluations were performed: 256 before D0, 76 at D0 and 218 after. Tumor GR differed according to the time period: 26.6% per month during pre-treatment period vs. 6.6% in experimental period (P<0.01). The GR was significantly higher in patients without DC during pre-treatment (30% vs. 19%; P=0.003) and experimental time periods (+13% vs. -9%; P=0.0005). There was a significant association between a time to progression > 12 weeks and a decrease in GR during the experimental period (P=0.01). Several discordances however were noted. Eight patients with a time to progression >12 weeks (8/46=17%) had an increased GR with the experimental treatment. Thirteen patients who progressed <12 weeks (13/22=59%) had a decreased GR with the experimental treatment. Conclusions: Pre-treatment growth dynamic may directly impact RECIST evaluation of tumor response and thus should be carefully documented. Patients with slow growing tumors tend to experience DC, even if treatment has little effect. The evaluation of response to treatment should take into account pre-treatment tumor GR.

No significant financial relationships to disclose.
Global drug development in cancer: A cross-sectional study of clinical trial registries
Authors: Hertz P. , Seruga B. , Le L. W. , Tannock I. F.
Published: August 2020

2520

Background: Clinical trials are increasingly funded by industry. High costs of drug development may lead to attempts to develop new drugs in more ‘profitable’ (i.e., more prevalent) as compared to ‘less profitable’ (i.e., more deadly) cancers. Here we determine the focus of current global drug development. Methods: We determined characteristics of phase II and III clinical trials evaluating new drugs in oncology, which were registered with WHO International Clinical Trial Registries between 01/2008 and 06/2008. Estimates of incidence, mortality, and prevalence in the more- and less-developed world (MDW, LDW) were obtained from GLOBOCAN 2002. Simple correlation analysis was performed between the number of clinical trials and incidence, mortality and prevalence per cancer site after log transformation of variables. Results: We identified 399 newly registered trials. Of 374 trials with information about recruitment, 322 (86.1%) and 39 (10.4%) recruited patients only from the MDW and LDW, respectively, while 13 (3.5%) had worldwide recruitment. 229 (58%) of trials were sponsored by industry and 324 trials were phase II (81%). Most trials (and most phase III trials) evaluated treatments for globally prevalent cancers: breast, lung, prostate, and colorectal cancer (Table). Prevalence of a particular cancer type in both the MDW and LDW correlated significantly with the number of clinical trials (Pearson r = 0.63 and 0.55; p = 0.01 and 0.03, respectively). In contrast, mortality in the MDW (Pearson r = 0.73; p= 0.002), but not in the LDW (Pearson r = 0.38; p= 0.17), correlated significantly with the number of clinical trials. Conclusions: Global drug development in cancer predominates in globally prevalent cancers, which are a more important cause of mortality in the MDW than in the LDW. Cancer sites that are major killers globally, and especially in the LDW (e.g., stomach, liver, and esophageal cancer) should receive priority for clinical research.

[Table: see text]

No significant financial relationships to disclose.
Population pharmacokinetics (PPK) of eribulin mesylate in patients with locally advanced or metastatic breast cancer (MBC)
Authors: Jansen M. , Vernaz-Gris M. , DesJardins C. , Wong N. , Campone M. , Cortes J. , Wanders J. , Shuster D. , Fuseau E.
Published: August 2020

2524

Background: Eribulin mesylate (E7389) is a non-taxane microtubule dynamics inhibitor with a novel mechanism of action. A study was conducted to evaluate efficacy, safety and pharmacokinetics of eribulin at a dose of 1.4 mg/m2 for locally advanced or MBC in patients previously treated with an anthracycline, a taxane, and capecitabine. Methods: Eribulin was administered intravenously over 2–5 minutes at a dose of 1.4 mg/m2 on days 1 and 8 of a 21- day cycle to 291 patients. Four plasma samples were collected between 5 min and 120 hours after the first dose. Plasma eribulin concentrations were determined by LC/MS/MS. A total of 774 samples, from 209 patients with complete dose and sampling information were included in the PPK analysis, which was conducted using nonlinear mixed effects modeling (NONMEM). Results: Eribulin PKs were best described by a three-compartment model, with elimination from the central compartment. Distribution was rapid and elimination slow. For a typical patient with AST<ULN and CLCR=101mL/min (Cockroft-Gault), clearance (CL) was 2.98 L/h and central volume of distribution 3.72 L (V1). Volumes and inter-compartmental clearances for the two peripheral compartments were 3.60 L (V2), 126 L (V3), 2.7 L/h (Q2) and 5.6 L/h (Q3). Inter-patient variability on CL was 57%, and ranged from 26- 98% for other parameters. Residual error was 21% (proportional). CL was on average 38% lower in patients with AST>ULN and positively correlated with renal function. The covariate effects only explained a minor fraction of inter-patient variability in this single study dataset. Conclusions: Eribulin PKs were described by a three-compartment model with rapid distribution and slow elimination. Appreciable interpatient PK variability exists, a minor fraction of which was explained by measures of liver and renal function.

[Table: see text]
Interethnic differences in Cyp3A4 inhibition by ketoconazole on docetaxel pharmacokinetics (PK) and pharmacodynamics (PD)
Authors: Lim Y. , Goh B. , Wang L. , Cordero M. T. , Chuah B. Y. , Lim S. , Tan S. , Buhari S. A. , Soo R. , Lee S.
Published: August 2020

2526

Background: Use of concomitant medications that inhibit drug metabolizing enzymes such as Cyp3A4 is common and may affect chemotherapy PK/PD. We studied the effects of Cyp3A4 inhibition with ketoconazole on docetaxel PK/PD in 3 Asian ethnic groups. Methods: Two cohorts of chemonaive breast cancer patients were compared. The first cohort comprised of 95 patients (62 Chinese, 26 Malay, 7 Indian) treated with 75mg/m2 docetaxel unmodulated by ketoconazole, while the second cohort comprised of 31 patients (14 Chinese, 14 Malay, 3 Indian) treated with docetaxel 70mg flat dose modulated by oral ketoconazole, a regimen we previously reported to result in comparable docetaxel AUC as 75mg/m2 docetaxel. Plasma docetaxel concentrations were obtained at 0, 0.5, 1, 2, 5, 7 and 24 hours, and blood counts monitored on days 8 and 15 of cycle 1. Results: No significant differences in docetaxel PK or neutropenia between the races were observed in response to 75mg/m2 docetaxel unmodulated by ketoconazole (docetaxel clearance 36.4±16.9, 34.3±12.5, 44.2±27.7L/h, p=0.702; docetaxel AUC 3.6±2.7, 3.5±1.2, 2.9±1.3mg/L h, p=0.418; day 8 neutrophil count 0.5±0.6, 0.8±0.8, 0.4±0.3x109/L, p=0.138; grade 4 neutropenia 66%, 50%, 86%, p=0.157). In contrast, when docetaxel was administered with ketoconazole to inhibit Cyp3A4, inter-ethnic differences in docetaxel PK/PD were observed, with Chinese having the lowest docetaxel clearance and highest docetaxel AUC, followed by Malays and Indians (docetaxel clearance 18.6±5.7, 23.7±9.3, 30.6±6.7L/h, p=0.048; p=0.017 trend test; docetaxel AUC 4.2±1.4, 4.1±3.9, 2.4±0.5 mg/L h, p=0.048, p=0.017 trend test), although there were no statistically significant differences in body weight or surface area between the races. In concordance, Chinese patients experienced greatest degree of myelosuppression, followed by Malays and Indians (day 8 neutrophil count 0.8±0.8, 1.5±1.1, 1.7±1.1x109/L, p=0.046, p=0.013 trend test), and were more likely to develop grade 4 neutropenia (57%, 14%, 0%, p=0.024) from docetaxel + ketoconazole. Conclusions: Inter-ethnic differences in CYP3A inhibition by ketoconazole exist, and are important when evaluating the impact of concomitant medications with chemotherapy that may inhibit Cyp3A4.

No significant financial relationships to disclose.
Repeatability of [18F] fluoro-deoxyglucose positron emission tomography (FDG-PET) in a multicenter phase I oncology study in patients with gastrointestinal malignancies
Authors: Velasquez L. M. , Kollia G. , Hayes W. , Galbraith S.
Published: August 2020

2530

Background: FDG-PET is used to monitor response in multi-center oncology clinical trials. This study assessed the repeatability of select semi-quantitative standardized uptake values (SUV) as measured by double baseline FDG-PET studies in a multi-center phase I oncology trial. Methods: Double baseline FDG-PET studies were acquired on 62 sequentially enrolled patients. Tumor metabolic activity was assessed by SUVmean, SUVmax, SUVpeak and SUV70%. Compliance with image acquisition guidelines and quality assurance (QA) standards were assessed as to their effect on SUV repeatability. Summary statistics for baseline absolute differences relative to the average of baseline values and repeatability analysis were performed for all patients (full dataset) and a subset with scans that passed QA (QA dataset), analyzed in both a multi-observer (site-reported) and single-observer (central-read) setting. Intra-subject precision of baseline measurements was assessed by repeatability coefficients, intra-subject coefficients of variation, and confidence intervals for all SUV parameters. Results: No statistically significant difference was noted between the two baseline measurements for any of the SUV parameters. Mean baseline differences for SUVmean, SUVmax, SUVpeak and SUV70% were not statistically significant for either dataset, in the multi- or the single-observer setting. The intra-subject coefficient of variation of the SUV parameters ranged from 11–14% (QA dataset) to 16% (full dataset). The 95% repeatability coefficients for individual patient differences, ranged from (-25%, 34%) to (-34%, 52%) for all SUV parameters. Conclusions: Repeatability results of double baseline FDG-PET scans were similar for all SUV parameters assessed in a variety of analysis settings. The variability was acceptable even in the absence of close compliance with current consensus recommendations, supporting the use of FDG-PET imaging as a robust tumor assessment tool in multi-center oncology clinical trials. The results of this study suggest thresholds for determining metabolic response may be on the order of -35%, 50%, allowing increased confidence that a true change from baseline has occurred.

[Table: see text]
A phase I study of vorinostat in combination with bortezomib in refractory solid tumors
Authors: Ninan J. A. , Bailey H. , Kolesar J. , Marnocha R. , Eickhoff J. , Wright J. , Espinoza-Delgado I. , Alberti D. , Wilding G. , Schelman W.
Published: August 2020

2531

Background: Vorinostat (suberoylanilide hydroxamic acid, SAHA) is an oral histone deacytlase (HDAC) inhibitor that has anti-tumor activity in hematologic malignancies and advanced solid tumors. Vorinostat has been postulated to act synergistically with bortezomib at the level of aggresome inhibition with creation of reactive oxygen species. We previously conducted a study of this combination with once-daily dosing of vorinostat with bortezomib (Step A). This study (Step B) was conducted to evaluate twice daily dosing of vorinostat during administration of bortezomib to determine safety and efficacy, pharmacokinetics, and activity this combination. Methods: This study used standard eligibility criteria except patients must have had no prior bortezomib. The treatment plan initially consisted of vorinostat given orally twice daily on days 1–14 with bortezomib IV on days 1, 4, 8, and 11 of a 21 day cycle. Two DLTs (elevated ALT and fatigue) were observed at level 1, and the protocol was amended to administer vorinostat twice daily on days 1–4 and 8–11. Starting dose was vorinostat 200 mg and bortezomib 1 mg/m2. RECIST was used to measure response. Results: 29 pts have been enrolled; 13 men and 16 women. Tumor types include: Prostate (1), Colorectal (3), Pancreatic (6), Sarcoma (7), Biliary (1), Thymus (1), GIST (2), Mesothelioma (1), ovarian (1), Neuroendocrine (1), Lung (1), Head and Neck (1), Breast (2), and Cervical (1). Grade 3–4 toxicities possibly related to SAHA at any dose level were as follows: thrombocytopenia (5), fatigue (3), increased ALT (1), elevated INR (1), anemia, (1), hypotension (1), diarrhea (3), anorexia (1), dizziness (1), nausea/vomiting (1), and hypoalbuminemia (1). The only dose limiting toxicities included elevated ALT (1), fatigue (1). There were two deaths but neither was felt to be related to the drug. The MTD for Step B was established at vorinostat 300 mg BID and bortezomib 1.3 mg/m2. Conclusions: The MTD for Step B was established at vorinostat 300 mg BID and bortezomib 1.3 mg/m2. Subjective evidence of clinical activity has been observed in patients with refractory solid tumors. These studies were supported by NCI, UO1, CA062491, SAIC 25XS097, and 1ULRR025011.

No significant financial relationships to disclose.
Is positron emission tomography (PET) with FDG an early predictor of the RECIST morphological response to chemotherapy in metastatic colorectal cancer patients (mCRC)?
Authors: Hendlisz A. , Emonts P. , Covas A. , Ameye L. , Paesmans M. , Castany Prado Maria del Rosario R. , Machiels G. , Van den Eynde M. , Vanderlinden B. , Flamen P.
Published: August 2020

2533

Background: Reliable early assessment of response would help identify active treatments and avoid unnecessary side effects. Our hypothesis was that FDG-PET metabolic changes 2 weeks after the first dose of chemotherapy predict standard morphological response. Methods: 45 mCRC patients undergoing 1st or 2nd-line chemotherapy are planned to be included in a prospective trial comparing early metabolic changes, as measured by serial FDG-PET, with the standard RECIST- based response assessment using multi-slice CT. A signed informed consent was obtained in all cases. For the lesion-by-lesion analysis, according to the EORTC recommendations, a metabolic response was defined as a ≥ 15% decrease of the standardized FDG uptake (SUVmax) on day 14. A patient was classified as having overall metabolic responsive disease if the majority or all lesions observed on the baseline PET showed a metabolic response, without any progressive lesion ( ≥25% increase). Results: At interim analysis, 28 patients (median age 65.9 yrs) were available for comparative metabolic and morphological analysis of 88 lesions. Mean number of lesions per patient was 3 (range 1–8). Patients received FOLFOX (18), FOLFIRI (9), and capecitabine (1) as first- (19) or second-line (9) treatments. Metabolic assessment showed 49 (56%) responding and 39 (44%) nonresponding lesions. The morphological response rate in metabolically non-responding lesions (5/39; 13%) was lower than in responding lesions (22/49; 45%) (p = 0.001; Fisher's exact test). A mixed metabolic response, combining responding and non-responding lesions within the same patient, was seen in 21/28 (75%) pts. A RECIST response was observed in 6/14 (43%) PET responding and in 0/14 (0%) PET nonresponding patients (p = 0.02; Fisher's Exact test). Updated results of this ongoing trial will be presented. Conclusions: Serial FDG PET seems able to identify non-responding mCRC disease after one course of chemotherapy.

No significant financial relationships to disclose.
Clinical and pharmacokinetic (PK) findings in a phase I study of 7-t-butyldimethylsilyl-10-hydroxycamptothecin (AR-67) in patients with refractory solid tumors
Authors: Arnold S. M. , Horn J. , Eckardt J. R. , Rinehart J. J. , DeSimone P. , Fields S. Z. , Kee B. K. , Moscow J. A. , Houchins J. C. , Leggas M.
Published: August 2020

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Background: AR-67 is a 3rd generation camptothecin analog selected for development based on the high in vitro stability of its pharmacologically active lactone form and high potency in preclinical models. This report describes the initial phase I study of intravenous AR-67 in adults with refractory solid tumors. Methods: AR-67 was infused over 1 hour for 5 days of a 21-day cycle using an accelerated titration phase I trial design. PK was performed on the 1st and 4th day of cycle 1. AR-67 was assayed with a validated chromatography method. Toxicity and response were assessed using NCI CTC (v3) grading scale and RECIST. Results: In total, 26 patients were treated at 9 dose levels (mg/m2/day): 1.2 (n=2), 1.67 (n=3), 2.34 (n=3), 3.2 (n=3); 4.5 (n=1), 6.3 (n=1), 7.5 (n=7), 8.9 (n=4) and 12.4 (n=2). Median age 62 (range 31–79), 15M/11F, median prior therapies 3 (range 1 to 6). Tumor types included: colorectal (8), non-small cell lung (NSCLC) (4), small cell lung (3), soft tissue sarcoma, (3), head and neck (2), prostate (2), and other (4). 21 subjects completed 2 or more cycles of therapy, 5 subjects received 1 cycle of therapy and had rapid disease progression (1 received 2d of drug prior to PD), 1 subject is still under treatment after 9 cycles. DLTs were observed in 5 patients: 2 of 2 at 12.4 mg/m2/day (Gr 4 febrile neutropenia, Gr 3 fatigue); 2 of 4 at 8.9 mg/m2/day (Gr 4 thrombocytopenia), 1 of 7 at 7.5 mg/m2/day (Gr 4 thrombocytopenia). Common C1 worst-grade drug related toxicities (CTC I/II % vs III/IV %): Hg (27/8), WBC (11/19), ANC (19/8), platelets (19/12), fatigue (15/8) insomnia (8/0), flushing (15//0), constipation (8/0), nausea (23/0), ALT elevation (12/0), hiccups (8/0). Antitumor activity, assessed by development of PR and SD, was observed in NSCLC, SCLC, colon and bladder cancer. The lactone form was predominant in plasma (>85% of AUC) at all time points. Clearance was constant with increasing dose and exposure (AUC) correlated with toxicity. Conclusions: AR-67 has superior lactone stability compared to approved analogs, has a predictable toxicity profile that did not include diarrhea and has activity in NSCLC. The RP2D is 7.5 mg/m2/day for 5 days of a 21-day cycle. This work was supported by R21-CA-123867 and Arno Therapeutics.

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Evaluation of indibulin, a novel tubulin targeting-agent, in combination with capecitabine, with mathematically optimized dose scheduling
Authors: Lewis J. J. , Galsky M. D. , Camacho L. H. , Loesch D. M. , Komarnitsky P. B. , Norton L.
Published: August 2020

2538

Background: Indibulin (IDB) is a novel, orally available tubulin-targeting molecule that perturbs cancer cell migration and mitosis. It is active against taxane-resistant cell lines and is synergistic with 5-FU in vitro and in vivo. Two translational studies have been conducted: a Phase IB study of IDB in combination with capecitabine (CAP) in patients with advanced solid tumors, and mathematical modeling applying Norton-Simon models to breast carcinoma MX-1 xenografts to further develop Phase II dose. Methods: IDB is administered continuously starting at 400 mg BID. CAP is administered for 2 weeks with 1 week rest, starting at 875 mg/m2 BID. IDB and CAP are escalated to MTD: IDB 600 mg BID & CAP 1000 mg/m2 BID. Efficacy is evaluated every 9 weeks using RECIST. In the xenograft model indibulin is administered at dose levels from 12 to 28.7 mg/kg/day to nude mice carrying MX-1 breast carcinoma. Tumor growth is analyzed using a Gompertzian-type growth model to determine via calculus of variations the optimal schedule to maximize the efficacy/toxicity ratio. Results: To date, 7 patients have been treated and are evaluable for safety. Median age 62 yrs; ECOG ≤1; median prior therapies 3. Four patients are evaluable for efficacy and all have stable disease (3 for 6 cycles, 1 for 3 cycles). AEs include hand-and-foot syndrome (CAP), fatigue, vomiting, anorexia, and headache. Neither DLTs nor grade ≥3 AEs have been observed. In MX-1 xenografts, indibulin demonstrates linear dose-efficacy relationship over the range of 12 to 22 mg/kg. At all dose levels the first 5 days of administration are associated with a rapid accumulation of anticancer effect with lesser effects over the next 5 days to a peak of efficacy at day 10 Conclusions: IDB + CAP is well tolerated, without neurotoxicity. There is preliminary evidence of clinical activity even with this sub-optimal, continuous schedule of IDB. Formal analyses suggest that an intermittent schedule could optimize efficacy, minimize acquired resistance and allow for host recovery from drug-induced toxicity. Pre- clinical evaluation in a breast cancer model supports an intermittent dosing schedule to further increase the activity of IDB.

[Table: see text]
Decitabine effect on human tumor expression of various transporters
Authors: Stewart D. J. , Nunez M. I. , Jelinek J. , Guo Z. , Hong D. , Gupta S. , Oki Y. , Issa J. , Kurzrock R. , Wistuba I. I.
Published: August 2020

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Background: We reported that immunohistochemistry (IHC) expression of the platinum/copper transporter CTR1 in human tumors correlated inversely with DNA methylation and was increased by the DNA demethylating agent decitabine (D. Stewart et al, Proc ASCO 2008). Decitabine also increased expression of folate transporters in platinum-resistant cell lines that have decreased expression of folate transporters and of small GTPases such as RHOA that regulate endocytosis (D Shen et al. Br J Cancer 2004). Methods: Tumors were biopsied pre decitabine and on cycle 1 day 12 in 31 patients with refractory malignancies in a phase I study of decitabine given days 1–5 ± 8–12 each cycle. We used IHC to assess the folate carriers FOLR1 and RFC1, the glucose transporter GLUT4 and the endocytosis regulating small GTPase RHOA. Scores of 0–300 were calculated by multiplying staining intensity (0–3) by % cells staining. LINE assays were used to assess % global DNA methylation. Results: DNA methylation did not correlate with FOLR1, RFC1 and GLUT4 scores but did correlate inversely with RHOA (r= -0.58, p=0.006). Median tumor IHC scores post vs pre decitabine were 80 vs 80 (range, 0–270 vs 0–210, p=0.89) for FOLR1, 90 vs 90 (range, 15–300 vs 0–300, p=0.17) for RFC1, 0 vs 0 (range 0- 140 vs 0–70, p=0.61) for GLUT4, and 77.5 vs 50 (range, 0–210 vs 0–210, p=0.03) for RHOA. If only tumors with pre decitabine scores <150 were included, post vs pre RFC1 differences were significant (95 vs 80, p=0.004). Outcomes were similar whether or not 4 melanoma patients (in whom melanin pigment decreased the reliability of IHC scoring) were included. Conclusions: As previously noted with the copper/platinum transporter CTR1, treatment with the DNA demethylating agent decitabine was associated with a significant increase in tumor expression of the endocytosis regulator RHOA in resistant human tumors. Expression of the folate transporter RFC1 was also increased if only patients with levels that were initially low were included. This suggests that decitabine should be tested for its ability to increase uptake of chemotherapy in resistant tumors. Promoter methylation for these transporters has not yet been assessed. Supported in part by NIH grant UO1 CA062461–10 & R21 CA112895–01A1.

No significant financial relationships to disclose.
Impacts of microRNA-215 on cell proliferation and chemotherapy resistance in colon cancer and osteosarcoma
Authors: Ju J. , Song B. , Wang Y.
Published: August 2020

2542

Background: Translational control plays a key role in resistance to anti-cancer drug treatment. MicroRNAs regulate gene expression at the post-transcriptional level, mainly by interacting with 3'-UTR of their mRNA targets. Methods: miR-215 was ectopically expressed by transient transfection in both human colon cancer cell lines and osteosarcoma cell lines. The impact of miR-215 on cell proliferation, cell cycle control, chemosensitivity and down stream targets were characterized. The expression of miR-215 in colorectal cancer specimens and normal adjacent tissues was quantified by real time-qRT-PCR analysis. Results: In this study, we discovered that miR-215 down-regulates the expression of both dihydrofolate reductase (DHFR) and thymidylate synthase (TS), two of the most important chemotherapeutic targets, in human osteosarcoma U-2 OS and colon cancer HCT-116 (wt-p53) cell lines. Cells with elevated miR-215 expression are more resistant to DHFR inhibitor methotrexate (MTX) or TS inhibitor Tomudex (TDX) treatment. Ectopically over-expressing miR-215 triggers reduced cell proliferation and increased G2 arrest, at least in part, through the induction of p53 and p21. miR-215 transfected cells with reduced proliferating phenotype were resist to MTX or TDX treatment due to deceased cell cycle in S phase. The expression of endogeneous miR-215 was highly elevated in CD133+/HI CD44+/HI colon cancer stem cells compared to CD133- CD44- colon cancer cells, suggesting that tumor stem cells may be avoiding cellular and DNA damage caused by chemotherapy with a reduced proliferating phenotype mediated by certain miRNAs such as miR-215. The elevated expression of miR-215 in colon cancer stem cells with slow proliferation rate and resistance to chemotherapy further supports the role of miR-215 in cell proliferation and chemotherapy resistance. Conclusions: miR-215 may have a unique potential as a novel therapeutic target and biomarker candidate in cancer.

No significant financial relationships to disclose.
Predictive value of Ile105Val polymorphism of the gluthatione-S-transferase P1 in patients with metastatic colorectal cancer (m CRC) treated with the triplet combination of irinotecan, oxaliplatin, and capecitabine
Authors: Zarate R. N. , Rodriguez J. , Bandres E. , Bitarte N. , Ramirez N. , Ponz M. , Chopitea A. , Viudez A. , Garcia-Foncillas J.
Published: August 2020

2544

Background: Several phase I/II trials have shown that the triplet combination of oxaliplatin, irinotecan and capecitabine is a feasible and active in solid tumors. We aimed to investigate whether germline polymorphisms may be predictors of clinical outcome in mCRC pts treated with this combination. Methods: The following genetic polymorphisms were analysed: glutathione S-transferase (GSTP1-Ile105Val, GSTT1 and GSTM1 deletion), TYMS (TS-5´UTR 2R/3R; TS-5´G/C; TS-3´UTR 6-bp deletion), MTHFR 1298A>C, UGT1A1, ERCC1, XPD. Polymorphisms from peripheral lymphocytes were detected using the TaqMan genotyping assays (Applied Biosystems, CA). Univariate analysis (Fisher´s exact test for response; log-rank test for TTP and OS) was performed to examine associations between polymorphisms and clinical outcome. Results: Blood samples for 63 out of 72 prospectively enrolled pts were tested for genomic analysis. Median age was 57 (32–78), median ECOG 1(0–2), median number of cycles administered 6 (1–13), median number of metastatic sites was 1 (1–4). M/F: 50/22. Risk according to Köhne classification was low (52.8% of pts), intermediate (26.4%) and high (8.3%). Overall response rate (ORR) was 62.5%. Median progression-free survival (PFS) was 9.87 months (95% CI; 7.6–12) and median overall survival was 24.6 months (95% CI; 19.5–29.7). A significant association was observed between MTHFR 1298A>C and haematological toxicity, with C/C genotype pts being at higher risk of grade 3–4 neutropenia (50% vs. 28%, p = 0.035) and leucopenia (50% vs. 15%, p = 0.04). Heterozygous and homozygous GSTP-105Val showed a significant superior response rate (80%) compared to only 40% in pts harbouring the GSTP1–105Ile/Ile genotype (p = 0.008, Fisher´s exact test). PFS was also adversely affected in pts with GSTP1–105Ile/Ile (5.2 months vs. 12.3 months in those pts with at least one GSTP1–105Val allele, p = 0.001). In the multivariate analysis, the relative risk for progression was 3.4 (95% CI; 1.3–9.1) for the GSTP1–105Ile/Ile genotype (p = 0.01). Conclusions: The GSTP1-Ile105Val polymorphism is a strong predictor of clinical outcome for XELOXIRI therapy in mCRC pts.

No significant financial relationships to disclose.
Evaluation of the relationship between patient factors and the reduction in clearance of pegylated liposomal doxorubicin
Authors: La-Beck N. M. , Zamboni B. A. , Tzemach D. , Schmeeda H. , Sapir R. , Gabizon A. , Zamboni W. C.
Published: August 2020

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Background: The reticuloendothelial system (RES), which includes monocytes, may have a key role in clearance (CL) of nanoparticle sized pegylated liposomes. However, the factors affecting the CL of liposomes are unclear. Age, body composition, and monocyte count have been related to CL of liposomal agents (Zamboni, ASCO '07; Maruca, ASCO '07; Sidone, AACR- NCI-EORTC '07). The CL of pegylated liposomal doxorubicin (PLD) decreases significantly from cycle 1 to 3 (Gabizon, Cancer Chemother Pharmacol 2008). The objectives of this study were to evaluate factors associated with decreases in PLD CL. Methods: Patients (pts) with various solid tumors were randomized to PLD administered IV every 28 days at 30, 60 and 45 mg/m2 (n = 6) or 60, 30 and 45 mg/m2 (n = 6) on cycles 1, 2 and 3 respectively. Serial plasma samples for PLD pharmacokinetic (PK) analysis were obtained prior to and at 1 h, 24 h, 72 to 96 h, 7 d, 14 d, 21 d, and 28 d after PLD infusion on cycles 1, 2, and 3. Samples were processed to measure sum total (encapsulated + released) doxorubicin by HPLC with fluorescence. PLD CL was calculated by noncompartmental methods. Precycle monocyte count, age, and ratio of total body weight to ideal body weight were compared to PLD CL. Results: Mean + SD PLD CL on cycles 1 and 3 were 23.7 + 7.7 mL/h and 16.4 + 5.4 mL/h, (P < 0.0001). Pts with a reduction as compared with an increase in precycle monocyte count from cycle 1 to 3 had a mean + SD change in PLD CL of -11.5 + -3.5 mL/h and -5.3 + -3.0 mL/h, respectively (P = 0.09). Median age was 61 years old (yo). Pts > 61 yo and < 61 yo had a mean + SD change in PLD CL from cycles 1 to 3 of - 8.7 + -4.3 mL/h and -5.2 + -5.4 mL/h, respectively (P = 0.16). Conclusions: PLD CL decreased significantly from cycle 1 to 3. Decreased precycle monocyte count was associated with a larger decrease in PLD CL compared to increased monocyte count. Pts > 61 yo had a larger decrease in CL compared to pts < 61 yo. These results suggest monocytes are involved in the CL of PLD and that older pts may have less RES reserve and thus may be more likely to have a larger decrease in PLD CL with subsequent treatment cycles. Statistical significance was not met due to small sample size; however, further investigation of the association between changes in PLD CL and patient age and monocyte count is warranted.

[Table: see text]