bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dasatinib (BMS-354825) pharmacokinetics correlate with pSRC pharmacodynamics in phase I studies of patients with cancer (CA180002, CA180003)
Authors: Luo F. R. , Luo F. R. , Barrett Y. , Ji P. , Holly P. , McCann E. , Rhyne P. , Clarke E. , He K. , Bleichardt E. , Blackwood-Chirchir M. 
Published: March 2020

3046 Background: Dasatinib - an inhibitor of several oncologenic kinases including BCR-ABL and SRC - has demonstrated efficacy in CML and Ph+ ALL, and is being evaluated in patients with solid tumors. Studies CA180–002, and CA180–003 were multiple ascending dose studies of dasatinib in patients with refractory Ph+ leukemia, and solid tumors, respectively. We have analyzed the preliminary results of pharmacokinetics (PK) and pharmacodynamic (PD) biomarker phospho-SRC (pSRC) combined across the CA180002 and CA180003 studies. Methods: Dasatinib was administered orally at doses of 15 - 180 mg QD or 25 - 160 mg BID. Dasatinib PK was determined by LC MS/MS. The level of phospho-SRC in peripheral blood mononuclear cells (PBMCs) was determined by an ELISA and was used as a surrogate biomarker of the level of kinase activity of the SRC family members. PK-PD modeling was performed using a two-compartment PK model with first-order absorption kinetics and an indirect inhibitory Emax model as the PD model. Results: On the BID regimen, pSRC inhibition was approximately dose-dependent across the dosing range. Inhibition also appeared to be directly correlated with dasatinib plasma concentration, with maximal inhibition achieved at ∼2.5 hr. Based on PK-PD modeling, the estimated EC50 (the plasma concentration required to achieve 50% inhibition of pSRC) is 14.4 ng/mL. Conclusions: SRC family kinase activity is substantially inhibited at the exposures of dasatinib achieved to date. The optimal regimens of dasatinib to achieve both target inhibition and solid tumors efficacy will be determined based on biomarkers, clinical responses, and toxicity profiles. [Table: see text]
Apo2L/TRAIL pharmacokinetics in a phase 1a trial in advanced cancer and lymphoma
Authors: Ling J. , Herbst R. S. , Mendelson D. S. , Eckhardt S. G. , O’Dwyer P. , Ebbinghaus S. , Osborne R. , Cheu M. , Lieberman G. , Lum B. L. 
Published: March 2020

3047 Background: Apo2L/TRAIL (Apo2L ligand/tumor necrosis factor-related apoptosis-inducing ligand) is the first recombinant human protein that selectively induces apoptosis or programmed cell death in cancer cells while sparing normal cells. The molecule used in this joint clinical development between Genentech, Inc. and Amgen, Inc., is an optimized recombinant human Apo2L/TRAIL protein produced in E. coli. It displays broad activity in preclinical models of a variety of solid and hematologic cancers. This is the first report of the pharmacokinetics of Apo2L/TRAIL in humans. Methods: Thirty-nine patients enrolled in a phase 1a study had PK assessments at dose levels ranging from 0.5–15 mg/kg in two cohorts, those with and those without liver metastases. Recombinant human Apo2L/TRAIL was administered as a 1-hr IV infusion for 5 consecutive days over a 21-day cycle. Serum concentrations were determined using a sensitive ELISA assay. PK calculations were performed using Non-compartmental analyses. Results: Currently Apo2L/TRAIL PK data are available for 27 patients, 15 in cohort 1 (no liver metastases) and 12 in cohort 2 (liver metastases). Mean (± SD) PK data for patients in cohort 1 and cohort 2 did not differ. PK data for cohort 1 are outlined in the table below. Apo2L/TRAIL clearance appeared proportional to dose and consistent with that predicted from nonclinical models. Cmax achieved at doses ≥ 4 mg/kg are equivalent to or greater than those displaying activity in preclinical models. There was no evidence of drug accumulation between day 1 and day 5 of treatment. Conclusions: Apo2L/TRAIL at doses which can be safely administered in humans produces serum concentrations consistent with those demonstrating efficacy in tumor xenograft models. Hepatic metastases with or without mild liver dysfunction do not appear to influence the PK of Apo2L/TRAIL. [Table: see text] [Table: see text]
A phase 1 dose finding study of CHR-2797, an inhibitor of M1 aminopeptidases, in patients with advanced solid tumours
Authors: Reid A. , Protheroe A. , Attard G. , Cowsill C. , Spicer J. , Vidal L. , Bone E. , Hooftman L. , Harris A. , De-Bono J. S. 
Published: March 2020

3053 Background: CHR-2797 is a novel, orally bioavailable inhibitor of the M1 family of aminopeptidases, in particular PuSA, and LTA4 hydrolase. Exposure of cancer cells to CHR-2797 results in the generation of the active metabolite CHR-79888 which is poorly membrane-permeable, resulting in intracellular accumulation. CHR-2797 has shown anti-proliferative activity in syngeneic (rat) and xenograft (mouse) cancer models, and is anti-angiogenic in vitro. Methods: Patients (pts) (ECOG PS ≤ 2) with histologically confirmed advanced solid tumors resistant or refractory to standard therapy were eligible. The accelerated titration design of the trial involved two phases for evaluation of schedule and dose: 1) fixed dose with increasing duration, and 2) dose escalation over a fixed duration (28 days). Results: 16 pts (median age: 64.5 years [range 48.8–80.1], 13M/3F)were treated with once daily doses ranging from 10mg to 130mg. The first four patients received a 10mg dose for 7, 14, 21 or 28 days respectively. Five subsequent cohorts received 28 days continuous dosing, with dose doubling in single patient cohorts until drug-related toxicity ≥ Grade 2. Thereafter dose was escalated in ≤ 40% increments in 3-patient cohorts. The most frequent adverse events were: gr 1–2 thrombocytopenia (44%), gr 1 diarrhea (25%), gr 1–2 transaminitis (19%), gr 1–2 fatigue (13%), gr 1 hot flushes (13%), and gr 1 lightheadedness (13%). There were no DLTs. Five patients continued therapy after 28 days; stable disease has been achieved in 1 pt for 6 months with granulosa cell carcinoma of ovary, who was progressing prior to study entry. CHR-2797 and CHR-79888 demonstrate dose proportional increases in AUC and Cmax. The terminal half-life for CHR-2797 is around 1–2 hours, whereas it is between 9 and 11 hours for CHR-79888. Intracellular (packed blood cells) exposure to both CHR-2797 and CHR-79888 is good, with CHR-79888 accumulating over 28 days, such that by day 28 the intracellular levels are comparable to plasma. Conclusions: CHR-2797 is well tolerated and can be safely administered at doses that reach plasma concentrations associated with activity in pre-clinical models. Accrual into the study continues. No significant financial relationships to disclose.
A prospective pharmacogenomic (PG), pharmacodynamic (PD), and pharmacokinetic (PK) study of determinants of erlotinib toxicity
Authors: Rudin C. M. , Desai A. A. , Janisch L. , Carducci M. , Karrison T. , Liu W. , Fleming G. F. , Ramirez J. , Innocenti F. , Ratain M. J. 
Published: March 2020

3080 Background: A strong but unexplained association between skin toxicity (rash) and survival from erlotinib therapy has been noted for patients with several epithelial malignancies. The correlation between rash and clinical benefit appears to extend across classes of epidermal growth factor receptor (EGFR)-targeted agents. Several hypothetical explanations for this association have been suggested including polymorphisms of the EGFR locus as well as PD and PK variability. Methods: We conducted this 80-subject prospective study in patients with lung (N=43), head and neck (N=9), and ovarian cancer (N=28) given erlotinib 150 mg daily to evaluate several of these hypotheses. Patients underwent toxicity monitoring, response assessment, skin biopsies pretreatment and after 28 days for immunohistochemical (IHC) analysis, as well as blood collection for PK analysis and evaluation of EGFR genetic polymorphisms reported to influence EGFR expression level. Results: 72/80 subjects are evaluable for toxicity. Response correlates with both worst grade diarrhea (p=0.003) and rash (p=0.044). Initial PK analysis suggests a positive association between d15 erlotinib trough level and both diarrhea (p=0.091) and rash (p=0.076). Controlling for d15 erlotinib level, EGFR intron 1 CA repeat length is also associated with rash (p=0.030). Polymorphisms in the EGFR promoter (216 G/T and 191 C/A) correlated with diarrhea (p=0.053 and 0.005 respectively) but not rash. IHC analyses including EGFR, p-EGFR, Akt, p-Akt, ERK, and p-ERK have been completed on 35 paired, pre-post treatment skin biopsies and demonstrate no strong correlations with toxicity. Conclusions: These data suggest that both interindividual PK variability and EGFR polymorphisms may contribute to erlotinib toxicity. Erlotinib effects on EGFR signaling in skin do not appear to correlate with toxicity. Samples obtained in this study are available for analysis of other candidate PG determinants of both toxicity and PK variability. [Table: see text]
A phase I, open-label study of the safety and pharmacokinetics (PK) of pazopanib (P) and lapatinib (L) administered concurrently
Authors: Dejonge M. , Savage S. , Verweij J. , Collins T. S. , Eskens F. , Whitehead B. , Suttle A. B. , Pandite L. B. , Ho P. T. , Hurwitz H. 
Published: March 2020

3088 Background: P is a potent tyrosine kinase inhibitor of VEGF-R1, -R2, and R3, PDGF-α/β, and c-Kit. L is a potent inhibitor of ErbB1 and ErbB2 tyrosine kinases. Several lines of evidence support combined inhibition of VEGFR and Erb in the treatment of malignancies. Methods: Patients (pts) with solid tumors received P and L daily. Safety, limited PK, biomarkers, and clinical activity were evaluated. Dose escalation occurred in cohorts of 3–6 pts based on DLT. Results: Thirty-three pts received L/P doses of 750/250 (n=4), 750/500 (n=6), 1000/250 (n=3), 1000/400 (n=2), 1000/500 (n=4), 1250/250 (n=6), 1250/400 (n=5) and 1500/200 (n=3) mg once daily (qd). Preliminary mean plasma P concentrations 24 h after administration (C24) on Day 22 were ∼19 μg/mL and 23 μg/mL after administration of 250 mg and 500 mg, respectively. These values are similar to mean C24 values observed after administration of 800 mg P alone (23.1 μg/mL). Plasma L concentrations at 750 - 1500 mg qd were similar to those observed after monotherapy. The most frequent AE’s were diarrhea (Grade (G)1 n=10, G2 n=2, G3 n=3), fatigue (G1: n=7, G2 n=5, G4 n=1), nausea (G1 n=9, G2 n=2), anorexia (G1 n=8, G2 n=3), vomiting (G1 n=9), hair depigmentation (n=7), rash (G1 n=6, G2 n=1) and abdominal cramps (G1 n=3, G2 n=2, G3 n=1). Prolonged disease stabilization of > 16 wks (median 21.5 wks) occurred in 10 pts (RCC n=3, CRC n=3, GIST n=1, mesothelioma n=1, adenocarcinoma GE junction n=1, aggressive fibromatosis n=1). 3 pts (renal cancer n=2, and giant cell tumor of the bone n=1) demonstrated tumor shrinkage of < 30% (i.e. SD by RECIST). Conclusions: Concurrent administration of pazopanib and lapatinib was generally well tolerated. Coadministration of lapatinib may alter the PK of pazopanib. [Table: see text]
Relationship between tumor gene expression and recurrence in stage II/III colon cancer: Quantitative RT-PCR assay of 757 genes in fixed paraffin-embedded (FPE) tissue
Authors: O’Connell M. J. , Paik S. , Yothers G. , Costantino J. P. , Cowens J. W. , Clark K. M. , Baker J. , Hackett J. , Watson D. , Wolmark N. 
Published: March 2020

3518 Background: As an initial step in developing abetter method of assessing prognosis following potentially curative surgery for colon cancer, we performed an exploratory gene identification study. Methods: RNA was extracted from three 10-micron sections of the FPE tumor tissue obtained at the initial diagnosis from 353 patients entered between 1977 and 1984 into the surgery-only or surgery-plus BCG arms of NSABP C-01/C-02. Expression was quantified for 757 cancer-related and reference genes with RT-PCR. Results: Blocks from 270 patients were evaluable after pre-specified exclusions: 128 were stage II and 142 were stage III. All patients had ≥ 5-year follow up. In univariate Cox proportional hazard analyses, 148 genes exhibited a nominally significant (unadjusted p-value <0.05) linear association with recurrence-free interval (RFI) (7 genes p≤0.001, 66 genes 0.001<p<0.01; 75 genes 0.01≤p<0.05). False discovery rate calculations suggest that about 25% of the 148 genes are expected to be false positives. Higher expression was associated with shorter RFI for 118 genes including SERPINB5, DUSP1, AKT3, TIMP1, ANXA2, RHOB (p≤ 0.001) and with longer RFI for 30 genes including BRCA1 (p≤0.001). The relationship between gene expression and RFI was similar for stage II and stage III patients for 143 of the 148 genes found to be significant. The largest cluster of genes is functionally related to extracellular matrix remodeling. The magnitude of the hazard ratios is similar to that observed in the early Oncotype DX studies in breast cancer and should allow clinically useful separation into low/intermediate/high risk groups. Conclusions: Quantitative RT-PCR assay of FPE colon cancer tissue can be used to identify large numbers of genes associated with RFI in patients with stage II and III colon cancer. If these results are confirmed by additional studies in progress, this technique has promise to improve selection of colon cancer patients for adjuvant chemotherapy. Funded in part as a collaborative arrangement under contract between the NSABP Foundation, Inc., and Genomic Health, Inc. [Table: see text]
Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer. A meta-analysis of two randomized trials
Authors: Mitry E. , Fields A. , Bleiberg H. , Labianca R. , Portier G. , Tu D. , Torri V. , Lazorthes F. , Van Cutsem E. , O’Callaghan C. J. , Rougier P. 
Published: March 2020

3524 Background: Adjuvant systemic chemotherapy (CT) administered after resection of colorectal cancer (CRC) metastases (M) may reduce the risk of recurrence and improved survival but its benefit has never been demonstrated. Two phase III trials (FFCD 9002 and EORTC/NCIC CTG/GIVIO (ENG) trials) with a very similar design showed a trend for improvement in survival after adjuvant CT but had to close prematurely because of slow accrual, lacking the statistical power to demonstrate any significant difference in survival. We report here a pooled analysis based on individual data from these trials. Methods: Patients were required to have a WHO performance status ≤2 and a histologically proven CRC with a complete (R0) surgical resection of the primary tumour and of ≤4 liver or lung metastases. They were randomized between chemotherapy (CT arm) [5FU 400 mg/m2 (FFCD) or 370 mg/m2 (ENG) IV q.d. x 5 days plus dl-leucovorin 200 mg/m2 (FFCD) or l-leucovorin 100 mg/m2 (ENG) IV q.d. x 5 days, 6 cycles at 28 days intervals] or surgery alone (S arm). Results: 129 pts were included in the ENG trial between 1994 and 1998, 173 in the FFCD trial between 1991 and 2001. 24 pts (ENG: 22, FFCD: 2) were excluded from analysis for missing post-baseline data: 278 pts were included in the present analysis (CT: 138, S: 140). Patients’ characteristics by treatment arm (% CT/S): males 58.0/63.6, age <70 years: 79.7/79.3, stage IV primary tumor: 29.0/47.1 (p=0.02), liver M 94.2/93.6, ≥2 M resected: 33.3/31.4. Conclusion: Adjuvant CT with a 5FU bolus based regimen tends to improve survival after complete resection of CRC metastases. The observed improvement in median PFS was almost statistically significant whereas the improvement in median OS (more than 1 year) was not (lack of statistical power?). This pooled analysis supports the use of adjuvant CT, with a more effective regimen, after potentially curative resection of CRC metastases. Updated results will be presented. (Supported by AROLD) [Table: see text] No significant financial relationships to disclose.
A meta-analysis of two randomized, double-blind, placebo-controlled, phase III studies in patients (pts) with metastatic colorectal cancer (mCRC) receiving FOLFOX4 and PTK/ZK to determine clinical benefit on progression-free survival (PFS) in high LDH pts
Authors: Major P. , Trarbach T. , Lenz H. , Kerr D. , Pendergrass K. , Douillard J. , Chen B. , Laurent D. , Jacques C. , Van Cutsem E. 
Published: March 2020

3529 Background: PTK/ZK is an oral, antiangiogenic inhibitor of tyrosine kinase signaling of all known vascular endothelial growth factor receptors (VEGFR). PTK/ZK in combination with FOLFOX4 has been investigated in first line (CONFIRM 1[C1]) and second line (CONFIRM 2 [C2]) mCRC pts. Methods: In both trials, pts were randomized to receive PTK/ZK or placebo. Since high LDH and poor performance status (PS) have been shown to indicate poor prognosis in mCRC, pts were stratified by baseline serum LDH (≤ or > 1.5 X ULN) and PS (0, 1–2), yielding 4 strata per trial. Exploratory analysis of the high LDH strata in C1 indicated that these pts may derive the most benefit from PTK/ZK treatment. The purpose of this pre-planned meta-analysis of C1 and C2 is to determine whether the treatment effect of C1 and C2 are consistent. Results: Both trials showed strikingly similar results. High LDH pts comprise approximately 30% of the total pt population. PTK/ZK seems to have the same strong effect on PFS in high LDH pts in both 1st and 2nd line mCRC with a HR for PFS of 0.67 (p =0.010) for C1 and 0.63 (p < 0.001) for C2 (N=250 and N=316, respectively). The safety profile of PTK/ZK was highly consistent. The most frequent grade 3/4 AEs attributable to PTK/ZK were hypertension, diarrhea, fatigue, nausea, vomiting and dizziness. Increases in AEs associated with antiangiogenic therapy such as bowel perforations and bleeding complications were not observed in the PTK/ZK arms of both trials. In the meta-analysis, PTK/ZK effect on PFS is moderate in the overall population (HR 0.85, p-value 0.005). In contrast, the effect on PFS is strong and clinically meaningful in the high LDH population (HR 0.65, p-value < 0.001, N=566). Conclusion: This meta-analysis is the largest study of poor prognosis pts with high serum LDH in metastatic colorectal cancer. These data suggest that PTK/ZK significantly improves PFS in high LDH pts. Further evaluation of PTK/ZK in this pt population is planned. [Table: see text]
Alterations in molecular networks of metastatic colorectal carcinoma reveal organ-specific signatures: Implications for targeted therapy of metastatic disease
Authors: Pierobon M. , Calvert V. , Lipsky M. , Sheehan K. , Speer R. , Mammano E. , Belluco C. , Wulfkuhle J. , Nitti D. , Liotta L. , Petricoin E. 
Published: March 2020

3532 Background: Proteomic analysis of aberrant protein kinase activity is poised to provide crucial knowledge that could drive molecular-targeted therapeutics and personalized medicine. Many cancers are detected at late stages when metastasis has already occurred. Knowledge about the molecular derangements in the metastatic lesion is crucial for the rational selection of therapeutics. Very little is known about the signaling networks in the metastatic microenvironment. We employed reverse phase protein microarrays coupled to laser capture microdissection for a multiplexed phosphoproteomic fingerprint of colorectal metastatic disease to begin to understand the molecular functional changes that occur upon metastasis. Methods: 68 frozen cases of patient-matched colorectal cancer and hepatic metastasis, 15 cases of pulmonary metastasis, and 27 cases of hepatic metastasis of other primary cancers including breast, melanoma, pancreatic, ovarian, and stomach cancers (all taken at the same time at surgery), were subjected to laser capture microdissection. Procured tumor epithelia (20,000 cells per sample), were lysed and subjected to reverse phase protein microarray analysis. Using this technique, we measured the phosphorylation state of 75 kinase substrates. Molecular network analysis was performed using commercially available software. Results: Our results indicate that, unlike analysis of gene microarray data, we observe a significant difference between the molecular networks of activated kinase substrates within the metastatic lesion compared to the patient-matched primary tumor. In fact, despite overall patient-specific heterogeneity of the portraits, organ specific signatures that were independent of the primary origin of the tumor were identified. Conculsions: Effective treatment in the new era of personalized targeted therapeutics will require the ability to understand the functional activation of cellular signaling pathways since these are the drug targets themselves. Our results indicate that treatment of metastatic disease, and patient stratification for matching with the appropriate therapy may be organ-specific and not predicated upon the primary site of the disease. No significant financial relationships to disclose.
Preliminary results of a phase I study of external beam radiation therapy (EBRT), oxaliplatin (OX), bevacizumab (BV), and capecitabine (CAP) for locally advanced or metastatic adenocarcinoma of the rectum
Authors: Czito B. , Bendell J. , Willett C. , Vaccaro G. , Morse M. , Yu D. , Honeycutt W. , Franklin A. , Hurwitz H. 
Published: March 2020

3543 Background: BV, a monoclonal antibody against vascular endothelial growth factor, increases survival when added to first and second line chemotherapy for metastatic colorectal cancer. Preclinical studies suggest BV may enhance tumoral radiation sensitivity. Preliminary studies of OX and 5-FU based chemoradiation therapy for rectal cancer have suggested improved pathologic CR rates compared to 5-FU/ radiation alone. CAP allows fluoropyrimidine treatment without the inconvenience of an infusion pump. We investigated CAP + BV + OX + EBRT for pts with rectal cancer to evaluate for the MTD and preliminary efficacy results. Methods: Pts with adenocarcinoma of the rectum and no prior pelvic irradiation received 5040 cGy EBRT (180 cGy/fx), CAP (625–825 mg/m2 PO BID on EBRT days), BEV (15 mg/kg d1 and 10 mg/kg d8 and d22), and OX (50–75 mg/m2/week during radiation, weeks 1–5) in dose-escalating fashion. DLT was defined as any grade 3 heme tox ≥ 7d, grade 4 heme tox, grade 4 non-heme tox during chemoradiation, or inability to deliver >85% of planned treatment. Pts eligible for surgical resection could have surgery 6–8 wks after treatment completion. After recovery from surgery, patients could be treated with CAP, BV, and OX. Results: 11 patients (5 men/6 women) have been enrolled. All have completed chemoradiation and resection. At dose level 1 (CAP 625 mg/m2 BID, OX 50mg/m2) there were no DLT’s in 3 pts. 1/3 pts had G3 subarachnoid hemorrhage during adjuvant chemotherapy. At dose level 2 (CAP 825 mg/m2, OX 50 mg/m2) 2/2 pts had DLT (1 G4 diarrhea; 1 G2 rectal pain, causing treatment hold for study-defined DLT). 6 more pts were treated at dose level 1. 1pt had DLT of G3 diarrhea. G2 toxicities included diarrhea (3/11), fatigue (2/11), skin changes (2/11), and pain (2/11). 9/11 patients were downstaged. 2/11 patients had pCR at surgery and 2/11 microscopic disease only. Conclusions: CAP + BEV + OX + EBRT is a well-tolerated, active regimen for the treatment of rectal cancer. MTD was determined to be CAP 625 mg/m2 BID + BEV 15 mg/kg d1 + 10 mg/kg d 8 and 22 + OX 50 mg/m2/week. Further study of efficacy at the MTD is warranted. [Table: see text]