bluuebunny/crossref_metadata_2025_split huggingface dataset:
Change in circulating endothelial cells (CEC) predicts progression free survival (PFS) in patients (pts) with hormone receptor positive metastatic breast cancer (MBC) receiving letrozole (L) and bevacizumab (B)
Authors: Rugo H. S. , Dickler M. N. , Traina T. A. , Scott J. H. , Moore D. H. , Bruckner J. , Hudis C. , Park J. W. 
Published: March 2020

3039 Background: Antiangiogenic therapy has demonstrated efficacy in the treatment (tx) of metastatic breast cancer. Mechanism-based biomarkers of antiangiogenic therapy, if clinically validated, offer the potential to optimize this novel therapy. CECs have been proposed as a marker of tumor progression and/or response to antiangiogenic therapy with B. We performed a feasibility study testing B combined with L for the tx of hormone receptor-positive MBC. To explore markers of activity and response, we assayed CECs and circulating tumor cells (CTCs) at weeks (wks) 0 (baseline), 3, 12, and then Q 12 wks. Methods: CECs were defined as CD34/31+, CD45-. Progenitor (CD133+) (CECp) and activation markers (CD106+) were also measured. For CECs, 50 ul of blood was stained with the indicated MAbs; after RBC lysis, flow cytometry (FC) was performed for total CEC and CECp. For CTCs, 20 ml of blood was subjected to immunomagnetic capture using anti-EpCAM ferrofluid, followed by FC for EpCAM, CD45, and nucleic acid content. The log rank test was used to test for significant differences related to response. Results: 32 of 42 pts have been enrolled. As separately reported, prior non-steroidal AI (NSAI) use without progression is permitted; median (med) time on L before start of B was 6 mo (1–52). 28 pts have at least baseline and week 3 CEC and CTC along with clinical response data. Med CEC level at baseline was 10.4 CEC/ul (4–38); the peak value at any time point was 107. CTC levels were much less frequent with a med of 0.3 CTC/ml (0–95, and highest value 1153). An increase in CECs at wk 3 compared to wk 0 predicted worse PFS (p = 0.015). CTCs were ≤ 0.1 at study start in 40% of pts and ≥ 1.0 in only 17%, likely due to length of prior L; change in values at wk 3 did not correlate with PFS in this pretreated group. Conclusions: Consistent with our previous results in a separate trial of B containing treatment in MBC, changes in CEC levels appear to be a biomarker of response/progression on antiangiogenic therapy. CTCs did not reflect response or progression in this population of patients, likely due to lengthy prior exposure to letrozole. Supported in part by Genentech and Novartis. [Table: see text]
Phase I dose escalation study to determine the safety, pharmacokinetics and pharmacodynamics of BMS-582664, a VEGFR/FGFR inhibitor in patients with advanced/metastatic solid tumors
Authors: Rosen L. S. , Wilding G. , Sweeney C. , Casale D. , Kollia G. , Wu C. , Ayers M. , Hill C. , Galbraith S. M. 
Published: March 2020

3051 Background: This is the first multiple-dose study with BMS-582664, an oral VEGFR/FGFR tyrosine kinase inhibitor (IC50 34, 10, 145, 125 nM for VEGFR2, VEGFR3, FGFR1 and FGFR2 respectively). Patients (pts) with metastatic solid tumors refractory to standard therapy were enrolled. Part A of this study has completed. Part B is ongoing to evaluate the effect of BMS-582664 on dynamic contrast enhanced MRI (DCE-MRI) parameters. Methods: Part A: Open label dose escalation, continuous qd schedule, 3 patients per cohort. The starting dose was 180 mg. Dose escalation continued until dose limiting toxicities (DLTs) at 1000 mg in 2/3 pts were observed. The next lower dose level (800 mg) was expanded to 6 pts. Blood sampling for pharmacodynamic [circulating endothelial cells (CECs) and Collagen IV ELISA] and PK analysis was performed on Days 1, 8 and 26. BMS-582664 (prodrug) and its active metabolite, BMS-540215 were analyzed using an LC/MS/MS assay. DCE-MRI was performed at 320 mg, 600 mg and 800 mg at baseline ×2, Days 2, 8 and 26. Results: Negligible BMS-582664 was detected. BMS-540215 AUC increased proportionally to dose increase across 180 mg to 1000 mg. The accumulation ratio (Day 26:Day 1) of C24hr, Cmax and AUC was 4.8, 2.0 and 2.1 respectively at 1000 mg, but close to 1 at lower doses. The median time on study for all patients in Part A was 84 days. Conclusions: DLT was dizziness/fatigue. BMS-582664 has pharmacodynamic and anti-tumor activity and was well tolerated at ≤ 800 mg qd. [Table: see text] [Table: see text]
Phase I study of low-dose hypomethylating agent azacitidine (5-AC) combined with the histone deacetylase inhibitor valproic acid (VPA) in patients with advanced cancers
Authors: Braiteh F. , Soriano A. , Luis C. H. , David H. S. , Ng C. , Garcia-Manero G. , Kurzrock R. 
Published: March 2020

3060 Background: By inhibiting DNA methyltransferase, 5-azacytidine (5-AC) reverses epigenetic silencing of aberrantly hyper-methylated genes restoring activity of tumor suppressor and pro-apoptotic genes. In leukemia, the responses achieved with the hypomethylating agent decitabine are considerably greater at low doses than at high dose levels. We explored the tolerance to a combination of valproic acid (VPA), a histone deacetylase inhibitor, given together with low-dose 5-AC and the ability of this combination to induce DNA hypomethylation. Methods: Every 28-day cycle, 5-AC was givenSC daily for 10 days, and VPA was administered orally daily in doses titrated up to therapeutic levels (75–100 mcg/mL). Planned dose-levels of 5-AC (6-patients/cohort) were determined per an adaptive algorithm based on toxicity in the previous cohort (toxicity-based adaptive dosing model (TAD model) with a starting dose of 20 mg/m2. The methylation status of long interspersed nuclear elements (LINE) was used as a surrogate marker of global methylation, and was performed on peripheral blood mononuclear cells on day 1 and 10 of the first 4 cycles for each patient. Results: To date, twenty-two patients have enrolled at 20, 25, 37.5 and 47 mg/m2 dose-levels. The VPA dose was titrated up to 18.8 ± 6.9 mg/kg. Side effects include mainly drowsiness (N = 5), tremor (N = 4), hypomagnesemia (N = 2), grade 1–2 anemia (N = 2), and neutropenia (N = 2). One DLT (neutropenic fever) occurred at a dose of 37.5 mg/m2. One patient with rapidly progressive disease (renal cell carcinoma) experienced stable disease (6 months), and three patients (adenocystic carcinoma = 1, leiomyosarcoma of the uterus = 2) experienced stable disease for 4 months. Eighty-two blood samples were obtained. Median LINE methylation pretreatment was 65% (range 59–70%, it declined to 61% (range 53–63%) by day 10 (p = 0.001)and returned to baseline by day 0 of the following cycle. Conclusions: Our preliminary data suggest that low-dose 5-AC combined with VPA (median = 17 mg/kg) is well tolerated and exhibits biological activity in patients with advanced cancer. Western blot assays for histone acetylation are in process. The trial is currently accruing at dose-level 47 mg/m2. [Table: see text]
A phase I study of two administration schedules of the Polo-like kinase 1 inhibitor BI 2536 in patients with advanced solid tumors
Authors: Munzert G. , Steinbild S. , Frost A. , Hedborn S. , Rentschler J. , Kaiser R. , Trommeshauser D. , Hoffmann M. , Steegmaier M. , Mross K. 
Published: March 2020

3069 Background: BI 2536 is a novel highly potent and selective inhibitor of the serine-threonine Polo-like kinase 1 (Plk1), a key regulator of cell cycle progression. Objectives of this trial were the assessment of the maximum tolerated dose (MTD), overall safety, pharmacokinetics and preliminary efficacy of BI 2536 given intravenously. Methods: Sequential cohorts of 3–6 patients (pat) with advanced or metastatic solid tumors received infusions of BI 2536 following a toxicity guided dose escalation design. In the first part of the trial, a single administration was given every 21 days (d1). After completion of accrual BI 2536 was administered on three consecutive days (d1–3) in a dose intensified schedule in additional patient cohorts. Further treatment courses were given in the absence of disease progression and after recovery of toxicity after a 3-week observation period. Results: Of the 52 entered patients a total of 40 pts were treated at doses of 25 (n=3), 50 (n=3), 100 (n=3), 200 (n=25) and 250 mg (n=6) in the d1 schedule. The MTD for the d1 schedule was defined at 200 mg. Dose limiting toxicity (DLT) consisted of neutropenic infection and occurred in 2/6 patients at 250 mg. Reversible CTCAE grade ≥ 3 neutropenia represented the main drug related toxicity with an incidence of 13/25 in the 200 mg and 5/6 in the 250 mg dose cohorts. Alopecia was reported in 20% of pat. Further common drug related adverse events (AE’s) consisted of nausea (38%), anorexia (25%) fatigue (18%), vomiting (18%) and mucositis (12%) and were mostly of mild to moderate intensity (CTCAE grade ≤ 2). PK analysis showed dose proportionality of Cmax and AUC0-∞ with a high clearance (∼ 1400 mL/min) and a high volume of distribution (∼ 1200 L). A correlation between exposure and neutropenia was observed. Patients were treated for up to 10 courses without evidence of accumulating toxicity. One partial response was observed in a patient with metastatic squamous cell head and neck cancer treated at 250 mg. The DLT was determined at 3x70 mg in the dose intensified schedule with the MTD still pending. Conclusion: In summary BI 2536 is a Plk1 inhibitor with a favorable safety and PK profile. Neutropenia as a mechanism-related toxicity indicates target inhibition in vivo. First signs of antitumor activity were observed. [Table: see text]
Randomized, phase II study of two doses of pemetrexed as first-line chemotherapy for locally advanced or metastatic breast cancer (MBC): Clinical results and exploratory pharmacogenomic analysis
Authors: Llombart-Cussac A. , Martin M. , Harbeck N. , Anghel R. , Eniu A. , Melemed A. , Clark R. , Simms L. , Kaiser C. , Ma D. 
Published: March 2020

3077 Background: Pemetrexed, a folate antimetabolite, has shown varied response in MBC, depending on the dose, vitamin supplementation, and patient pre-treatment status. We conducted a randomized, double-blind, phase II study, in patients with locally advanced or MBC to evaluate 2 doses of pemetrexed. Primary objective was to assess the response rates on the 2 arms. Methods: Women with histologic/cytologic diagnosis of breast cancer, evidence of locally recurrent disease or distant metastasis, not amenable to local therapy were eligible. Patients received pemetrexed (600 mg/m2 Arm A; or 900 mg/m2 Arm B), on D1 of a 21-day cycle. All patients received folic acid and vitamin B12 supplementation. Forty-three patients were planned on each arm. Results: Ninety-two patients (median age 57 years, range 33–81) enrolled: 47 on arm A and 45 on arm B. Arms A and B had response rates of 17.0% (95% CI, 7.7%-30.8%), and 15.6% (95% CI, 6.5%-29.5%), median progression free survival times of 4.2 and 4.1 months, and median times to tumor progression (TtTP) of 4.2 and 4.6 months, respectively. On both arms, a median of 6 cycles was delivered. Toxicity was mild (grade 3/4 toxicity on both arms; neutropenia <20%, leucopenia <9%). Primary tumor samples from 49 patients were assessed for 10 folate or pyrimidine metabolism related gene expressions by reverse transcriptase-polymerase chain reaction methodology. Two markers, folypolyglutamate synthase (FPGS) and thymidine phosphorylase (TP), showed significant results. Best response rates and median TtTP for high vs low FPGS expression subgroups were 37.5% vs 10.0% and 8.6 vs 3.0 months. The corresponding results for TP were 27.6% vs 6.3% and 5.4 vs 1.9 months. Conclusions: Efficacy and safety of the two pemetrexed doses were similar; thus, the lower dose (600 mg/m2) is suitable in patients with MBC. Exploratory biomarker analysis suggests efficacy correlation for FPGS and TP. Further evaluation of these markers appears warranted. [Table: see text]
Lack of association with epidermal growth factor receptor gene polymorphisms with clinical outcome in patients with advanced colorectal cancer treated with platinum-based chemotherapy
Authors: Park D. J. , Zhang W. , Gordon M. , Yang D. Y. , Ladner R. , Iqbal S. , Groshen S. , Vallbohmer D. , Lenz H. , Fazzone W. 
Published: March 2020

3079 Background: We had previously shown an association between functional polymorphisms of the epidermal growth factor receptor gene and clinical outcome to platinum-based chemotherapy in advanced colorectal cancer in a retrospective study. Specifically, patients with <20 CA repeats in intron-1 of the EGFR gene were shown to have increased risk of disease progression. Here in, we report our findings of a confirmatory prospective study. Methods: Between September 2001 and August 2004, 173 patients with advanced refractory colorectal cancer were enrolled. Patients received 5-FU 200 mg/m2/day as continuous infusion and oxaliplatin 130 mg/m2, in three week cycles. Blood samples for genomic analysis were available for 152 patients. EGFR intron 1 CA-repeat and HER1- R497K polymorphisms and their relationship with clinical response, time-to-progression, overall survival, and toxicity, either alone or in combination were assessed prospectively. In addition, we were able to perform quantitative gene expression analysis of EGFR through RT-PCR in a subset of 58 patients. Results: Our cohort of 152 patients comprised 78 males and 74 females, with a median age of 60. There were 105 Caucasians, 24 Asians, 5 Blacks, and 18 Hispanics. The median number of cycles received was 5. The median survival was 10.3 months with a median follow-up of 18.6 months. There were 28 responders (19%). Asians were more likely to possess longer CA repeats and the HER1- 497K variant (Fisher’s exact test p<0.05). Neither EGFR intron-1 CA repeat nor the HER1- R497K polymorphisms were associated with clinical response, time-to-progression, overall survival, toxicity (p>0.10). EGFR gene expression was not associated with clinical outcome (p>0.10). Shorter EGFR intron-1 CA repeats (<20) was associated with higher EGFR gene expression (Kruskal-Wallis t test p=0.013)Conclusion: We were not able to confirm prospectively a previously reported association between functional EGFR gene polymorphisms and clinical outcome to platinum-based therapy in patients with advanced colorectal cancer. In-vitro studies assessing differential oxaliplatin sensitivity with respect to EGFR expression are on-going. [Table: see text]
Phase I clinical trial of CX-3543, a pro-apoptotic antitumor agent
Authors: Marschke R. F. , Ricart A. D. , Von Hoff D. D. , Lim J. K. , Papadopoulos K. 
Published: March 2020

3082 Background: CX-3543 is a novel small molecule specifically designed to target three dimensional nucleic acid motifs, and thus induce apoptosis in cancer cells. Preclinically, CX-3543 demonstrated potency in suppressing xenograft tumor growth with a broad therapeutic window. The objectives of this phase I study are: to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs), to establish the pharmacokinetics (PKs), and to determine the recommended dose for further clinical development of CX-3543. Methods: Eligible patients with advanced solid tumors or lymphomas whose tumors progressed on standard therapy or for whom there are no standard therapies receive CX-3543 in successive dose cohorts at: 10, 20, 40, 80 and 160 mg/m2. Dosing is by one hour intravenous infusion daily for five consecutive days repeated on a three week cycle. Therapy is continued until the patient shows signs of intolerance to CX-3543 or evidence of advancing disease. Response by RECIST criteria is determined after every 2 cycles. Results: Ten patients with solid tumors (3–4 per cohort) have received intravenous CX-3543. Doses have been well tolerated. Seven grade 3 adverse events have been reported during the study, but none of these are related to CX-3543. To date no objective responses have been observed. One patient with advanced refractory prostate cancer has stable disease of longer than 4 months duration. CX-3543 has demonstrated good linearity in PK parameters between the dose cohorts with a terminal half life of approximately 12 hours following the first dose. Conclusions: To date, CX-3543 has shown no drug related toxicity and has predictable PKs. No DLTs have yet been observed, and the MTD remains to be defined in this Phase I study. Further enrollment to the planned dose escalation cohorts is ongoing. [Table: see text]
Optimal dose of cetuximab (C) given every 2 weeks (q2w): A phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of weekly (q1w) and q2w schedules in patients (pts) with metastatic colorectal cancer (mCRC)
Authors: Tabernero J. , Cervantes A. , Martinelli E. , Vega-Villegas E. , Rojo F. , Pérez-Fidalgo A. , Casado E. , Ciardiello F. , Zubel A. , Baselga J. 
Published: March 2020

3085 Background: The anti-EGFR Mab C is active in mCRC. Since C has a long terminal half-life and it is frequently given in combination with q2w chemotherapy, we decided to compare the safety and PK/PD of a more convenient q2w schedule with the currently approved q1w schedule in pts with EGFR-expressing mCRC. Methods: In this study C was given q2w at the standard q1w regimen (400 mg/m2 initial dose and 250 mg/m2 weekly) to 10 pts as a comparator. In the experimental arm, C was given q2w with a dose escalation in sequential steps for cohorts of 10 pts each (400, 500, 600 & 700 mg/m2). Dose levels were escalated if no dose-limiting toxicities (DLTs) were observed. DLTs were defined as grade 3–4 toxicities (except for hypersensitivity reactions and grade 3 skin toxicity), and/or administration of less than 66% of the assigned dose due to toxicity. In order to conduct the PK/PD studies, all treatment groups were given C alone for 6 weeks and subsequently, the FOLFIRI regimen was added. Complete PK profile was obtained during the initial 6 weeks of treatment. Skin and tumor biopsies for PD profiling were obtained prior to therapy and on day 28 (steady state) and have been analyzed by IHC for total (t) and phospho (p)-EGFR, p-MAPK, p-Akt, proliferation (Ki67) & p27 expression. Results: 29 pts have been included so far: 9 in the q1w group and 20 in the q2w group (10 pts each at 400 and 500 mg/m2). To date there have been no DLTs. PK data are predictable (Cmin, AUC) and comparable (t1/2, CLss) between both regimens (see table below). Preliminary skin PD studies show no major difference in the EGFR-signaling inhibition by C in the q1w and q2w regimens. Conclusions: C can be safely administered in a q2w regimen at 400 and 500 mg/m2. The MTD of q2w C has not yet been reached and dose escalation is ongoing. Our findings show no major difference in PK and PD profiles with the q1w and q2w schedules. C given q2w may be an alternative and convenient schedule of administration. [Table: see text] [Table: see text]
Clinical pharmacokinetics (PK) of AMN107, a novel inhibitor of Bcr-Abl, in healthy subjects and patients with imatinib resistant or intolerant chronic myelogenous leukemia (CML) or relapsed/refractory Ph+ acute lymphocytic leukemia (Ph+ALL)
Authors: Tanaka C. , Smith T. , Kantarjian H. , Giles F. , Ottmann O. , Bhalla K. , Grouss K. , Sethuraman V. , Thomas K. , Schran H. 
Published: March 2020

3095 Background: AMN107, a selective and potent inhibitor of Bcr-Abl tyrosine kinase, has demonstrated activity against imatinib resistant forms of Bcr-Abl in patients with CML or Ph+ALL in a phase I study. This study characterizes clinical PK of AMN107 for the safe and effective use of the drug. Methods: Serum samples were collected in 119 patients with CML or Ph+ALL treated with once (QD) or twice daily (BID) oral AMN107 (doses of 50 to 1200 mg/day). PK parameters were derived from serum concentration-time data by non-compartmental methods. In separate multi-period crossover studies 92 healthy subjects were treated with single doses of AMN107 to assess the food effect on PK, and to assess the potential for drug-drug interactions with medications which inhibit (ketoconazole) or are metabolized by CYP3A4 (midazolam). Results: Steady-state AMN107 PK in patients were stable over time, and showed a dose-dependency with less than dose-proportional increases in systemic exposure at dose levels higher than 400 mg QD. Daily exposure at 400 mg BID, which maintains serum AMN107 levels at least 30 times higher than the IC50 of cellular phosphorylation of Bcr-Abl, was greater than at 800 mg QD. The effective half-life was 15 hours. Bioavailability of AMN107 administered with a high-fat meal was increased by 82% compared to fasting. CYP3A4 inhibition by concomitantly administered ketoconazole produced 3-fold increases in systemic exposure to AMN107, whereas AMN107 appeared a weak inhibitor of CYP3A4 with 30% increase in systemic exposure of midazolam given concomitantly. Conclusions: Systemic AMN107 levels at an oral AMN107 dose of 400 mg BID in patients with CML or Ph+ALL were well above the IC50 of Bcr-Abl. The food/drug interaction results provide further guidance for the safe use of AMN107 in the clinical setting. [Table: see text]
Response rate using conventional criteria is a poor surrogate for clinical benefit on progression-free (PFS) and overall survival (OS) in metastatic colorectal cancer (mCRC): A comparative analysis of N9741 and AVF2107
Authors: Grothey A. , Hedrick E. E. , Mass R. D. , Sarkar S. , Ramanathan R. K. , Hurwitz H. , Goldberg R. M. , Sargent D. J. 
Published: March 2020

3516 Background: A previous report noted that patients (pts) in the phase III study of IFL ± BV who received BV had significantly longer PFS and OS regardless of whether or not they responded according to RECIST criteria (Mass et al, ASCO 2005). It is unclear if this phenomenon is specific to the addition of a biologic to chemotherapy (CT) or a more general benefit from improved therapy since it has been suggested that stable as well as responding disease is beneficial for pts. We repeated the analysis of Mass et al on pts enrolled in N9741, a study which established the superiority of FOLFOX over IFL and contained no biologic compound. Methods: For this retrospective analysis, pts were defined as ‘responders‘ or ‘nonresponders‘ according to whether criteria for complete or partial response (by RECIST -AVF2107g or WHO criteria -N9741) were either achieved (responders) or not achieved (nonresponders). PFS and OS were estimated from Kaplan-Meier curves; hazard ratios (HR) for progression and death in each subgroup were estimated by Cox regression. Results: In both trials, response was associated with superior outcome. However, statistically significant improvements in PFS and OS were observed in both responders and non-responders treated with either IFL + BV or FOLFOX versus IFL, and the magnitude of improvement was similar regardless of response ( Table ). Conclusions: Analysis of two large recent mCRC phase III trials clearly demonstrate that pts who do not achieve a response according to traditional criteria still have significant benefit from the superior regimen, with a similar magnitude of benefit for responders and non-responders, regardless if the regimen called for CT alone or included the antiangiogenic biologic BV. These data support the conclusion that PFS and the percentage of pts experiencing tumor control may more accurately reflect pt benefit than does response rate in phase III trials in mCRC. [Table: see text] [Table: see text]