bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi-institutional phase I trials involve more patients and longer accrual time compared to single institution trials
Authors: Dowlati A. , Manda S. , Patrick L. , Remick S. , Gibbons J. , Fu P. 
Published: March 2020

2500 Background: There has been a suggested increase in the number of multi-institutional phase I trials over the past decade. Methods: We reviewed all published phase I studies between 1/98 and 12/05 from the Journal of Clinical Oncology and Clinical Cancer Research. 452 phase I studies were identified. The following data were obtained from each study: sponsor (NIH/foreign equivalent vs. pharma), year published, number of participating institutions, mechanism of drug action (8 categories; most common are cytotoxic and targeted therapies), country, number of patients accrued, accrual time and study endpoint (maximum tolerated dose-MTD vs. optimal biological dose- OBD). Results: 55% of phase I trials were single institutional and 21% accrued patients from = 3 institutions. There was no increase over time in the number of multi-institutional studies and no significant association was seen between sponsor and number of institutions. No association was seen between mechanism of drug action and number of participating institutions. There was a highly significant association between number of institutions and number of patients enrolled with multi-institutional studies having higher number of patients per trial (p=0.0003). Pharmaceutical sponsored studies are associated with a greater number of patients per trial (mean 32.8±0.9) as compared to government sponsored (28.4±1) (p<0.05). Only 34% of trials report accrual time. Accrual time is increased in multi-institutional studies (= 3 centers) as compared to single institutional studies (mean 25 vs 22.5 mos) but does not reach statistical significance (p=0.613). No correlation was seen between endpoint of the phase I trial (MTD vs OBD) and number of institutions. OBD studies were strongly associated with agents defined as “targeted”. Studies of cytotoxic agents defined the MTD in 99% of trials versus only 64% of agents categorized as targeted therapies (p<0.0001). Conclusions: Although there has been no increase in the number of published multi-institutional phase I studies, these multi- institutional trials accrue more patients only to reach the same study endpoint but at a cost of greater accrual time. The clinical value of multi- institutional phase I studies is not apparent. Supported by K23 CA109348–01 No significant financial relationships to disclose.
Effects of CYP2A6 genotype and plasma level of 5-chloro-2,4-dihydroxipyridine (CDHP) on pharmacokinetics (PK) of tegafur (FT) and 5-fluorouracil (5-FU) in the patients treated by S-1
Authors: Fujita K. , Yamamoto W. , Endo H. , Nagashima F. , Ichikawa W. , Miya T. , Araki K. , Kodama K. , Narabayashi M. , Sasaki Y. 
Published: March 2020

2504 Background: S-1, which is an oral anticancer agent comprised of FT, CDHP and potassium oxonate, is one of the most widely prescribed agents in the treatment of gastric and colorectal cancer in Japan. CYP2A6 is involved in the bioactivation of FT to 5-FU. Dihydropyrimidine dehydrogenase which is responsible for the detoxification of 5-FU is inhibited by CDHP to increase plasma exposure of 5- FU. The dose of S-1 is determined by body surface area (BSA) of the patients. We prospectively analyzed contribution of CYP2A6 genotype, plasma level of CDHP, and BSA on the PK of FT and 5-FU. Methods: Forty Japanese patients with metastatic/ recurrent cancers who received S-1 were enrolled. Genetic polymorphisms in CYP2A6 (*4, *7 and *9) related to deficient or reduced activity were analyzed. CYP2A6 genotypes were defined as wild (*1/*1), one-reduced allele (*1/*4, *1/*7 or *1/*9) and two-reduced alleles (*4/*4, *4/*7, *4/*9, *7/*7, *7/*9 or *9/*9). On the first day of the treatment, plasma concentration of FT, 5-FU and CDHP were measured. Multivariate linear regression analysis was used identifying association or correlation between oral clearance (CL/F) for FT or area under the time-concentration curve (AUC) for 5-FU and possible factors including CYP2A6 genotype, AUC for CDHP and patient’s characteristics including BSA. Results: CL/F for FT was significantly associated with CYP2A6 genotype (ANOVA, P=0.0000787, R2=50.1%), but not with other factors. CL/F for FT in patients with one- and two-reduced allele(s) were significantly lower than that in wild patients (P=0.0126 and 0.000128, respectively; Wilcoxon test). AUC for 5-FU was significantly correlated with AUC for CDHP (ANOVA, P=0.000534, R2=39%), but not with others. AUC for CDHP was correlated with creatinine clearance (Ccr) (ANOVA, P=0.00056, R2=27.2%). Conclusions: PK of FT and 5-FU are significantly affected by CYP2A6 genotype and exposure of CDHP, respectively. In addition, AUC for CDHP, which is correlated with Ccr, is the more critical factor to regulate AUC for 5-FU than BSA. Ccr-based dosing will be more rational than the conventional BSA-based dosing in the prescription of S-1. No significant financial relationships to disclose.
Cigarette smoking during irinotecan therapy: Effects on pharmacokinetics and neutropenia
Authors: de Jong F. A. , van der Bol J. M. , Mathijssen R. H. , Loos W. J. , Friberg L. E. , van Schaik R. H. , de Jonge M. J. , Planting A. S. , Sparreboom A. , Verweij J. 
Published: March 2020

2506 Background: Irinotecan is mainly metabolized by CYP3A-mediated oxidation to form inactive substances and by esterase- cleavage to form its active metabolite SN-38, which is further conjugated by UGT1A-isozymes. Variability in the pharmacokinetics of irinotecan is extensive and largely unexplained. Several constituents of cigarette smoke are known to interact with drug metabolizing enzymes, e.g. CYPs and UGTs, and potentially affect treatment outcome with substrate drugs. Here, we retrospectively explored the effects of cigarette smoking on the pharmacokinetics and adverse effects of irinotecan. Methods: A total of 190 patients (49 smokers and 141 non-smokers) were eligible and had received irinotecan as a 3-weekly 90-minute infusion. Individual pharmacokinetic parameters were obtained using NONMEM. Complete toxicity data were available in a subset of 134 patients receiving the registered dose of 350 mg/m2 irinotecan or its flat- fixed dose-equivalent of 600 mg. Results: In smokers, the dose-normalized area under the plasma-concentration versus time curve of irinotecan was significantly lower (15% reduction: median, 28.7 versus 33.9 ng×h/mL/mg; P =.001) compared with non-smokers. In addition, smokers showed an almost 40% lower exposure to SN-38 (median, 0.54 versus 0.87 ng×h/mL/mg; P<.001), and a higher relative extent of glucuronidation of SN-38 into SN-38G (median, 6.6 versus 4.5; P=.006). Smokers experienced considerable less hematological toxicity. In particular, the incidence of grade 3–4 neutropenia was 6% in smokers versus 38% in non-smokers (OR, 0.10; 95%CI, 0.02–0.43; P<.001). There was a non-significant 60% lower incidence of delayed-onset diarrhea in smokers (6% versus 15%; OR, 0.34; 95%CI, 0.07–1.57; P=.149). Conclusions: This study indicates that smoking cigarettes significantly affects both the pharmacokinetic and toxicity profile of irinotecan. Although the underlying mechanism is not entirely clear, modulation of CYP3A and UGT1A may be part of the explanation. The data suggest that further investigation is warranted to determine whether smokers are at increased risk for treatment failure indeed, as is suggested by the lower exposure to the active metabolite SN-38 and by the lower incidence of SN-38 exposure related neutropenia in smokers. No significant financial relationships to disclose.
Individual genotyping to optimize chemotherapy in metastatic colorectal cancer (MCRC): The COLOGEN trial
Authors: Falandry C. , You B. , Milano G. , Chatelut E. , Rebischung C. , Glehen O. , Mille D. , Delord J. , Lledo G. , Trillet-Lenoir V. , Freyer G. 
Published: March 2020

2510 Background: Thymidilate synthase (TS) and UGT1A1 genetic polymorphisms assessment helps to predict 5-FU efficacy and irinotecan toxicity - SN38 inactivation - respectively. We used this information to individualize MCRC first-line chemotherapy in the multi-centre COLOGEN trial. Methods: Were included first-line histologically proven MCRC patients (pts) aged 18–85, PS=2. Genotyping was performed on pts’ lymphocytes sampled at most 10 days before chemotherapy. Pts with 2R/2R or 2R/3R TS profile had subsequent UGT1A1 polymorphism determination. Those with 6/6 or 6/7 UGT1A1 profile received high dose bimonthly FOLFIRI (Irinotecan 260 mg/m2), whereas those with “defavorable” 7/7 polymorphism received standard FOLFIRI (Irinotecan 180 mg/m2). In pts with overexpressed TS (3R/3R), chemotherapy was left to investigator’s decision. Results: To date, 32 pts/65 planned have been included, aged 44 to 83 (mean: 65,2, median: 64). Six pts (19 %) had 3R/3R TS profile. Among those with 2R/2R or 2R/3R profile, 15 % (4/26) had defavorable 7/7 UGT1A1 profile. Median time for genotypic determination was 5 days for UGTA1 and 5 for TS. Treatment was: high-dose FOLFIRI, 23 pts (72 %); standard FOLFIRI ± bevacizumab, 3 pts (9 %); other regimens including capecitabine and/or oxaliplatin, 6 pts (16 %). Toxicities: we observed no toxic death. Serious adverse events were: febrile neutropenia (1, high dose FOLFIRI regimen) and grade 4 hypokaliemia (1, non FOLFIRI regimen). Eight patients over 70 years old and 3 over 80 received high-dose FOLFIRI without significant toxicity. Conclusions: Those preliminary results are the first ever reported on individual genotyping as a tool for treatment optimization in a multi-centre setting. This strategy appears clearly feasible and allows to safely intensify chemotherapy, even in elderly patients. No significant financial relationships to disclose.
Prognostic significance of nuclear excision (NER) and base excision (BER) DNA repair gene polymorphisms in esophageal cancer
Authors: Bradbury P. A. , Marshall A. L. , Kulke M. H. , Zhou W. , Heist R. S. , Su L. , Lynch T. J. , Shepherd F. A. , Christiani D. C. , Liu G. 
Published: March 2020

2511 Background: DNA repair pathways are involved in cisplatin-induced damage (NER pathway) & radiation damage (BER pathway). Some single nucleotide polymorphisms (SNPs) of DNA repair genes are associated with DNA repair capacity, cancer risk & outcomes. We investigated the prognostic significance of 7 NER/BER SNPs on disease free (DFS) & overall survival (OS) in esophageal cancer. Methods: 150 patients with esophageal cancer treated with cisplatin-based chemoradiation & surgery were genotyped for BER (XRCC1 Arg399Gln; APE1 Asp148Glu; hOGG1 Ser326Cys) & NER (ERCC1 8092C/A; ERCC1 codon 118 C/T; XPD Asp312Asn; XPD Lys751Gln) SNPs. Analysis involved Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models. Results: Median age: 63 years (range 28–80); 91% male; 100% ECOG performance status (PS) 0–1; adenocarcinoma 79%; stages IIA 22%, IIB 30%, III 33%, and IVA 15%. No SNPs were associated with stage or PS. Multiple NER SNP was independently prognostic for OS and DFS (see Table ). When compared to individuals who were wildtype in all four studied NER SNPs, individuals with variants in all four NER SNPs were associated with substantial improvement in OS (Adjusted Hazard Ratio (AHR) = 0.40, 95% confidence interval (CI) = 0.2–0.7) and DFS (AHR = 0.44, 95%CI = 0.2–0.8). Furthermore, increasing numbers of variant genotypes were associated with a progressive increase in OS & DFS when all seven NER/BER pathway SNPs were analysed together ( Table ). There was a 3.8- fold increase in OS (75 vs. 20 months) and five-fold increase in DFS (51 vs. 10 months) when comparing individuals with 6–7 SNPs with variant alleles to individuals with 0–1 SNPs with variant alleles. Conclusions: The ERCC1 8092 C/A, XPD Asp312Asn & XPD Lys751Gln SNPs in the NER pathway are associated individually with prognosis in esophageal cancer patients treated with cisplatin-based trimodality regimens. In addition, as the number of NER and BER SNPs carrying variant alleles increased, OS and DFS improved dramatically. [Table: see text] No significant financial relationships to disclose.
ERCC1 mRNA expression and XRCC1 polymorphism as predictive factors for overall survival in gastric cancer patients receiving platinum based chemotherapy
Authors: Wei J. , Liu B. , Zou Z. , Qian X. , Zhang W. , Yu L. 
Published: March 2020

2512 Background: DNA repair was considered to play the key role in the platinum chemotherapy. ERCC1, XPD and XRCC1, three major components of the DNA repair pathway, are critical to outcome for patients treated with platinum based chemotherapy. Methods: Overall survival times in 48 stage III (47.9%) and IV (52.1%) gastric cancer patients were investigated. mRNA was isolated from formalin- fixed paraffin-embeded pretreatment primary tumor specimens and the relative expression of ERCC1 to the internal reference geneβ-actin was measured using real-time quantitative reverse transcriptase polymerase chain reaction. Two single nucleotide polymorphisms (SNPs) (XPD Lys751Gln and XRCC1 Arg399Gln) were also investigated using 5’ nuclease allelic discrimination assay (TaqMan). Results: Median age was 55 years (range: 23 to 75 years); 35 males and 13 females; median survival time was 397 days. The median ERCC1 gene expression level from all 48 gastric tumors was 1.16, and the cutoff values for chemotherapy was 0.30. The median survival time for patients with lower ERCC1 expression (31 of 48 patients) was 496 days, compared with 218 days for patients with higher ERCC1 expression (P < 0.0001). SNP of XRCC1 Arg399Gln was measured in 47 gastric cancer patients (97.92%). Median overall survival time was longer in patients with favorite allele G in codon 399 of XRCC1 (40 of 47 patients) than in others (respectively 420 days vs 218 days, P = 0.017). No significant relationship was found between SNP of XPD Lys751Gln and outcome of gastric cancer patients. Conclusions: These findings suggested that intratumoral ERCC1 mRNA expression and polymorphism of XRCC1 might be prominent predictive factors for overall survival of gastric cancer patients treated with platinum based chemotherapy. Multi-center clinical trial has been suggested. No significant financial relationships to disclose.
Phase I evaluation of a 24-h infusion of TAS-106 every 3 weeks (wks) in patients (pts) with solid tumors
Authors: Takimoto C. H. , Ricart A. , Mita M. , Mita A. C. , Chu Q. , Tolcher A. W. , Sarantopoulos J. , Mita A. , Rowinsky E. K. 
Published: March 2020

2513 Background: The nucleoside 3’-C-ethynylcytidine (TAS-106) is metabolized in cancer cells to ethynylcytidine triphosphate (ECTP), an inhibitor of RNA polymerases I, II, and III. TAS-106 has potent anticancer activity in broad range of human tumor xenografts. In prior clinical studies, bolus intravenous (IV) TAS-106 caused reversible dose-limiting peripheral neuropathy and the recommended phase II dose (RP2D) was 4.21 mg/m2 every 3 wks. Myelosuppression, asthenia, and mild nausea and vomiting were also common. In rats, 24-h TAS-106 infusions are better tolerated with equivalent efficacy. Therefore, a Phase I study of 24-h infusions of TAS-106 was initiated. Methods: Escalating doses TAS-106 infused over 24-h every 3 wks were administered to cancer patients with pharmacokinetic (PK) monitoring during the initial cycle. Toxicity and response were assessed using NCI CTC (v2) grade (gr) and RECIST, respectively. Plasma and urine TAS-106 concentrations were monitored using LC/MS/MS methods. Results: Overall, 33 pts were treated at the following dose levels: 2.82 (4 pts), 3.5 (5 pts), 4.38 (6 pts), 5.48 (4 pts) 6.85 (6 pts) and 8.56 mg/m2 (8 pts). At 8.56 mg/m2, 2 of 5 pts experienced neutropenic DLTs (febrile neutropenia and gr 4 neutropenia lasting greater than or equal to 3 days) No neuropathy DLTs were observed. At 6.85 mg/m2, gr 3 peripheral neuropathy in cycle 1 was observed in 1 patient, but no other DLTs occurred in 5 patients. Other common drug related toxicities occurring in any cycle included gr 1–2 fatigue (13 pts), gr 3–4 neutropenia (10 pts), gr 1 hand/foot syndrome (9 pts), gr 2–3 anemia (9 pts) gr 1 rash/skin exfoliation (10 pts), and peripheral neuropathy gr 1–2 (5 pts). No objective responses were seen; although 3 pts with parotid, adenoid cystic, and breast cancers demonstrated stable disease for 5, 6, and 7 months, respectively. Plasma concentrations increased with increasing dose, and at 6.85 mg/m2, the Cmax was 77.4±7.3 ng/mL, AUC 1,892±54 ng·h/mL, CL 102±13 mL/h/kg, VDss 1.37±.05 L/kg, and t1/2 was 9.85±1.47 h. Over 48 h, 62.1% of the administered dose of TAS-106 was excreted into the urine. Conclusions: Compared with bolus dosing, 24-h infusions of TAS-106 are better tolerated with less peripheral neuropathy. The RP2D for TAS-106 infused over 24-h every 3 wks is 6.85 mg/m2. [Table: see text]
A phase I trial of E7974 administered on days 1, 8, and 15 of a 28-day cycle in patients with solid malignancies
Authors: Zojwalla N. J. , Takimoto C. H. , Lucarelli A. G. , Clark R. , Mita A. C. , Mita M. M. , Romero O. , Schuck E. L. , Krivelevich I. , Sweeney C. J. 
Published: March 2020

2543 Background: E7974 is a synthetic hemiasterlin analogue exhibiting binding to a and β tubulin. It induces disruption of spindle formation and mitotic arrest characteristic of anti-tubulin cancer drugs. Unlike taxanes and vincas, E7974 is a poor substrate for the PgP drug efflux pump, potentially overcoming this common mechanism of drug resistance. E7974 demonstrates broad anti-tumor activity against a number of human tumor xenografts. Methods: We conducted the initial Phase I trial using an accelerated dose escalation design to determine the maximum tolerated dose (MTD) and pharmacokinetic (PK) profile of E7974 administered IV over 2–5 minutes on Days 1, 8, and 15 of a 28-day cycle. Results: Sixteen patients (7 male, 9 female) with a variety of tumor types and a median age of 54 yrs.(range: 33–78 yrs) were treated at doses of 0.15 mg/m2, 0.21 mg/m2, and 0.29 mg/m2. In the accelerated phase, 0.15 mg/m2 and 0.21 mg/m2 were tolerated. At the 0.29 mg/m2 dose level, one patient experienced grade 4 neutropenia after Day 8. Expansion of the 0.21 mg/m2 dose level resulted in one patient experiencing grade 4 neutropenic fever. Two other patients experienced grades 2 and 3 neutropenia, resulting in delayed dosing beyond Cycle 1. Five additional patients were treated at 0.15 mg/m2; none experienced a DLT or dose delay, thus confirming 0.15 mg/m2 as the MTD. Other observed drug- related toxicities included mild to moderate fatigue, nausea, vomiting, constipation, neuropathy, and myalgias. The PK profile of E7974 can be characterized by moderate to large distribution (Vss = 50 - 133 L), slow clearance (CL = 1.4 - 9 L/hr) and moderate to slow elimination (t1/2 = 6.3 - 31 hr). Approximately 34 - 84% of the administered dose was recovered unchanged in the urine 48 hours post-dose. Stable disease was seen in one patient with colorectal cancer (6 cycles). The MTD cohort has been expanded to a total of 16 evaluable patients for confirmation of tolerability and PK. Conclusions: The recommended Phase 2 dose on Days 1, 8, and 15 of a 28-day schedule is 0.15 mg/m2. Observed toxicities were manageable and reversible. Enrollment is ongoing. [Table: see text]
Pharmacokinetic (PK) interactions between capecitabine (X), oxaliplatin (O) and bevacizumab (A) when used in combination for first-line treatment of metastatic colorectal cancer (MCRC)
Authors: Brennan B. , Siu L. , Dhesy-Thind B. , Cripps C. , Gandhi A. , Abt M. , Smith K. , Rittweger K. , Hussain S. , Choudhury S. 
Published: March 2020

2554 Background: X + O in combination (XELOX) has similar efficacy to FOLFOX-4 in untreated MCRC patients (pts) [1]. The addition of A to irinotecan/5-FU/LV improves progression-free survival (PFS) and overall survival [2], and the potential improvement of adding A to XELOX in MCRC is currently being investigated. Here we present the first PK evaluation of the effects of X on O, O on X, X+A on O, and O+A on X in a multicenter open-label study of pts with untreated MCRC. Methods: Pts received treatment for up to 16 cycles with blood samples for PK analysis taken during cycles 1–3. Treatment: cycle 1: X 1000 mg/m2 orally on morning of d1, O 130 mg/m2 i.v. infusion d2, X 1000 mg/m2 bid orally d5–14, rest d15–21; cycle 2: O 130 mg/m2 i.v. infusion d1 + X 1000 mg/m2 bid orally d1–14, rest d15–21; cycle 3 (XOA): A 7.5 mg/kg i.v. infusion d1 + O 130 mg/m2 i.v. infusion d1 + X 1000 mg/m2 bid orally d1–14, q3w. Treatment with the XOA regimen continued for a further 13 cycles. Safety was evaluated throughout. Results: 36 pts were enrolled; 26 pts completed cycles 1–3 and were evaluable for PK analysis; all pts were evaluable for safety. Baseline characteristics were: M/F 42%/58%; median age 60 years (range 22–74). The primary parameter for PK analysis of X, AUC0-8 of 5’-DFUR, was slightly lower in cycle 2 d1 (XO) and cycle 3 d1 (XOA) vs. cycle 1 d1 (X) (10% and 13% lower, respectively, with CV 27–33%); a decrease in the Cmax of 5’-DFUR was also observed (26% and 36% lower, respectively, with CV 48–54%). However these differences were not considered clinically important. The primary parameter for PK analysis of O, AUC0-8 of free platinum, was very similar among cycle 2 d1 (XO), cycle 3 d1(XOA), and cycle 1 d2 (O), with geometric mean ratios very close to 1. Treatment with X, O and A in combination was generally well tolerated. Conclusions: No large differences in exposure of X or its metabolites, free platinum or total platinum occur when X, O and A are administered in combination. This provides further support for the development of the above dosing regimen in MCRC. References: 1. Cassidy J et al. J Clin Oncol 2004;22:2084–91. 2. Hurwitz H et al. N Eng J Med 2004;350:2335–42. No significant financial relationships to disclose.