bluuebunny/crossref_metadata_2025_split huggingface dataset:
An open-label phase II study of first- and second-line treatment with brivanib in patients with hepatocellular carcinoma (HCC)
Authors: Raoul J. L. , Finn R. S. , Kang Y. K. , Park J. W. , Harris R. , Coric V. , Donica M. , Walters I. 
Published: August 2020

4577 Background: Brivanib is an orally available dual inhibitor of vascular endothelial growth factor and fibroblast growth factor (FGF) signaling. FGF pathway activation is of increasing importance in the setting of liver fibrosis and HCC. This phase II study aimed to assess the efficacy and safety of brivanib in patients (pts) with unresectable, locally advanced or metastatic HCC who had received either no prior systemic therapy (Cohort A) or one prior regimen of angiogenesis inhibitor (Cohort B). Methods: Eligible pts had biopsy-proven HCC or had radiological evidence of HCC and were serology positive for Hep B or C with alpha fetoprotein levels ≥ 400 μg/L. Pts received brivanib 800 mg qd. Efficacy endpoints included OS, PFS, TTP, ORR, and DCR. Safety was assessed throughout the study. Serum levels of a biomarker, Collagen IV (a component of the basement membrane of blood vessels), were measured on day 1, weeks 3 and 6, and at end of treatment. Results: Interim results are reported. From December 2006 to October 2008, 96 patients were enrolled (Cohort A: 55 pts; Cohort B: 41 pts). In Cohort B, 38 pts had failed sorafenib and 3 had failed thalidomide. In Cohort A, median OS (95% CI) was 10 (6.8,-) months. Most frequently reported grade 3/4 AEs were fatigue (16%), AST elevation (19%), and hyponatremia (41%) in Cohort A and hypertension (7.3%), diarrhea (4.9%), and headache (4.9%) in Cohort B. 24 pts died in Cohort A and 5 pts in Cohort B, none were considered treatment-related. Treatment-induced reductions in serum Collagen IV appear to correlate with long term outcome (PFS and OS). Conclusions: Brivanib has activity as both first-line and second-line post-sorafenib systemic treatment in HCC. Collagen IV, a novel serum angiogenic biomarker, appears to be associated with outcome. [Table: see text] [Table: see text]
Phase II trial of erlotinib in advanced pancreatic cancer (PC)
Authors: Tang P. , Gill S. , Au H. J. , Chen E. X. , Hedley D. , Leroux M. , Wang L. , Moore M. J. 
Published: August 2020

4609 Background: The epidermal growth factor receptor (EGFR) is a potentially important target in PC. Benefit from erlotinib (Tarceva), an oral EGFR tyrosine kinase inhibitor has been associated with the presence of a skin rash. The purpose of this study was to determine the efficacy of erlotinib, dosed to achieve a rash, in patients (pts) with PC. Methods: Erlotinib was given at an initial dose of 150 mg/day to eligible pts with locally advanced (LA) or metastatic PC who had progressed or were unable to tolerate gemcitabine-based chemotherapy. The dose of erlotinib was increased by 50mg every 2 weeks (maximum 300 mg/day) until > grade 1 rash (CTCAE v 3.0) or other dose-limiting toxicities occurred. Erlotinib pharmacokinetic (PK) studies were performed. Baseline tumor tissue was collected for analysis of Kras mutations, EGFR by IHC and FISH. The primary endpoint of this two- stage phase II trial was prolonged disease control (PR + SD > 8 wks) with a rate of >20% assumed to be significant . Results: Fifty pts were accrued (median age 61, M:F = 25:25, ECOG 0:1:2 = 5:41:4, LA:Metastatic = 5:45, prior gemcitabine none:adjuvant:palliative = 2:16:35). 47 and 40 pts were evaluable for toxicity and response, respectively. Dose-escalation to 200–300 mg of erlotinib was possible in 9 pts. Most common treatment adverse events (TAEs) of any grade were: rash (35 pts, 74.5%), diarrhea (18 pts, 38.3 %), and fatigue (8 pts, 17%). Grade 3+ TAEs were rash in 2 pts and diarrhea in 2 pts. Best response was SD in 14 pts, 0.35 (95% CI: 0.2–0.5). Prolonged disease control (SD > 8 wks) was observed in 10/40 evaluable pts, 0.25 (95% CI: 0.12–0.38), which met the primary study endpoint. Median TTP was 1.6 mo (95% CI:1.6–2.1), mOS 4.1 mo (95% CI:3.2–7.3), and 6 mo OS rate was 39% (95%CI: 24–61%). PK and correlative data are being analyzed and will be presented. Conclusions: Erlotinib is associated with prolonged stable disease in a subset of pts with advanced refractory PC. Dose escalation in the absence of toxicity is feasible and safe. [Table: see text]
Use of a genome-wide association study to detect candidate polymorphisms associated with overall survival in stage IV pancreatic adenocarcinoma patients receiving gemcitabine monotherapy
Authors: Ueno H. , Okusaka T. , Furuse J. , Ishii H. , Saijo N. , Saito Y. , Sawada J. , Sakamoto H. , Yoshida T. , Sato Y. 
Published: August 2020

4611 Background: Individual variations in overall survival time (OS) or antitumor effects may be partly explained by host genetic factors, which have not yet been identified. We performed a genome-wide association study (GWAS) in Japanese patients with stage IV pancreatic adenocarcinoma receiving gemcitabine (Gem) monotherapy. Methods: Metastatic pancreatic ductal adenocarcinoma patients who had previously received neither radiation nor chemotherapy were eligible in this study. Gem was administered as a 30-min i.v. infusion at either 800 or 1000 mg/m2. The peripheral blood leukocyte DNA samples were genotyped at 110,000 SNPs using Illuimina's Human-1 Genotyping BeadChip. Statistical analyses were performed by the log-rank test and Cox proportional hazards model in consideration of linkage disequilibrium. Results: From Jul 2002 to Jul 2006, 67 patients (male/female: 44/23, PS 0/1/2: 31/32/4, 36–78 (median: 62) years of age were enrolled. The median survival time (MST) of these 67 patients was 5.8 months. In the GWAS, we detected 11 candidate SNPs which were associated with significantly shortened OS. Eventually, 6 SNPs were MAF>5% and remained statistically significant even after multiple comparison adjustment: rs1861674 in the LOH12CR1 gene (MST for CC [n=60] and CT [n=7] + TT [n=0] were 6.4 and 1.6 months, respectively; P=1.0×10-7, HR=8.25 (3.3–20.9)), rs10504551 in the TCEB1 (MST for CT [n=28] + CC [n=36] and TT [n=3] were 5.8 and 1.0 months. P=1.1×10-7, HR=14.9 (3.9–56.1)), rs1132750 (MST for AC [n=18] + AA [n=45] and CC [n=4] were 6.3 and 1.1 months. P=4.6×10-11, HR=23.5 (6.1–91.7)), rs2055943 in the GABRA4 (MST for AC [n=27] + CC [n=36] and AA [n=4] were 6.3 and 1.2 months. 1.3×10-11, HR=26.1 (6.4–107), rs2589506 in the MAPK10 (MST for AG [n=29] + GG [n=31] and AA [n=7] were 6.4 and 1.1 months. P=3.2×10-6, HR=5.9 (2.6–14.1)) and rs2586404 in the DNM3 (MST for CT [n=30] + CC [n=33] and TT [n=3] were 5.8 and 0.62 months. P=3.4×10-9, HR=18.6 (4.9–71.5)). Conclusions: GWAS is a powerful tool to search for new prognostic biomarkers for patients with stage IV pancreatic adenocarcinoma receiving Gem monotherapy and may reveal as yet unexplored molecular pathways which correlate with drug response. [Table: see text]
A phase II study of radiation and docetaxel and cisplatin in the treatment of locally advanced pancreatic carcinoma. FNCLCC-ACCORD 09 /0201 trial
Authors: Viret F. , Ychou M. , Baey C. , Bennouna J. , Adenis A. , Peiffert D. , Mornex F. , Celier P. , Montoto-Grillot C. , Ducreux M. 
Published: August 2020

4625 Background: Locally advanced pancreatic carcinoma remains a challenging tumor with no clear standard of care in terms of radio-chemotherapy. The purpose of this phase II trial was to determine the efficacy and the toxicity of radiotherapy and docetaxel and cisplatin in histologically proven adenocarcinoma of the pancreas. Methods: Patients (pts) received external beam radiotherapy (54 Gy in 1.8 Gy fractions, six weeks) and weekly chemotherapy regimen of association docetaxel and cisplatine (20 mg/m2/weeks each) for six weeks. Results: 51 pts (20 women and 31 men, with median age of 62 years) with disease considered to be unresectable but confined to pancreas area and celiac nodes were included between 06/10/2003 and 15/02/2008. Location of the tumor: head (33 pts), body (13 pts), and tail (5 pts). The median dose of radiotherapy received by the patients was 54 Gy. The median dose of docetaxel and cisplatin administered was 19.8 mg/m2/w (relative dose intensity 97%). Radiotherapy has to be interrupted in 7 pts. 30 pts experienced at least one episode of grade 3 or 4 toxicity (asthenia 12 pts, anorexia 11 pts, vomiting 10 pts, nausea 9 pts, abdominal pain 5 pts). No toxic death was observed. 6 pts underwent secondary pancreatic resection (4 compete resection and 1 pt with histological complete remission). The objective response rate (CR 5 pts, PR 3 pts), was 16% with a median duration of 7.6 months. At 6 months, 30 pts had progressed. Median progression free survival was 5.8 months. With a 21 months median follow up, median overall survival was 9.6 months and 18 months survival rate of 31%. Conclusions: The association docetaxel+cisplatin+radiotherapy has limited effect in patients with locally advanced pancreatic carcinoma but major objective responses have been observed allowing secondary resections. Grant by sanofi-aventis, Amgen, and Ligue Nationale Contre Le Cancer. No significant financial relationships to disclose.
Comparison of two standard chemotherapy regimens for good-prognosis germ-cell tumors: Updated analysis of a randomized trial with 8 years follow-up
Authors: Grimison P. S. , Stockler M. R. , Thomson D. B. , Olver I. N. , Harvey V. J. , Gurney H. , Lewis C. R. , Gebski V. J. , Boland A. L. , Toner G. C. ,   Australia and New Zealand Germ Cell Trials Group
Published: August 2020

5016 Background: We performed a multicentre randomised trial for good-prognosis germ-cell tumours of two standard chemotherapy regimens containing bleomycin (B), etoposide (E) and cisplatin (P). Accrual was stopped early, after interim analysis with a median follow-up of 33 months found a survival benefit for the regimen similar to Indiana University BEP, compared with the less dose-intense regimen (Toner, Lancet 2001). Here we report on long-term outcomes and patterns of relapse. Methods: Patients with a good prognosis defined by modified Memorial Sloan-Kettering criteria were randomised to 3B90E500P (3 cycles every 21 days of B 30 kU on days 1, 8 and 15, E 100 mg/m2 on days 1–5, and P 20 mg/m2 on days 1–5); or 4B30E360P (4 cycles every 21 days of B 30 kU on day 1, E 120 mg/m2 on days 1–3, and P 100 mg/m2 on day 1). Overall survival was the primary endpoint. Progression-free survival (PFS) was a secondary endpoint. All analyses were by intention-to-treat and with 2-sided p-values. Results: 166 patients were randomised, 83 to each regimen. Median follow-up is now 8.5 years and all but 5 have been followed ≥ 5 years. Overall survival remains substantially better with 3B90E500P than 4B30E360P (8YS 92% vs 83%, hazard ratio 0.38, 95% CI 0.15 to 0.97, p=0.037), and remains significant when analyses were restricted to 138 patients with good prognosis by IGCCCG criteria (p=0.035). Trends for PFS favour 3B90E500P but are not statistically significant (8YPFS 86% vs 79%, hazard ratio 0.6, 95% CI 0.3 to 1.1, p=0.15). 7 of 15 relapses occurring within 2 years after randomisation were fatal, but all 4 relapses occurring > 2 years after randomisation were fatal. Conclusions: The survival benefit of 3B90E500P compared to 4B30E360P was maintained with long-term follow-up. The occurrence of relapses beyond 2 years affirms the importance of long-term follow-up. Late relapses in this study were associated with uniformly poor outcomes. [Table: see text] No significant financial relationships to disclose.
Neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients
Authors: Gronwald J. , Byrski T. , Huzarski T. , Dent R. , Bielicka V. , Zuziak D. , Wisniowski R. , Lubinski J. , Narod S. 
Published: August 2020

502 Background: Neoadjuvant chemotherapy is administered to control disease, make surgical resection possible and increase the possibility of breast tissue conservation. A further advantage of neoadjuvant therapy is that it helps to assess chemo-sensitivity to a particular agent. Induction of a pathological complete response (pCR) is one of the primary goals of neoadjuvant therapy in order to achieve a better disease-free and overall survival. Experimental data suggest that BRCA1 related breast cancer may have increased sensitivity to platinum-based chemotherapy, but clinical data are limited. The aim of this study was to evaluate the frequency of complete pathologic response after neo-adjuvant treatment with cisplatin chemotherapy in women with breast cancer and a BRCA1 mutation. Methods: Twenty five women with breast cancer and a BRCA1 mutation with stage I, II, and III breast cancer between December 2006 and December 2008 were entered into this study. Patients were treated with cisplatin 75 mg/m2 intravenously every three weeks for four cycles. After chemotherapy, patients underwent surgery and were assessed for pathologic response in both the breast and axillary lymph nodes. Complete pathologic response was defined as no residual invasive disease in both the breast and axilla, however ductal carcinoma in situ was allowed. Results: Twenty five patients were enrolled in the study. Thirteen patients had tumors of greater than two centimeters (52%) and seven patients had positive lymph nodes at diagnosis (28%). Twenty two patients completed four cycles of cisplatin (88%) and three patients completed two cycles (12%). Clinical complete response was observed in eighteen patients (72%). Pathologic complete response was observed in eighteen patients (72%). Conclusions: Platinum-based chemotherapy is effective in a high proportion of patients with BRCA1-associated breast cancers. Clinical trials are warranted to determine the optimum treatment for this subgroup of breast cancer patients. No significant financial relationships to disclose.
A phase II trial of high-dose chemotherapy (HDCT) supported by haematopoietic stem cell transplantation (HSCT) in patients (pts) with disseminated germ-cell tumors (GCTs) failing chemotherapy and with adverse prognostic factors: The TAXIF II protocol
Authors: Lotz J. , Selle F. , Fizazi K. , Gravis G. , Bui B. , Delva R. , Bay J. , Baron A. , Robain M. , Biron P. 
Published: August 2020

5028 Background: HDCT using the etoposide-carboplatin ± ifosfamide regimen is able to circumvent resistance in GCT pts, even when used as third-line or later therapy (Lotz, Ann Onco.l 2005 / Einhorn, N Eng J Med. 2007). Pts whose relapses occur more than 4 w after CDDP-based CT are probably the best candidates for HDCT. Epirubicine (E) and paclitaxel (P) possess interesting activity in GCTs. Thiotepa (TTP) and P can be safely combined at HD with good efficacy. The ICE regimen is a well-known worldwide used regimen. Methods: Non-resistant/refractory GCTs pts failing CT and with adverse prognostic factors were planned to receive 2 cycles combining (mg/m2) E (100) and P (250), given on day 1 and 14 supported by filgrastim (F), followed by 3 consecutive HDCTs [1 course combining a 3-d combination of P (360) + TTP (720), followed by 2 ICE regimens (IFM, 12 g/m2, CBDCA, AUC 20, VP16, 1,500 mg/m2), given on 5 days with HSCT and F]. Inclusion criterias were mainly: radiologically and/or biologically mesurable disease, seminomatous GCT in relapse after 2 lines of CT (BEP/VeIP), non-seminomatous GCT in relapse after 1 or 2 lines of CT or in PR after 1 line of CT, primary mediastinal GCT in first relapse. Resistant / refractory pts were excluded. PBSC were collected after the first ± the second courses of EP (aim: 9x10E6 CD34+/kg BW). We report herein on the preliminary results of this multicentric study. Results: From 09/04 to 12/07, 45 pre-treated (BEP ± VeIP) pts with gonadal (89%) or extra-gonadal T (11%) were treated in second-line (27%), 3rd-line (44 %) or more (29 %). Thirty-five pts received 1 HDCT, 29 two HDCTs and 21 pts could receive the whole protocol. At the time of analysis (12/08), the final overall response rate was 47%, 10 pts were in continuous CR (median time, 8 m; range, 1–18), and 37 pts (82%) were alive at a median F/U of 9 m (range, 1–26). The 1-y survival rate was 90%. The 1-y PFS rate was 62%. One pt died of multi-organ failure and 7 died of disease progression. Conclusions: This HDCT program preceded by 2 semi-intensive cycles of E-P is highly effective in non-resistant/refractory pts with disseminated GCTS failing CT and with adverse prognostic factors. No significant financial relationships to disclose.
Phase II study of perifosine in metastatic renal cell carcinoma (RCC) progressing after prior therapy (Rx) with a VEGF receptor inhibitor
Authors: Vogelzang N. J. , Hutson T. E. , Samlowski W. , Somer B. , Richey S. , Alemany C. , Loesch D. , Richards P. , Gardner L. , Sportelli P. 
Published: August 2020

5034 Background: Perifosine, a synthetic alkylphospholipid, inhibits or modulates a number of different signal transduction pathways (AKT, MAPK and JNK). In a prior trial, 15 RCC patients (pts) were enrolled in a randomized dose finding study, 9 were evaluable for response and 3 (33%) had a partial response (PR). Thus phase II trials were begun for pts who had been treated with one prior VEGFr inhibitor (Group A) or with a prior VEGFr inhibitor and prior mTOR inhibitor (Group B). We report the results of Group A (closed), and Group B (enrollment open). Methods: To measure the objective response rate (RECIST) and PFS to single agent perifosine (100 mg qhs with food) after 3 mos of Rx; Prior Rx with vaccine therapy, bevacizumab and/or cytokines was permitted. Normal organ/marrow function was required. Results: From 12/07–12/08, 46 pts (31 Group A/ 15 Group B) were treated at 13 sites. Median age 64 (range 46–80) and 36 were male; Median prior Rx was 2 (range 1 - 5); Clear cell = 37, non clear cell = 6, data n/a = 3. Prior sunitinib = 35, prior sorafenib = 10, 1 unknown due to blinded study. Prior mTOR; Tem = 9 and Rad001 = 6. As of 12/08, 44 pts were evaluable for response and PFS (two pts not eval; 1 withdrew consent, 1 toxicity < 5 days on Rx). Results listed in the table below. As of 12/08, 12/44 pts (5 Group A/ 7 Group B) remain on treatment. Median survival; not reached. Most common toxicity was grade 1 & 2 nausea (56%), arthralgia (47%), vomiting (36%), fatigue (33%) and cognitive changes (28%). Grade 3 & 4 toxicity was uncommon; arthralgia (14%) and hyperuricemia/gout (8%). Conclusions: Perifosine, similar to mTOR inhibitors, appears to have clinical benefit in mRCC as reflected by the PR rate and a 15 wk median overall PFS. This is most notably in patients who failed both a prior VEGFr and mTOR inhibitor where 7/14 remain on study as of 12/08. Randomized studies are under consideration to further evaluate perifosine's clinical benefit as 2nd or 3rd line therapy of mRCC. [Table: see text] [Table: see text]
Prognostic factors for overall survival (OS) in patients with metastatic renal cell carcinoma (RCC) treated with vascular endothelial growth factor (VEGF)-targeted agents: Results from a large multicenter study
Authors: Heng D. Y. , Xie W. , Regan M. M. , Cheng T. , North S. , Knox J. J. , Kollmannsberger C. , McDermott D. , Rini B. I. , Choueiri T. K. 
Published: August 2020

5041 Background: Prognostic factors (PF) for OS have yet to be fully defined for patients with metastatic RCC in the era of VEGF-targeted therapy. This study identifies PFs in this population and updated survival and validation results are presented. Methods: Baseline characteristics and outcomes on anti-VEGF-naïve metastatic RCC patients were collected from three US and four Canadian centers. Using a Cox proportional hazards model, 3 risk categories for predicting survival were identified on the basis of 6 pretreatment clinical features. Results: Six-hundred forty-five patients were included. The median (m) OS was 22 months (95% CI: 20.0–24.8) with a median follow-up of 25 months. Patients were treated with sunitinib (n = 396), sorafenib (n = 200) or bevacizumab (n = 49); 33% had prior immunotherapy. Four of the five PFs previously identified by MSKCC were independent predictors of short survival, including hemoglobin below the lower limit of normal (LLN) (p < 0.0001), corrected calcium above the upper limit of normal (ULN) (p = 0.0006), Karnofsky performance status <80% (p < 0.0001) and time from initial diagnosis to initiation of therapy ULN (pULN (p = 0.012) were independent adverse PFs. Patients were assigned one point for each poor PF and were segregated into three risk categories: favorable-risk (0 PFs, n = 133) median OS (mOS) 37.0 months; intermediate-risk (1 - 2 PFs, n = 292) mOS 28.5 months; and poor-risk (3–6 PFs, n = 139) mOS 9.4 months (log rank p < 0.0001). This model produced a c-index of 0.74 and the bootstrap procedure confirmed good internal validity. The discriminatory ability of the model and its parameter estimates were not affected after adjusting for prior use of immunotherapy or the type of anti-VEGF drug used. Conclusions: These data validate components of the MSKCC model with the addition of platelet and neutrophil counts. This model derived from a large population can be incorporated into patient care and clinical trials of VEGF-targeted agents. [Table: see text]
Diastolic blood pressure (dBP) and pharmacokinetics (PK) as predictors of axitinib efficacy in metastatic renal cell cancer (mRCC)
Authors: Rixe O. , Dutcher J. , Motzer R. , Wilding G. , Stadler W. M. , Garrett M. , Pithavala Y. , Kim S. , Tarazi J. , Rini B. I. 
Published: August 2020

5045 Background: Axitinib (AG-013736) is an oral, potent, and selective inhibitor of VEGF receptors 1, 2, 3. An association between dBP elevation and clinical outcome has been previously reported (Rini, ASCO. 2008). The objective of this pooled analysis of two phase II mRCC studies was to explore the relationship between PK, dBP, and clinical efficacy. Methods: PK data from two phase II studies in cytokine-refractory mRCC patients (pts) and 8 single-dose healthy volunteer (HV) studies were included (n = 109 mRCC pts and 240 HV) in the population PK analysis; the efficacy analysis included mRCC pts only. PK data was analyzed using nonlinear mixed-effects modeling to estimate population PK parameters (mean and inter-individual variability). Mean steady-state area under the plasma concentration-time curve (AUC) at the end of cycle 1 and the dBP during axitinib therapy were utilized as predictors of clinical efficacy in the mRCC pts using logistic regression and Kaplan-Meier analyses. Results: The median overall survival (mOS) for mRCC pts with at least 1 dBP measurement ≥90 mmHg (n = 59) during axitinib therapy was 130 weeks vs. 42 weeks (p < 0.01) for pts without any dBP ≥90 mmHg (n = 50). The mOS of pts with an AUC below the median (605 ng.hr/ml; n = 54) was 69 weeks vs. 88 weeks (p > 0.05) for pts with an AUC above the median (n = 55). Among pts with dBP ≥90 mmHg, mOS was 120 weeks and 131 weeks (p > 0.05) for pts with AUC below and above the median (n = 23 and 36), respectively. Among pts without dBP ≥90 mmHg, mOS was 42 weeks and 43 weeks (p > 0.05) for pts with AUC below and above the median (n = 31 and 19), respectively. An 82% increase in probability of a partial response was predicted for a 10 mmHg higher dBP during therapy. There was no apparent correlation between the AUC and maximum dBP during axitinib therapy. Conclusions: dBP ≥90 mmHg during axitinib therapy is a strong predictor of clinical efficacy in patients with mRCC, and is not merely a reflection of higher axitinib drug levels. These data support an ongoing pivotal phase III trial in previously treated mRCC that incorporates a dose-titration scheme based on patient tolerance and BP. [Table: see text]