bluuebunny/crossref_metadata_2025 huggingface dataset:
Camrelizumab combined with capecitabine and oxaliplatin followed by camrelizumab and apatinib as first-line therapy for advanced or metastatic gastric or gastroesophageal junction cancer: Updated results from a multicenter, open label phase II trial.
Authors: Shen Lin , Peng Zhi , Zhang Yan-Qiao , Wei Jia , Wang Feng , Ying Jieer , Deng Yanhong , Gu Kangsheng , Cheng Ying , Yuan Xianglin , Xiao Juxiang , Wang Linna , Zou Jianjun
Published: May 2019

4031

Background: Capecitabine plus oxaliplatin (CAPOX) is one of the standard first-line treatments for advanced or metastatic gastric cancer. Camrelizumab (SHR-1210, an anti–PD-1 antibody) shows promising anti-tumor activity in patients (pts) with advanced or metastatic gastric or gastroesophageal junction (G/GEJ) cancer. Camrelizumab combined with CAPOX for untreated G/GEJ cancer was assessed as a part of an ongoing multicenter, open-label phase 2 trial (cohort 1), and encouraging preliminary results were reported. Here, we present the updated safety and efficacy data. Methods: In this cohort, systemic treatment naïve pts with HER2– advanced or metastatic G/GEJ adenocarcinoma were given camrelizumab 200 mg on Day 1, capecitabine 1000 mg/m2 bid on Days 1–14 and oxaliplatin 130 mg/m2 on Day 1 of each 21-day-cycle for 4 to 6 cycles followed by camrelizumab 200 mg every 3 weeks plus apatinib 375 mg qd until disease progression or intolerable toxicity. The primary endpoint was objective response rate. Results: At data cutoff (Jan 20, 2019), 43 of the 48 enrolled pts were evaluable. Partial response was observed in 28 pts (65%), and 19 (44%) were confirmed. Stable disease in 14 pts and progressive disease in 10 pts were reported. Median estimates for duration of response and progression-free survival were not reached. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 9 pts (21%), included neutropenia, diarrhea, rash and elevated ALT, whereas none of the TRAEs was fatal. Ten pts without progression after 4–6 cycles of camrelizumab and CAPOX combination therapy all received camrelizumab plus apatinib as sequential therapy, and no new safety signals were observed. Conclusions: The updated results confirmed that camrelizumab plus CAPOX followed by camrelizumab plus apatinib was well tolerated with noteworthy responses as first-line therapy in advanced or metastatic G/GEJ cancer pts. Expansion of this cohort in a phase 3 study are under way. Clinical trial information: NCT03472365.
Trifluridine/tipiracil (FTD/TPI) in patients (pts) with metastatic gastroesophageal junction cancer (mGEJC): Subgroup analysis from TAGS.
Authors: Mansoor Wasat , Arkenau Hendrik-Tobias , ALSINA MARIA , Shitara Kohei , Tejani Mohamedtaki Abdulaziz , Thuss-Patience Peter C. , Cuffe Sinead , Dvorkin Mikhail , Park David , Ando Takayuki , Van Den Eynde Marc , Beretta Giordano D. , Zaniboni Alberto , Doi Toshihiko , Tabernero Josep , Ilson David H. , Makris Lukas , McGuigan Sandra , Van Cutsem Eric
Published: May 2019

4038

Background: The incidence of GEJC is increasing in North America and Europe, especially among white men. Many pts present with metastatic disease or relapse locally or systemically after resection of early-stage disease. The global phase 3 study TAGS (NCT02500043) demonstrated the efficacy and safety of FTD/TPI in previously treated pts with metastatic gastric cancer (mGC)/mGEJC. Here we report results in the mGEJC subgroup from TAGS. Methods: Pts with mGC/mGEJC treated with ≥2 prior chemotherapy regimens were randomized (2:1) to receive FTD/TPI (35 mg/m2 BID on days 1–5 and 8–12 of each 28-day cycle) or placebo, plus best supportive care. A preplanned efficacy and safety analysis was performed in pts with mGEJC. Results: Of 507 randomized pts, 145 (29%) had GEJC as the sole primary disease site (FTD/TPI, 98/337; placebo, 47/170). Of pts with mGEJC, 85% were male and 83% were white (overall population, 73% and 70%). Baseline characteristics were generally balanced for pts with mGEJC across treatment groups, except for fewer pts having prior gastrectomy (40% vs 55%) and more pts having received ≥3 prior regimens (74% vs 66%) in the FTD/TPI group than in the placebo group. FTD/TPI had an efficacy benefit in pts with mGEJC, and the FTD/TPI safety profile was similar in this subgroup and the overall population (table). Conclusions: FTD/TPI showed a manageable safety profile and efficacy benefit in pts with mGEJC in the TAGS trial, despite heavier pretreatment of the FTD/TPI than the placebo group. Clinical trial information: NCT02500043. [Table: see text]
Homologous recombination deficiency as prognostic marker in metastatic gastric cancer.
Authors: Sousa Nuno , Faustino Catia , Aguas Lucia Maria Nunes , Freire João , Coutinho Camila , Faustino Ilda , Capela Andreia , Costa Telma , Costa Andreia Sofia Alves , Coelho Sara , Pereira Filipa , Abreu Sofia Coelho , Rolo Ana Sofia , Albergaria Andre , Lima Jorge , Wen Xiaogang , Mesquita Carina , Dias Claudia Camila , Azevedo Luis Filipe , Carneiro Fatima
Published: May 2019

4040

Background: Gastric cancer is the 5th cancer diagnosis and 3rd cause of cancer death worldwide. Metastatic gastric cancer (mGC) has a median survival of 11 months. mGC is an heterogeneous disease and different biologic characteristics may justify differential therapeutic opportunities. Tumors with homologous recombination (HR) deficiency may benefit with treatment with PARP inhibitors or immune checkpoint inhibitors. The purpose of this study was to evaluate the prevalence and prognostic impact of altered expression of HR proteins as surrogates for homologous recombination deficiency (HRD) in mGC. Methods: Multicenter retrospective cohort of mGC treated with platinum-based chemotherapy. HRD defined as absence of at least one of the following proteins: ATM, ATR, CHK2, RAD51, RAD52, BRCA1, BRCA2, MRE11 by immunohistochemistry. Survival time calculated as the difference between first cycle of platinum-based chemotherapy and death or last observation. Association between HRD and survival examined with log-rank test. Results: 440 patients included, of which 70% male, with mean age of 58 years (SD: 11). 75% of patients had mGC at diagnosis, 43% had 2 or more organs involved and 63% were registered as ECOG 0 or 1 at the start of first line chemotherapy. The most common histologic subtype was tubular adenocarcinoma (44%) followed by diffuse carcinoma (32%). HRD was noted in 196 (45%) cases (95%CI: 40%-49%). The most commonly altered proteins were ATM (21%) and BRCA2 (18%). In HRD tumors, 99 (51%) had altered expression of only one HR protein; 47 (24%) had altered expression of two HR proteins; the remaining cases had altered expression of 3 or more proteins. After a median follow up of 11 months, median survival for the cohort was 11 months (95% CI 9-12). HRD was associated with an improved survival, HR = 0.61 (95%CI: 0.48-0.78, p < 0.001), that remained significant after adjustment for sex, age, performance status and disease status (HR = 0.63; 95%CI: 0.48-0.82; p < 0.001). Conclusions: HRD phenotype was present in 45% of mGC cases and is associated with improved prognosis for mGC treated with platinum-based first line chemotherapy.
Analysis of symptoms and functional HRQoL scales in TAGS, a phase III trial of trifluridine/tipiracil (FTD/TPI) in metastatic gastric cancer (mGC).
Authors: Alsina Maria , Tabernero Josep , Shitara Kohei , Doi Toshihiko , Dvorkin Mikhail , Mansoor Wasat , Arkenau Hendrik-Tobias , Prokharau Aliaksandr , Ghidini Michele , Faustino Catia , Gorbunova Vera , Zhavrid Edvard , Nishikawa Kazuhiro , Ando Takayuki , Yalcin Suayib , Van Cutsem Eric , Skanji Donia , Leger Catherine , Sabater Javier , Ilson David H.
Published: May 2019

4043

Background: The phase 3, randomized, double-blind, placebo-controlled study (TAGS) evaluated the efficacy and safety of FTD/TPI (35 mg/m² given orally twice a day on days 1–5 and 8–12 of a 28-day cycle) in mGC patients who had previously received≥2 prior regimens for advanced disease and demonstrated a clinically relevant and statistically significant benefit in OS and PFS with a predictable and manageable safety profile. HRQoL data and association between QoL and time to ECOG status deterioration (2 or more) are reported here. Methods: HRQoL was evaluated using EORTC QLQ-C30 and the gastric-specific module (QLQ-STO22) questionnaires at baseline and at every 4 weeks thereafter until treatment discontinuation. Prespecified key HRQoL were changes from baseline and time to deterioration. Changes ≥10 points were deemed clinically relevant. A time-dependent Cox-regression analysis was performed to evaluate the association of 10-point Global Health Status deterioration with worsening ECOG status. Results: Of 507 patients randomized, 332/337 (98.5%) of FTD/TPI and 164/170 (96.5%) of placebo had baseline QoL data. Overall compliance was 84% for both questionnaires. Demographic and disease were generally balanced between the two groups; QoL scores were also similar between groups. HRQoL was largely maintained during treatment in both arms for most items; mean changes from baseline remained under the 10-point threshold. Clinically relevant changes from baseline were observed only for pain relief at cycle 2 (favouring FTD/TPI); and improved role functioning at cycle 3 (favouring placebo). In a sensitivity analysis including death or progression as an event, FTD/TPI was associated with a positive trend suggesting a reduced risk of QoL deterioration across all scales compared to placebo (HRs ranged from 0.57 to 0.74. A 10-point Global Health Status deterioration was associated with a worsening ECOG status (HR, 95% CI, 1.5, 1.2 to 1.86). Conclusions: During the treatment period, HRQoL remained stable for most functional and symptom scales in both arms, suggesting that HRQoL is largely maintained with FTD/TPI. Treatment with FTD/TPI was associated with a positive trend toward a lower risk of QoL deterioration than placebo across all scales. Changes in QoL were informative for patients ‘expected ECOG status. Clinical trial information: NCT02500043.
Best supportive care (BSC) with or without low-dose chemotherapy (chemo) in frail elderly patients with advanced gastroesophageal cancer (aGOAC): The uncertain randomization of the GO2 phase III trial.
Authors: Swinson Daniel , Hingorani Mohan , Stokes Zuzana , Dent Jo , Guptal Kamalnayan , Chatterjee Anirban , Kamposioras Konstantinos , Grumett Simon Aird , Khan Mohammad , Marshall Helen , Ruddock Sharon , Allmark Christine , Katona Eszter , Howard Helen C , Velikova Galina , Lord Simon , Hall Peter S , Seymour Matthew T.
Published: May 2019

4051

Background: Before 2000, trials comparing BSC +/- chemo for aGOAC showed overall survival (OS) benefit, but in predominantly fit patients (pts). We have revisited this question in a modern context, using low-dose chemo in a frail population, with comprehensive baseline health and frailty assessment. Methods: In the GO2 trial, elderly and/or frail aGOAC pts with a “certain” indication for chemo were randomised between 3 chemo doses. In this GO2 substudy, pts with an “uncertain” indication for chemo were instead randomised to BSC ± the lowest dose chemo. Pts were eligible if clinician and pt agreed the indication for chemo was uncertain. There was no PS threshold, but eGFR ≥30 and bili < 2xULN were required. Baseline assessment included global QL, symptom & functional scales, frailty and comorbidity. Randomisation was 1:1 to BSC alone, or with oxaliplatin 78 mg/m2 d1, capecitabine 375 mg/m2 bd d1-21 (modified if eGFR 30-50 ml/min or bili 1.5-2.0 xULN), q21d. QL was reassessed after 9 and 18 wks. The primary endpoint analysis was OS, adjusted for baseline factors. The sample size for this exploratory sub-study was not pre-set, but around 60 pts were anticipated. Results: 558 pts entered GO2 at 61 centres 2014-17, of whom only 45 pts (8%) at 21 centres entered this uncertain randomisation. This would provide 80% power at p = 0.05 (2-tailed) to detect an OS HR of 0.3. OS was shorter in pts with worse baseline PS (p<0.01) or distant mets (p<0.05). OS was not significantly improved with chemo; however we cannot exclude HR >0.32. QL deteriorated less with BSC+chemo than with BSC alone. Conclusions: In this frail, poor PS population, we observed a small survival benefit with chemo but this did not reach statistical significance. Clinicians should carefully consider BSC alone as a valid treatment option for aGOAC pts with poor PS and/or frailty. Clinical trial information: 44687907. [Table: see text]
Phase 1 open label trial of intraperitoneal paclitaxel (IPP) in combination with intravenous cisplatin (C) and oral capecitabine (X) in patients with advanced gastric cancer and peritoneal metastases.
Authors: Vatandoust Sina , Bright Tim F , Abbas M Nazim , Roy Amitesh Chandra , Watson David I. , Gan Susan S H , Scott-Hoy Alex , Bull Jeff A , Karapetis Christos Stelios
Published: May 2019

4061

Background: IPP is a potential treatment option in patients with gastric cancer with peritoneal metastasis. IPP with a dose of 20 mg/m2 is well tolerated in combination with S1; however, this has been achieved in a specific genetic pool (Japanese population), and S1 is not available in some countries. We investigated the Maximum Tolerated Dose (MTD) of IPP in addition to a standard chemotherapy combination in an Australian population. Methods: Study population included synchronous or metachronous metastatic HER-2 non-amplified gastric adenocarcinoma with histologically/cytologically proven peritoneal involvement and adequate organ function. Intra-peritoneal catheter was placed surgically. 3 + 3 standard dose-escalation design was used. MTD was defined as the highest dose level at which ≤ 33% of patients had Dose Limiting Toxicity (DLT). DLT was defined within the first 3 cycles. Recommended Phase-2 Dose was defined as equal to the MTD, or cohort-3 dose if MTD was not reached. Treatment: maximum of six 21-day cycles of C (80mg/m2 IV day 1) + X (1000mg/m2 PO BD days 1-14) + IPP (days 1 and 8). IPP doses for Cohort-1, 2 and 3 were 10, 20 and 30mg/m2 respectively. Primary endpoint was the MTD of IPP. Secondary endpoints included safety, tolerability, overall response rate, ascites response rate, progression free survival and overall survival. Results: 15 patients were recruited in 3 cohorts: 9 males (60%), median age at study entry: 61y (range 32-82). All had synchronous metastatic disease and were chemo-naïve. Cohort-1 expanded to 6 patients due to 1 DLT (grade 3 diarrhea), cohort-2 included 3 patients (no DLT) and cohort-3 was expanded to 6 patients as planned and 1 DLT occurred (febrile neutropenia). MTD was not reached and Recommended Phase 2 Dose was determined as 30mg/m2. 8 patients (53%) completed all 6 cycles of treatment. The last patient on the study has completed 3 cycles and is expected to complete 6 cycles by April 2019. No grade 4 or 5 toxicity was recorded. Conclusions: MTD of IPP was not reached. IPP is safe in combination with C + X and the Recommended Phase 2 Dose is 30 mg/m2. Survival data will be presented when available. Clinical trial information: ACTRN12614001063606.
Impact of adjuvant therapy in patients with a microscopically positive margin after resection for gastroesophageal cancer.
Authors: Ma Lucy Xiaolu , Espin-Garcia Osvaldo , Lim Charles Henry , Sun Peiran , Jiang Di Maria , Sim Hao-Wen , Natori Akina , Chan Bryan Anthony , Yokom Daniel , Moignard Stephanie , Suzuki Chihiro , Chen Eric Xueyu , Liu Geoffrey , Swallow Carol Jane , Darling Gail Elizabeth , Wong Rebecca , Hafezi-Bakhtiari Sara , Conner James , Elimova Elena , Jang Raymond Woo-Jun
Published: May 2019

4069

Background: A microscopically positive (R1) resection margin following resection for gastroesophageal (GE) cancer has been documented to be a poor prognostic factor. The optimal strategy and impact of different modalities of adjuvant treatment for an R1 resection margin remain unclear. Methods: A retrospective analysis was performed for patients (pts) with GE cancer treated at the Princess Margaret Cancer Centre from 2006-2016. Electronic medical records of all pts with an R1 resection margin were reviewed. Kaplan-Meier and Cox proportional hazards methods were used to analyze recurrence free survival (RFS) and overall survival (OS) with stage and neoadjuvant treatment as covariates in the multivariate analysis. Results: We identified 78 GE cancer pts with an R1 resection. 11% had neoadjuvant chemotherapy, 14% chemoradiation (CRT), 75% surgery alone. 28% had involvement of the proximal margin, 13% distal, 56% radial, 3% had multiple positive margins. By the American Joint Committee on Cancer 7th edition classification, 88% had a pT3-4 tumour, 66% pN2-3 nodal involvement, 64% grade 3, 68% with lymphovascular invasion. 3% were pathological stage I, 21% stage II and 74% stage III. Adjuvant therapy was given in 46% of R1 pts (24% CRT, 18% chemotherapy alone, 3% radiation alone, 1% reoperation). Median RFS for all pts was 12.6 months (95% CI 10.3-17.2). Site of first recurrence was 71% distant, 16% locoregional, 13% mixed. Median OS was 29.3 months (95% CI 22.9-50) for all pts. The 5 year survival rate was 23% (95% CI 12%-43%). There was no significant difference in RFS (log-rank test p = 0.63, adjusted p = 0.14) or OS (log-rank test p = 0.68, adjusted p = 0.65) regardless of adjuvant therapy. Conclusions: Most pts with positive margins after resection for GE cancer had advanced pathologic stage and prognosis was poor. Our study did not find improved RFS or OS with adjuvant treatment and only one pt had reresection. The main failure pattern was distant recurrence, suggesting that pts being considered for adjuvant RT should be carefully selected. Further studies are required to determine factors to select pts with good prognosis despite a positive margin, or those who may benefit from adjuvant treatment.
Ramucirumab (RAM) for sorafenib intolerant patients with hepatocellular carcinoma (HCC) and elevated baseline alpha fetoprotein (AFP): Outcomes from two randomized phase 3 studies (REACH, REACH2).
Authors: Llovet Josep M , Yen Chia-Jui , Finn Richard S. , Kang Yoon-Koo , Kudo Masatoshi , Galle Peter R. , Assenat Eric , Pracht Marc , Lim Ho Yeong , Rau Kun-Ming , Borg Christophe , Hiriart Jean-Baptiste , Daniele Bruno , Berg Thomas , Chung Hyun Cheol , Godinot Nathalie , Wang Chunxiao , Hsu Yanzhi , Schelman William R. , Zhu Andrew X.
Published: May 2019

4073

Background: Oral multikinase inhibitors that have shown improvements in overall survival (OS) in HCC are associated with clinically important toxicities that commonly require dose adjustment or discontinuation (D/C) due to intolerance. REACH and REACH-2 studied RAM in patients (pts) with HCC who progressed on or were intolerant to sorafenib (SOR), and REACH-2 only enrolled pts with baseline AFP ≥400 ng/mL. In REACH-2 RAM treatment (trt) improved OS compared to placebo (P), supporting findings in REACH pts with baseline AFP ≥400 ng/mL. An exploratory analysis of outcomes by reason for D/C of SOR was performed. Methods: Pts had advanced HCC, Child-Pugh A, ECOG PS 0-1, and prior SOR. Pts were randomized to RAM 8 mg/kg or P Q2W. A pooled independent pt data analysis (stratified by study) of REACH-2 and REACH pts (AFP ≥400 mg/mL) was performed. Results are reported by reason for SOR D/C (intolerance or disease progression). OS and PFS were evaluated using Kaplan-Meier method and Cox proportional hazard model. Objective response rate (ORR), disease control rate (DCR) and safety are reported. Results: Baseline characteristics in the pooled population were generally balanced between trt arms in each subgroup. Median durations of prior SOR were 2.5 mo for SOR intolerant (n = 70) and 4.0 mo for SOR progressors (n = 472). Median OS (RAM v P) was 10.2 v 6.7 mo for SOR intolerant and 8.0 v 4.7 mo for SOR progressors (Table). Rates of D/C due to trt-related adverse events (AEs) (Table) (7% in each subgroup), and Grade ≥3 AEs (most frequently hypertension) were consistent with those observed in each study. Conclusions: Acknowledging limitations of sample size, the RAM trt benefit in SOR intolerant pts was consistent with that in the ITT population. RAM was well tolerated in SOR intolerant pts with low rates of D/C due to related-AEs. Clinical trial information: NCT01140347, NCT02435433. [Table: see text]
Multicentric prospettive study of validation of angiogenesis-related gene polymorphisms in hepatocellular carcinoma patients treated with sorafenib: Interim analysis of INNOVATE study.
Authors: Casadei Gardini Andrea , Marisi Giorgia , Dadduzio Vincenzo , Faloppi Luca , Ielasi Luca , Vivaldi Caterina , Rizzato Mario Domenico , Fornaro Lorenzo , Lonardi Sara , Gramantieri Laura , Pecora Irene , Foschi Giuseppe Francesco , Silvestris Nicola , Fornari Francesca , Orsi Giulia , Rovesti Giulia , Santini Daniele , Zagonel Vittorina , Cascinu Stefano , Scartozzi Mario
Published: May 2019

4075

Background: In the ePHAS study we analyzed three eNOSpolymorphisms and at univariate analysis, patients with eNOS-786 -TTgenotype had significantly shorter median Progression Free Survival (PFS) and Overall Survival (OS) compared to those with other genotypes. On the basis of these preliminary results, our aim is to validate in a prospective study this data in patients with HCC treated with sorafenib. Methods: This is a prospective Italian multicenter study, that includes 141 HCC patients receiving sorafenib. We analyzed eNOS-786and itwas analyzed by Real Time PCR in relation to the primary end point (OS). Event-time distributions were estimated using the Kaplan-Meier method and survival curves were compared using the log-rank test. Results: 141 HCC patients (122 males and 19 females), prospectively treated with sorafenib from May 2015 to September 2018 were included. Median age was 69 years (range 28-88 years). 120 patients had Child-Pugh A and 21 had Child-Pugh B7. 43 had BCLC-B and 98 patients had BCLC-C. Atunivariate analysis, we confirmed that eNOS-786 TT genotype were significantly associated with a lower median OS than the other genotypes (8.8 vs 15.7 months, HR 1.69, 95% CI 1.02-2.83 p=0.0424). Following adjustment for clinical covariates (age, gender, etiology, BCLC stage, serum α-FP level, MELD score), multivariate analysis confirmed eNOS- 786 and BCLC stage as the independentsprognostic factors predicting OS (TTvsTC+CC; HR: 2.39, 95% CI 1.14-5.03 p=0.0211; C vs B;2.23, 95% CI 1.44-4.77 p=0.039). Conclusions: Our prospective study confirms the prognostic role of eNOS-786 in advanced HCC patients treated with sorafenib. Clinical trial information: NCT02786342.
IGF-Child-Pugh score as a predictor of treatment outcome in advanced hepatocellular carcinoma patients treated with sorafenib.
Authors: Abugabal Yehia I. , Hassan Manal , Pestana Roberto , Xiao Lianchun , Girard Lauren , Raghav Kanwal Pratap Singh , Morris Jeffrey , Abdel-Wahab Reham , Wolff Robert A. , Yao James C. , Amin Hesham M. , Kaseb Ahmed Omar
Published: May 2019

4076

Background: Our recent published studies concluded that Lower levels of Insulin like growth factors-I (IGF-I) is correlated with shorter overall survival (OS) in HCC, and IGF-CP scores assigned based on serum bilirubin, serum albumin level, prothrombin time, and plasma IGF-1 provides better prognostic stratification. Sorafenib is the first frontline drug approved for the treatment of CP class A patients with advanced HCC. CP class A is the standard criterion for active therapy and trials entry in HCC. In this study we aimed at evaluating the predictive ability of IGF-CP to sub-stratify old CP classes and better predict sorafenib outcomes. Methods: Total of101 patients were prospectively enrolled from MD Anderson Cancer Center (MDACC). Blood sample were collected and tested for IGF-I and IGF-CP was calculated into class A, B and C. Median OS and progression free survival (PFS) were analyzed, and log rank test was used to compare PFS and OS between subgroups of IGF-CTP score of patients. Results: Among CP class, patients who were reclassified as IGF-CP (B) (Old A/new B) had significantly shorter OS in months (m) was 7.6m (95% CI= 5.23-26.51m ) and PFS of 2.99m (95% CI=2.53-5.26m) with (P<0.001) in both, as compared to patients’ who classified as class A by both scoring systems (AA), who had OS of 15.43m (95% CI=12.3-31.18m) and PFS of 4.97m (95% CI=3.26-7.2m), (P<0.001) in both. Conclusions: IGF-CTP score sub-stratified CP A class, and provided better prognostic stratification and accuracy than CP score in predicting sorafenib survival outcomes in HCC. This approach may lead to a paradigm shift in predicting efficacy and toxicity of systemic HCC therapies and in stratifying patients for active therapy and selection in HCC clinical trials.
Randomized clinical trial of transcatheter arterial chemoembolization plus radiofrequency ablation versus transcatheter arterial chemoembolization for hepatocellular carcinoma with intermediate stage (BCLC stage B) hepatocellular carcinoma beyond Milan criteria.
Authors: Yin Xin , Tang Bei , Gan Yu-Hong , Wang Yan-hong , Chen Yi , Ge Ning-lin , Chen Rongxin , Zhang Lan , Zhang Boheng , Ren Zhenggang
Published: May 2019

4077

Background: To determine treatment efficacy and safety of transarterial chemoembolization (TACE) combined with radiofrequency ablation (RFA) (hereafter, TACE+RFA) in patients with intermediate stage (BCLC stage B) hepatocellular carcinoma (HCC) beyond Milan criteria. Methods: In this randomized clinical trial, 110 patients with intermediate stage HCC beyond Milan criteria (single tumor with diameter 5-7cm, median; 3-5 multiple nodules with diameter less than 5cm) were included and randomly assigned to TACE+RFA group (n=55) and TACE group (n=55) at liver cancer institute, Zhongshan hospital. The primary endpoint was overall survival (OS). The secondary end point was progression-free survival (PFS) , time to progress (TTP) and best objective response (BOR). Results: The median OS in TACE+RFA and TACE group were 29 and 18 months, respectively. The median TTP and BOR were 15.7 months and 69.1 % in TACE+RFA group and 12.4 months and 40.0 % in TACE group (P=0.004). The 1-, 3-, and 4-year overall survivals for TACE+RFA group and TACE group were 97.2%, 67.9% and 59.4% versus 84.0%, 46.7% and 37.3% , respectively (P = 0.008). The corresponding PFS were 47.3%, 27.2% and 21.7% versus 35.6%,15.3% and 11.4% , respectively (P = 0.04).The incidences of major complications in TACE+RFA group were comparable to those in TACE group (P=0.14). Conclusions: TACE+RFA was superior to TACE in improving tumor response and overall survival for patients with intermediate stage (BCLC stage B) hepatocellular carcinoma beyond Milan criteria. Clinical trial information: NCT03636620.
Final analysis of phase II trial of regorafenib (REG) in refractory advanced biliary cancers (BC).
Authors: Kim Dae Won , Sanoff Hanna Kelly , Poklepovic Andrew Stewart , Tariq Fatima , Nixon Andrew B. , Liu Yingmiao , Kim Richard D.
Published: May 2019

4083

Background: While gemcitabine plus cisplatin has demonstrated significant antitumor activity as 1st line therapy of BC, there is no effective treatment after failure of gemcitabine-based therapy. REG is an oral multi-kinase inhibitor that targets angiogenesis, oncogenesis and cancer proliferation/metastasis. We evaluated the efficacy of REG in BC. Methods: Patients (pts) with histologically proven BC who progressed on at least one line of systemic therapy received REG 160 mg daily 21 days on 7 days off, in 28 day cycles. The primary endpoint was 6-month (mo) overall survival (OS) and the secondary endpoints were median OS, progression free survival (PFS) and response rates (RR). Pre and post-treatment plasma were collected for cytokine evaluation. Results: A total of 39 pts received at least 1 dose of REG; 32 pts were evaluable for efficacy. Median age was 62 (range: 27-88) years and the primary sites of tumor were intrahepatic cholangiocarcinoma (68.8%), extrahepatic (18.8%), and gallbladder (12.5%). Pts were considered evaluable for efficacy if patients received more than 1 cycle of REG. For 32 evaluable pts, 6 mo OS was 52% with median PFS of 2.8 mo (95% CI: 1.1-4.5) and median OS of 7.9 mo (95% CI: 0-18.7). Median PFS and OS of the pts (n=20) failed 1 line of therapy were 3.7 mo (95% CI: 3.2-4.1) and 13.8 mo (95% CI: 1.8-25.8), respectively. Median PFS and OS of the pts (n=12) failed 2 lines were 1.8 mo (95% CI: 1.63-1.97) and 4.5 mo (95% CI: 2.6-6.3), respectively. RR was 9.4% (2 PR and 1 unconfirmed PR) and DCR was 62.5%. Total 71.8% of grade 3/4 adverse events (AE) were observed, and the most common AE were fatigue (56.4%) and hypertension (53.8%). Dose modification was required in 49% of the pts. Among the 23 cytokines analyzed, elevated baseline VEGF-A was associated with good prognosis (HR 0.62, p=0.01). Elevated baseline TIMP-1 (HR 1.79, p=0.04) and IL-6 (HR 1.33, p=0.05) were associated with poor prognosis. REG treatment decreased BMP-9, GP130, VEGF-R2 and VEGF-R3 and increased IL-6, PIGF, TIMP-1, VCAM-1 and VEGF-A significantly. Conclusions: The primary endpoint was met in this study. VEGF-A may be further evaluated as a predictive biomarker for REG in BC. Further randomized trials are warranted to confirm the efficacy and the correlative data. Clinical trial information: NCT02115542.
Clinical and molecular features of patients with cholangiocarcinoma harboring FGFR genetic alterations.
Authors: Boileve Alice , Baiev Islam , Dinicola Caroline , Horick Nora K , Tazdait Melodie , Zhu Andrew X. , Hollebecque Antoine , Goyal Lipika
Published: May 2019

4084

Background: Genetic alterations (GAs) in the fibroblast growth factor receptor (FGFR) pathway are emerging as promising therapeutic targets in CCA. The clinical and molecular features of patients (pts) with CCA harboring FGFR GAs are reported here. Methods: A retrospective chart review was performed in pts with CCA who were found to have an FGFR GA on tumor molecular profiling as part of routine care. Data on demographics, risk factors, pathology, systemic therapy, radiographical response, progression free survival (PFS), and overall survival (OS) were collected. Results: Among 65 pts, the median age at diagnosis was 55 years old (range = 27-92), and 38 (58%) pts were female, 63 (97%) had intrahepatic CCA, and 5 (11%) had chronic HBV. At presentation, 37% of pts had resectable disease. Of 47 pts with a known CA 19-9 at the time of initial diagnosis, 21 (45%) had a value < 35U/mL. FGFR2 fusions were the most common FGFR GA (78%), followed by FGFR2 mutations (14%), FGFR3 mutations (4%), FGFR3 fusion (2%) and FGFR1 amplification (2%). The most common fusion partners were BICC1 (20%), POC1B (6%), SORBS1 (6%), DBP (4%), and TACC2 (4%). The most common co-alterations were in ARID1A, CDKN2A/B, TP53, BAP1, IDH1, HER2, BRCA2, and PTEN. The median lines of palliative systemic therapies received was 3 (range = 0-8), and 9/65 (14%) pts had > 1 FGFR inhibitor (FGFRi). For the 30 (46%) pts with FGFR2 fusions who received gemcitabine/platinum as first line palliative systemic therapy, the median PFS was 4.7 months (95% CI: 2.1-6.0). In the overall population, the median OS from time of initial diagnosis was 35.8 months (95% CI:29.7-52.7). Among 46 pts who received an FGFRi on a clinical trial and had ≥ 1 follow-up scan, the overall response rate (ORR) by RECIST v1.1 in pts with FGFR2 fusions, was 35.8% (14/39) on their first FGFRi; ORR was 16.7% (1/6) for pts with FGFR2 mutations. Conclusions: Pts with CCA harboring FGFR GAs were found to have a high rate of normal CA 19-9 and short median PFS on first line gemcitabine/platinum compared to historical controls but additional comparative studies are necessary to evaluate these findings.
Nab-paclitaxel plus S-1 as first line treatment for advanced or metastatic biliary tract adenocarcinoma: A phase 2 study.
Authors: Sun Yongkun , Zhou Ai-Ping , Zhang Wen , Yang Lin , Cui Chengxu , Jiang Zhichao
Published: May 2019

4089

Background: Gemcitabine plus cisplatin or S-1 can be used as first-line treatment for advanced or metastatic biliary tract adenocarcinoma. Multiple phase 2 studies found that gemcitabine, oxaliplatin, capecitabine, S-1 were not superior to gemcitabine plus cisplatin. Nab-paclitaxel plus S-1 was effective and well-tolerated in pancreatic cancer. Methods: Patients with pathological confirmed advanced or metastatic biliary tract adenocarcinoma (gallbladder carcinoma, intrahepatic cholangiocarcinoma ICC, extrahepatic cholangiocarcinoma ECC) were treated with Nab-paclitaxel plus S-1(Nab-paclitaxel 120mg/m2, d1 and d8; S-1 80-120mg/d, d1-14; q21d). Patients that received PR or SD (RECIST1.1)after 6 cycles were given S-1 maintenance treatment. The primary endpoint was ORR. The study used Simon’s Two Stage design. Results: From March 2016 to September 2018, we recruited 54 patients, with 27 males (50%). The median age was 58(34-73yrs). As of Dec 31 2018, the median treatment cycle was 4(1-6 cycles). 51 patients were evaluable for efficacy: PR 14(27.5%), SD 22 (DCR=PR+SD: 70.6%), PD 15 (29.4%). The median PFS was 6 months, and the median OS was 13.2 months. The response rate varied in different tumor location: gallbladder carcinoma 53.8% (7/13), ICC 18.2% (6/33), ECC 20% (1/5).Common grade 3/4 AEs were: leucopenia 17 (31.5%), hyperbilirubinemia 5(9.3%), Mucositis 4 (7.4%), neurotoxicity 2 (3.7%), diarrhea 2 (3.7%), omit 1(1.9%), fatigue 1 (1.9%), thrombocytopenia 1 (1.9%), ALT increase 1 (1.9%). Conclusions: Nab-paclitaxel plus S-1 as first line treatment for advanced or metastatic biliary tract adenocarcinoma was effective and well-tolerated, especially for gallbladder carcinoma (ORR 53.8%). This regimen need further exploration. Clinical trial information: NCT03830606.
A phase I study of H3B-6527 in hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC) patients (pts).
Authors: Mercade Teresa Macarulla , Moreno Victor , John Binu , Morris John Charles , Sawyer Michael B. , Yong Wei Peng , Gutierrez Martin , Karasic Thomas Benjamin , Sangro Bruno , Sheng-Shun Yang , Gentry Carleen , Kim Amy , Kumar Pavan , MacKenzie Crystal , Rioux Nathalie , Schindler Joanne , Selvaraj Anand , Finn Richard S.
Published: May 2019

4095

Background: FGF19 overexpression is hypothesized to hyperactivate FGFR4 and its downstream signaling pathway leading to enhanced tumor growth in HCC/ICC. Targeting FGFR4 may have therapeutic benefit in HCC/ICC with altered FGF19 signaling. A phase 1 study (NCT02834780) was initiated to assess H3B-6527, an investigational highly selective covalent FGFR4 inhibitor. Methods: Adult pts with advanced HCC or ICC, ECOG PS 0-1, well compensated liver function, and who progressed after at least one prior therapy, were administered H3B-6527 orally QD (once daily) on a 21-day cycle following a 3+3 design. Patients in the dose escalation phase were treated regardless of FGF19 status. Adverse events (AEs), pharmacokinetics (PK), and pharmacodynamics (PD) were assessed. Response was determined by RECIST 1.1 or modified RECIST every 6 weeks. Results: As of 06-Jan-2019, 37 pts have been treated with H3B-6527 at doses of 300 to 1400 mg QD (23 pts in escalation; 14 in expansion). In dose escalation, a total of 17 patients with HCC, Child-Pugh A received prior systemic therapy including 100% with prior TKI and 35% with prior IO. 12% had hepatitis B virus and 47% had hepatitis C virus. H3B-6527 plasma levels increased with dose from 300 to 1000 mg QD and plateaued. H3B-6527 was rapidly absorbed with a tmax of ~2-3 h and showed a terminal half-life of ~4-5 h, following administration of 1000 mg (fasted). No dose-limiting toxicities or ≥ Grade 3 treatment-related AEs (TRAE) have been observed in escalation. Most common TRAEs (≥ 10%) were diarrhea, nausea, and vomiting. Based on safety, PK, and PD, 1000 mg QD was the recommended phase 2 dose. Durable stable disease and partial responses (PR) have been observed on the once daily fasted schedule; 2 of 17 pts with HCC achieved PRs and an additional 7 with stable disease were on treatment for ≥ 5 months. Conclusions: H3B-6527 is well tolerated and demonstrates early signs of clinical activity. Dose expansion on QD schedule and exploration of BID (twice daily) schedule is ongoing. Clinical trial information: NCT02834780.
A phase II, open label, multicenter trial of avelumab in patients with advanced, metastatic high-grade neuroendocrine carcinomas NEC G3 (WHO 2010) progressive after first-line chemotherapy (AVENEC).
Authors: Fottner Christian , Apostolidis Leonidas , Ferrata Martina , Krug Sebastian , Michl Patrick , Schad Arno , Roth Wilfried , Jaeger Dirk , Galle Peter R. , Weber Matthias M.
Published: May 2019

4103

Background: High grade Neuroendocrine Neoplasias (NEN) are rare tumors with a poor prognosis and no established second line therapy when progressive after first line platinum-based chemotherapy resulting in a median overall survival (OS) of 5 months. This study aims to evaluate the efficacy and safety of the anti-programmed death ligand-1 (PD-L1) antibody Avelumab in patients (pts) with NEN G3 progressing after first-line chemotherapy. Methods: In a multicenter, national, single-arm, open-label, phase II trial the efficacy and safety of Avelumab was evaluated in patients with metastatic progressive Neuroendocrine Carcinomas (NEC G3) according to WHO 2010, excluding Merkel cell carcinoma and small cell lung cancer. Results: From 12/2017-11/2018 a total of 29 pts (20 male, 69%), were enrolled (16 NEC G3 and 11 moderately differentiated NETG3). Mean age was 59.2±10.2 ys (range 33-75), median follow up 16.5 weeks (3-48). Median Ki67 was 60% (range 20-95%). Site of origin included pancreas (12), genito-urinary tract (4), stomach-esophagus (3), colo-rectum (3), lung (2), ear-nose-throat (2), papilla of Vater (1). In an interim analysis the DCR (stable disease or partial remission according to irRECIST) after 8 weeks was 32% (4 SD, 2 PR). In responders, mean duration of disease control was 20 (±13.8) weeks, with 4 pts. showing stable disease or partial remission ≥6 months. Median OS was 4.2 months (range 1- >12). Treatment-related adverse events occurred in 11 of 29 pts (38%) and were mainly mild to moderate (CTCAE-grade 1 [52%], 2 [44%] and 3 [4%]) and included fatigue (n=6; 20.6%), diarrhea (n=4; 13.7%), fever/chills after infusion (n=4; 13.7%), loss of appetite and nausea (n=4; 13.7%), skin rash (n=1; 3%), deterioration of preexisting psoriasis (n=1; 3%) and abdominal pain (n=1; 3%). Conclusions: Immune checkpoint blockade with avelumab in pretreated high grade NEN shows relevant activity in a subset of patients with excellent tolerability. Clinical trial information: NCT03352934.
Oxaliplatin and 5-fluorouracil (FOLFOX) in advanced well-differentiated digestive neuroendocrine tumors: A multicenter national retrospective study from the French Group of Endocrine Tumors (GTE).
Authors: Girot Paul , Baudin Eric , Senellart Helene , Bouarioua Nadia , Hentic Olivia , Guimbaud Rosine , Walter Thomas , Ferru Aurelie , Roquin Guillaume , Cadiot Guillaume , Pracht Marc , Girot Jean-Baptiste , Malka David , Ducreux Michel , Hadoux Julien , Matysiak-Budnik Tamara , Touchefeu Yann ,   French Group of Endocrine Tumors (GTE)
Published: May 2019

4104

Background: Oxaliplatin-based regimens have shown promising antitumor activity in digestive neuroendocrine tumors (NETs), however the available data are limited. Our aim was to assess the tumor response and survival in a large series of patients treated with oxaliplatin and 5-fluorouracil (FOLFOX) for advanced digestive NETs.Oxaliplatin-based regimens have shown promising antitumor activity in digestive neuroendocrine tumors (NETs), however the available data are limited. Our aim was to assess the tumor response and survival in a large series of patients treated with oxaliplatin and 5-fluorouracil (FOLFOX) for advanced digestive NETs. Methods: All patients with advanced well-differentiated digestive NETs treated with at least 3 cycles of FOLFOX between 2004 and 2018 in 12 centers of the French GTE, were retrospectively included. Best response according to the RECIST 1.1 criteria, progression-free survival (PFS) and overall survival (OS) were evaluated. The prognostic factors for PFS were investigated by multivariate analysis using a Cox proportional hazard model including variables with a p value ⩽ 0.20 in univariate analysis. Results: One hundred and forty-nine patients were included. Primary tumor location was pancreas (n = 88), small intestine (n = 37), stomach (n = 7), rectum (n = 4) and unknown without lung tumor at CT scan (n = 13). Partial response rate was of 31% for pancreatic NETs, 13% for small intestine NETs, 14% for gastric NETs, 25% for rectal NETs and 38% for unknown primary NETs. Median PFS were, respectively, 9, 9, 14, 4 and 6 months, and median OS were 30, 28, 31, 25 and 15 months. Significant poor prognostic factors for PFS after FOLFOX in digestive NETs were: progressive disease (HR = 2.5, p = 0.018), hepatic involvement > 50% (HR = 1.8, p = 0.009), prior targeted therapy (HR = 1.5, p = 0.048) and rectal primary tumor (HR = 4.2, p = 0.01). Among pancreatic NETs, the 9 insulinomas had a 22 months PFS versus 9 months for the others (p = 0.025), and serum glucose normalization was obtained in 8 out of 9 cases. Conclusions: FOLFOX has a promising clinical activity for gastroenteropancreatic NETs, especially in insulinomas.
Impact of gender on multikinase inhibitors (MKIs) toxicity in patients (pts) with advanced pancreatic and gastrointestinal neuroendocrine tumors (NETs): A pooled analysis of two phase II trials with pazopanib and lenvatinib.
Authors: Hernando-Cubero Jorge , Grande Enrique , Castellano Daniel E. , Ibrahim Toni , Fazio Nicola , Lopez Carlos , Teule Alex , Valle Juan W. , Garcia-Carbonero Rocio , Diez Marc , Acosta Daniel , Roca Maria , Capdevila Jaume
Published: May 2019

4109

Background: Retrospective data in some cancer types suggested a possible different toxicity profile with chemotherapy and targeted therapies according to gender. However, data from prospective studies are still very limited, especially in infrequent tumors such as NETs. Methods: Pts with advanced pancreatic and gastrointestinal NETs treated with pazopanib or lenvatinib in the multicenter open-label phase II studies PAZONET and TALENT respectively, were included in the analysis. Both studies were performed by Spanish Task Force Group for Neuroendocrine Tumors (GETNE). All toxicity grades with an incidence higher than 5% were considered for univariate review. Additionally, all grade 3-4 toxicities were analyzed separately. Results: 155 pts (47.7% female) with 1213 adverse events (AEs) (20% G3-4) divided in 121 categories were included. In female patients, liver toxicity, headache, pyrexia, nausea/vomiting, hair/skin disorders and dizziness were significantly more common (table). The only toxicity with higher incidence in men was dysphonia (OR 0.42, 95% CI 0.2-0.9, p 0.02). There were no gender differences in grade 3-4 toxicities. Conclusions: We observed significant differences in toxicity AEs by gender in two prospective phase II studies with MKIs in NETs patients. Potential different approach to manage toxicity may be adopted based on gender. [Table: see text]
Blood-based next-generation sequencing analysis of neuroendocrine tumors.
Authors: Shaib Walid Labib , Roberts Ali , Zakka Katerina Mary , Akce Mehmet , Wu Christina , Alese Olatunji B. , El-Rayes Bassel F. , Kasi Pashtoon Murtaza , Starr Jason Scott
Published: May 2019

4110

Background: Neuroendocrine tumors (NET) comprise around 2% of all malignant tumors of the gastrointestinal system. The genomic landscape of NET has not been well studied. The aim of this study was to confirm the feasibility of next generation sequencing (NGS) using ctDNA in NET and characterize common alterations in the genomic profile. Methods: Molecular alterations in 114 plasma samples from 114 patients with NET using clinical-grade NGS of ctDNA (Guardant360Ò) across multiple institutions were evaluated. The test detects single nucleotide variants in 54-73 genes, copy number amplifications, fusions, and indels in selected genes. Results: A total of 114 NET patients were evaluated, of which 64 (56.1%) were female. Mean age was 59.7 years with a range between 23-89 years. ctDNA NGS testing was performed on 114 plasma samples; 1 patient had testing performed twice. Genomic alterations were defined in 94 (n = 94/114, 82.5%) samples with a total of 289 alterations identified after excluding variants of uncertain significance (VUSs) and synonymous mutations. Alterations were identified in at least one sample from 83 patients; TP53 associated genes were most commonly altered (n = 83/289, 28.7%), followed by KRAS (n = 22, 7.6%), PI3CA (n = 15, 5.2%), CCNE1 (n = 15, 5.2%), BRAF (n = 13, 4.5%), MYC (n = 12, 4.1%), ERBB2 (n = 11, 3.8%), APC (n = 10, 3.5%), EGFR (n = 10, 3.5%), MET (n = 10, 3.5%), PTEN (n = 9, 3.1%), RB1 (n = 9, 3.1%), CDK6 (n = 7, 2.4%), AR (n = 5, 1.7%), ARID1A (n = 5, 1.7%), FGFR1 (n = 5, 1.7%), and PDGFRA (n = 5, 1.7%). Other genomic alterations of low frequency, but clinical relevance included: CDK4 (n = 4, 1.3%), NF1 (n = 4, 1.3%), RAF1 (n = 4, 1.3%), GNAS (n = 3, 1.0%), KIT (n = 3, 1.3%), BRCA2 (n = 2, 0.7%), CCND2 (n = 2, 0.7%), CTNNB1 (n = 2, 0.7%), JAK2 (n = 2, 0.7%), NRAS (n = 2, 0.7%), SMAD4 (n = 2, 0.7%), and TERT (n = 2, 0.7%). Alterations in AKT1, ALK, ATM, BRCA1, CCND1, CDKN2A, FGFR2, MTOR, RHOA, SMO and STK11 were all reported once (n = 1, 0.3%). Conclusions: Evaluation of ctDNA is feasible among individuals with NET. Liquid biopsies are not invasive and can provide personalized options for targeted therapies in NET patients.
Clinical efficacy and toxicity data on phase I study of fosbretabulin in combination with everolimus in neuroendocrine tumors.
Authors: Chauhan Aman , Arnold Susanne M. , Wu Jianrong , Nair Rashmi T , Slone Stacey A. , Dressler Emily Van Meter , Flynn Heather , Adams Val R. , Weiss Heidi , Evers Mark , Anthony Lowell Brian
Published: May 2019

4114

Background: Fosbretabulin, a synthetic, water-soluble, phosphorylated prodrug of the natural product combretastatin A4 (CA4P), initially isolated from the bark of the South African bush willow, Combretum caffrum, is the lead compound in a class of agents termed vascular disrupting agents (VDAs). Everolimus, an mTOR inhibitor, is FDA approved for the management of well-differentiated NETs. A Phase I trial combining fosbretabulin and everolimus to determine the recommended Phase II trial dose (RP2D), safety data and early clinical efficacy in metastatic GEPNET patients was conducted. Methods: An investigator-initiated, single center, open-label, phase I study involving GEPNETs incorporated partial order continual reassessment method (PO-CRM) to define the dose escalation. The primary objective was to establish the maximum tolerated dose (MTD) of the combination of everolimus and fosbretabulin in NETs that have progressed after at least one prior regimen for metastatic disease. Secondary objective included identifying the safety profile of the combination using NCI CTCAE4 reporting criteria. Patients received daily oral everolimus (2.5 mg, 5 mg, 7.5 mg, and 10 mg). Fosbretabulin was administered IV 60 mg/m2 either q3 weekly or q weekly based on PO-CRM. Patients were treated for 12 weeks with all combinations. RECIST 1.1 was used to evaluate radiological responses at 3 month. Results: Of the 17 patients enrolled, 16 completed the 12-week trial. One patient was not evaluable due to noncompliance. No DLTs were observed at day 21. The highest dose of 10 mg daily oral everolimus in combination with weekly 60mg/m2 IV fosbretabulin is the RP2D. No grade 4 or 5 toxicities were noted. Grade 3 toxicities were seen in 5 patients; abdominal pain and hyperglycemia (not related to study drug), fatigue (possibly related), decreased lymphocyte count and anemia (related). Several patients had delay in treatment due to grade 2 AE’s (GI symptoms, rash, thrombocytopenia) and one patient was unable to complete treatment due to pneumonitis. All evaluable patients except one had stable disease at 3 months. One patient showed SD but non target lesion demonstrated PD. One patient had > 30% decrease in tumor size but overall sum of lesions showed SD. A detailed table with all grade toxicities and waterfall plot of RR will be presented at the meeting. Conclusions: Ten mg PO daily everolimus plus 60 mg/m2 fosbretabulin IV weekly is the RP2D. Early clinical data suggests clinical activity and stable disease in all but one patient at 3 months. Clinical trial information: NCT0301429.