bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I clinical trial of MLN8054, a selective inhibitor of Aurora A kinase
Authors: Jones S. F. , Cohen R. B. , Dees E. C. , Lee Y. , Papas J. A. , Cooper M. R. , Galvin K. M. , Burris H. A. 
Published: March 2020

3577 Background: MLN8054 is a small molecule inhibitor of Aurora A kinase, with > 150-fold greater potency against this enzyme than the structurally related but functionally distinct Aurora B kinase. Because of its structural similarity to benzodiazepines, MLN8054 binds to the gamma-aminobutryic acid alpha 1 benzodiazepine (GABAA a1 BZD) receptor and in preclinical studies caused benzodiazepine-like CNS effects. Methods: MLN8054 was given as capsule by mouth for 7 consecutive days, repeated every 21 days. Cohorts of 3- 6 patients (pts) were enrolled to successively increasing doses until dose-limiting toxicity was seen in = 2 pts at a given dose level. Serial blood samples were collected to estimate PK; skin biopsies were obtained before and 6 hours after the first dose to assess inhibition of Aurora A kinase in basal epithelial cells. Results: 22 pts were enrolled to evaluate single daily doses of 5, 10, 20, 30 and 40 mg/day. MLN8054 was in general rapidly absorbed, displayed dose-proportionate exposure, and had a mean elimination half-life of 35 hours. The ratio of peak to trough plasma concentrations was approximately 5. Reversible grade 2 somnolence was first seen in 3 patients treated at 20 mg/day, and 2/4 patients treated at 40 mg/day experienced reversible grade 3 somnolence. In order to reduce the sedative effects of MLN8054, 16 additional pts were enrolled to doses of 25, 35, 45 and 55 mg/day given as divided doses on a QID schedule. Two of 4 pts treated at the 55 mg/day dose experienced reversible grade 3 somnolence, establishing 45 mg/day as the maximum tolerated total daily dose on a QID schedule. No myelosuppression or mucosal toxicity was seen at any dose with either schedule. Immunohistochemical analysis of skin biopsies from pts treated with once daily dosing did not demonstrate accumulation of cells in mitosis. Three pts with metastatic colorectal cancer treated with single daily doses of MLN8054 received = 8 cycles of treatment. Conclusions: The study is now escalating divided daily dosing of MLN8054 with the co-administration of methylphenidate. Post-treatment skin biopsies are now obtained on Day 7. Duration of treatment will be extended to 14 days, since steady-state concentrations of MLN8054 require 5–7 days of dosing, and because the effects of Aurora A kinase inhibition are duration-dependent. No significant financial relationships to disclose.
A pharmacogenetic study of docetaxel and thalidomide in patients with androgen-independent prostate cancer (AIPC) using targeted human DMET genotyping platform
Authors: Deeken J. F. , Cormier T. , Price D. K. , Steinberg S. , Tran K. , Liewehr D. J. , Ockers S. B. , Hardenbol P. , Dahut W. , Miao X. , Figg W. D. 
Published: March 2020

3580 Background: Pharmacogenetic research holds the promise of individualizing cancer therapy by reducing inter-individual variability in drug response, thus enhancing efficacy and reducing toxicity. Past research has been limited due to the lack of a robust genotyping platform that can screen for single nucleotide polymorphisms (SNPs) in the dozens of genes known to be involved in drug disposition. We pilot tested the new Affymetrix Targeted Human Drug Metabolizing Enzymes and Transporter (DMET) 1.0 panel in an exploratory study of docetaxel and thalidomide. The DMET 1.0 panel tests for 1,229 genetic variations in 169 drug disposition genes, including 49 CYP450 genes, 73 non-CYP genes, and 47 transporters. Methods: DNA samples from 47 patients with AIPC enrolled in a randomized phase II trial using docetaxel and thalidomide vs. docetaxel alone were genotyped using the DMET 1.0 panel. Patients’ response was determined using RECIST criteria. Toxicities were graded using the NCI-CTC, and patients were identified if they experienced grade 3 or 4 toxicity. Given the distinct side effect profiles of these two drugs, specific toxicities were assigned as being due to either docetaxel or thalidomide. An association between the SNP parameters and clinical response or toxicity was tested using Mehta’s modification to Fisher’s exact test. Reported results were limited to those where p<0.01. Results: Six SNPs in three genes were associated with response to therapy: PPAR-delta (p=0.0011), SULT1C2 (p=0.0083), and CHST3 (4 SNPs, p=0.0001 to 0.0034). For toxicities associated with docetaxel, five SNPs in three genes were identified: UGT1A1 (2 SNPs, p=0.0009 to 0.0094), UGT1A9 (2 SNPs, p=0.0016 to 0.0096), and CYP2A7 (p=0.0027). SNPs in CYP2B6 (p=0.0033), ABCC1 (p=0.0036), and ABCC6 (p=0.0075) were associated with toxicities from thalidomide. Conclusion: We identified nine genes in which SNPs were potentially significantly associated with clinical response and toxicity to treatment. These results highlight the important role that non-CYP450 and phase II drug metabolizing enzymes may play in the efficacy and disposition of docetaxel and thalidomide. Confirmatory studies are warranted. No significant financial relationships to disclose.
A phase I study of intravenous tetra-O-methyl nordihydroguaiaretic acid in patients with refractory malignancy
Authors: Goel S. , Burris H. , Mendelson D. , Gollamudi R. , Stern J. , Frazer N. , Jones S. , Gordon M. , Mani S. 
Published: March 2020

3584 Background: Tetra-o-methyl nordihydroguaiaretic acid (terameprocol-also EM-1421 or M4N) is a semi-synthetic derivative of a naturally occurring plant lignan. Terameprocol blocks cell cycle progression by inhibiting expression of the Sp1-dependent cdk1 gene and promotes apoptosis by inhibiting survivin. Methods: A dose escalation, open-label study enrolled patients (pt) with malignancies refractory to surgery, radiation therapy, and/or chemotherapy. Terameprocol was administered daily by intravenous infusion for 5 days (d) every 28 d over 30 minutes, with dose escalation (100, 200, 375, 750, 1,500, 2,200, and 3,300 mg) in cohorts of 3–6 pt. Tumor measurement (CT and PET scans) was performed at baseline and every 2 to 4 cycles. Pt at the 2,200mg and 3,300mg doses had circulating tumor cells (CTC) measured prior to dosing. Pharmacokinetics (PK) was evaluated for the first 2 cycles. Results: Twenty nine pt (17 male), median age 61 years, with gynecological (21%), lung (17%), colorectal (17%), or other cancer (45%) were enrolled. All pt were evaluable for toxicity and 21 pt for efficacy. At the highest dose (3,300 mg/d), dose limiting toxicity (DLT) of metabolic acidosis/respiratory failure considered drug related was observed in 1 of 3 pt, and no additional pt was enrolled at this dose. The next lower dose cohort (2,200 mg/d) was expanded (11 pt) and no DLT has been observed. Best response by RECIST criteria included a partial response in 1 pt and stable disease in 6 pt. Three pt discontinued for reason other than progression, and 11 had progressive disease. Pharmacokinetics demonstrated dose linearity. The volume of distribution was 300–1,000 liters, and the half-life ∼ 20–30 hours. No obvious trend was seen in CTCs. Across all doses, 108 adverse events, with 10 severe events, were observed. Conclusions: Terameprocol is well tolerated up to a dose of 2,200 mg and warrants further evaluation. Expansion continues at this dose level. There is clinical benefit in this refractory population that warrants further investigation. No significant financial relationships to disclose.
Pharmacodynamic properties of the anti-IGF-IR monoclonal antibody CP-751,871 in cancer patients
Authors: Pollak M. N. , Lacy M. Q. , Lipton A. , Demers L. , Leitzel K. , de Bono J. S. , Yin D. , Roberts L. , Sharma A. , Gualberto A. 
Published: March 2020

3587 Background: The Insulin like Growth Factor I receptor (IGF-IR), a tyrosine kinase, is widely expressed in human tissues. IGF- IR and its ligands (IGF-I and IGF-II) are expressed by many human cancers (e.g., breast, prostate, colorectal and non-small cell lung). Binding of the ligands to the IGF-IR activates key cellular signaling pathways important for stimulating cellular proliferation and inhibiting apoptosis. IGF- I and IGF-II are present in the circulation, but also locally expressed in neoplastic tissue. Bioavailability of these ligands is regulated by a family of IGF binding proteins (IGFBPs1–6). CP-751,871, a fully human monoclonal antibody, is a highly specific and potent inhibitor of IGF-IR activation. In vitro experiments show that binding of CP 751,871 to IGF-IR induces receptor internalization and degradation. This antibody has been shown to have antineoplastic activity using both in vivo and in vitro pre-clinical models. Methods: Blood samples were collected for characterization of the pharmacokinetic and pharmacodynamic properties of CP-751,871 in phase 1 trials of this agent given to cancer patients either alone or in combination with chemotherapy. The endpoints assessed included among others: CP-751,871 plasma concentrations, total and free IGF-I, IGFBP-3, soluble IGF-IR and IGF-IR expression on granulocytes and tumor cells. Results: CP 751,871 exposure increased with dose over the 800-fold dose range investigated. Pharmacokinetic profiles were consistent with target-mediated disposition. A dose-dependent downregulation of soluble IGF-IR serum concentration and IGF-IR expression was observed, with sustained inhibition for the entire dosing period (3–4 week cycles) observed at doses ≥ 1.5 mg/kg. As predicted for an agent that interferes with IGF-I action, IGF-I and IGFBP-3 serum levels were up-regulated in a similar dose-dependent manner. Conclusions: The pharmacodynamic endpoints of clinical trials provide evidence that CP-751,871 targets IGF-IR in granulocytes, tumor cells and tissues involved in regulation of the growth hormone -IGF-I axis. These data provide proof of principle for the use of CP-751,871 as a first-in-class therapeutic approach to inhibit the IGF-IR pathway in cancer patients. No significant financial relationships to disclose.
Phase I dose escalation pharmacokinetic study of erlotinib after failure of prior chemotherapy in patients with advanced NSCLC who continue to smoke
Authors: Hughes A. N. , O’Brien M. , Dunlop D. , Petty W. , Rankin E. , Chick J. , Conlan M. , Woll P. , Nicolson M. , Price A. 
Published: March 2020

3597 Background: The survival benefit associated with erlotinib is greater in never smokers than in current smokers. Former/never smokers experience a higher incidence of toxicity (e.g., rash) than current smokers, potentially due to greater erlotinib exposure. A higher dose of erlotinib, if feasible, may improve outcome in current smokers. Methods: A 2-part study was initiated to investigate the feasibility of escalating erlotinib to define the MTD in smokers and evaluate pharmacokinetics in patients (pts) dosed at this MTD versus 150 mg/d. Part I: sequential cohorts of advanced NSCLC pts currently smoking =10 cigarettes/d for = 1yr, ECOG PS 0–1, adequate organ function, and no prior EGFR inhibitor, received escalating doses of erlotinib for 14 days until DLT was seen in 2/6 pts. Part II: Upon identification of the MTD, pts were randomized between MTD and 150 mg/d erlotinib and PK assessed at D14. Pts could receive erlotinib beyond D14 until PD or toxicity. Results: Twenty-two pts were enrolled in Part I at 4 dose levels (#pts (MTD-evaluable pts)/dose level in mg/d): 3(3)/200, 6(3)/250, 8(6)/300 and 5(5)/350). Median/range age was 61 yrs (45–69) with 13 males and 9 females. Histology was Adenocarcinoma (9/22), Squamous (6/22) and other (7/22). Fourteen pts had prior RT and all had prior CT (median/range # prior regimens 1 (1–2)). Median/range # cigarettes smoked and duration of smoking was 18/d (10–40) and 42 yrs (10–54), respectively. DLT was observed in 1/6 MTD- evaluable pts at 300 mg/d (G3 rash) and 2/5 pts at 350 mg/d (G3 acneiform dermatitis and G3 fatigue/decreased ECOG PS). Otherwise treatment was well tolerated with common G1/2 toxicities limited to skin toxicity (59%), diarrhea (55%), and nausea, vomiting and metabolic or eye disorders (each 14%). Conclusions: The MTD of erlotinib in NSCLC pts who continue to smoke was 300 mg/d. Part II continues to compare the steady state PK of erlotinib at 300 versus 150 mg/d. The potential benefits of a higher dose of erlotinib in current smokers may warrant further evaluation. No significant financial relationships to disclose.
First-in-human study of the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PF-00299804, a small molecule irreversible panHER inhibitor in patients with advanced cancer
Authors: Schellens J. H. , Britten C. D. , Camidge D. R. , Boss D. , Wong S. , Diab S. , Guo F. , Maguire R. P. , Letrent S. P. , Eckhardt S. G. 
Published: March 2020

3599 Background: There are scientific rationale for inhibitors which provide combined and irreversible blockade of HER family members. PF-00299804 is an orally available, potent, irreversible small molecule inhibitor of the HER tyrosine kinases. Methods: The safety, tolerability, PK, PD, and efficacy of PF-00299804 administered orally once daily in 3-week cycles were assessed in patients with advanced solid tumors using an accelerated dose-escalation design. Safety assessments included adverse event (AE), laboratory, ECG, and LVEF assessments. PK parameters were determined after a single lead-in dose and on Day 14 by non-compartmental techniques. PD measures included assessment of HER-related signaling pathways via IHC analyses of serial skin and, in some patients, tumor biopsies. Serial 18F-FDG- PET/CT has been performed on a subset of patients with scans being classified according to modified EORTC criteria by a central reader. Results: 32 pts have been treated across 8 sequential dose levels ranging from 0.5 to 60 mg. The most common AEs were diarrhea, fatigue, nausea, and rash. 3/6 patients at 60 mg experienced a DLT [hand-foot syndrome (1), dehydration related to diarrhea(1), mucositis(1)]. Cmax and AUC of PF-00299804 increased with dose in an approximately proportional manner. Accumulation ranged from 3.3 to 6.8, suggesting a terminal t1/2>24 h. At the 30 mg dose level, mean Day 14 drug concentration was above the predicted efficacious concentration for tumor growth inhibition based on A431 xenograft model. Of 7 sets of PET data evaluated thus far, partial responses (PR) have been observed in 2 patients. A PR as assessed using RECIST criteria has been reported in 1 of 2 patients with advanced refractory NSCLC treated to date. Conclusions: Daily administration of PF-00299804 across many dose levels appears safe and tolerable. Diarrhea, fatigue, nausea, and rash are the most frequent AEs. Evaluation of 45 mg/d as the potential MTD is ongoing. Systemic exposures at doses = 30 mg exceed the threshold for efficacy as predicted from preclinical studies. Clinical and biological activity of PF-00299804 was observed including a PR in 1 of 2 patients with advanced refractory NSCLC. No significant financial relationships to disclose.
Quality of life in patients with advanced colorectal cancer treated with cetuximab: Results of the NCIC CTG and AGITG CO.17 trial
Authors: Au H. , Karapetis C. , Jonker D. , O’Callaghan C. , Kennecke H. , Shapiro J. , Tu D. , Wierzbicki R. , Zalcberg J. , Moore M. 
Published: March 2020

4002 Background: Cetuximab prolongs survival in pretreated advanced colorectal cancer (CRC) patients (pts). For these pts, the effect of palliative treatment on quality of life (QOL) is also an important outcome. Methods: CO.17 was a randomized controlled trial (n=572) of cetuximab combined with best supportive care (BSC) vs BSC alone in pts with pretreated epidermal growth factor receptor-positive advanced CRC. Primary endpoint was survival. QOL was a secondary endpoint using the EORTC QLQ-C30 at baseline, 4, 8, 16, and 24 weeks (wks). Primary endpoint for QOL compared physical function (PF) and global health status (Global) mean changes from baseline to 8 and 16 wks using Wilcoxon test. Negative change scores denote worsening QOL. The proportion of pts in either arm with at least a 10 unit deterioration at 8 and 16 wks from baseline was compared using Fischer’s exact test. Kaplan-Meier estimates and logrank tests on median time to definitive QOL deterioration, defined as at least a 10 unit deterioration in PF or Global, were evaluated. Exploratory analyses of all other scale and symptom change scores at 8 and 16 wks were also performed. Results: Compliance rates for QOL questionnaires was high at baseline, 94% each arm, but did drop off over time: 73% vs 60% at week 8 and 60% vs 39% at week 16 for cetuximab vs BSC, respectively. PF change scores at 8 wks were -3.9 for cetuximab vs -8.6 for BSC (p=.046); at 16 wks -5.9 vs -12.5 (p=.027). Global change scores were -0.5 vs -7.1 (p=.008) and -3.6 vs -15.2 (p=.008) at 8 and 16 wks respectively. The proportion of pts with deteriorating PF was 25% for cetuximab vs 35% for BSC at 8 wks (p=.051) and 30 vs 43% at 16 wks (p=.069). Deteriorating Global was seen in 23 vs 38% at 8 wks (p=.004) and 31 vs 49% at 16 wks (p=.0011). Time to PF deterioration was 5.4 months [95% CI 3.8–5.7] for cetuximab vs 3.7 months [2.0–3.9] for BSC (p=.022). Time to Global deterioration was 5.4 [3.9–5.7] vs 3.7 months [2.1–3.9] (p=.062). Exploratory analyses of all other scale and symptom change scores at 8 and 16 wks showed all differences of p<.05 also favored cetuximab. Conclusions: Cetuximab provides palliation in pretreated pts with advanced CRC, delaying deterioration in QOL as well as improving survival. [Table: see text]
A pooled safety and efficacy analysis examining the effect of performance status (PS) on outcomes in nine first-line treatment (rx) trials (cts) of 6,286 patients (pts) with metastatic colorectal cancer (MCRC)
Authors: Goldberg R. M. , Köhne C. H. , Seymour M. T. , de Gramont A. , Porschen R. , Saltz L. , Rougier P. , Tournigand C. , Grothey A. , Sargent D. J. 
Published: March 2020

4011 Background: While pt PS is a known prognostic factor in MCRC, most phase III CTs enroll < 10% PS2 pts. This pooled analysis compares safety and efficacy in PS 0–1 versus (v) PS 2 MCRC pts on first-line CTs testing both single agents and combination rx. Methods: This retrospective analysis included 6,286 MCRC pts (509 PS 2) from 9 CTs (control arms: 5 5FU/LV, 2 FOLFOX, 1 FUFOX, 1IFL). Five CTs specifically compared mono to combination rx (3,814 pts; 335 PS 2). The primary endpoint was progression-free survival (PFS). Other endpoints included grade 3+ adverse events, 60-day all cause mortality, overall survival (OS), and response rate (RR). Efficacy endpoints were explored in both the full set of 9 CTs & the subset of 5 CTs that compared mono to combination rx. Results: Severe (grade 3+) nausea (7.0% v 13.0%; P < .0001), vomiting (6.4% v 10.5%; P = .0002), and stomatitis (2.0% v 4.2%; P = .0332) were significantly higher in PS 2 pts. PS 2 was not associated with incidence of severe diarrhea or neutropenia. 60-day all cause mortality was significantly higher in PS 2 pts (2.8% v 12.0% in PS 0–1 v PS 2 respectively, P <.0001). PS 2 was a prognostic factor for PFS (HR=1.52, P < .0001, median 7.6 v 4.9 months (mos) in PS 0–1 v 2), OS (HR=2.18, P < .0001, median 17.3 v 8.5 mos in PS 0–1 v 2), & RR (OR=0.60, P < .0001, 43.5% v 32.0% in PS 0–1 v 2). The relative benefit of experimental (exp) v control rx did not differ in PS 0–1 v PS 2 pts for RR, PFS, or OS (see table ). This was true both when assessing all 9 CTs and the subset of 5 mono v combination rx CTs. Conclusions: In CTs, pts with PS 2 derive similar advantages with regard to efficacy from superior Rx as do pts with PS 0–1, but with higher risk of some gastrointestinal toxicities. Twelve percent of PS 2 pts die within 60 days of rx start. Median OS is < 9 months. While current Rx does provide benefit, new approaches are required to approach 1 year median survival for PS 2 pts. [Table: see text] No significant financial relationships to disclose.
Meeting the 12 lymph nodes (LN) benchmark in colorectal cancer surgery: A comparison of NCCN and SEER data
Authors: Rajput A. , Skibber J. , Engstrom P. , Weiser M. , Wilson J. , Shibata S. , Romanus D. , terVeer A. , Earle C. , Schrag D. 
Published: March 2020

4015 Background: The American College of Pathology has suggested that 12 or more LN be examined from colorectal cancer surgical specimen. Both ASCO and NCCN have considered adopting the 12 LN threshold as a quality metric. The purpose of this study was to determine whether the 12 LN benchmark is achieved at NCCN specialty centers. Methods: Patients with newly diagnosed stage I-III colon or rectal cancer, who had primary surgery at NCCN centers in 2005–6 were selected (n=345). Similarly, data from 14,019 stage I-III colorectal patients diagnosed in 2002 in a SEER region were obtained to determine the extent to which this goal was met in a population-based sample. Patient characteristics of age, gender, location, stage and number of positive nodes were compared for NCCN and SEER data in regards to number of nodes evaluated. Univariate logistic regression models were developed to identify factors associated with the 12 LN target at the NCCN. Factors evaluated were number of positive nodes, age, gender, comorbidity score, ECOG performance status, insurance, location, stage, surgery technique, and NCCN center. Results: As detailed in the Table , 89% of the 2005–6 NCCN sample and 45% of the SEER sample had at least 12 LN evaluated. For patients treated at NCCN centers, stage I compared to stage III (OR=0.20; 95% CI=0.08 to 0.48, p<0.0001) and rectal cancer (OR=0.44; 95% CI=0.22 to 0.88, p=0.02) were each less likely to achieve the 12 LN target. Conclusions: For patients operated on at NCCN centers, at least 12 LN are almost always removed and examined as part of an oncologic resection. In population based samples, this target is achieved in less than half of cases. With longer follow-up we will be able to link this potential quality metric directly to outcomes and thereby better inform whether increasing the number of nodes evaluated is an important priority for cancer control. Table 1 . Characteristics of CRC patients who did and did not have 12 or more LN evaluated at primary resection. [Table: see text] No significant financial relationships to disclose.