bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of predictive markers of clinical activity from a phase II trial of single agent pertuzumab (rhuMab 2C4), a HER dimerization inhibitor, in advanced ovarian cancer (OC)
Authors: Amler L. , Gordon M. S. , Strauss A. , Rabbee N. , Derynck M. K. , Krueger K. , Eberhard D. A. , Matei D. , Karlan B. Y. 
Published: March 2020

3001 Background: Pertuzumab (P), a humanized HER2 antibody, represents a new class of targeted agents called HER dimerization inhibitors (HDIs). P inhibits dimerization of HER2 with EGFR, HER3 and HER4, and subsequently inhibits signaling through MAP and PI3 kinases. Interim data from a phase II trial suggested that P has activity in OC, especially in a subset of tumors with activated HER2 (Abstract #5051 ASCO 2005). Methods: 123 pts with relapsed OC were treated with P. Cohort 1 was treated with 840mg followed by 420mg and cohort 2 with 1050mg every 3 weeks. Fresh tissue biopsies were mandated from Cohort 1, and archival formalin fixed paraffin tissue (FFPET ) were obtained from both cohorts. Molecular expression studies from FFPET and fresh tissue were conducted. Results: From final data of 117 evaluable pts, 5 pts had objective partial responses (RR = 4.3%). Eight pts (6.8%) had SD for ≥ 6 months, and an additional 4 pts (3.4%) had SD with CA-125 reduction of ≥50%. Overall rate of activity = 14.5%. Of the 65 fresh tumor biopsies, 28 were evaluable and 8 (28.6%) were positive for phosphorylated HER2 (pHER2) by ELISA. Among pts who had pHER2 status determined, TTP was 20.9 weeks for pHER2+ pts (n=8), compared to 5.8 weeks for pHER2- (n = 20). Data from microarray expression profiling were analyzed with respect to pHER2 status from the same tumors. The expression levels of HER2, EGFR and HER3 in combination with the expression of certain HER ligands may be predictive of pHER2 status. We have extended these analyses to qRT-PCR from macrodissected FFPET of HER receptors and ligands. This was analyzed with respect to clinical outcome. Preliminary analyses of expression data suggest that HER receptors and ligands may be promising candidates for diagnostic markers. Updated data in 78 OC pts will be presented. Conclusions: Clinical activity was observed in 14.5% of pts with heavily pretreated OC (PRs, SD ≥ 6 months, and SD with CA-125 reductions of ≥50%). This study suggests that P may be active in OC, and that specific HER receptors and ligands may be promising diagnostics for identifying tumors responsive to P. [Table: see text]
A phase I study of YM155, a novel survivin suppressant, administered by 168 hour continuous infusion to patients with advanced solid tumors
Authors: Tolcher A. W. , Antonia S. , Lewis L. D. , Mita A. , Mahany J. , Reddy N. J. , Till E. , Buell D. , Keating A. T. 
Published: March 2020

3014 Background: Survivin is one of the family of inhibitor of apoptosis proteins (IAP) that suppresses apoptosis through inhibition of caspases and procaspases. Survivin is selectively expressed in most solid tumors but not normal tissues. In a PC-3 cell model YM155 inhibited survivin mRNA transcription and survivin protein expression and showed potent (nM) anti-proliferative activity in preclinical models including tumor regressions. Methods: The objectives were to determine the maximum tolerated dose (MTD) of 168 hour continuous infusion of YM155 every 3 weeks, to evaluate toxicity, characterize the pharmacokinetics and observe anti-tumor activity. Standard 3+3 dose escalation scheme was utilized. Additional pts were added to fully characterize toxicities at the MTD. Pharmacokinetic sampling was performed during cycles 1 and 2. Results: 41 pts (M/F: 31/10, median age 61, range 28–78) with performance status of 0–2 were enrolled into 4 dose cohorts [1.8 mg/m2/day (N = 8), 3.6 (6), 6.0 (2) and 4.8 (25)]. Most common tumor types were prostate (9), NHL (5), and colorectal (5). 2/2 pts experienced DLTs at 6.0 (renal tubular necrosis with grade 3 mucositis and increased serum creatinine), thus the MTD was 4.8 mg/m2/day. The most frequent AEs were: pyrexia, arthralgia, nausea, fatigue and diarrhea. The most common grade 3 or 4 drug related AEs were: mucosal inflammation (N = 2, 4.9%) and increased INR (N = 2, 4.9%). At MTD, the median clearance was 47 L/hr with a median steady state concentration of 7.5 ng/mL and a median terminal half-life of 22 hours. Two pts with chemotherapy refractory intermediate grade NHL had marked reduction of lymph nodes including one that was durable (PR reviewed independently). This pt went onto BMT and was in remission at the time of this submission. Two HRPC pts exhibited PSA response (> 50% reduction). Conclusions: YM 155, the first survivin inhibitor, was well tolerated, had a MTD of 4.8 mg/m2/day × 7 days and exhibited provocative anti-tumor activity in 4 pts that warrant broad phase II evaluation. No significant financial relationships to disclose.
VEGF, sVEGFR-2, bFGF, and IL-8 as biomarkers of the pharmacological activity of BAY 57–9352, an oral VEGFR-2 receptor tyrosine kinase inhibitor, in patients with solid tumors
Authors: Zuehlsdorf M. , Christensen O. , Strumberg D. , Mross K. , Eskens F. , Gelderblom H. , Verweij J. , Rajagopalan P. , Voliotis D. , Wensing G. 
Published: March 2020

3035 Background: BAY 57–9352 (BAY) is a potent anti-angiogenic drug that inhibits VEGFR-2, as well as VEGFR-1, VEGFR-3, PDGFR-β, and c-Kit tyrosine kinases. Molecular biomarkers of angiogenesis (VEGF165, soluble VEGFR-2 [sVEGFR-2], basic FGF [bFGF], and interleukin-8 [IL-8]) were used to assess the pharmacodynamic effects of BAY. Methods: Patients with advanced solid tumors from two Phase I studies received oral BAY on either an intermittent 21 day cycle (14 days on drug, 7 days off drug) or continuous schedule (21 day cycle). Doses were escalated from 20 mg once daily (od) to 1500 mg twice daily (bid). Molecular biomarkers were measured at baseline, pre-dose, and 8 hours post-dose on Days 1 and 14 of each cycle. Pharmacokinetic parameters of BAY were also assessed. Results: Plasma samples from 130 patients were analyzed for angiogenic biomarkers. Increased VEGF165 and decreased sVEGFR-2 clearly correlated with the dose of BAY, respectively. All clinical responders (as shown by tumor shrinkage) were located within the upper 10% of the total response distribution for these markers. Subgroup analysis in the three more prevalent tumors showed that patients with colorectal, renal cell, and hepatocellular carcinoma all showed biomarker responses exceeding the mean overall responses. Biomarker levels reached a plateau at daily doses of approximately 900 mg bid or 1800 mg, suggesting a saturated pharmacodynamic effect. There were no consistent changes in bFGF and IL-8. Conclusions: Both VEGF and sVEGFR-2 demonstrated a dose-dependent change with BAY 57–9352. VEGF and sVEGFR-2 may be appropriate biomarkers of the therapeutic effects of BAY, and may be useful as potential predictors of early response. [Table: see text]
Sunitinib-related thyroid dysfunction: A single-center retrospective and prospective evaluation
Authors: Schoeffski P. , Wolter P. , Himpe U. , Dychter S. S. , Baum C. , Prenen H. , Wildiers H. , Bex M. , Dumez H. 
Published: March 2020

3092 Background: Sunitinib is a multi-target tyrosine kinase inhibitor with anti-angiogenic and anti-proliferative activity mediated by signal blockade of VEGFR1/2, KIT, PDGFRα/β, and FLT-3. Phase II/III trials have demonstrated efficacy of the oral agent in Imatinib-resistant GIST and advanced renal cell cancer (RCC). We observed several cases of thyroid dysfunction in GIST during treatment with sunitinib suggesting that the drug may be associated with hypothyroidism. We therefore assessed the incidence and severity of thyroid dysfunction in cancer patients treated with sunitinib. Methods: Thyroid function (serum TSH, T3 and free thyroxin index) and thyroid antibodies (anti-TPO, -Tg and TSH-R-Ab) were evaluated retrospectively in a cohort of patients with GIST in a Phase III trial and in an expanded access program (1st part of the investigation) and in a prospective cohort of RCC and GIST patients treated in the framework of expanded access programs (2nd part). Sunitinib was given at a daily oral dose of 50 mg 4 weeks on, 2 weeks off. Thyroid parameters were assessed on days 1 and 28 of each treatment cycle in the prospective cohort. We report here the first TSH results, the full data set will be available at ASCO. Results: We identified a total of 46 patients who received sunitinib, and 33 of these patients were evaluable for thyroid function. 14 patients were analyzed retrospectively (all GIST), 19 patients prospectively (8 GIST, 11 RCC). 7 of these 19 patients (37%) showed an elevated TSH (>5 mIU/L) during treatment. In the retrospective analysis of 14 patients with a median treatment duration of 44 weeks, 8 patients (57%) had developed hypothyroidism. All patients with GIST in randomized Phase III trial remaining under active treatment with sunitinib for 58–80 weeks show an increased TSH (up to 83 mIU/L) during the course of treatment, requiring hormone substitution. In a cohort of 11 patients with RCC, after 6 weeks of treatment, 3 patients already have an increased TSH. Conclusions: Sunitinib is associated with a high incidence of thyroid dysfunction which requires further study. The mechanism by which Sunitinib induces thyroid dysfunction is yet unclear. No significant financial relationships to disclose.
Preliminary results of a phase I study of bevacizumab (BV) in combination with everolimus (E) in patients with advanced solid tumors
Authors: Zafar Y. , Bendell J. , Lager J. , Yu D. , George D. , Nixon A. , Petros W. , Beci R. , Arrowood C. , Hurwitz H. 
Published: March 2020

3097 Background: BV is a potent inhibitor of vascular endothelial growth factor (VEGF) with broad clinical activity. E is an mTOR (mammalian target of rapamycin) inhibitor in development for cancer and solid organ transplant therapy. VEGF and mTOR inhibitors have anti-tumor and anti-angiogenesis effects alone and in combination in preclinical models. As a combination anti-angiogenesis therapy, we evaluated BV + E in a phase I, pharmacokinetic (PK), biomarker study. Methods: BV was dosed at 10mg/kg IV q14d. E was dosed at 5mg PO QD, escalating to 10mg QD. Cycle length was 28 days. DLT was defined as any grade 4 heme or grade 3/4 non-heme event in Cycle 1 related to treatment. Pts had advanced solid tumors, adequate organ function, and no increased risks for class-related toxicities. Serial blood samples were collected for PK studies of E. Dermal wound angiogenesis assays were performed pre and on treatment for phospho VEGFR2, AKT, mTOR, and S6K. Results: 14 pts have been enrolled (8 F, 6 M), 12 evaluable for toxicity, 14 for efficacy. Median age is 58y (range 29–73). At dose level 1 (BV 10mg/E 5mg) there were no DLT’s in 5 pts. At dose level 2 (BV 10mg/E 10mg), no DLT’s were noted in the initial 3 pts and the cohort was expanded to 9 pts. Side effects were primarily grade 1–2: pain (10/14), mucositis (9/14), anorexia (8/14), rash (7/14), bleeding (7/14), hyperlipidemia (6/14), fatigue (6/14), and HTN (4/14). 1 pt had a myocardial infarction at day 72 and one pt developed nephrotic syndrome at day 70. 7/14 pts had stable disease as best response (70–278d). Conclusions: BV + E is generally well-tolerated. Preliminary clinical activity and class-related side effects were noted. The recommended phase II dose is BV 10mg/kg IV q14d and E 10mg PO QD. [Table: see text]
Percutaneous radiofrequency ablation of inoperable pulmonary metastases from colorectal cancer
Authors: Yan T. D. , King J. , Glenn D. , Steinke K. , Morris D. L. 
Published: March 2020

3502 Background: This current study was an open, prospective and nonrandomized phase II study, which critically evaluated the prognostic parameters for local disease-free survival (DFS) and overall survival (OS) in patients who underwent percutaneous radiofrequency ablation (RFA) for inoperable colorectal pulmonary metastases (CRPM). Methods: The inclusion criteria were patients who had inoperable CRPM, due to number, distribution, poor performance status or patients’ refusal to accept surgery. The exclusion criteria were lesions > 6 per hemithorax; diameter of metastases > 5 cm; bleeding diathesis; and/or significantly compromised lung function. All patients underwent percutaneous RFA with a radiological clear margin of at least 2 cm. The end-points of this study were local DFS and OS, determined from the time of RFA intervention. Ten clinical and six treatment-related prognostic parameters were assessed in univariate and multivariate analyses. All patients were reviewed at one week, one month and every three months thereafter with chest CT. Fifty-five patients entered into the study. The follow-up was complete and the median follow-up was 24 months (6 to 40). Results: The median local DFS was not reached and 2-year local DFS was 57%. Univariate analysis demonstrated that largest size of lung metastasis, location of lung metastases, post-RFA CEA at 1 month and 3 months were significant for local DFS. In multivariate analysis, largest size of lung metastasis of ≤ 3 cm and post-RFA CEA of ≤ 5 ng/ml at 1 month were independently associated with an improved local DFS. The median OS was 33 months (4 to 40), with 1-, 2-, and 3-year survival of 85%, 64% and 46%, respectively. Univariate analysis demonstrated that interval between the diagnoses of colorectal cancer and pulmonary metastasis; largest size of lung metastasis and location of lung metastases were significant for OS. In multivariate analysis, only size of lung metastasis of ≤ 3 cm was independently associated with an improved OS. Conclusions: Percutaneous RFA of inoperable CRPM may have a useful role in patients with a lesion of ≤ 3 cm. No significant financial relationships to disclose.
Safety and efficacy of oxaliplatin/fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer (mCRC): Final analysis of the TREE-Study
Authors: Hochster H. S. , Hart L. L. , Ramanathan R. K. , Hainsworth J. D. , Hedrick E. E. , Childs B. H. 
Published: March 2020

3510 Background: The addition of bevacizumab (bev) to fluorouracil-based combination chemotherapy results in statistically significant improvement in survival among patients (pts) with mCRC. This randomized, multicenter trial was designed to assess the safety, tolerability and efficacy of each of three oxaliplatin (OX) plus bolus (b), infusional, or oral fluoropyrimidine (FP) regimens without (TREE1 cohort) or with (TREE2 cohort) bev for 1st line tx of mCRC. Methods: Eligibility included age ≥ 18 years, measurable, untreated mCRC, ECOG performance status ≤1. Primary endpoint: incidence of grade (gr) 3–4 toxicities (tox) on each arm during the 1st 12 weeks of therapy; secondary endpoints: ORR, TTP, OS. Regimens TREE-1: FOLFOX: OX 85mg/m2, leucovorin (LV) 350mg, 5-FU bolus 400mg/m2 and 2400mg/m2 CIV over 46 hours ; bFOL : OX 85mg/m2 days (d) 1&15, LV 20 mg/m2 and bolus 5-FU 500mg/m2 d 1,8,15 q 4 wks; CapeOx: OX 130 mg/m2 d 1, Capecitabine 1000–850 mg/m2 bid for 14 d. In TREE-2 bev 5 mg/kg q14 or 7.5 q 21 d was added. Results: 147 pts were treated in TREE1 and 213 treated in TREE2. Overall, incidence of any gr 3–4 toxicity (TREE1 vs. TREE2 respectively) = FOLFOX 75% vs. 66%, bFOL 42% vs. 59%, CapeOx 73% vs. 54%. Addition of bev in TREE2 caused more gr 3–4 hypertension, impaired wound healing, and bowel perforation in each arm. Confirmed ITT ORR (TREE1 vs TREE2 respectively) = FOLFOX 41% vs.52%, bFOL 20% vs.39%, CapeOx 27% vs. 46%. Median TTP (months) + 95% CI (TREE1 vs TREE2 respectively) = FOLFOX 8.7 (6.5, 9.8) vs. 9.9 (7.9, 11.7), bFOL 6.9 (4.2, 8.0) vs. 8.3 (6.6, 9.9), CapeOx 5.9 (5.1, 7.4) vs.10.3 (8.6, 12.5). Probability of survival at 18 months (TREE1 vs. TREE2 respectively) = FOLFOX 53% vs. 63%, bFOL 50% vs. 63%, CapeOx 49% vs. 68%. As of January 9, 2006, 56 TREE1 pts (38%) and 122 TREE2 pts (57%) are alive. Conclusions: These data demonstrate these three Ox/FP regimens to be tolerable and effective. Addition of bev to Ox/FP regimens improves response rate and TTP with acceptable tolerability, and no unexpected toxicity. [Table: see text]
Local recurrence after rectal cancer resection is strongly related to the plane of surgical dissection and is further reduced by pre-operative short course radiotherapy. Preliminary results of the Medical Research Council (MRC) CR07 trial
Authors: Quirke P. , Sebag-Montefiore D. , Steele R. , Khanna S. , Monson J. , Holliday A. , Thompson L. , Griffiths G. , Stephens R. 
Published: March 2020

3512 Background: The MRC CR07 trial compared routine short course pre-operative radiotherapy (PRE) with selective post-operative chemo-radiation if there was involvement of the circumferential resection margin (CRM) (POST) and included a prospective pathological assessment of the quality of resection of the surgical specimen. Methods: A total of 1350 patients were randomised from 52 centres between March 1998 and August 2005. Median follow-up is 3 years. Trial pathologists were trained in histopathological assessment and reporting of the involvement of the CRM and plane of surgery (PoS) according to pre-set criteria describing the plane of dissection (Grade 1-muscularis plane: 2-intramesorectal plane: 3-mesorectal plane). 1232 patients were prospectively assessed for CRM and 1119 for PoS. Results: The CRM was involved (tumour ≤1mm) in 139 (11%) of resected specimens, and for these patients the 3-year local recurrence (LR), disease-free survival (DFS) and overall survival rates were 18%, 50% and 57%. For the 1093 patients with CRM-ve the respective rates were 7%, 81% and 84%. LR and DFS rates were associated with PoS (log-rank test p=0.0019 and p=0.0506 respectively), and in addition there was clear evidence of a reduction in LR and improvement in DFS rates in favour of PRE for all grades of quality of surgical assessment as shown in the table . Conclusions: The results indicate a strong association between the quality of surgery and the rates of local recurrence and disease-free survival, as well as a clear benefit from the addition of PRE to all grades of surgical dissection. Thus for patients with rectal cancer short-course pre-operative radiotherapy and good quality surgery can almost completely eliminate local recurrence. [Table: see text] No significant financial relationships to disclose.
Capecitabine, oxaliplatin, radiotherapy, and excision (CORE) in patients with MRI-defined locally advanced rectal adenocarcinoma: Results of an international multicenter phase II study
Authors: Rutten H. , Sebag-Montefiore D. , Glynne-Jones R. , Rullier E. , Peeters M. , Brown G. , Van Cutsem E. , Ricci S. , Van de Velde C. J. , Quirke P. 
Published: March 2020

3528 Background: The addition of chemotherapy to preoperative radiotherapy (RT) may reduce distant recurrence and increase tumor resectability. The CORE study evaluated oxaliplatin, capecitabine, and RT (XELOX-RT) followed by total mesorectal excision (TME), then adjuvant XELOX in patients (pts) with MRI-defined locally advanced rectal cancer. Methods: MRI inclusion criteria: tumor beyond mesorectal fascia, tumor ≤2 mm from mesorectal fascia, or T3/4 tumor <5 cm from anal verge. Chemoradiation (CRT) was 45 Gy RT (1.8 Gy/dose) 5 days/wk for 5 wks, weekly oxaliplatin 50 mg/m2, and twice-daily capecitabine 825 mg/m2 on each day of RT. Surgery was 6–8 wks after completing XELOX-RT. Pts with R0-R1 resection were to receive XELOX for 6 cycles. Central radiologic and histopathologic review were key study components. Processes to determine histopathologic response and circumferential resection margin (CRM) were predefined. The primary endpoint was pCR rate (planned n=70 evaluable pts). Results: Between July 2003 and Dec 2004, 87 pts were enrolled; 85 pts received XELOX-RT and 79 had TME. Seventy pts (82%) had R0-R1 resection, with a 67% R0 rate (n=57) by Quirke methodology (CRM >1 mm). The pCR rate was 13% (10/78 pts assessable for tumor response; 95% CI, 5.46–20.34%). Tumor regression grading showed excellent response in 35% and poor response in 64% of pts. Of 60 pts evaluated by central MRI review for response by RECIST, the overall response rate was 70% (7% complete; 63% partial response). Preoperative grade (G) 3/4 adverse events (% of pts; evaluable n=85) included diarrhea 16% (12% G3), sensory neuropathy 1% (G3), neutropenia 1% (G3), and hand-foot syndrome 1% (G3). More than 90% of pts received full dose radiotherapy. Conclusions: Significant tumor regression and a high R0 resection rate were achieved using a CRT regimen of preoperative oxaliplatin, capecitabine, and 45 Gy RT, with acceptable toxicity. Central histopathologic and radiologic review data, together with safety and efficacy results for both preoperative CRT and postoperative chemotherapy, will be presented. [Table: see text]
Patient-reported neurotoxicity with FULV versus FLOX in patients with stage II or III carcinoma of the colon: Results of NSABP Protocol C-07
Authors: Land S. R. , Kopec J. , Cecchini R. , Ganz P. A. , Wieand H. , Colangelo L. , Sharif S. , Kuebler J. P. , Costantino J. , Wolmark N. 
Published: March 2020

3564 Background: NSABP Phase III Protocol C-07 compared the efficacy of FULV versus FLOX in patients with stage II or III colon cancer. The definitive analysis revealed an increase in 3-year disease-free survival from 71.6% to 76.5% (HR=0.79, p=0.004) in favor of FLOX. The present study compares patient-reported neurotoxicity between the treatment groups. Methods: Patients were randomized to either FULV (5-FU, 500 mg/m2 iv bolus weekly x 6; LV, 500 mg/m2 iv weekly x 6, each 8-week cycle x 3) or FLOX (FULV with oxaliplatin 85 mg/m2 iv administered on weeks 1, 3 and 5 of each 8-week cycle x 3). A subset of patients (planned sample size 400) at select institutions completed the validated FACT/GOG Oxaliplatin-Specific Neurotoxicity Scale (NTX-12) at baseline, week 4 of cycle 2, and at 6, 12 and 18 months. Mean NTX-12 scores were compared between treatments at 18 months using a t-test and longitudinally with mixed effects modeling. Item responses were compared between treatments with logistic regression. Results: From February 2000 to July 2001, 395 patients with follow-up (206 FULV, 189 FLOX) were enrolled in the neurotoxicity study. They were comparable by disease stage and site, age, and sex to the 759 concurrently accrued C-07 patients not in the sub-study (data not shown). NTX-12 form submission rates were high (with a low of 77% at 12 months). Mean neurotoxicity was higher in the oxaliplatin arm throughout the period of study (p<0.0001) and remained higher at 18 months (p=0.009). During therapy, FLOX patients experienced significant increases in hand/foot neuropathy and overall weakness, and an improvement in hearing ( Table ). At 18 months, hand neurotoxicity resolved, but patients who received oxaliplatin experienced ringing in the ears and continued foot discomfort. Conclusions: This presentation provides the first public review of the severity and persistence of neurotoxicity associated with oxaliplatin in this study. [Table: see text] [Table: see text]