bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I pharmacokinetic study of dasatinib (BMS-354825) in patients with advanced malignancies and varying levels of liver dysfunction: S0711, a SWOG early therapeutics committee study.
Authors: Sarantopoulos John , Hoering Antje , Synold Timothy W. , Mahalingam Devalingam , Wang Ding , Lenz Heinz-Josef , O'Rourke Pat , Sexton Rachel , Van Veldhuizen Peter J. , Mita Monica M. , Wong Lucas , Mita Alain C. , El-Khoueiry Anthony B. , Chung Vincent M. , Gandara David R. , Tejwani Sheela , Takebe Naoko , Takimoto Chris H.M. , Ivy S. Percy , Kurzrock Razelle 
Published: March 2020

3078 Background: Dasatinib (D) is a first in class Src kinase inhibitor, and inhibits BCR-Abl, c-Kit, PDGFR-beta, EPHA2 and Src family kinases including Src, Lck, Yes, Fyn at nanomolar concentrations. Initially FDA approved for use in imatinib resistant CML. It is a small molecule targeted therapy hepatically metabolized primarily by CYP3A4. We conducted a phase I study to determine maximum tolerated dose (MTD) and pharmacokinetics (PK) of D in patients (pts) with liver dysfunction (LD). Methods: Pts with advanced solid tumors or lymphoma, Zubrod ≤2, no baseline ascites or pleural effusions, adequate renal and bone marrow function, received PO D daily. Cycles q28 days. Pts stratified into 4 LD groups: normal, mild, moderate, severe, using Child-Pugh classification (CPC). Data also collected for NCI ODWG Organ Dysfunction Working GroupCriteria. D dose was escalated in sequential cohorts of pts within each LD category. Blood analysis for D concentrations were determined during cycle 1 using a validated LC-MC/MS assay. Study objectives included characterizing safety, tolerability, PK, identifying the MTD and obtaining preliminary evidence of efficacy. Results: 54 registered pts, 51 pts received 51 cycles of D at doses starting at 100 mg in mild LD (50-140 mg). Median age 60, male 55%, Zubrod 1 70%. CRC 27%. Groups: normal-17, mild-20, moderate-13, severe-1 pt(s). Related AEs include fatigue 35%, diarrhea 27%, anemia 27%, nausea 25%, vomiting 21%, lymphopenia 13%, rash 13%, pleural effusion 8%. 1 DLT of increased CK in a pt in moderate LD with past history of similar episode with previous sorafenib. Previous linear PK disposition, and no accumulation. No apparent PK differences between normal and mild groups. Cycle 1 Day 1 D 140 mg Normal Group: Cmax 129 ng/mL. Mild Group 140mg: Cmax 157 ng/mL. Prolonged disease stabilization (≥4 cycles) in 6 pts, 3 CRC (4,5,8); 1 Pancreas, HCC, Bladder (4,5,6). Conclusions: Recommended dose for Dasatinib given PO QD for pts with mild, moderate, or severe LD using clinical criteria with CPC and no baseline ascites, are 140 mg, 70 mg, insufficient pts, respectively. Dose adjustment not necessary in pts with mild LD.
Phase IB study of an all-oral chemotherapy regimen, tesetaxel plus capecitabine, in patients with advanced solid tumors.
Authors: Martin Michael Gary , Fryar Beverly B. , Danesi Hassan , Schwartzberg Lee Steven 
Published: March 2020

3085 Background: Tesetaxel is a novel oral taxane that is not a substrate for P-glycoprotein, does not cause hypersensitivity, and may cause less neurotoxicity. The anticancer activity of tesetaxel exceeds other taxanes in various cell lines and xenografts. Phase II studies showed overall response rates [ORRs] of 50% and 38% in patients (pts) treated for 1st- and 2nd-line breast cancer, respectively, and 20% in pts with 2nd-line gastric cancer. Neutropenia was dose-limiting, and the maximally tolerated dose (MTD) was 27 mg/m2 once every 3 weeks. Capecitabine, an oral fluoropyrimidine, is commonly used for treatment of breast and gastric cancer. While the approved capecitabine dose is 2500 mg/m2/day x 14 days, most pts are unable to sustain treatment at this dose due to hand-foot syndrome (HFS). A prior PK study suggested that short courses of tesetaxel could be combined with capecitabine at the recommended MTDs of both drugs with non-overlapping adverse events (AEs) (Cancer Chemother Pharmacol. 68:1565, 2011). We conducted a phase IB study of the tesetaxel/capecitabine regimen in pts using lower doses of capecitabine to confirm a tolerable combination dose for extended treatment. Methods: Eligibility included: solid tumor treated with ≤ 1 line of chemotherapy; no prior taxane exposure; adequate organ function; ECOG PS ≤ 1. Pts received tesetaxel 27 mg/m2 on Day 1 and capecitabine 1500-2000 mg/m2/day (in divided doses on Days 1-14) every 3 weeks. Results: To date, 10 pts have been treated. AEs were largely Grade 1-2 (83%) and consistent with those for each drug as a single agent. Grade 3-4 neutropenia occurred in 3 pts (30%) and HFS in 4 (40%). Tesetaxel dose reduction was required in 1 pt for neutropenia; capecitabine dose reduction was required in 3 pts (30%) (2 for hand-foot syndrome, 1 for diarrhea). Comprehensive toxicity data will be presented. Conclusions: This combination of all-oral chemotherapy is generally well-tolerated, although lower than maximally approved doses of capecitabine are required, similar to other regimens that employ this agent. AEs are largely non-overlapping, which suggests this combination may be clinically useful in pts with advanced breast and gastric cancer.
Phase l study assessing a two-consecutive-day (QD x 2) dosing schedule of the HSP90 inhibitor, AT13387, in patients with advanced solid tumors.
Authors: Do Khanh Tu , Speranza Giovanna , Chen Alice P. , Trepel Jane B. , Lee Min-Jung , Lee Sunmin , Phillips Larry , Collins Jerry M. , Weil Marcie K. , Kinders Robert J. , Khin Sonny , Allen Deborah , Parthasarathy Ramya , Doroshow James H. , Kummar Shivaani 
Published: March 2020

3087 Background: AT13387, a synthetic, non-ansamycin, small molecule inhibitor of HSP90 (Kd 0.71 nM), binds to the N-terminal ATP-binding site resulting in down-regulation of key oncoproteins (HER2 and ERK). In xenograft models AT13387 produced tumor growth inhibition on a QD x 2 dosing schedule. Objectives: To determine toxicity, MTD, PK, and pharmacodynamic (PD) effect of AT13387 given IV QD x 2, 3 weeks out of 4. Methods: Adult patients (pts) with advanced cancers progressing following standard therapy; ECOG ≤ 2; adequate organ function. One pt cohorts for first three dose levels (DLs, 20, 40, 80 mg/m2), planned 3+3 design at DL 4 (120 mg/m2). PK evaluations on C1D1 and C1D15. Mandatory tumor biopsies in expansion cohort at MTD for HER2+ tumors (baseline, C1D17) to evaluate HSP70 and HSP27 mRNA by RT-PCR; and client protein by IHC and immunoassay. HSP70 in PBMCs as a PD marker (pre-dose, D2, D15, D16) assessed by Western blot; serum markers of cell death, M30 and M65 (baseline and pre-dose C1D16), assessed by ELISA. Results: 12 pts treated up to DL 5 (160 mg/m2). Median age, 59; median # prior therapies, 3; diagnosis (# pts): colorectal (7); esophageal (2), liposarcoma (1); head and neck (1); synovial sarcoma (1). Drug-related toxicities (gr ≤ 2; # pts) in 9 evaluable pts: fatigue (5), rash (2), nausea (5), diarrhea (7), QTc prolongation (2), thrombocytopenia (5), AST (3) and ALT (2). Vision disorder (2 pts): gr 1, reversible, no objective findings on eye exams. DLT (1 pt, with liver metastases): DL 5, gr 3 AST/ALT. PK was dose proportional; T1/2 8 hrs. In one paired tumor biopsy (DL 3) an increase in HSP70 (> 1.5 fold) and HSP27 (2 fold) mRNA and a decrease in pERK was observed. M30 and M65 increased in 5/6 pts (p-value n.s.). Induction of HSP70 (1.48 - 5.01 fold) in PBMCs was noted at all time points following first dose (≥ DL 2). 3/9 pts had SD after 2 cycles. Conclusions: Preliminary data indicate that AT13387 QD x 2 is well tolerated and produces a sustained induction of HSP70 in PBMCs. Accrual is ongoing to establish the MTD and obtain further tumor biopsies for assessment of drug effect. Optional Indium-labeled trastuzumab scan will be used to evaluate drug effect on HER2 levels in pts with HER2 expressing tumors.
BI 836845, a fully human IGF ligand neutralizing antibody, to improve the efficacy of rapamycin by blocking rapamycin-induced AKT activation.
Authors: Adam Paul J. , Friedbichler Katrin , Hofmann Marco H. , Bogenrieder Thomas , Borges Eric , Adolf Guenther R. 
Published: March 2020

3092 Background: Analogs of rapamycin (rapalogs) targeting mammalian target of rapamycin complex 1 (mTORC1) have shown clinical activity in several cancers. Nonetheless, preclinical and clinical data suggest that there may be intrinsic resistance to rapalogs through a feedback loop which activates upstream signaling when mTORC1 is blocked. BI 836845 is a fully human antibody, currently in phase I clinical trials, which potently neutralizes both IGF-1 and IGF-2. We tested whether BI 836845 is able to improve the efficacy of rapamycin by inhibiting upstream signaling in preclinical models. Methods: Cancer cell lines were profiled in vitro and in vivo for sensitivity to BI 836845 and rapamycin, alone or in combination. Mitogenic signaling was examined by measuring levels of phosphorylated AKT (pAKT) using Western blot analysis. IGF bioactivity was determined using a cellular IGF-1R phosphorylation ELISA. Results: The combination of BI 836845 and rapamycin was more effective than either agent alone at inhibiting the proliferation of Ewing’s sarcoma cells cultured in vitro as well as in a nude mouse xenograft model in vivo. Analysis of cell signaling upstream of mTOR demonstrated that treatment with rapamycin alone resulted in elevated pAKT, indicating feedback loop activation. BI 836845 treatment alone or in combination with rapamycin inhibited AKT phosphorylation, demonstrating that the rapamycin-induced increase in pAKT was due to elevated IGF bioactivity. Consistent with this we demonstrated that rapamycin increased IGF bioactivity in mice and that this could be inhibited by BI 836845. We extended these studies to include other cancer cell lines and profiled the correlation between improved efficacy of the combination with BI 836845 inhibition of rapamycin-induced feedback. A correlation has been observed for cancer cells derived from several indications. Conclusions: Rapamycin treatment increases AKT activation via elevated IGF ligand bioactivity. This effect can be inhibited by BI 836845, thus explaining the improved pre-clinical efficacy seen when both agents are combined. These data provide a rationale for the clinical combination of rapalogs and BI 836845.
Phase I dose-finding and pharmacokinetic study of a combination of elisidepsin (E) and erlotinib (T) in patients (pts) with advanced solid tumors.
Authors: Goel Sanjay , Moran Teresa , Coronado Cinthya , Viteri Ramirez Santiago , Chaudhary Imran , Ghalib Mohammad Haroon , Swami Umang , Hou Yijuan , Carcereny Enric , Alcantara Jose , Iglesias Dios Jorge Luis , De Miguel Bernardo , Buges Cristina , Rosell Rafael 
Published: March 2020

3093 Background: E is a new marine compound that has shown synergism with T in vitro even in T-resistant non-small-cell lung cancer (NSCLC) cell lines. Based on these findings, a phase I clinical trial was undertaken to identify the maximum tolerated dose (MTD) and recommended dose (RD) of E (3-h iv, days 1, 8 and 15) followed by T (once daily) in 3-week cycles. Secondary objectives were evaluation of safety and feasibility, PK and preliminary efficacy results. Methods: Patients (pts) with advanced solid tumors with no standard therapeutic option were recruited. Cohorts of 3-6 pts were included at each dose level (DL), with escalating doses of E in increments of 25-50% according to toxicities, and 2 different T doses (100 and 150 mg/day). Results: Thirty pts (median age, 57 years; 19 females) were evaluable. Main tumor types included NSCLC, colorectal, melanoma, and ovarian cancer. Six DLs were assessed. Starting DL was E 0.33 mg + T 100mg. One dose-limiting toxicity (DLT) out of 6 pts (grade 3 bilirubin increase) was observed at DL3 (E 0.75 mg + T 150 mg). Another DLT (dose omissions due to ALT increase) was found at DL6 (E 2.25 mg + T 100 mg). Frequent toxicities were diarrhea (53%), nausea (23%), vomiting (33%), rash (47%), pruritus (43%), dry skin (27%) and acneiform dermatitis (17%). Grade 3/4 toxicities included diarrhea (2 pts), rash (2 pts) and pruritus (1 pts). Main biochemical abnormalities were ALT (grade 3/4 in 4 pts) and total bilirubin increase (grade 3 in 2 pts). No severe hematological abnormalities were observed. Most toxicities were related to T; therefore, T dose was reduced to 100 mg/day. No PK interaction between E and T was observed. No objective responses were reported. Six pts attained stable disease >3 months (3 NSCLC; 1 ovarian cancer, 1 colorectal cancer, 1 invasive thymoma). Conclusions: E + T was a manageable combination; however, the difficulty of combining E with the standard dose of T (150mg) and the lack of activity made this combination unattractive for further development in the current schedule. Possibly, other schedules may demonstrate more efficacy.
The PI3K/mTOR inhibitor BEZ235 given twice daily for the treatment of patients (pts) with advanced solid tumors.
Authors: Arkenau Hendrik-Tobias , Jones Suzanne Fields , Kurkjian Carla , Infante Jeffrey R. , Pant Shubham , Burris Howard A. , Moore Kathleen N. , McMeekin D. Scott , Greco Frank A. , Ramsey Sara , Bendell Johanna C. 
Published: March 2020

3097 Background: The PI3 kinase (PI3K) pathway is the most deregulated pathway in cancers and is an attractive target for antitumor therapy. BEZ235 is an oral highly specific and selective inhibitor of the PI3K and TORC1/2. The MTD (1200 mg) and toxicity profile of BEZ235 once daily dosing has been established. This study was designed to evaluate twice daily dosing of BEZ235 and its effect on treatment tolerability, PK, PD, and preliminary efficacy. Methods: Pts with advanced disease were enrolled in a 3+3 dose escalation schedule starting at 200 mg PO BID in 28 day cycles. For intrapatient PK comparison the first week pts received the total dose in a QD schedule. DLT assessment was in Cycle 1. Efficacy evaluations were every 2 cycles, and PK and PD were assessed. Results: 12 pts were enrolled at the following dose levels: 200 mg (n=3), 400 mg (n=3), 600 mg (n=3), and 600 mg (BID only, no QD lead-in) (n=3). No G4 AEs were reported. G3 related AEs were mucositis (n=2), AST/ALT elevation (n=2), anorexia (n=1) and diarrhea (n=1). The most common related G1/2 adverse events (AEs) were anorexia (n=6), diarrhea (n=3), fatigue (n=2), and headache (n=2). DLTs of G3 mucositis were observed in 2 patients at the 600 mg BID dose level with 1 week 1200 mg QD lead-in, which were attributed to the QD lead-in dosing during the first week. 3 pts then enrolled at 600 mg BID without lead in and had no further DLT. PK shows consistent increase in PK parameters with dose level. Of 10 evaluable, 3 pts had stable disease (13+ to 21+ weeks, 2 colorectal, 1 endometrial). Of 9 evaluable, 4 pts at various dose levels had decreased PET SUV uptake by greater than 25%. Conclusions: BEZ235 is tolerable at a dose of 600 mg BID, with less toxicity than has been seen with equivalent QD dosing. Preliminary signs of clinical and PD activity are noted.
Validation of two gene-expression risk scores in a large colon cancer cohort and contribution to an improved prognostic method.
Authors: Roth Arnaud , Di Narzo Antonio Fabio , Tejpar Sabine , Bosman Fred , Popovici Vlad Calin , Wirapati Pratyaksha , Xie Tao , Estrella Heather , Pavlicek Adam , Mao Mao , Martin Eric , Weinrich Scott , Hodgson John Graeme , Van Cutsem Eric , Delorenzi Mauro 
Published: March 2020

3509 Background: Prognosis prediction for resected primary colon cancer is currently based on the tumor, nodes, metastasis (TNM) staging system. Gene expression based risk scores have been proposed, but need to be validated and integrated with clinical and TNM variables. We performed an independent assessment of the individual recurrence signatures developed for commercial use by Veridex and Genomic Health. Methods: The Veridex (aVDS) and Genomic Health (aGHS) risk scores were applied to existing gene expression data of 580 stage III and 108 stage II tumors from the PETACC-3 trial. Association of the scores with relapse-free (RFS) and overall survival (OS) of the patients was assessed singularly, and in a combination with TNM and other clinico-pathological variables, by univariate and multivariate Cox regression models and logrank methods. Results: Both risk scores were significantly associated with RFS in univariate and multivariate models (Table) for the stage III cohort. The scores contributed different and additive prognostic information, and reached highest effect sizes (approximate p-value 0.001 and HR per interquartile range 1.4 each) in a combined model (Table) that includes both scores as well as T-stage, N-stage and MSI status as significant factors. Analysis in the stage II cohort gave similar effect estimates. Conclusions: This study confirms in an independent colon cancer patient cohort that gene expression based risk scores improve current prognostic models. The best prognostic model was obtained by using clinico-pathological variables and both gene-expression risk-scores. [Table: see text]
Epiregulin (EREG) and amphiregulin (AREG) gene expression to predict response to cetuximab therapy in combination with oxaliplatin (Ox) and 5FU in first-line treatment of advanced colorectal cancer (aCRC).
Authors: Adams Richard A. , Fisher David , Farragher Susan , Scott Alastair , Smith Christopher G , James Michelle D , Cheadle Jeremy , Nichols Laura L , Meade Angela M. , Kaplan Richard S. , Wilson Richard H. , Wasan Harpreet S , Maughan Tim 
Published: March 2020

3516 Background: Previous data suggest the EGF ligands EREG/AREG may predict outcome of KRAS wt patients (pts) in the chemo-refractory setting but has not been previously reported from first line randomised trials. Methods: FFPE samples from primary tumors of pts in Arms A&B of the COIN trial of Ox fluoropyrimidine (Fp) +/- cet were analysed for EGFR IHC, KRAS/NRAS/BRAF mutation and EREG/AREG expression by RT-PCR. Ligand levels were assessed against baseline data, prognostic markers as uni/multivariate analyses and as predictive markers in wild type (wt) and mutant (mt) cohorts and separately by Fp backbone [capecitabine (CapOx) or 5FU (FOLFOX)]. Tests for interaction were performed with EREG/AREG continuous, using Flexible Parametric survival analysis. Optimal cutoffs for predictive effects were defined using point at which 95% CI first excluded zero. Results: 952/1630 (57%) of pts were evaluable for all parameters. EREG/AREG were highly correlated Pearson’s rho (ρ) = 0.74; p<0.0001. High EREG/AREG levels were associated with KRAS wt (p<0.005) and with primary tumor in left colon/rectum, presence of liver metastases and high CEA (p<0.05). In the control arm, high EREG/AREG conferred a better prognosis among KRAS wt pts in multivariate. EREG superseded AREG in a combined model. High EREG predicted for OS benefit in KRAS wt pts treated with FOLFOX +cet, with optimal cut-off 80th centile. OS HR for ±cet ≥80th centile =0.33, 95% CI 0.14-0.78, p=0.011; <80% centile HR=0.99, 95% CI 0.67-1.47, p=0.96; interaction p=0.059; ≥50th centile HR=0.66, 95% CI 0.40-1.09, p=0.11; <50% centile HR=1.09, 95% CI 0.66-1.81, p=0.73; interaction p=0.17. Similar results were seen for PFS, with optimal cut-off 50th centile. There was no predictive effect for pts treated with CapOx. Conclusions: The data suggest a prognostic effect of EREG/AREG in aCRC. The original hypothesis, that KRAS wt patients with high EREG expression have improved outcome with cet, seems to be limited to patients treated with FOLFOX in the first-line setting.
A novel interaction of genotype, gender, and adjuvant treatment in survival after resection of stage III colon cancer: Results of CALGB 89803.
Authors: Warren Robert S. , Atreya Chloe Evelyn , Niedzwiecki Donna , Mayer Robert J. , Goldberg Richard M. , Compton Carolyn C. , Weinberg Vivian K. , Bertagnolli Monica M. 
Published: March 2020

3517 Background: The p53 tumor suppressor is frequently mutated in colon cancer, but the influence of such mutations on survival is remains undefined. We investigated whether domain-specific mutations in p53 are predictive of survival in stage III colon cancer. Methods: p53 was evaluated in an intergroup trial (CALGB 89803) of patients with stage III colon cancer who were randomized to receive adjuvant 5-fluorouracil/leucovorin (5FU/LV) or 5FU/LV with irinotecan (IFL) Tissue was collected to allow correlation of molecular markers with outcomes. p53 was genotyped in 607 patient tumors. Results: p53 mutations were identified in 274 tumors, divided ~ equally between zinc binding and non-zinc binding regions of the DNA binding domain. Overall, p53 status was not predictive of benefit from either adjuvant regimen. Unexpectedly, the 5 year overall survival (OS) of women with tumors harboring non-zinc binding mutations treated with 5FU/LV was 97% compared to OS of 72% for women with p53 wild-type (wt) tumors (p =0.004). Adding irinotecan to 5FU/LV negated this survival benefit (5 year OS of 81% vs. 72%). Conversely, 5 year OS of women harboring tumors with zinc binding mutations who received 5FU/LV was 50% compared to 72% for women with p53 wt tumors (p=0.04). Adding irinotecan to 5FU/LV reversed the poor survival of women with tumors harboring zinc binding mutations and improved 5 year OS (50% vs. 73%; p=0.1). No difference in OS was observed for men on either treatment arm or when genotype was considered. Conclusions: CALGB 89803 demonstrated a lack of survival benefit for stage III colon cancer patients when irinotecan was added to 5FU/LV (IFL). We now show that in the setting of a large clinical trial, refined stratification of women, based upon domain- specific mutations of p53 identifies subsets of patients likely to benefit from, or respond poorly to, adjuvant 5FU/LV. The interaction of p53 genotype, gender, and adjuvant therapy regimen has the potential to be paradigm changing in the treatment of colon cancer, and possibly other malignancies. These data, if validated, suggest that evaluation of p53 genotype and gender may guide clinicians to make rational choices of adjuvant therapy.