bluuebunny/crossref_metadata_2025 huggingface dataset:
Polymorphisms in UGT1A gene family and irinotecan toxicity in patients with advanced colorectal cancer
Authors: Chiara S. , Lastraioli S. , Marroni P. , Gargiulo L. , Leonardi F. , Ponzanelli A. , Franzini E. , Boni L. , Paganuzzi M. , Notaro R.
Published: March 2020

13049

Background: The irinotecan active metabolite, SN38, is inactivated through glucuronidation mainly by uridine diphosphate glucuronosyltransferase (UGT) 1A1. The (TA)7 allele of a polymorphism in UGT1A1 promoter has been associated with reduced SN38-glucuronidation rate and more severe toxicity. Since other UGT1A family isoforms, the extrahepatic UGT1A7 and the hepatic UGT1A9, are involved in SN38 glucuronidation, it has been suggested that also polymorphic variants of these genes may affect irinotecan toxicity. Methods: 84 patients with advanced colorectal cancer received an irinotecan-based (180 mg/m2 q.2wks) combination treatment. Polymorphisms of UGT1A1 [(TA)6>7], UGT1A7 [387T > G, 391–2CG > AA, 622T > C] and UGT1A9 [-118(T)9>10, -87G > A, 98T > C, I152G > A] were identified by sequencing on DNA from blood samples obtained under an IRB approved protocol. Toxicity has been graded according to NCI-CT criteria. Results: Patient median age was 64 y (range: 31–82); median PS was 0 (range: 0–2). Severe toxicity (diarrhea or/and neutropenia ≥G3) has been observed in 32 patients: diarrhea in 11, neutropenia in 25 (4 patients had both). The estimated allele frequencies were as follows: UGT1A1, (TA)7 (0.35); UGT1A7, 387T and the completely linked 391–2CG (0.39), 622C (0.39); UGT1A9, -118(T)10 (0.39), -87A (0.05), T98C (0.02), I152A (0.21). Severe toxicity was significantly associated only with: (a) the UGT1A1 (TA)7 allele [severe toxicity in 25% of (TA) 6/6, in 46% of (TA) 6/7, in 55% of (TA) 7/7 (Mantel-Haenszel trend test, P < 0.03)]; and (b) the low activity UGT1A7 622C allele [severe toxicity in 26% of 622 T/T, in 39% of 622 T/C, in 67% of 622 C/C (Mantel-Haenszel, P < 0.02)]. In addition, the analysis of the combined genotypes [(TA)6>7 and 622T > C] has shown severe toxicity in 21% of patients with none of (TA)7 and of 622C alleles, in 43% of patients in which the sum of the number of (TA)7 and of 622C alleles is 1 or 2, in 57% of patients in which this sum is ≥3 (the latter includes all patients with both toxicities) (Mantel-Haenszel, P < 0.02). Conclusions: These data show that both the low activity UGT1A1 (TA)7 and UGT1A7 622C alleles are significantly associated with irinotecan severe toxicity. It is to evaluate if their combined genotype may be a better predictor of toxicity.

No significant financial relationships to disclose.
Preclinical pharmacodynamic studies of Aurora A inhibition by MLN8054
Authors: Galvin K. M. , Huck J. , Burenkova O. , Burke K. , Bowman D. , Shinde V. , Stringer B. , Zhang M. , Manfredi M. , Meetze K.
Published: March 2020

13059

Background: The mitotic kinase Aurora A is implicated in the development of multiple tumor types. MLN8054 is an oral, potent and selective small-molecule inhibitor of Aurora A with broad efficacy in preclinical models of cancer. Inhibition of Aurora A by MLN8054 induces accumulation of mitotic cells, followed by apoptosis. This study explores relationships between Aurora A inhibition, mitotic index, and tumor growth inhibition for xenograft models with different sensitivity to MLN8054. The marker response in mouse skin was also studied. Methods: Mice bearing subcutaneous xenografts were dosed orally qd or bid with MLN8054 for 21 days. Pharmacodynamic markers were studied after 1–2 doses. Formalin-fixed xenograft tissues were stained with the mitotic markers pHisH3 and MPM2, or with an antibody to the T288 autophosphorylation site on Aurora A. Tumor growth inhibition (TGI) was calculated using the formula 100 - [ΔT/ΔC * 100], where ΔT is the volume change for treated tumors, and ΔC is the volume change for control tumors. Results: HCT116 human colon xenografts were sensitive to MLN8054 on a qd or bid schedule (84% and 96% TGI respectively for 30mg/kg dose). The T288 autophosphorylation site was used to directly demonstrate inhibition of Aurora A, which resulted in dose-dependent duration of the elevation in mitotic index. Efficacy was similar for qd vs bid dosing of 30mg/kg MLN8054, and accordingly we found that a single dose was sufficient to elevate the mitotic index for about 20–24h in this model. SW480 human colon xenografts have MLN8054 sensitivity similar to that of HCT116, but more modest effects on mitotic index were observed. The mitotic index profile of SW480 is similar to that of MDA-MB-231 xenografts, the most insensitive model studied. Elevated mitotic index was also observed in mouse skin. Conclusions: We found that mitotic index measurements coupled with the T288 autophosphorylation site as a direct marker of Aurora A activity are useful for monitoring inhibition of Aurora A by MLN8054 in tumor and/or skin biopsies. In a sensitive model, greater duration of mitotic index elevation results in greater efficacy. Our continuing work aims to better understand the differences in marker and efficacy responses between xenograft lines, incorporating the pT288 antibody as a direct marker of Aurora A inhibition.

[Table: see text]
Impact of polymorphisms in the CYP2B6 gene on the pharmacokinetics of cyclophosphamide and thiotepa
Authors: Ekhart C. , Huitema A. , Rodenhuis S. , Beijnen J. H.
Published: March 2020

13062

Background: Cyclophosphamide and thiotepa are frequently used simultaneously as part of high dose chemotherapy regimens for solid tumours. Although generally well tolerated, severe toxicity may occur. Relationships between pharmacokinetics and toxicity have been identified. Cyclophosphamide and thiotepa are both metabolised by cytochrome P450 (CYP)enzymes, resulting in the active metabolites 4-hydroxycyclophosphamide and tepa respectively. CYP2B6 and CYP3A4 are the major metabolising isozymes for both compounds. In this study we investigated the relationship between polymorphisms of the CYP2B6 gene and the hepatic clearance of cyclophosphamide and thiotepa in order to identify a priori patients at risk for severe toxicity. Methods: CYP2B6*2 (C64T) and variants A785G, C1459T and G516T were identified by PCR and sequencing samples from 82 patients receiving a high dose regimen consisting of cyclophosphamide (4–6 g/m2), thiotepa (320–480 mg/m2) and carboplatin (AUC 13–20 mg*min/ml). Plasma concentrations of thiotepa, cyclophosphamide and metabolites were determined using a validated LC-MS/MS method. Individual pharmacokinetic parameters were obtained using nonlinear mixed effects modelling. Results: A total of 82 patients was included. Not all data of the various variants were available. All investigated variants had an allele frequency of > 3% in the population. While 94% of the patients had the wildtype genotype for CYP2B6*2, 6% were heterozygous. Heterozygous patients for *2 had a lower hepatic clearance of thiotepa compared to wildtype patients (11.7 l*h−1 vs 14.4 l*h−1) (P=0.03). All other allelic variants investigated showed no effect on either hepatic clearance of thiotepa or cyclophosphamide. Conclusions: This study demonstrates that the hepatic clearance of thiotepa is reduced in patients with a heterozygous CYP2B6*2 genotype. Patients with this genotype may have an increased exposure to thiotepa and may, therefore, be at increased risk for organ toxicity.

No significant financial relationships to disclose.
Correlation between thymidylate synthase (TS) genotype, clinical outcome, and TS mRNA expression in subjects treated with oxaliplatin (OX) and capecitabine (Cape)
Authors: Grem J. L. , Nguyen D. , Uchida K. , Salonga D. , Danenberg K. D. , Danenberg P. V.
Published: March 2020

13073

Background: TS mRNA has a unique tandemly repeated 28-base pair sequence in the 5’ UTR & is polymorphic in the number of this repeat (2 or 3). Homozygosity for the 3-repeat sequence has been associated with increased TS protein content in tumor samples, & decreased likelihood of clinical benefit with TS-directed therapy. This study assessed the possible association of TS genotype with clinical outcome in subjects receiving OX &Cape in an IRB-approved Phase I clinical trial. Methods: Pre-therapy genomic DNA was isolated from peripheral blood mononuclear cells in 88 subjects treated with OX 130 mg/m2 day 1 & Cape 600–1500 mg/m2 twice daily days 1–5 & 8–12 every 3-weeks. The number of tandem repeats was determined by the size of the PCR-amplified DNA fragments by staining after 3% agarose gel electrophoresis. The genotype was also compared to TS mRNA expression that was previously determined by quantiitative real-time PCR in microdissected specimens of metastatic tumor tissue. Results: The majority of subjects participating in this trial had colorectal cancer, & most had prior 5-FU & irinotecan (median of 2 prior chemotherapies). The distribution of TS genotypes among 84 informative samples was 2/2, 12%; 2/3, 70%; 3/3, 18%. The objective response rate (CR + PR) according to genotype was 22% (2/2), 21% (2/3) & 13% (3/3). No appreciable difference was seen in the median time to treatment failure (150 vs 156 vs 156 days) or median survival (379 vs 323 vs 332 days) among the 2/2, 2/3 or 3/3 genotype cohorts. There was no significant difference in the distribution of TS intratumoral gene expression according to TS genotype: median (25th & 75th percentiles): 2/2, 3.96 (2.93, 5.3); 2/3, 4.11 (2.52, 6.62); & 3/3, 2.66 (1.73, 5.23). Conclusions: In this study involving mostly pre-treated subjects with colorectal cancer receiving OX/Cape, those homozygous for 3-tandem repeats in the 5’ UTR of TS did not experience a significantly worse clinical outcome. There was no relation between TS genotype in genomic DNA & TS mRNA expression in tumor tissue; this observation is consistent with information suggesting that the 3-repeat sequence of TS mRNA increases translational efficiency.

[Table: see text]
In vivo synergy combining oxaliplatin with AVE8062, a vascular-disrupting agent
Authors: Demers B. , Vrignaud P. , Bissery M.
Published: March 2020

13074

Background: AVE8062 is a synthetic, water-soluble compound, analog of Combretastatin A4, currently in Phase I clinical trials. It inhibits tubulin polymerization through binding to the colchicine site of tubulin. In vivo, it induces rapid tumor blood flow shutdown and necrosis, leading to tumor regressions (Proc AACR, 2002). Previously (Proc AACR, 2003), we reported a high synergy resulting from the combination of AVE8062 with either cisplatin or carboplatin in a preclinical in vivo model. We report here the combination data of AVE8062 with oxaliplatin. Methods: A 3-arm dose-response study was performed comparing the single agents and their combination. Synergy was defined as a log cell kill (lck) of at least 1 log superior to the lck of the best single agent. The AVE8062 / oxaliplatin simultaneous combination was evaluated in female BALB/c mice bearing advanced stage (250mg) SC murine colon C51 adenocarcinoma. Drugs were administered IV with 2 intermittent injections, 4 days apart. The combination arm was evaluated over 7 dose levels. Results: At the Highest nontoxic dose (HNTD - 58 mg/kg/inj), AVE8062 was found active: 0.9 lck, 1/5 partial regression (PR) and no complete regression (CR). At the HNTD (7 mg/kg/inj), oxaliplatin was found highly active [5.8 lck, 5/5 CR, no tumor free survivors (TFS)]. The HNTD for the combination (58 mg/kg/inj of AVE8062 with 7 mg/kg/inj of oxaliplatin) was well tolerated with 11.7% body weight loss at nadir. The combination was highly active over the 2 highest dose levels with TFS on day 148 post tumor implantation (4/6 TFS at combination HNTD and 6/6 TFS at 80% HNTD). A high antitumor activity was maintained at 60% HNTD (5.9 lck, 6/6 CR and no TFS). The lowest dose tested, corresponding to 1/10 of the HNTD fractions, was found active with a lck of 1.0 and no regression. Conclusions: The combination of AVE8062 with oxaliplatin was found highly synergistic (superior activity than either of the single agents alone). The combination was well tolerated with a combination toxicity index of 2, indicating that there was no overlap in host toxicity. These data provide a good rationale to perform Phase I combination trials combining AVE8062 with oxaliplatin.

[Table: see text]
Model development of human sarcomas for identification and validation of new targets
Authors: Bagley R. G. , Rouleau C. , Weber W. , Cao X. , Teicher B. A.
Published: March 2020

13080

Background: Soft tissue sarcomas are malignant tumors that can develop from a variety of tissues. There is a lack of targeted therapies directed specifically against sarcomas with surgery, radiation, and chemotherapy being the standard of care. By employing multiple strategies, new targets that may advance sarcoma therapy can be identified. Methods: Profiling of secreted cytokines that may drive tumor growth was performed on cell lines representing osteosarcomas, liposarcomas, fibrosarcomas, and rhabdomysarcomas. Of 27 cytokines analyzed from cultured media, the following were most highly expressed: IL-6, IL-8, IL-12p40, SDF-1, and MCP-1. Results: Results were compared against gene expression data from publicly available oligonucleotide microarrays derived from human tumors. Ewing’s sarcoma and rhabdomysarcoma samples confirmed higher expression levels of VEGF. Further analysis of array data from 16 classes of sarcomas and 181 tumors indicated that IL-7 was more predominantly expressed than IL-6 and IL-8. To evaluate efficacy of novel agents, xenograft models were established using human cell lines A673 rhabdomyosarcoma and SW872 liposarcoma. Tumor growth and response to therapy was characterized. Paclitaxel (75 mg/kg, days 7, 9, 11) delayed tumor growth for about one week following treatment in both models, however only SW872 liposarcoma tumors responded after dosing with anti-angiogenic agent, Avastin (5 mg/kg, days 4, 7, 11, 14, 17, and 21). Conclusions: In addition to killing cancer cells, destabilization of the vasculature/stroma may be beneficial. Immunohistochemical (IHC) analysis was performed on sarcoma tumors from the clinic. CD31 and SMA staining identified vasculature and stromal regions. Subsequent to identification of novel targets specific to sarcomas, IHC methods can further define localization of antigens between various tumor components. A variety of techniques are being utilized in order to recognize new targets in sarcomas. Cell-based assays and preclinical models are incorporated into the drug development pathway to evaluate novel drugs. Analysis of differential gene expression between tumor types and amongst sarcoma subtypes will be essential in identifying which patient population will gain the greatest benefits from targeted therapies.

[Table: see text]
A phase I trial of erlotinib (E), cisplatin (C) and radiotherapy (RT) for patients with locally advanced squamous cell cervical cancer
Authors: Ferreira C. G. , Salgado M. , Lima R. , Viegas C. , Small I. A. , Fontão K. , Herchenhorn D. , Madeira D. M. , Martins R. G. , Rodrigues A. N.
Published: March 2020

13081

Background: Pre-clinical data indicates that inhibition of epidermal growth factor receptor (EGFR) potentiates the effect of RT. This phase I trial aims to determine the maximal tolerated dose (MTD) of erlotinib, an oral EGFR tyrosine kinase inhibitor, when administered concurrently with standard chemoradiation (CRT) for cervical cancer. Methods: In a modified Fibonacci design, two cohorts of three patients received escalating doses of E (50 mg/100 mg) one week before and combined with C (40 mg/m2, weekly, 5 cycles) and RT (external beam RT - 5040 cGy in 28 fractions, followed by 4 fractions/700 cGy/weekly of brachytherapy). Eligibility criteria included histologically proven squamous cell cervical carcinoma, stage III; no prior therapy; ECOG PS <3 and adequate end-organ functions. Patients were allowed four additional weeks of toxicity observation after CRT + E before proceeding to the next cohort. Frozen tissue for molecular studies was collected before treatment. Results: Considering the first two cohorts, patients presented median age 48 (36–59), stage IIIB (all patients). Median duration of treatment was 71 (70–104) days. Most common non-hematological toxicity were mild to moderate rash, fatigue, diarrhea (grade 3 in one patient), nausea and dysuria. Grade 3 leukopenia was observed in only one patient. Dose limiting toxicities have not been reported so far. Five patients had complete response and one patient had partial response (MRI). Of note, 5/6 patients reported clinical benefit (bleeding cessation) after one week on E alone. The third study cohort (E = 150 mg) is ongoing. Conclusions: This is the first report of a combination of erlotinib, cisplatin and pelvic RT. The addition of E to standard CRT does not appear to increase in-field or systemic toxicities. MTD has not been defined so far. Final results of the phase I will be presented at the meeting.

[Table: see text]
A Phase I pharmacokinetic (PK) study of single dose oral therapy with a uPA inhibitor (WX-671)
Authors: Bevan P. , Mala C. , Buergle M. , Schmalix W. A. , Neville N. G.
Published: March 2020

13091

Background: WX-671 is an orally available prodrug of WX-UK1, a serine protease inhibitor that inhibits uPA as well as other serine proteases. WX-UK1 (Setyono-Han et al., Thromb Haemost 2005) and WX-671 have shown to efficiently reduce primary tumor growth and metastasis formation in a variety of animal models. First PK and safety data of the prodrug WX-671 were obtained in healthy volunteers. Methods: Male healthy volunteers received WX-671 as hydrogen sulfate given as single oral doses corresponding to 50, 100, 200 and 400 mg WX-671 free base. Each subject received two single doses, the first dose pre-prandially and the second dose one week later post-prandially. PK profiles were obtained over 48h for both the prodrug WX-671 and the active metabolite WX-UK1. Safety was assessed by measuring vital signs, laboratory parameters (hematology, blood chemistry, coagulation) and ECGs. Results: 16 healthy male volunteers were included, four per dose level. Both the Cmax levels as well as the plasma AUCs of both WX-671 and WX-UK1 were overproportionally related with dose levels. Administration with food slightly increased AUCs at the two higher doses. Terminal phase half life was fairly constant for WX-671 at all doses (approximately 5.8 h) and for WX-UK1 at least in the two highest dose groups with 17–21 h. Four subjects out of 16 (25%) experienced a total number of 11 adverse events. These events were nervous system disorders (headache, 7 events) and gastrointestinal disorders (diarrhea, 2 events; flatulence, 2 events). All adverse events occurred at the lower dose levels of 50 mg and 100 mg WX-671. No adverse events were observed at the dose levels of 200 and 400 mg WX-671. All adverse events were rated as mild and all subjects completely recovered within a maximum time period of 18h. Conclusions: The administration of oral doses of WX-671 (as hydrogen sulfate) resulted in the formation of WX-UK1 in the plasma uniformly across all individuals. At all dose levels tested, WX-671 was well tolerated systemically as judged by assessment of vital signs, ECG, general safety laboratory and coagulation data as well as by adverse event profiles. Two phase I PK and safety studies with daily dosing over 15 days at the above tested dose levels are currently ongoing, one in healthy volunteers and the other in patients.

[Table: see text]
A phase I study of bexarotene and rosiglitazone in patients with refractory cancers
Authors: Read W. L. , Baggstrom M. Q. , Adkins D. , Suresh R. , Ghalie R. , Wildi J. , Govindan R.
Published: March 2020

13094

Background: Preclinical studies have shown that ligands of the PPAR-γ receptor can slow growth and promote differentiation of malignant cells. Rosiglitazone is a high affinity PPAR-γ ligand approved for treatment of insulin resistant diabetes. After binding ligand, the PPAR-γ receptor heterodimerizes with the RXR receptor. Bexarotene is an RXR ligand with cytostatic properties similar to those of PPAR-γ agonists. Ligands of RXR and PPAR-γ are synergistic, causing cell differentiation and apoptosis. Methods: We conducted a phase 1 study of bexarotene and rosiglitazone in patients with resistant malignancies to define the MTD of rosiglitazone in this regimen. Patients received bexarotene 300 mg/m2 daily. The starting dose of rosiglitazone was 4 mg/day. This dose was escalated in five cohorts using the modified Fibonacchi scheme (4–6-8–10–12). Both drugs were continued until disease progression or toxicity. Patients received atorvastatin 10 mg daily, which was increased based on weekly triglyceride levels. Results: We enrolled 23 patients without encountering dose limiting toxicity. After reaching 12 mg/day of rosiglitazone, the study was closed because of laboratory evidence showing no further synergy at higher doses. Patient Characteristics: Histological type: NSCLC 8, sarcoma 3, prostate 2, and others (SCLC, thyroid/breast, mesothelioma, esophageal, breast, colorectal, renal, parotid, transitional cell, cervical). Median cycles of treatment delivered 1 (range 0–4). The primary serious adverse events (grade 3 or 4) were hyperglyceridemia (17%), dyspnea (9%), nausea (9%), dehydration (9%). Two patients expired, both due to disease progression. Responses: CR/PR none, SD 3, disease progression 14, not evaluable 4, patient withdrawal 2. Conclusions: The combination of bexarotene (300 mg/m2/day) and rosiglitazone (12 mg/day) is safe and feasible. No responses were seen in this heavily pretreated population, which is not surprising given that both agents are cytostatic, rather than cytotoxic. This combination might be studied in cutaneous T-cell lymphoma, or as adjuvant/maintenance therapy in other malignant diseases. Other areas for study might include inflammatory diseases where PPAR-γ ligands have activity. This study was supported by Ligand pharmaceuticals.

[Table: see text]
Phase I trial of a histone deacetylase inhibitor (HDACI) and retinoid acid (RA) in patients (pts) with advanced solid tumor malignancies
Authors: Atieh D. M. , Milowsky M. I. , Cobham M. , Kaplan J. , Smith C. , Gudas L. J. , Nanus D. M.
Published: March 2020

13114

Background: Transcription of RA responsive genes is inhibited by co-repressor complexes which have HDAC activity. Pre-clinical data demonstrates that addition of an HDACI to RA enhances transcription of genes that augment anti-tumor and differentiation response, and results in tumor inhibition in a RCC model (Clin Cancer Res. 2005;11:3558). Valproic Acid (VPA) has potent HDCAI activity and ATRA-IV is a liposomal RA with excellent bioavailability. The objective of this trial is to determine safety, pharmacokinetics (PK) of combination therapy, as well as correlative studies of RA receptor expression and histone acetylation status. Methods: Adults with a refractory metastatic solid tumor malignancy, KPS >60%, adequate organ function, life expectancy >3 months are eligible. 3-pt cohorts in a 2-step dose escalation: Oral VPA (Abbott Pharmaceutical) is dosed (starting at 10 mg/kg/d every 8 hrs) until trough VPA serum concentration of 50–80; 80–100 and 100–120 μg/ml. IV ATRA (Antigenics) is then administered at 60mg/m2 IV weekly. Once VPA MTD is determined, ATRA-IV is then escalated to 90, 120 and 140 mg/m2 unless DLT’s are seen. Dose levels are escalated in cohorts of 3–6 pts and cycle length is 4 weeks. Results: 9 pts have been enrolled and 5 are evaluable for toxicity of both drugs (renal cell, prostate, GE junction, bladder and small blue cell tumor). 4 pts withdrew from VPA toxicity prior to ATRA-IV. Median age 67 (range 26–79), pts received between 1–4 prior therapies (non-palliative surgery, chemotherapy, radiation, PBSCT). VPA did not alter ATRA-IV pharmacokinetics. The MTD of VPA has not yet been reached and the ATRA escalation phase has not yet been initiated. Most common toxicities observed were pain, dyspnea, gastrointestinal and neurologic. One grade 3 neurotoxic event occurred related to POD. 1 pt had a transient decline in PSA. Correlative studies are ongoing. Conclusions: Epigenetic modifications induced by HDACIs may allow the anti-tumor effects of retinoids to be realized. Toxicity of VPA has limited the addition of RA to this HDACI. HDACI + RA is a rationale approach to treat progressive RCC and future studies will incorporate more potent and less toxic HDACI + RA to treat RCC.

No significant financial relationships to disclose.
Mutations of HER2 gene in HER2-positive metastatic breast cancer
Authors: Prempree T. , Wongpaksa C.
Published: March 2020

13118

Background: HER2 status of Breast Cancer has been assessed by IHC and FISH and used for therapeutic decision with a high degree of success. However, there were numbers of HER2-positive MBC who finally failed the Trastuzumab treatment after initial good response. Mechanisms of intrinsic and acquired Trastuzumab resistance are not yet known. Our Objective is to identify factor or factors responsible for Trastuzumab resistance. Methods: DNA extraction and Sequencing of HER2 gene were performed on primary tumors of HER2-positive 14 MBC patients undergoing Trastuzumab therapy. Re-biopsy were done on new metstatic sites of those cases discovered to have Trastuzumab resistance. Results: Of 14 MBC cases whose tumors showing positive IHC and FISH, there were no mutation found in their HER2 gene, exons 18,19, 20 and 21. However, 3 of 14 cases of MBC undergoing continuous Trastuzumab therapy with excellent response for more than one year, developed the resistance. All three cases had new metstatic sites biopsied, and showed D880N and E837Y mutations in the exon 21 of their HER2 genes. All three cases showed no response to trastuzumab therapy. Conclusions: 1) HER2-positive MBC tumors did not have any HER2 gene mutations in them. 2) Mutations arised in their HER2 gene, exon 21 may be responsible for the intrinsic and acquired Trastuzumab resistance. Additional work in this area is needed to further substantiate our findings.

No significant financial relationships to disclose.
Comprehensive analysis of UGT1A polymorphisms predictive for pharmacokinetics and treatment outcome in non-small cell lung cancer patients treated with irinotecan and cisplatin
Authors: Han J. , Lim H. , Lee S. , Lee D. , Kim H. , Lee J.
Published: March 2020

13121

Purpose: To determine whether UGT1A1, UGT1A7, and UGT1A9 polymorphisms affect pharmacokinetics (PK) of irinotecan and treatment outcome of Korean patients with advanced non-small cell lung cancer (NSCLC). Methods: Eighty-one patients with advanced NSCLC were treated with irinotecan and cisplatin chemotherapy. Genomic DNA was extracted from peripheral blood and genotyped using direct sequencing. We analyzed the association of UGT1A genotypes with irinotecan PK and clinical outcomes. Results: In genotype-PK association analysis, UGT1A1*6/*6 (n = 6), UGT1A7*3/*3 (n = 6) and UGT1A9–118(dT)9/9 (n = 11) were associated with significantly lower AUCSN-38G/AUCSN-38 ratio (P = 0.002, 0.009and 0.001, respectively). In linkage disequilibrium (LD) analysis, the UGT1A7 variants were highly linked with UGT1A1*6 (D` = 0.85, r2 = 0.63) and UGT1A9*22 (D` = 0.95, r2 = 0.88), which was substantiated in haplotype analysis. Patients with UGT1A1*6/*6 had lower tumor response and higher incidence of severe neutropenia. UGT1A9–118(dT)9/9 also showed a trend for high incidence of severe diarrhea, but not tumor response. In survival analysis, patients with UGT1A1*6/*6 had significantly shorter progression-free survival (P = 0.001) and overall survival (P = 0.017). Conclusions: These findings suggest that UGT1A1*6 and UGT1A9*22 genotypes may be important for SN-38 glucuronidation and associated with irinotecan-related severe toxicity. Specifically, UGT1A1*6 might be useful for predicting tumor response and survival outcome of Korean patients with NSCLC treated with irinotecan-based chemotherapy. (Supported in part by NCC Grant 0210130 and 0510080 from National Cancer Center, Korea).

No significant financial relationships to disclose.
Phase I study of ON 01910.Na by 3-day continuous infusion (CI) in patients (pts) with advanced cancer
Authors: Ohnuma T. , Cho S. Y. , Roboz J. , Jiang J. D. , Lehrer D. , Silverman L. , Schwartz J. D. , Reddy E. P.
Published: March 2020

13137

Background: The benzyl styryl sulfone analog ON 01910.Na is a novel anticancer agent that inhibits mitotic progression and induces apoptosis; it has activity against most human cancer cells in vitro and against a broad spectrum of human xenografts in mice. Cell kill effects are exposure time-dependent in vitro. After 3d exposure 200 nM ON 01910.Na killed > 90% of Daudi lymphoma cells, whereas 40-fold higher drug concentration killed only 50% of cells after 24h exposure. Dogs that received CI of 325 mg/kg/d ×3 failed to reach MTD. Methods: Starting dose 50 mg/m2/d as a 72 hr CI was 1/10th MTD of rats’ daily dose given × 28 d. Treatment cycles were repeated every 2 wks until progressive disease, intolerable toxicity, or withdrawal of consent. Dose was escalated by Fibonacci progression in single pts until grade 2 toxicity when cohorts of 3 are to be studied. Volunteers may be retreated at a higher dose if tolerated by a preceding naïve subject. Results: One man and four women (61–77 yrs) have been studied in 21 cycles in 5 mos as of 1/10/06. Doses of 50, 100, 150 and 250 mg/m2/d × 3 have been given for 1 to 10 cycles. Grade 1 granulocytopenia (2/4 pts with carcinoma) indicates biologic activity. Grade 1 fatigue (3/5) was less than in prior chemotherapy regimens. No grade 2 toxicity has yet occurred. Cumulative toxicity has not been seen. Two pts have had stable disease 6+ and 22+ wks. After deproteinization with acetonitrile, plasma or serum samples were measured by mass spectrometry. At 100 mg/m2/d steady state levels were 730 nM after the 1st cycle and 1190 nM after the 4th cycle. Drug levels were maximal at 3 to 6 h despite CI suggesting induction of a metabolizing pathway. Levels fell precipitously at the end of infusion on the 1st cycle but a low level persisted in one pt for 48h after the major drop in the 4th cycle, suggesting drug accumulation. Conclusion: Levels effective in vitro have been obtained in vivo by CI without limiting toxicity. Hints of activity already seen suggest that this compound has clinical promise. This phase I study continues.

[Table: see text]
Safety and pharmacokinetics of intravenous VEGF Trap plus irinotecan, 5-fluorouracil, and leucovorin (I-LV5FU2) in a combination phase I clinical trial of patients with advanced solid tumors
Authors: Rixe O. , Verslype C. , Méric J. B. , Tejpar S. , Bloch J. , Crabbe M. , Khayat D. , Furfine E. S. , Assadourian S. , Van Cutsem E.
Published: March 2020

13161

Background: VEGF Trap is a potent angiogenesis inhibitor comprising portions of human VEGF receptor VEGFR1 (Flt-1) and VEGFR2 (Flk-1) extracellular domains fused to the Fc portion of human IgG. VEGF Trap binds VEGF and neutralizes all VEGF-A isoforms plus placental growth factor. I-LV5FU2 is an approved chemotherapy regimen for the first-line treatment of metastatic colorectal cancer. This study was designed to evaluate the safety and pharmacokinetics (PK) of VEGF Trap plus I-LV5FU2 administered intravenously. Methods: Successive cohorts of 3–6 patients (pts) with relapsed or refractory solid tumors received intravenous VEGF Trap plus I-LV5FU2 every 2 weeks. Study endpoints included safety, PK, and immunogenicity. Antitumor activity was assessed by CT scan. Results: Ten pts (3 male/7 female), median age 59 (34–67), ECOG PS 0/1/2: 8/2/0, with a variety of advanced solid tumors, including 5 colorectal and 2 ovarian, have received a total of 50 cycles of VEGF Trap plus I-LV5FU2 across 2 VEGF Trap dose levels (2.0 mg/kg, 4.0 mg/kg) to date. Only 1 dose-limiting toxicity (G3 proteinuria >2 wks with normal plasma creatinine levels) has been encountered so far (4.0 mg/kg, Cycle 2). This pt also had controlled G2 HTN (renal biopsy pending). No other G3/4 VEGF Trap-related AEs have been reported so far. Preliminary free VEGF Trap clearance was 15.4 mL/kg/day. Three pts (synovial sarcoma, ovarian and colon cancers) achieved partial responses. Conclusions: VEGF Trap may be safely combined with I-LV5FU2 at the dose levels studied. Preliminary free VEGF Trap clearance did not differ significantly from that seen with single-agent exposure; chemotherapy PK analysis is pending. The maximum tolerated dose has not yet been reached, and dose escalation continues. Updated safety, pharmacokinetic, and preliminary efficacy results from this ongoing study will be presented.

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ZD6474, an inhibitor of VEGFR and EGFR tyrosine kinases, blocks VEGF-C-induced activation of VEGFR-3 and cell proliferation in human colon cancer cell lines
Authors: Troiani T. , Lockerbie O. , Morrow M. , Ciardiello F. , Eckhardt S. G.
Published: March 2020

13171

Background: Vascular endothelial growth factor receptors 1, 2 and 3 (VEGFR-1, -2 and -3) have a key role in activation and proliferation of endothelial cells, with expression of VEGFR-3 largely restricted to lymphatic endothelial cells. Although high expression of VEGFR-3 and its specific ligands, VEGF-C and VEGF-D, has been associated with an increased incidence of lymph node metastasis and a poor prognosis in different human malignancies, little is known about the role of this signaling pathway in tumor cells. This study investigated VEGFR-3 and its specific ligands in human colon cancer cells, and the antiproliferative activity of ZD6474, an inhibitor of VEGFR, epidermal growth factor receptor (EGFR) and RET tyrosine kinases, and of the EGFR inhibitors gefitinib and cetuximab. Methods: The expression of VEGFRs and EGFR was determined by RT-PCR, immunoblotting, flow cytometry and immunohistochemistry in four human colon cancer cell lines (HCT-116, HT-29, HCT-15 and SW480). Secretion of transforming growth factor-α (TGF-α), VEGF-A and VEGF-C by cancer cells was determined by ELISA. The in vitro antiproliferative effects of ZD6474, gefitinib and cetuximab were determined using an MTT assay. Results: All four human colon cancer cell lines expressed functional EGFR and secreted high levels of TGF-α. All four cell lines expressed VEGFR-1 and VEGFR-3, but not VEGFR-2, and secreted both VEGF-A and VEGF-C. Treatment with ZD6474 resulted in a dose-dependent cell growth inhibition (IC50 3–5 μM), whereas treatment with gefitinib or with cetuximab produced little growth inhibition under the same culture conditions. Addition of VEGF-C induced a 2-fold increase in cell growth in vitro in all four colon cancer cell lines. Treatment with ZD6474 blocked both basal and VEGF-C-induced phosphorylation of VEGFR-3, as well as VEGF-C-induced cell proliferation. Conclusions: Human colon cancer cell lines express VEGFR-1 and VEGFR-3, and secrete VEGF-A and VEGF-C. A potential VEGF-C/VEGFR-3 autocrine loop has been identified in human colon cancer cells, which can be inhibited by ZD6474, suggesting that ZD6474 may have direct antitumor activity through inhibition of VEGFR signaling.

[Table: see text]
Results of a phase II trial of cetuximab+XELIRI as first-line therapy of patients with advanced and/or metastatic colorectal cancer
Authors: Cartwright T. H. , Kuefler P. , Cohn A. , Hyman W. , Boehm K. A. , Ilegbodu D. , Asmar L.
Published: March 2020

13502

Background: We have previously shown that capecitabine/irinotecan (XELIRI) is effective and well-tolerated in metastatic colorectal cancer (mCRC). Cetuximab targets EGFR and is active in mCRC either alone or combined with chemotherapy. This study evaluated potential improved outcomes with cetuximab+XELIRI in first-line treatment of mCRC. Subjects and Methods: Subjects had histologically confirmed colorectal adenocarcinoma with T4 lesions that were deemed unresectable after preoperative chemoradiation and/or metastatic disease. Treatment: capecitabine 1700 mg/m2 (850 mg/m2 PO BID Days 1–14), irinotecan 200 mg/m2 IV Day 1 every 3 weeks, and weekly cetuximab (initial dose 400 mg/m2 IV over 120 minutes, subsequent doses 250 mg/m2 over 30 minutes). Toxicity was assessed at each visit. Results: Between February and October 2005, 70 subjects enrolled. Baseline characteristics: 43 males (61%), 79% White, median age 61.5 years (range, 32.2 - 85.4), and ECOG PS 0/1= 66%/34%. 63% of subjects had Stage IV disease at diagnosis; 87% of subjects had adenocarcinoma. Prior therapy: surgery (n=60, 86%), chemotherapy (n=14, 20%), and radiotherapy (n=5, 7%). Grade 3–4 treatment-related toxicities in >1 subject included diarrhea (17%); neutropenia and rash (8.5% each); dehydration (7%); nausea/vomiting (5%); and anorexia, dyspepsia, and hypokalemia (3% each). 30 subjects discontinued due to progressive disease (PD) (n=9), toxicity (n=12), MD decision (n=2), patient request/withdrew consent (n=3), death (n=1) and other (n=3; doses delayed >3 weeks). To date 5 subjects have died; no death was treatment-related. Evaluation of tumor responses is ongoing. Conclusions: The combination of cetuximab+XELIRI is feasible and well-tolerated in first-line mCRC. Updated safety and efficacy data will be presented. Funded in part by Bristol-Myers Squibb, Plainsboro, NJ.

[Table: see text]
Cost-effectiveness of adjuvant capecitabine, Mayo Clinic and de Gramont regimens for stage III colon cancer in the French setting
Authors: Dufour P. R. , Douillard J. , Ychou M. , Seitz J. , Perrocheau G. , Tilleul P. , Maes P. , Husseini F.
Published: March 2020

13506

Background: The oral fluoropyrimidine capecitabine is as effective but better tolerated than i.v. 5-FU/LV as first-line treatment in patients (pts) with metastatic colorectal cancer. Costs associated with the administration route could vary widely according to national rules and medical practice. We compared costs and outcomes of capecitabine, the Mayo Clinic, and de Gramont regimens as adjuvant treatment for stage III colon cancer. Methods: We assessed the cost-effectiveness of the three regimens using the third-party payer perspective, time horizon and efficacy/safety data (adjusted for indirect comparisons) from two published clinical trials [Twelves et al. N Engl J Med 2005; Andre et al. J Clin Oncol 2003]. The costs of chemotherapy and the treatment of side effects were estimated from the clinical trials and expert opinion. We applied French standard costs to resources consumed and evaluated cost-effectiveness using relapse-free survival (RFS), defined in X-ACT study, as an efficacy indicator. One-way sensitivity analyses were performed varying the cost estimates for each treatment. Results: Capecitabine-treated pts had a mean life duration increase without treatment failure of 1.3 months vs. Mayo (see table). De Gramont was considered as effective as Mayo. In the base-case analysis capecitabine appeared to be dominant, more effective and less costly than either Mayo Clinic or de Gramont. In the sensitivity analyses, capecitabine remained dominant except for the minimum costs scenario vs. de Gramont. In this case, the cost-effectiveness ratio was estimated at 8997.55€ per year without relapse. Conclusions: As adjuvant treatment for colon cancer, capecitabine decreases medical resources consumed, mainly in hospitals. Its approval in this setting is expected to bring cost savings and better outcomes. [Table: see text]

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A phase I clinical and pharmacokinetic study of flavopiridol administered concurrently with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) for advanced solid tumors
Authors: Meng R. D. , Carvajal R. D. , Tse A. N. , Shah M. A. , Dials H. , Brukner D. , O’Reilly E. M. , Kelsen D. P. , Schwartz G. K.
Published: March 2020

13515

Background: Flavopiridol, a potent cyclin-dependent kinase inhibitor, enhances oxaliplatin-induced apoptosis in HCT116 colon cancer cells in vitro, especially with concurrent therapy. Significant tumor regressions were also observed in HCT116 xenografts treated with flavopiridol and oxaliplatin therapy versus either therapy alone. Methods: Therefore, an ongoing phase I trial in advanced solid tumors was designed in which flavopiridol at a fixed dose (40 mg/m2 over 1 hour) was administered concurrently with escalating doses of oxaliplatin (60 mg/m2 -> 80 mg/m2 over 2 hours), given as part of a modified FOLFOX6 regimen at standard doses every 14 days. Patients then received escalating doses of infusional 5-fluorouracil over 48 hours (900 mg/m2/day -> 1200 mg/m2/day). Standard phase I eligibility criteria apply. Prior FOLFOX or oxaliplatin was allowed. Results: Median characteristics of nineteen evaluable patients: age 54 (39–77), KPS 80% (70–90), 9 males/10 females, 3 prior regimens (range 1 to 10). The combination has been well-tolerated, with 1 dose limiting toxicity occurring with oxaliplatin at 85 mg/m2 and infusional 5-fluorouracil at 1200 mg/m2/day (grade 3 hyponatremia and grade 3 syncope). Pharmacokinetic studies for flavopiridol indicate no appreciable difference in Cmax despite escalation of oxaliplatin dose. We have observed 1 partial response to treatment in pancreatic cancer. Stable disease has been seen in 5 patients, including 1 breast cancer (3 months), 1 gastric cancer (2 months), 1 anal cancer (7 months) and 2 colorectal cancers (5+ months), with one patient previously treated with oxaliplatin. Conclusions: The combination of flavopiridol and modified FOLFOX6 can be given safely without a significant increase in toxicity. The pharmacokinetic data for flavopiridol remains unchanged despite escalating doses of oxaliplatin. Activity has been observed in several tumor types, with promising activity noted for colorectal cancers even with prior oxaliplatin chemotherapy. Therefore, further dose escalation of flavopiridol is currently planned.

No significant financial relationships to disclose.
Cetuximab use without chronic antihistamine premedication
Authors: Timoney J. , Chung K. Y. , Park V. , Trocola R. , Peake C. , Saltz L. B.
Published: March 2020

13521

Background: Cetuximab is a human-murine chimeric monoclonal antibody against EGFR with approximately a 3% reported incidence of severe (≥ grade 3) anaphylactoid reactions. The overwhelming majority of such reactions have been reported with the initial dose of cetuximab. Diphenhydramine (Benedryl)or a related antihistamine is often given as a premedication for cetuximab, however this may cause fatigue or other side effects. Most early clinical trials of cetuximab permitted investigator discretion in use of premedication beyond the initial cetuximab dose. Methods: We obtained an IRB waiver of authorization to review the records of patients treated with cetuximab at Memorial Sloan Kettering Cancer Center for the first year of commercial availability of cetuximb (Feb, 2004 through Feb, 2005). Computerized pharmacy records were reviewed to identify all patients who were treated with cetuximab (outside of a clinical trial) and use of premedication was then evaluated. Records of institutional adverse event reports regarding chemotherapy administration were reviewed, and, any moderate or severe/life-threatening reactions were evaluated for presence or absence of concurrent premedication. Results: As per our institutional guidelines, all patients received 50 mg of diphenhydramine prior to the initial loading dose of cetuximab, and 25 mg of diphenhydramine prior to the second dose. While there was inconsistency in terms of cessation of diphenhydramine, overall a total of 115 patients received one or more doses of cetuximab without premedication. A total of 746 doses of cetuxmab without diphenhydramine premedication were given over this time period. No severe/life-threatening reactions to cetuximab occurred during these doses given without premedication. Conclusions: Omission of diphenhydramine premedication after the initial two doses of cetuximab is our current institutional practice, and appears not to alter the safety profile of cetuximab. Considering the side effects of diphenhydramine, routine long tern use of antihistamine premedication with cetuximab administration does not appear to be warranted.

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Implementation of 18F-FDG PET/CT in the management of colon cancer
Authors: Manente P. , Chierichetti F. , Liessi G. , Sartor L. , Vicario G. , Bissoli S. , Medea S. , Scelzi E. , Mion M.
Published: March 2020

13526

Background: we began using PET in 1994 and since the beginning of 2000 we started with a PET/CT system. Aim of our study was to evaluate if PET/CT is a decision making tool in patients with a history of colon tumors. Methods: we performed PET/CT in 26 patients, 14 males and 12 females (mean age 60.9, range 42–75 years) already treated for a colon cancer. Each patient was submitted to two PET/CT scans in a period of 5–11 months. PET/CT was performed using 18F-FDG as radiopharmaceutical. In all patients other examinations were perfomed, such as liver ecography, pelvis MRI and CT scan. Results: in the first PET/CT imaging, 11/26 patients presented with normal tumor markers but suspected relapse on the basis of CI, 7/26 had increased markers but negative CI, the other 8 patients had both CI and tumor markers meaningful for recurrence. 7/26 PET/CT were normal: 5 cases with negative tumor markers but positive CI and 2 patients with increased CEA levels. Among the 19/26 positive PET/CT scans, 7 patients had normal marker levels. All positive PET/CT patients were treated and, at the second examination, progressive disease was evident in 11 out of 19. For the 7 previous negative PET/CT, the second findings showed tumor recurrence in 2 patients, but PET/CT became negative in 5 previously positive cases, submitted to surgery and/or chemotherapy. This method detected relapse in 73% of the patients and, during the follow up, it was sensitive to identify progressive disease or to prove treatment’colon cancer, based on tumoral marker assays and CI, is poorly sensitive to detect relapse. Our PET/CT data show that 37% of cases with normal marker levels have a recurrent disease. The overall results of our preliminary data lead to further considerations: 1) PET/CT gives a precise localization of lung or nodal metastases and local relapse; 2) the repeated PET/CT scan is reliable also to evaluate the effect of therapies; 3) this imaging modality may be crucial to detect relapse, but more data are needed to assess the proper time to perform PET/CT in the follow up to have a real gain in life expectancy.

No significant financial relationships to disclose.