bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II study of the antisense oligonucleotide GTI-2040 plus docetaxel and prednisone as first line treatment in hormone refractory prostate cancer (HRPC)
Authors: Sridhar S. S. , Canil C. M. , Hotte S. J. , Chi K. , Ernst S. , Pond G. R. , Dick C. , Zwiebel J. A. , Moore M. J. 
Published: March 2020

13015 Background: Despite initial responses to chemotherapy, median survival in HRPC remains a dismal 18 mos. Novel therapeutic approaches are clearly needed. The enzyme ribonucleotide reductase (RNR) composed of 2 subunits, R1 and R2 is essential for DNA synthesis and repair. The R2 subunit is often overexpressed in tumors increasing their malignant potential and promoting drug resistance. GTI-2040 (Lorus Therapeutics, Canada) is an antisense oligonucleotide to the R2 subunit downregulating its expression. In preclinical studies, GTI-2040 has shown antitumor activity in prostate cancer xenografts, synergy and non-overlapping toxicity with the taxanes. It is therefore a rational choice for combination with docetaxel in HRPC. Objectives: To determine efficacy of this regimen using PSA response rate. Secondary objectives include: duration of response, TTP, objective tumor response rate, safety and tolerability. Pharmacokinetic (PK) studies will be performed. PBMC will be used to determine RNR activity and R2 subunit quantitation. Methods: HRPC patients with PS 0–2, adequate organ function and no prior chemotherapy were treated with GTI-2040 5mg/kg/d continuous infusion for 14d, docetaxel 75 mg/m2 IV every 21d, and prednisone 5mg twice daily. Results: Twenty-two pts in 5 centers have been enrolled. Pts have received a total of 107 cycles to date. Median age 63 (52–77); median baseline PSA 140 (26–1256); ECOG 0:1:2: 14:7:1; prior radiotherapy in 14 pts. Pts received a median of 5 cycles (2–10). Grade 3/4 hematologic toxicities were lymphophenia (10pts), leukopenia (7pts), and neutropenia (7pts). Anemia (any grade) was seen in 19 pts across 92 cycles. Most frequent non-hematologic toxicities were fatigue and pain. PSA responses seen in 9/22 pts. Objective tumor response:1 PR, 9 SD, 3 PD, 3 off due to toxicity prior to objective response measurement, 3 no measureable lesions, 3 to be assessed. 19 pts off treatment: 9 PD, 4 toxicity (1 toxic death), 2 completed 10 cycles, 2 at investigator’s discretion and 2 withdrew consent. Three pts remain on study. Median TTP estimated at 17 wks. Accrual has been sufficient to meet stage 1 requirements. Final response, toxicity, pK, RNR and R2 subunit analysis will be available and presented. No significant financial relationships to disclose.
Results from a phase I dose escalation study of PEGylated glutaminase in combination with 6-diazo-5-oxo-L-norleucine (DON) in advanced malignant solid tumors
Authors: Unger C. , Müller C. , Jäger E. , Bausch M. , Roberts J. , Al-Batran S. , Sethuraman N. 
Published: March 2020

13017 Background: To cope with the increased demand with concomitant down-regulation of glutamine synthesis, tumor cells in general have an upregulated glutamine uptake. The rationale is based on the premise that the therapeutic effectiveness of the glutamine anti-metabolite 6-diazo-5-oxo-L-norleucine (DON) is enhanced by strong depletion of the available pool of glutamine through PEGylated glutaminase (PEG-PGA). The optimal dose of PEG-PGA was found in step one of this study. Methods: Step two of this Phase I study was designed to determine the safety and tolerability of 120 I.U./m2 PEG-PGA in combination with increasing dose levels of DON both administered i.v. twice weekly. DON was administered four hours after PEG-PGA at levels of 5–185 mg/m2 with cohorts of three patients. Cohorts were expanded in case of possibly drug related AEs≥G3. All patients exhibited solid tumors of various indications refractory to standard treatment. Toxicity was measured according to NCI-CTC criteria. Response was evaluated according to RECIST criteria. Results: 61 patients have been enrolled in step two of this study wherein 58 received at least one treatment and 46 (57% male) were available for preliminary evaluation. Median age was 62.5 years (range 43–79) and 36% had a Karnofksy-index <90%. At 25 mg/m2 of DON three patients exhibited G3 nausea and vomiting which was managed effectively with antiemetic therapy. Possibly drug related AEs ≥ G3 like dyspnoea (n = 1), allergic reaction (n = 1), haematemesis (n = 1), 1 thrombosis (n = 1) and neurological diseases (n = 4) were reported in 19.6% of the patients. Haematological toxicities were neither frequent nor severe. No G4 toxicity in any dose level has been observed. DLT (two AEs ≥ G3 in one cohort) was reached in the 11th escalation step resulting in an adequate MTD which will be used in the following studies. In 38 patients available for tumor response 1 confirmed PR (renal) and at least 12 SDs have been reported. Conclusions: PEG-PGA in combination with DON has shown promising efficacy in heavily pre-treated solid tumors with a favourable toxicity profile. A clinical proof of concept study with statistically sufficient number of patients is ongoing. [Table: see text]
Phase I study of ON-01910.Na, a novel cell cycle inhibitor in adult patients with solid tumors
Authors: Donehower R. C. , Jimeno A. , Li PhD J. , Galvin K. , Anthony F. , Reddy R. , Reddy P. , Messersmith W. , Laheru D. , Baker S. D. 
Published: March 2020

13026 Background: ON-1910.Na is a new chemical entity, novel cell cycle inhibitor which arrests cells in G2/M, affects phosphorylation of several regulatory kinases and lacks cross resistance to other standard chemotherapy agents. This is a first-in-man Phase I dose escalation study to determine the dose limiting toxicities, recommended Phase II dose, and pharmacokinetic (PK) profile, and to document any antitumor activity of ON-01910.Na. Methods: Patients had histologically confirmed solid tumors refractory to standard therapy. ON-1910.Na, formulated as a solution in PEG400, was administered as a 2-hour infusion on days 1, 4, 8, 11, 15, and 18 followed by a 10 day observation period for a total of 28 days per cycle. The initial dose was 80 mg and was escalated using an accelerated titration schedule; one patient was treated per cohort until grade 2 toxicity was documented. A dose confirmation cohort of up to 12 patients will be treated at the maximun tolerated dose (MTD). A comprehensive PK study was performed on days 1 and 15 of the first cycle, plus trough samples were collected. Results: Thirteen patients (7F, 6M; ages 46–73) have received 20 cycles. Dose levels of 80, 160, 320, 480, 800, 1280, 2080, and 3120 mg were evaluated in 8 patients, and a further dose of 4370 mg has been evaluated in 5 patients. Toxicities have been anemia (2 G1, 1 G2), leucopenia (1 G1, 1 G2), hyperglycemia (2 G1), elevated AST/ALT (1 G1, 1 G2), nausea (3 G1), diarrhea (3 G1), skeletal pain (5 G1, 1 G2), abdominal pain (2 G1), tumor pain (1 G2), and fatigue (3 G1, 1 G2), and have clustered at the latter 3 dose levels. PK analysis shows increasing ON-1910.Na exposure with increasing doses. ON-1910.Na has a low clearance (13 L/h), long half-life (20 h), distribution in excess of blood volume (58 L) and PK parameters are similar on days 1 and 15. Approximately 3-fold and 5-fold inter-subject variation in ON-1910.Na clearance was observed on days 1 and 15, respectively. No antitumor activity has been documented by standard criteria. Conclusions: Dose escalation is continuing. [Table: see text]
Clinical and immunological analysis of melanoma patients receiving immunization using particle-mediated gene transfer of genes for gp100 and GM-CSF into uninvolved skin
Authors: Cassaday R. , Sondel P. , King D. , Warner T. , Bridges A. , Gan J. , Schalch H. , Hank J. , Mahvi D. , Albertini M. 
Published: March 2020

13033 Background: To investigate a new method of activating melanoma-specific immune responses, we examined in vivo particle-mediated gene transfer (PMGT) of cDNAs for gp100 and GM-CSF into uninvolved skin of melanoma patients (pts). We now report the analysis of a completed Phase I clinical study. Methods: Two treatment groups of 6 pts each were evaluated. Group I received PMGT with cDNA for gp100 during each 3 week cycle; Group II received PMGT with cDNA for GM-CSF followed 3 days later by PMGT for gp100 at the same site. PMGT used 0.25 ug DNA and 250 ug gold/treatment. Endpoints included vaccine toxicity, transgene expression, immunological activation, and antitumor effects. Results: No systemic toxicity could be attributed to the vaccines, while local toxicity in both groups included mild erythema and induration which resolved within 2 weeks. Monitoring for autoimmunity showed no induction of pathologic autoantibodies. Biopsies of vaccine sites obtained 2 days after the gp100 PMGT showed 16% of gold beads to be in the dermis in Group I vs 3% in Group II, suggesting the prior GM-CSF PMGT inhibited bead penetration (p < 0.001 by chi-square; each bead penetration was analyzed as an independent event). Biopsies in Group I obtained 2 days after vaccination showed 16% of beads in the dermis vs 22% after 4 days (p < 0.001 by chi-square; each bead penetration was analyzed as an independent event). Transgene expression in vaccinated skin sites was detected by ELISA (GM-CSF) and IHC (gp100). One of 4 HLA-A2+ subjects showed a 5 × 5-mm DTH response to gp100 peptide 210M after Cycle 1. Preliminary in vitro studies suggest minimal immunological activation. Of 4 pts who enrolled with no evidence of disease, 2 remain disease-free after 61–73 months of follow-up. Conclusions: PMGT with cDNA for gp100 and GM-CSF yields transgene expression in normal human skin with minimal local or systemic toxicity. Pathologic autoimmunity was not demonstrated. Bead concentration in the dermis increases over time, suggesting persistence of beads in this skin level. Conclusions related to melanoma-specific immune induction await T-cell and antibody studies. Supported in part by the UW General Clinical Research Center (M01 RR03186). No significant financial relationships to disclose.
A phase 1, dose-escalation trial of STA-5312, a microtubule inhibitor with a novel binding site, in advanced or metastatic solid malignancies
Authors: Desai A. , Ratain M. J. , Moshier K. , Tipton M. , Dooley W. , Hocknell K. , Dahl T. , Sherman M. , Limentani S. 
Published: March 2020

13040 Background: STA-5312 is a novel microtubule inhibitor with a distinct binding site from other agents such as vincristine, colchicine, or paclitaxel, which has demonstrated antitumor activity against a range of solid tumors in chemotherapy-resistant cancer. Methods: The trial assessed the safety, toxicity, pharmacokinetics (PK) and maximum tolerated dose (MTD) level of STA-5312 when administered as an IV infusion weekly for the first 3 weeks of a 4 week cycle. Assessment of activity is a secondary objective. The starting dose level was 6mg/m2. Dose escalation was based on evaluation of toxicity through the first cycle, with dose doubling in cohorts of 1–2 patients (pts) until a grade (gr) 2 or greater toxicity occurred, followed by at least 3 pts/cohort and 50% dose escalations. After a dose limiting toxicity (DLT), cohorts were expanded to at least 6 pts and subsequent escalations limited to 33%. The dose below the lowest dose at which 1/3 of 6 or more patients show DLT will be declared the MTD. PK sampling was performed during cycle 1. Results: To date, 25 pts have been treated: median age 58 years (35–77), ECOG performance status of 0–2, and median treatment duration 43 days. No serious drug-related toxicity was observed until a DLT (ataxia) was reported in the only patient treated at 64mg/m2, leading to de-escalation to 48 mg/m2, where the only patient experienced aphasia and ataxia. Enrollment is being expanded at a lower dose level of 32 mg/m2. Other adverse events attributable to STA-5312 include (>10%) anemia, fatigue, constipation, nausea, and anorexia. Exposure (AUC) was linear with respect to dose. Five patients have had disease stabilization. Conclusions: STA-5312 appears to be well tolerated when given weekly in doses up to 32mg/m2. The MTD has not been determined and enrollment is ongoing. [Table: see text]
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]