bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I study of PM00104, a novel cytotoxic anti-cancer drug, administered to patients with advanced solid tumors or lymphoma
Authors: Gallerani E. , Yap T. A. , Lopez A. , Coronado C. , Shaw H. , Florez A. , de las Heras B. , Cortes-Funes H. , de Bono J. , Paz-Ares L. 
Published: March 2020

2517 Background: PM00104 (Zalypsis [Z]) is a novel synthetic alkaloid related to the marine compounds Jorumycin and the family of Renieramycins. Preliminary analyses of its mechanisms of action suggest effects on the cell cycle, DNA binding properties, as well as transcriptional inhibition. Z has shown antitumor activity in vitro (IC50 =10-8 M) and in xenografts models, and an acceptable toxicology profile. Methods: Patients (pts) with advanced cancers or lymphoma were enrolled to determine the safety, tolerability, maximum tolerated dose (MTD), recommended dose (RD), pharmacokinetics (PK) and antitumor activity of Z administered as a 1- hour IV infusion every 3 weeks. Sequential cohorts of 3–6 pts received the following doses: 0.225, 0.45, 0.9, 1.8, 3.0 and 3.6 mg/m2. Results: 27 pts were treated (19 M; median age: 58, range: 39–79; ECOG PS =2). 2 of 6 pts at 3.6 mg/m2 experienced dose-limiting toxicities (DLT), defining the MTD; 1 pt with colorectal cancer with extensive liver metastases developed grade 4 thrombocytopenia and neutropenia, grade 3 transaminase elevation, and grade 4 troponin I rise without cardiac symptoms or electrocardiogram alterations. These toxicities all resolved. Another pt with adrenal carcinoma developed grade 3 nausea, vomiting and asthenia despite anti-emetics, which resolved with dexamethasone 2 days after infusion. Other toxicities were =grade 2 and included: nausea, vomiting, transient transaminase elevation and asthenia at doses =0.225 mg/m2 and myelosuppression (neutropenia and leukopenia) at doses =3.0 mg/m2. No DLTs were seen in 6 pts at a dose of 3.0 mg/m2, establishing this dose as the RD. 3 more pts were added to complete the expanded cohort at this RD. To date, 2 pts have SD lasting >3 months. PK data indicate that drug AUC and Cmax increase proportionally across the dose range until doses =3.0 mg/m2, when a disproportionate increase in AUC and Cmax was seen. Z has a long half-life (=50 hours) and wide volume of distribution (Vss ∼500 l/m2). Conclusions: Z has a favorable safety profile. The MTD on this schedule has been established at 3.6 mg/m2. Alternative schedules are being evaluated to try and increase dose intensity. No significant financial relationships to disclose.
Calculating carboplatin doses using the 4-variable modification of diet in renal disease (4-v MDRD) estimate of glomerular filtration rate (GFR) in the Calvert formula
Authors: Poole S. G. , Dooley M. J. , Rischin D. 
Published: March 2020

2521 Background: The dose of carboplatin is usually calculated using the Calvert formula, with various bedside estimates utilized rather than directly measured GFR. The 4-v MDRD equation (Levey AS, et al. Ann Intern Med 2006; 145: 247–254) is now advocated as the routine method of estimating renal function from serum creatinine in all patients. Adoption in clinical practice is occurring despite lack of validation in oncology patients. The aim of this study was to compare carboplatin doses derived from the Calvert formula using measured GFR and the estimates of the 4-v MDRD equation and other established estimates. Methods: GFR was determined using technetium-99m diethyl triamine penta-acetic acid (Tc99mDTPA) clearance. Serum creatinine (Jaffe method) was measured and GFR estimates calculated using 4-v MDRD, Cockcroft and Gault formula (CGF), Wright, Martin, and Jelliffe (JF) formulae. Carboplatin doses were calculated using the Calvert formula, targeting an area under the curve of 7mg.ml- 1.min-1. Results: GFR was measured in 510 adult oncology patients (323 male, 187 female, mean age 63 years, range 17–87 years, mean GFR 84 mL/min, range 16–205 mL/min). The mean (range) carboplatin dose was 765 mg (287–1,610 mg), 681 mg (237–1,306 mg), 674 mg (249–2,044 mg), 721 mg (261–1,536mg), 741 mg (261–2,128mg), 620 mg (244- 1,329 mg) for measured GFR, 4-v MDRD, CGF, Wright, Martin, and JF formulas respectively. The accuracy (% within 20% of ‘true’ dose) was 58%, 63%, 73%, 72% and 49% for 4-v MDRD, CGF, Wright, Martin, and JF formulas respectively. Carboplatin doses derived using the 4-v MDRD estimate of GFR become increasingly less accurate with increasing GFR (see table ). All other formulas performed similarly. Conclusions: The 4-v MDRD equation resulted in an imprecise estimation of carboplatin doses with the degree of variability dependant on the level of renal function. [Table: see text] No significant financial relationships to disclose.
Identification of predictive markers to differentiate ixabepilone from paclitaxel activity in ER-negative breast cancer patients
Authors: Wu S. , Chasalow S. , Lee H. , Xu L. , Paul B. , Mokliatchouk O. , Symmans W. F. , Zerba K. E. , Pusztai L. , Clark E. 
Published: March 2020

2525 Background: Ixabepilone (BMS-247550) is a microtubule stabilizing agent with demonstrable therapeutic value in taxane- refractory breast cancer (BC) patients. Biomarkers to predict either ixabepilone or paclitaxel activity in BC patients have previously been reported. However, markers that differentiate response to the two agents have yet to be identified. This study sought to discover predictive markers that will enable patient selection to differentially enhance response to ixabepilone or paclitaxel in ER-negative (ER-) patients. Materials and Methodologies: Pre-treatment gene expression profiles were generated for 62 ER- patients treated with ixabepilone in clinical study CA163080, and 51 ER- patients treated with T/FAC (paclitaxel and fluorouracil-doxorubicin-cyclophosphamide) in clinical study MDA133. Biomarkers differentially predictive of complete pathological response in breast were identified through gene set enrichment analysis (GSEA) or classification by threshold gradient descent (TGD). Gene knockdown by siRNA was used to study some of these candidate markers. Results: Four candidate models that differentiate response to ixabepilone treatment and taxane-containing therapy were identified. Two of the models, found by GSEA, are based on expression levels for single microtubule-related genes: transforming, acidic coiled-coil containing protein 3 (TACC3) and chromosome condensation protein G (HCAP-G). The potential of HCAP-G as a differential marker was supported by siRNA studies. Two of the models, found by TGD, are based on expression levels for 26 and 20 genes. Areas under the ROC curves for the models applied to each study separately are given in the table . Conclusions: We have identified four predictive models that differentiate response in a clinical trial of ixabepilone from that in a trial of T/FAC. A clinical trial is under way to further evaluate their utility for differentiating response to ixabepilone- and taxane-containing regimens. [Table: see text] [Table: see text]
Relationship between glutathione-S-transferase P1 Ile105Val polymorphism and docetaxel neurosensory toxicity
Authors: Mir O. , Alexandre J. , Tran A. , Rabillon F. , Girre V. , Dieras V. , Pons G. , Treluyer J. M. , Goldwasser F. 
Published: March 2020

2527 Background: Glutathione-S-transferases (GST) regulate the cellular response to oxidative stress and various anticancer agents. We recently underlined the importance of oxidative stress in the side effects of taxanes [Alexandre et al,J Natl Cancer Inst 2006;98:236–44], and investigated the relationship between the GST isoforms M1, T1 and P1 genes polymorphisms and docetaxel-induced peripheral neuropathy. Methods: We retrospectively analysed GST polymorphisms in a cohort of cancer patients (pts) treated with docetaxel and entered in a clinical trial database. A clinical neurologic evaluation (according to the NCI-CTC v2.0) was performed at baseline and at each treatment cycle. The GST M1 (null genotype), GST T1 (null genotype), and GST P1 (Ile105Val and Ala114Val) polymorphisms were determined using PCR, followed by either sequencing or RFLP techniques. The relationship between GST polymorphisms and grade = 2 neurosenrory toxicity (NST) as primary endpoint was studied, using the Chi2-square (with Yates correction) and the Fischer’s two-tailed exact test. Results: Fifty-eight pts were included : F/M: 29/29; median age: 61 years (range: 47–75). Primary tumor: 27.6% breast, 27.6% prostate, 24.1% lung and 20.7% other cancers. Pts received docetaxel 75–100 mg/m2 given as single-agent. A total of 261 cycles were administered (median/pt: 4, range 2–12). Ten pts developed grade = 2 NST. Twenty-seven pts (47%) were homozygous for the GST P1 105Ile allele, and 31 pts were either homozygous or heterozygous for the GST P1 105Val allele. Grade = 2 NST was significantly more common in pts with GST P1 105Ile/105Ile genotype (8/27 pts, 30%) compared with patients with 105Ile/105Val or 105Val/105Val GSTP1 genotype (2/31 pts, 6,5%; P = 0.047). Pts who were genotyped as GST P1 105Ile/105Ile had a higher risk of developing a grade = 2 NST than did those with other GSTP1 genotypes (OR 6.11; 95% CI, 1.17–31.94; P < 0.05). Conclusions: We found a significant correlation between GST P1 105Ile homozygous genotype and the development of a docetaxel-induced peripheral neuropathy. No significant financial relationships to disclose.
Evaluation of pemetrexed (PEM) dosing paradigms using exposure-response relationships (ERRs)
Authors: Latz J. , Claret L. , Symanowski J. , Falcoz C. , Bruno R. , Smith I. , Calvert H. 
Published: March 2020

2530 Background: PEM is primarily renally eliminated and dosed based on body surface area (BSA). A direct relationship exists between creatinine clearance (CrCL) and PEM clearance (CL [and therefore exposure, AUC]). BSA-dosing has been increasingly challenged, especially for renally cleared drugs. ERRs and dosing paradigms (BSA, fixed, renal-based) were evaluated in silico for PEM. A superior dosing strategy is dependent on the strength of the ERR and results in decreased between-patient variability in both AUC and clinical outcome. Methods: An established pharmacokinetic model was used to estimate AUCs from CrCL for patients in malignant pleural mesothelioma (MPM) and NSCLC studies where patients with CrCL =45 mL/min received PEM 500 mg/m2 q3w. AUC was evaluated as a predictor of clinical outcome (survival, TTPD, toxicities) to identify ERRs. Efficacy models included previously identified prognostic factors and inverse of mean AUC over the treatment period as covariates. Probability of toxicity was modeled as a function of AUC at each cycle. Simulations were performed for statistically and clinically significant ERRs to compare distributions of outcome for the 3 dosing paradigms. Results: AUC was individually significant (or borderline) in the survival and TTPD ERRs for MPM (PEM + cisplatin; N=226) and NSCLC (PEM; N=258). AUC was independently significant only for the NSCLC TTPD ERR. The distribution of simulated TTPDs for the 3 dosing paradigms were similar (see table ). Model-predicted increase in incidence of Grade 3–4 hematologic toxicities with increasing AUC was statistically but not clinically significant. Graphical review of nonhematologic toxicities showed trends by AUC. The incidence of death due to drug-related toxicities was too sparse for modeling. Conclusion: Neither renal-based nor fixed dosing provides a clinical benefit over BSA-based dosing for patients with CrCL =45 mL/min based on ERRs and simulations using AUCs estimated from CrCL. [Table: see text] No significant financial relationships to disclose.
Patterns of HER-family receptor dimerization in trastuzumab susceptible and trastuzumab resistant cell lines
Authors: Dua R. , Nhonthachit P. , Rinehart C. , Arteaga C. L. , Nahta R. , Esteva F. J. , Winslow J. , Bates M. , Petropoulos C. 
Published: March 2020

2533 Background: HER2 overexpression is associated with accelerated disease progression and poor prognosis in breast cancer. Trastuzumab, a monoclonal antibody targeting the extracellular domain of HER2, is effective in the treatment of metastatic breast cancer. However, most patients treated with trastuzumab eventually develop clinical resistance. To investigate the role of HER-family receptors in trastuzumab resistance, we measured HER-family receptor expression, dimerization, and phosphorylation in trastuzumab susceptible and resistant cell lines. Methods: Cell lysates from trastuzumab susceptible and resistant BT474 and SKBR3 cell lines were obtained from the Arteaga and Esteva laboratories. Proximity-based, multiplexed assays were used to detect and quantify HER1, HER2, and HER3 expression and phosphorylation levels, as well as HER1/HER1, HER1/HER2, HER1/HER3, HER2/HER2, and HER2/HER3 dimers. Samples were incubated with a mixture of HER specific antibodies conjugated either with fluorescent reporter tags (eTags), or biotin, which binds a reporter tag releasing agent (chemical scissor). Reporter molecules are released based on proximity to the scissor in a photochemical reaction and separated by capillary gel electrophoresis. Results: In comparison to trastuzumab susceptible parental cell lines, both SKBR3 and BT474 trastuzumab-resistant cell lines displayed upregulated HER1 expression. Resistant BT474 cell lines exhibited markedly increased levels of HER1/HER2 heterodimers. Increases in HER2 phosphorylation in the trastuzumab resistant SKBR3 cell line were observed, consistent with previous studies implicating trastuzumab in the induction of HER2 phosphorylation. Total HER2 and HER3 levels were similar in trastuzumab susceptible and resistant BT474 cell lines. Conclusions: The development of trastuzumab resistance in these cell line models correlated with HER1 expression and the appearance of HER1:HER2 dimers. Since signaling initiated by such heterodimers is ineffectively antagonized by trastuzumab, these data suggest that selection for proliferative signaling mediated by HER1:HER2 dimers may represent a mechanism of trastuzumab resistance in breast cancer. No significant financial relationships to disclose.
A genomic approach to identify mechanisms associated with chemotherapy resistance
Authors: Riedel R. F. , Porrello A. , Chenette E. , Potti A. , Nevins J. R. , Febbo P. G. 
Published: March 2020

2534 Background: Gene expression profiling has shown an ability to predict chemotherapeutic response (Potti et al. Nature Medicine 2006). Building on this work, we used a genomic strategy to explore the biology associated with the development of chemotherapy resistance and sought to determine if disease context impacted results. Methods: Gene set enrichment analysis (GSEA) was performed on expression data for NCI60 cell lines sensitive and resistant to specific chemotherapeutic agents (adriamycin, cyclophosphamide, docetaxel, etoposide, 5-fluoruracil, paclitaxel, topotecan). GSEA was additionally performed on a series of lung cancer cell lines with a defined sensitivity to cisplatin and docetaxel. Sensitive and resistant cell lines with individual mean and confidence intervals greater than 1SD from the mean across all samples were included. Adjusting for multiple hypothesis testing, gene sets with a false discovery rate (FDR) <0.25 were deemed statistically significant. In the discovery mode, gene sets with a nominal p-value <0.05 were also of interest. Finally, overlapping gene sets between agents were assessed. Results: Statistically-significant gene sets, representing biologic pathways associated with resistance, were identified for the various chemotherapeutic agents (i.e., cell death, erbb3, and bad pathways associated with docetaxel resistance). No gene sets with FDR <0.25 or nominal p-value <0.05 were common to all drugs. In assessing disease specific resistance, 22 lung cancer cell lines for cisplatin (15 sensitive, 7 resistant) and 14 lung cancer cell lines for docetaxel (10 sensitive, 4 resistant) were analyzed. GSEA identified the bcl-2 pathway (p<0.002) to be associated with cisplatin resistance. In contrast, the proteosome (p=0.01) and akt (p=0.02) pathways were associated with docetaxel resistance. Pathways involved in the production of V-H+-ATPase were enriched in cisplatin and docetaxel resistant lung cancer cell lines suggesting a global mechanism of resistance. Conclusions: These results support the use of a genomic approach to identify unique drug-specific and global therapeutic targets associated with the development of chemotherapy resistance. Interestingly, disease context appears important in identifying novel targets. No significant financial relationships to disclose.
Results of a phase I study of DTS-201, a peptidic prodrug of doxorubicin, in patients with solid tumors
Authors: Delord J. , Schöffski P. , Brain E. , Dumez H. , Robert J. , Faivre S. , Dubois V. , Vialatte K. , Deshayes J. , Ravel D. 
Published: March 2020

2547 Background: DTS-201 is a promising prodrug of doxorubicin (dox) designed to preferentially deliver the parent compound to tumor cells and to limit cardiotoxicity. Based on animal studies showing that DTS-201 was markedly safer and more active than conventional dox, a phase I trial was conducted to determine safety, pharmacokinetics and the recommended dose (RD) for phase II studies. Methods: DTS-201 was given as 1-hour infusion every 3 weeks. Four dose levels were tested: 80, 160, 250 and 400 mg/m2 equivalent to 45 to 225 mg dox/m2. Toxicity was evaluated according to CTCAE v3.0 with specific attention to cardiotoxicity assessed by troponin I, echocardiography or cardio MUGA scan and 12-lead ECG. Results: Nineteen cancer patients (pts) with solid tumors (age range: 30–72 yrs) received DTS-201. Tolerance was good at 80 and 160 mg/m2. Three dose limiting toxicities (DLTs) were observed at cycle 1, one at 250 mg/m2 (grade 3 diarrhea) and two at 400 mg/m2 (one grade 3 vomiting and one grade 4 neutropenia = 5 days). Myelosuppression was the most common toxicity with 5 of the 6 pts treated at 400 mg/m2 experiencing transient asymptomatic grade 3–4 neutropenia on day 15 that spontaneously resolved. Other adverse reactions included mild to moderate asthenia, alopecia, anorexia and nausea. Neither cardiotoxicity or dox unrelated toxicities were observed. Disease stabilization for more than 4 cycles was observed in three pts with prostate cancer, pleural mesothelioma or bronchoalveolar carcinoma at 250 and 400 mg/m2. The pt with prostate cancer treated at 250 mg/m2 experienced a 60% decrease in serum PSA and a 23% reduction in lymph node size. The plasma AUCs and Cmax for DTS-201 and dox increased linearly with dose. At 400 mg/m2, the AUC of dox was within the range of values observed in pts receiving 60 mg/m2 of conventional dox. However the Cmax of dox, observed at 1 to 1.5 hours following DTS-201 administration, was 20 to 25 times lower. Conclusion: DTS-201 was well tolerated up to 400 mg/m2, corresponding to 3.750-fold the standard dose of dox. This dose, with no evidence of cardiac toxicity, was proposed to be the RD for future phase II studies. Six additional pts will be treated at that dose level to better characterize safety. No significant financial relationships to disclose.
Phase I clinical and pharmacokinetic (PK) trial of the kinesin spindle protein (KSP) inhibitor MK-0731 in patients with solid tumors
Authors: Stein M. N. , Tan A. , Taber K. , Fernandez R. , Agrawal N. G. , Vandendries E. , Hsu K. , Walker A. , Holen K. , Wilding G. 
Published: March 2020

2548 Background: KSP is essential for the separation of spindle poles during mitosis and inhibition results in mitotic arrest. MK- 0731 is a potent inhibitor of KSP, with an IC50 of 2.2 nM, and >20,000 fold selectivity against other kinesins. MK-0731 causes mitotic arrest with an EC50 in several tumor cell lines of 3–5 nM. Methods: Phase I study to determine the safety and tolerability, MTD, and PK of MK-0731 administered IV over 24 hrs every 21 days. In part 1, dosing started at 6 mg/m2/24 hr and was escalated until the MTD was reached. In part 2, pts with measurable taxane-resistant cancer were treated at the MTD established in Part 1 (target accrual =22 pts in part 2). Interim Results: 35 pts with solid tumors (M/F 23/12), median age 63 yrs (23 - 79), were treated at doses of 6 to 48 mg/ m2/24hrs (median cycles 3, range 1–10, total cycles=128). Frequent tumor types included prostate (8), ovarian (4), colon (3), bladder (2), neuroendocrine (2), lung (2), breast (2). Prolonged (>5 days) grade 4 neutropenia was observed in 2 pts at 48 mg/m2/24hrs (11 days duration) and 2 pts at 24 mg/m2/24hrs (7 days duration) leading to expansion of cohorts at lower dose levels. At the MTD of 17 mg/ m2/24, there were no DLTs. 14 patients have been enrolled at the MTD in part 2 of the study. Drug related grade 3/4 toxicities were anemia (1), AST (1), hyperglycemia (1), nausea/vomiting (1), neutropenia (7), syncope (1). PK results from the first 20 patients suggest that MK- 0731 concentrations appear to decline monoexponentially or biexponentially following the infusion with terminal t1/2 from ∼4 to 22 hrs. In some patients, steady-state concentrations may not be achieved by the end of the 24 hr infusion. Mean values at the 17 mg/m2/24hrs dose level were Cmax=599 nM, AUC8=14.56 μM·hr, and CL=119 mL/min. AUC, exposures, and end of infusion concentrations appear to increase proportionally with dose. Stable disease for = 4 cycles (range 4- 10) was seen in 16 patients. Conclusion: Treatment with MK-0731 at the MTD of 17 mg/m2/day every 21 days in patients with advanced solid tumors was well tolerated with consistent dose limiting toxicity of myelosuppression. No significant financial relationships to disclose.
Elucidating the mechanisms responsible for the previous failure of phase III clinical trials with eniluracil (EU) and development of a novel scheduling approach to optimize the efficacy of EU/5-fluorouracil (5-FU) combination therapy
Authors: Guarcello V. , Fourie J. , Lawton M. J. , Peters W. W. , Heslin M. J. , Diasio R. B. 
Published: March 2020

2557 Background: Irreversible inhibition of dihydropyrimidine dehydrogenase (DPD) by EU blocks 5-FU catabolism allowing for oral 5-FU administration with complete bioavailability. Unfortunately, phase III trials with co-administered EU/5-FU showed inferiority vs. 5-FU/leucovorin, and were discontinued. We recently reported that competitive inhibition of human uridine phosphorylase (UP) and thymidine phosphorylase (TP) 5-FU-anabolic enzymes by EU is an important mechanism potentially responsible for clinical failure of the combined EU/5- FU regimen. We hypothesize that EU inhibition of UP and TP is transient, while that of DPD is prolonged, allowing for novel schedule dependent optimization of EU/5-FU dosing regimens with improved efficacy. Methods: In this phase I study, five patients received a single oral dose (2 mg, 5 mg or 10 mg) of EU 12–14 hours prior to scheduled resection of primary/metastatic colorectal cancer. Dosage was as follows: Two patients received the 2 mg dose, one patient received the 5 mg dose and two patients received the 10 mg dose. Matched normal and tumor tissue biopsies were immediately snap frozen and subsequently UP, TP and DPD activity was measured in vitro via HPLC detection of [6- 14C]-5-FU catabolites/anabolites. Peripheral blood mononuclear cell (PBMC) DPD activity was determined at baseline prior to EU administration, 30 min prior to surgery (Day 1), and on Days 2, 5 and 14 following EU administration. Results: At 12–14 hours following EU administration, there was an absence of inhibition of UP and TP, while DPD was significantly inhibited in matched tumor and normal tissue. Importantly, PBMC DPD activity was significantly inhibited by EU on Day 1 (12–14 hours after EU administration) and Day 2 (36 hours after EU administration) at 0 ± 0% and 17 ± 11% (mean ± SD) of baseline, respectively. Conclusions: These data demonstrate a differential recovery time of EU mediated inhibition of UP and TP compared to DPD, which permits future schedule dependent optimization of EU/5-FU therapy. No significant financial relationships to disclose.