bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
Phase I combination study of plitidepsin and carboplatin in advanced solid tumours
Authors: Oaknin A. , Plummer R. , Salazar R. , Robinson A. , Pardo B. , Razak A. A. , Cuadra C. , Flores L. , Izquierdo M. A. , Calvert H.
Published: March 2020

2558

Background: Plitidepsin is a cyclic depsipeptyde isolated from the marine tunicate Aplidium albicans, nowadays manufactured by synthesis. It is a rapid and potent inductor of apoptosis. In phase I trials, muscle (myalgia and CPK increase) and liver toxicities were dose-limiting and preliminary activity was observed in malignant melanoma, renal, head and neck, lung, neuroendocrine, colorectal and hematological malignancies. Preclinical synergism with carboplatin (CBCDA) against solid tumors and acute leukaemia suggest plitidepsin can reverse platinum chemoresistance in vivo through reduction of glutathione levels. This phase I trial was initiated in order to evaluate the safety, pharmacokinetics (PK) and antitumour activity of the combination of CBCDA and weekly administration of plitidepsin (Recommended dose (RD) in monotherapy: 3.2 mg/m2). Methods: Patients (pts) with advanced solid tumours and good performance status (WHO PS = 2) were enrolled. Plitidepsin was given over 1 hr infusion on days 1 , 8 and 15 every 4 weeks followed by CBDCA (AUC 5) as a 1 hr infusion on day 1. Dose levels planned for plitidepsin were 1.8, 2.4 and 3.0 mg/m2 in cohorts of 3 pts. PK sampling was performed during the first cycle (cy) of treatment. Results: 18 pts have been treated to date (8M/10F). Median age (range): 59 (39–73) yrs. WHO PS>0: 3pts. Tumour types included colorectal (5), malignant melanoma (4), ovary (2), other gastrointestinal tumors (7). No DLT was observed at plitidepsin 1.8 and 2.4 mg/m2 (3 pts treated in each cohort). Two out of 5 pts exhibited DLT at pltidepsin 3.0 mg/m2, consisting of delay of second cy >2 weeks (grade 3 transaminitis and grade 3 thrombocytopenia) and omission of second infusion in first cy (grade 3 ALT increase). Plitidepsin at 2.4 mg/m2 was expanded to 8 pts. There were 4 pts with stable disease (cholangio, liver, colorectal, gatro-esophageal junction and esophagus carcinomas). Conclusions: The RD for the combination is plitidepsin 2.4 mg/m2 (0.8 mg/m2 lower than in monotherapy) days 1, 8 and 15 every 4 weeks followed by CBDCA (AUC 5). DLTs of the combination at the highest dose were different vs single plitidepsin (liver and haematological vs muscular). PK analyses from the three cohorts to detect interactions and updated safety data for the RD cohort are in progress.

[Table: see text]
Phase I clinical trial of ixabepilone and pegylated liposomal doxorubicin in patients with advanced breast or ovarian cancers: New York Cancer Consortium Trial P7229
Authors: Chuang E. , Vahdat L. , Caputo T. , Goldberg G. , Flam A. , Christos P. , Colevas A. , Muggia F. , Wadler S.
Published: March 2020

2570

Background: Ixabepilone (IX) is a semisynthetic epothilone B analog with activity in patients (pts) with taxane refractory cancer. Two phase III clinical trials in breast cancer (BC) and a phase II study in ovarian cancer (OC) have recently been completed. Pegylated liposomal doxorubicin (PLD) is used for the treatment of platinum refractory OC and has activity in patients with metastatic BC. Methods: We have completed enrollment of a phase I study of PLD IV and ixabepilone IV over 3 hours. 18 pts with metastatic cancer (10 BC and 8 OC) with median age 51 were enrolled from 1/13/06 to 12/22/06. A total of 60 cycles has been administered to date. 3 OC patients enrolled at dose level 3 have not yet completed 2 cycles of treatment and are not yet evaluable. Results: Dose limiting toxicities (DLT) based on toxicities experienced during the first 2 cycles is provided in the table below. Adverse events (AE) occurring in any cycle were: Grade 4 AE: neutropenia < 7 days (1 pt). Grade 3 AE: palmar plantar erythrodysesthesia (PPE) (4), mucositis (3), infection (2), fatigue (2), neutropenia (2), thrombocytopenia (2), anemia (1), neuropathy (1), bilirubin (1). Non-hematological grade 2 AEs included: mucositis (4), PPE (3), infection (2), neuropathy (2), rash (3), pain (3), fever (1), myalgias (1), and anorexia (1). Responses so far for 10 BC pts are PR (1) SD (3) PD (6) and for 5 OC pts are PR (1) SD (2) PD (2). Updated results will be presented. Conclusions: Although the recommended phase II dose when given every 3 weeks is 30 mg/m2 for PLD and 32 mg/m2 for IX by our criteria, PPE and mucositis became problematic when treatment was continued beyond 2 cycles. We are therefore exploring a 4 week PLD schedule, evaluating IX given either every 4 weeks (as shown) or weekly (on days 1, 8, and 15). A phase II trial of the combination in platinum refractory OC will be initiated upon completion of the phase I. Supported by N01-CM-62204

[Table: see text]

[Table: see text]
Phase I trial of KOS-1584 (a novel epothilone) using two weekly dosing schedules
Authors: Stopeck A. , Moulder S. , Jones S. , Cohen J. , McDowell M. , Cropp G. , Zhong Z. , Wells S. , Hannah A. , Burris H.
Published: March 2020

2571

Background: KOS-1584 is an epothilone with increased potency and improved pharmacologic profile (enhanced water solubility, tumor penetration and reduced CNS exposure). Methods: Define the MTD, toxicity, PK, pharmacodynamics (PD), and early activity of KOS-1584 when administered to pts with advanced malignancies via 1-hr infusion on one of 2 schedules: Days 1, 8 & 15 every 4 weeks and Days 1 & 8 every 3 weeks. PD: assessed by serial sampling of PBMCs for soluble and polymerized microtubules by immunoblot. Methods: 37 pts enrolled in 10 cohorts (0.8 - 25 mg/m2) on the 4-week schedule (22 F; median age/ECOG/prior regimens of 56, 1 and 4, respectively). One pt has been enrolled at 16 mg/m2 on the 3-week schedule. For the 4-week schedule: DLTs were observed at 20 and 25 mg/m2; the 16 mg/m2 cohort is being expanded (using antidiarrheal prophylaxis). All episodes of DLT except 1 involved diarrhea with increasing severity after successive infusions despite maximal supportive care; 1 pt had typhlitis upon biopsy. An ovarian cancer pt experienced DLT consisting of Grade 3 weakness, neutropenia and peripheral sensory neuropathy (this pt had high plasma drug concentrations, possibly related to pre-existing severe hypoalbuminemia and ascites). Common all-grade drug- related toxicities (n=37): nausea (51%), diarrhea, fatigue (both 49%), vomiting (32%), anorexia (24%), constipation (24%), peripheral sensory neuropathy (19%) and anemia (16%). Neutropenia/leucopenia (Grade 1–2) observed at 16–25 mg/m2 dose levels. Except for the DLT involving peripheral neurotoxicity, all neurotoxicity was mild-to-moderate. PK (n=37): t½ 28.1 ± 8.7, Vz 627 ± 291 L, CL 18.0 ± 8.3 L/h. Cmax/AUC (25 mg/m2): 1,069 ± 2,456 ng/mL, 3,764 ± 2,579 ng/mL*h. Dose proportional increase in AUC and Cmax observed. ↑polymerized microtubules observed with maximal effect at end of infusion. Antitumor activity: NSCLC (1pt: confirmed PR; 10 cycles), ovarian cancer (1pt: 40% ↓CA125; 6 cycles), and H&N (1 pt: SD), these pts had all received doses ≥ 7.5 mg/m2. Conclusions: Accrual continues to define the optimal dose on both schedules; use of aggressive anti-diarrheal prophylaxis has been implemented.

No significant financial relationships to disclose.
Clinical and Immunological responses in patients with malignant melanoma treated with a dendritic cell-based vaccine. Preliminary report from a multi-institutional phase II clinical trial
Authors: Ross M. , Camacho L. H. , Hersh E. M. , Brown C. K. , Richards J. , Mitsky P. , Wasserman E. , Lee S. , Bercovici N. , Landais D. , Ribas A.
Published: March 2020

3004

Background: We have previously reported that vaccination with IDM therapeutic vaccine (IDD-3/Uvidem [Uvidem is co-developed with SANOFI-AVENTIS]) composed of dendritic cells (DC) loaded with three allogeneic lysates from tumor cell lines can elicit immune and anti-tumor responses. We describe here the preliminary results from a phase II clinical trial in metastatic melanoma patients. Methods: DC-MEL-202 is a single arm, two-stage phase II trial designed to evaluate clinical and immunological activities and the safety of a multivalent DC vaccine in patients with in-transit or low volume metastatic melanoma. There was no HLA restriction. Autologous DC were generated, under GMP conditions, from monocytes cultured in GM-CSF and IL-13, loaded with three allogeneic melanoma tumor lysates (M44, SK-MEL 28 and COLO 829) and matured with a combination of bacterial extract (FMKP) and IFN-γ, generating up to 15 doses of the vaccine containing 25x106 DC. Patients received six bi-weekly and two 6-weekly injections (id and sc). Clinical responders were eligible to receive additional doses. Immune response against tumor-associated antigens (TAA) peptides was assessed, at several time points, by detection of IFN-γ producing cells by flow cytometry Results: 33 patients were treated. To date: Vaccination is well tolerated with toxicity limited to mild events (only one possibly related SAE, age-related macular degeneration, was reported). Clinical response (RECIST): 6 patients showed evidence of clinical benefit (1CR, 1PR and 4 SD) with duration of response ranging from 7.5 to 22 months. Assessment of pathological response in target sites in 2 pts (1 PR, 1 SD) showed no residual disease.. 23/33 patients are still alive with a mean follow-up of 11mo (range 3–22mo). Mature data of PFS and OS will be presented. Immune response: 21 (84 %) out of 25 evaluated patients showed detectable TAA-specific CD8+ T cells with ten showing boosted or appearance of anti-TAA specific CD8+ T cells. Conclusions: Vaccination with IDD-3/Uvidem is safe and can elicit tumor specific CD8+ T cells not limited to HLA-A2+ patients. Substantial clinical benefit warrants further development of IDD3.

No significant financial relationships to disclose.
A safety and efficacy trial of lethally irradiated allogeneic pancreatic tumor cells transfected with the GM-CSF gene in combination with adjuvant chemoradiotherapy for the treatment of adenocarcinoma of the pancreas
Authors: Laheru D. , Yeo C. , Biedrzycki B. , Solt S. , Lutz E. , Onners B. , Tartakovsky I. , Herman J. , Hruban R. , Piantadosi S. , Jaffee E.
Published: March 2020

3010

Background: Pancreatic cancer remains the fourth leading cause of cancer related deaths in the US in 2006. Surgical resection provides the only possibility of cure. A standard adjuvant treatment approach for patients with resected disease has not yet been determined. We have developed an irradiated GM-CSF transfected allogeneic whole cell line pancreas adenocarcinoma vaccine. We have previously reported a follow-up 60 patient study in this same population using the highest bioactive vaccine dose identified in the initial phase I study. Methods: Single institution phase II study of 60 patients with resected pancreatic adenocarcinoma administered a total of 5 vaccines using two pancreatic cancer cell lines each delivering 2.5 X 10 8 cells ID. Vaccine one was administered 8–10 weeks following surgical resection. Patients subsequently were treated with 5-FU CI based chemotherapy integrated with radiotherapy. Patients who were disease-free one month after completion of chemoradiotherapy received vaccines 2–4, each 1 month apart. A fifth and final booster vaccine was administered 6 months after vaccine 4. The objectives of the study were: 1. To estimate overall survival and disease-free survival in patients with minimal residual disease treated with adjuvant chemoradiotherapy in sequence with the irradiated allogeneic GM-CSF transfected pancreatic tumor cell lines. 2. To characterize toxicities associated with intradermal injections of the vaccine. Results/Conclusions: The study completed enrollment of new patients in January 2005. Median follow-up for these patients is approximately 36 months. 1) The administration of a GM-CSF allogeneic pancreas cancer vaccine is safe and well tolerated; 2) The median survival is approximately 26 months. These results compare favorably with published data for resected pancreas cancer; 3) A matched cohort analysis comparing patients enrolled on this adjuvant vaccine study to the Johns Hopkins Surgery database of patients receiving surgery followed by chemoradiotherapy alone will be presented at this meeting; 4) Immune correlates will be presented at this meeting.

No significant financial relationships to disclose.
Prospective evaluation of front-line chemo-immunotherapy (C-IT) with oregovomab (2 alternative dosing schedules) carboplatin-paclitaxel (C-P) in advanced ovarian cancer (OC)
Authors: Braly P. , Chu C. , Collins Y. , Edwards R. , Gordon A. , McGuire W. , Smith L. M. , Nicodemus C. , Method M.
Published: March 2020

3024

Background: Chemotherapy (C) induced bone marrow suppression has been assumed to inhibit the generation of augmented immune responses. This has limited investigation of front-line C-IT in OC. Temporal relationship of IT administration relative to C has not been established. Oregovomab is a CA125 specific MAb in development as an OC adjuvant treatment to induce tumor specific immunity. Methods: Patients (pts) awaiting staging laparotomy for presumptive OC were consented to the study and contributed primary tumor samples. Qualifying pts were subsequently randomized to concurrent C-IT with antibody administered at cycles 1, 3, and 5 (Arm A) or 8 ± 2 days following cycles 1, 3, and 5 (Arm B) of standard C-P. Both arms received additional infusions of oregovomab every 12 weeks until progression; response to C-IT was assessed at 36 weeks. Results: Forty stage III/IV pts (18 Arm A; 22 Arm B) were randomized and dosed. More pts in Arm A (39%) were stage IV vs Arm B (14%) however 27% of Arm B pts had >2cm residual disease vs. 11% in Arm A. Complete clinical response (CR) to surgery and C-IT was achieved in 15 pts (83%) in Arm A and 17 pts (77%) in Arm B. For pts with = 2 cm residual disease, 88% in Arm A had = 65 U/mL CA125 prior to/at cycle 3, normalized CA125 and a CR post C-IT compared to 75% of pts in Arm B. Robust Ab2 antibody response (>100 ng/mL) was achieved in 94% of Arm A and 68% of Arm B pts. The immune response developed earlier in Arm A. After one injection of oregovomab, 31% of pts in Arm A vs. 0% in Arm B generated HAMA > 3000 ng/mL and Ab2 > 100 ng/mL (P=0.016 Fisher’s Exact Test). Such an early and vigorous response pattern has not been seen in previous oregovomab studies which have not included concomitant front-line C. There were no IT related serious adverse events. Conclusions: Contrary to expectations, concurrent C-P resulted in enhanced immune stimulation with oregovomab. Interestingly, concurrent infusion of oregovomab was more immunogenic than delayed infusion. Clinical activity was favorable and safety profiles were similar to that expected for C alone. Further randomized evaluation of front-line CP-oregovomab vs CP is warranted.

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A phase Ib trial of atacicept (TACI-Ig) to neutralize APRIL and BLyS in patients with refractory or relapsed B-cell chronic lymphocytic leukemia (B-CLL)
Authors: Kofler D. M. , Elter T. , Gianella-Borradori A. , Busby S. , Wendtner C. M. , Hallek M.
Published: March 2020

3029

Background: B-CLL cells are resistant to apoptosis and thus exhibit prolonged survival and accumulation in vivo. Exogenously added soluble BLyS (B-Lymphocyte Stimulator) and APRIL (A PRoliferation-Inducing Ligand) have been shown to protect B-CLL cells from apoptosis in vitro. Nurse-like cells derived in vitro from CLL patients express high levels of APRIL and BLyS and thereby support CLL cell survival. Inhibition of APRIL significantly reduces CLL viability in vitro, indicating an important role for APRIL in this setting. Methods: This is an open-label, dose-escalation phase I trial to assess the safety, pharmacokinetics and biological effects of atacicept administered intravenously once weekly for 5 weeks to patients with refractory or relapsed B-CLL. Eligible patients are being enrolled in sequential cohorts of 3 to receive atacicept at 1, 4, 10, 15, 20 or 27 mg/kg. Evaluation of response is being assessed using NCI-WG criteria. Results: Preliminary results of the first 4 cohorts of the dose-escalation study are reported. Twelve CLL patients have entered the trial. No dose limiting toxicity has been observed and no SAE related to study drug has been reported to date. One case of mild nausea is the only drug-related toxicity reported to date. Three of six patients treated with 10 mg/kg and 15 mg/kg experienced a stabilization of their disease during the treatment period; prior to start of atacicept treatment, all had rapidly increasing leukocyte counts. One of these patients (10 mg/kg cohort), who was refractory to fludarabine therapy, has had stable disease according to NCI-WG criteria for over six months and is still receiving atacicept treatment. This same patient had a slight decrease (approximately 14% change from baseline) in absolute CLL cell concentration by Day 29 before final dosing. At lower dose levels all patients demonstrated progressive disease. Conclusions: Treatment with atacicept was well tolerated at the dose levels tested so far. The multiple cases of disease stabilization at higher dose levels in this heavily pre-treated patient population are promising, and support further study with atacicept in CLL. Accrual of patients at higher dose levels is ongoing.

No significant financial relationships to disclose.
BK viral infections in patients treated with alemtuzumab
Authors: Sharma K. , Wilson W. H. , Dunleavy K. , Shovlin P. M. , Chen H. X. , Janik J. E. , Gea-Banacloche J.
Published: March 2020

3033

Background: Alemtuzumab is a humanized monoclonal antibody against CD52 resulting in profound, prolonged T-cell depletion that may be associated with opportunistic infections and reactivation of latent viruses (e.g., CMV). BK virus is a polyomavirus that infects most humans during childhood and remains latent in the urinary tract. Reactivation of BK virus is an important cause of tubular nephropathy following renal transplantation and hemorrhagic cystitis after allogeneic stem cell transplant. Methods: A single institution pilot trial of alemtuzumab and Dose-Adjusted (D-A) Etoposide, Prednisone, Doxorubicin, Vincristine, and Cyclophosphamide (EPOCH) investigating efficacy and toxicity in chemotherapy naïve aggressive T- and NK-cell lymphomas was undertaken. BK virus was detected in urine by polymerase chain reaction (PCR) methods to quantify genomic copies in pts with dysuria and hemorrhagic cystitis. Results: Four of 20 pts treated with alemtuzumab and DA-EPOCH developed five episodes of hemorrhagic cystitis. One had grade 1 and 2 cystitis, two had grade 2 cystitis and one had grade 3 cystitis. In contrast, only one of over 200 pts treated with EPOCH alone or in combination with rituximab developed hemorrhagic cystitis. Hemorrhagic cystitis occurred at a median of 88 days after initiation of therapy and lasted a median of 22 days. Even if considered an unlikely cause, steps to minimize cyclophosphamide toxicity were taken; in one, mesna was given during the fifth cycle and cyclophosphamide was withheld from the final cycle of therapy. Another received a reduced dose of cyclophosphamide during the final cycle of therapy and the third did not receive the final cycle of therapy altogether. The fourth pt developed hemorrhagic cystitis after completion of therapy. PCR for BK virus showed a median of 8.87 x 108 (range 2.3 x 105-8.7 x 109) genomic copies per ml. Conclusions: Hemorrhagic cystitis secondary to BK virus reactivation may occur following Alemtuzumab therapy. Symptoms tend to abate after 1 to 7 weeks with conservative measures alone.

[Table: see text]

No significant financial relationships to disclose.
Prospective phase II study of post-surgical adjuvant chemo-immunotherapy using autologous dendritic cells and activated killer cells from tissue culture of tumor draining lymph nodes in primary lung cancer patients
Authors: Kimura H. , Iizasa T. , Ishikawa A.
Published: March 2020

3048

Background: We conducted a phase II study to evaluate the efficacy and toxicity of adjuvant chemo-immunotherapy using dendritic cells and activated killer cells from tissue culture of tumor-draining lymph nodes (TDLN) in primary lung cancer patients. Methods: Pathological N2 lung cancer patients were selected for the post-surgical adjuvant chemo-immunotherapy. Activated killer cells and dendritic cells obtained from tissue cultures of TDLN or TDLN co-cultured with peripheral blood lymphocytes (TDLN-Pb) were used for the adoptive transfer of immunotherapy. Patients received 4 courses of post-surgical chemotherapy or chemotherapy along with immunotherapy (immunotherapy group) every 2 months for 2 years. Results: There were 57 N2 patients eligible for the study, 28 for immunotherapy and 29 for chemotherapy. For the 28 immunotherapy cases, a total of 313 courses of immunotherapy were administered. The main toxicities were fever (78.0%), chill (83.4%). The 5-year survival rates in the immunotherapy and chemotherapy groups were 56.5% and 12.5% respectively. Among the variables analyzed, immunotherapy was the most significant independent prognostic factor (p=0.0042.) Conclusions: Adoptive transfer of activated killer cells and dendritic cells from the tumor draining lymph nodes of primary lung cancer patients is safe and feasible, and a large-scale multi-institutional study is necessary for the evaluation of the efficacy of this treatment.

No significant financial relationships to disclose.
A dose finding pharmacokinetic study of the tumor-targeting human L19-IL2 monoclonal antibody-cytokine fusion protein in patients with advanced solid tumors
Authors: Curigliano G. , Spitaleri G. , De Pas T. , Noberasco C. , Giovannoni L. , Menssen H. , Zardi L. , Milani A. , Neri D. , de Braud F.
Published: March 2020

3057

Background: L19-IL2 is a tumor targeting immunocytokine constituted by a single chain Fragment variable format directed against ED-B domain of fibronectin and the human cytokine interleukin-2 (IL-2). It has striking anticancer activity in preclinical models. We evaluated safety, pharmacokinetic profile (PK) and activity of L19-IL2 in advanced cancer patients. Patients and Methods: Five cohorts of patients with recurrent/refractory solid tumors received a dose escalation intravenous infusion of L19-IL2 (5, 10, 15, 22.5 e 30 Mio IU IL2 equivalent dose) on days 1, 3 and 5 every 21 days. Serum samples for PK assessment, immunophenotyping and assays for detection of human antifusion protein antibodies to L19 (HAFA) were collected at screening and on day 1, 3, 5 and 10 of each cycle. Results: Eighteen solid cancer patients were enrolled from 11/05 to 9/06 (6 colorectal and 3 renal cell cancer (RCC) patients, 3 with melanoma, and 1 neuroendocrine tumor, thymic carcinoma, biliary tract carcinoma, breast cancer, peritoneal mesothelioma and parotid gland carcinoma). Median age was 49 years (range 35–69), 14 patients were male and 4 female. All patients were evaluable for safety and activity. The maximum tolerated dose was determined to be 22.5 Mio IU IL-2 equivalent. Drug-related dose-limiting toxicities at 30 Mio IU L19-IL2 were hypotension requiring vaso-pressor support and acute renal failure. Treatment-related deaths did not occur, and all toxicities were reversible. Five patients achieved stable disease (RCC, n=3; biliary tract carcinoma, n=1; peritoneal mesothelioma, n=1). All other patients progressed. Immunophenotyping disclosed IL2-typical transient activation of T-cell subsets. Very preliminary data showed a weak induction of HAFA at day 10 in 5 patients. These data could not be confirmed by competition ELISA experiments. Conclusions: Up to 22.5 Mio IU IL2 equivalent of L19-IL2 can be safely administered to advanced solid cancer patients in an outpatient setting. Some evidence of clinical activity in patients susceptible to immunomodulatory therapy (RCC) was found. All observed toxicity was mild and reversible. An expanded study at recommended dose in RCC patients is currently ongoing.

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Assessment of circulating tumor cell (CTC) patterns among disease-free breast cancer patients vaccinated with a preventive HER2/neu E75-peptide vaccine
Authors: Amin A. , Stojadinovic A. , Holmes J. P. , Storrer C. E. , Smith A. M. , Jama Y. H. , Craig D. , Ponniah S. , Peoples G. E.
Published: March 2020

3059

Background: The quantity of CTC and post-treatment reduction predict outcome in medically treated metastatic breast cancer patients (BCa); however, the impact on survival of CTC in patients at risk for recurrence rendered free of disease after multimodality treatment is unknown. We conducted a pilot study to assess CTC in clinically disease-free node-positive (NP) BCa patients, and to determine the effect on CTC of vaccination with the immunogenic HER2/neu peptide E75. Methods: The CellSearch System (Veridex, LLC Warren, NJ) was used to enumerate total CTC and HER2/neu+ CTC in 20 ml of blood from selected samples obtained from patients (n=16) throughout and after the E75 vaccination series. Standard prognostic factors were collected on these patients as were measures of their immunologic response to the vaccine. Results: 14/16 patients (88%) had at least 1 CTC and 10/16 (63%) had 2 or more CTC identified. Standard clinical prognostic factors (tumor size, grade, lymph nodes and HER2/neu overexpression) did not correlate with number of CTC. Thus far, 9 patients have had multiple samples collected prior to, during and/or after the vaccine series. Early levels of CTC were significantly higher (mean±SE=5.2±0.5) vs. post-vaccination levels (0.3±0.1, p=0.005). Levels of HER2/neu+ CTC were also significantly different (early 3.4±0.3 vs. post 0.4±0.1, p=0.01). All patients showed a decline in CTC from early to post levels while demonstrating HER2/neu immunity as measured by DTH to the E75 peptide post- vaccination (22.9±1.8 mm vs. control 4±0.9 mm, p=0.006). Conclusions: CTCs are readily demonstrated in clinically disease-free NP BCa patients. Prognostic indicators do not seem to correlate with the number of CTCs. CTCs decline during the course of vaccination. These data suggest a potential role for the CTC assay in assessing response to preventive vaccine-based immunotherapy. The views expressed in this abstract are those of the authors and do not necessarily reflect the official policy or position of the Departments of Army or Navy, Department of Defense or the U.S. Government.

No significant financial relationships to disclose.
Cytotoxicity of bevacizumab is enhanced by β-glucan in tumors expressing membrane-bound VEGF
Authors: Salvador C. , Li B. , Hansen R. , Cramer D. , Yan J.
Published: March 2020

3060

Background: Bevacizumab (B-Mab) is a murine-derived monoclonal antibody with human IgG1 framework against vascular endothelial growth factor (VEGF). Soluble PGG β -glucan functions with complement activation product iC3b to activate complement receptor 3 (CR3) and recruit neutrophils and macrophages leading to CR3 (iC3b-receptor)-dependent cytotoxicity of tumors coated with iC3b. In mouse xenograft models, PGG β-glucan has a synergistic effect with human anti-tumor antibodies. Consequently, we hypothesized that the IgG1 antibody B-Mab is capable of binding surface VEGF (sVEGF) on tumor cells thereby activating complement, and synergizing with PGG β-glucan to elicit CR3-dependent cytotoxicity. Methods: SCID mouse xenografts with SKOV-3 human ovarian carcinoma cells were established in groups treated intravenously as follows: PBS treated as control (C), PGG β-glucan alone (B), B-Mab alone (A) and combination PGG β-glucan + B-Mab (B+A), twice weekly for 4 weeks. After implantation, tumors were allowed to grow until they were 300 mm3 before treatment. Results: SKOV-3 tumors in SCID mice showed sVEGF expression and had a complement deposition after B-Mab treatment. In vitro CR3-dependent cytotoxicity assay of B-Mab alone and B-Mab plus active moiety of β-glucan resulted in 0.2% and 19% cytotoxicity respectively. Tumor-bearing SCID mice treated with combination (A+B) showed significant difference in tumor growth inhibition and long-term survival as compared to the other treated groups. Moreover, neutrophil infiltration was markedly increased in the combination (A+B) group compared to the other groups. Conclusions: We have shown that combination treatment with bevacizumab and β -glucan imparts synergistic tumor cytotoxicity that achieves growth inhibition of VEGF-expressing tumor in vivo. Combination therapy should be considered as a potential therapeutic approach in patients with sVEGF positive tumors. (Supported by NIH grant RO1 CA86412 and gift research fund from Biothera, Inc.)

No significant financial relationships to disclose.