bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I study of the gamma-secretase inhibitor RO4929097 and capecitabine in refractory solid tumors.
Authors: LoConte Noelle K. , Tevaarwerk Amye , Kolesar Jill , Holen Kyle D. , Lubner Sam Joseph , Mulkerin Daniel , Schelman William R. , Razak Albiruni R.A. , Siu Lillian L. , Eickhoff Jens C. , Carmichael Lakeesha , Wilding George , Ivy S. Percy , Liu Glenn 
Published: March 2020

3101 Background: RO4929097 is a oral inhibitor of gamma-secretase, which results in Notch signaling inhibition. Prior work has demonstrated that Notch-signaling inhibition enhances chemosensitivity of colon cancer cells. This study sought to combine RO4929097 with capecitabine (cape) and determine maximum tolerated dose (MTD), toxicities and efficacy. Preclinical and prior phase I work demonstrated possible autoinduction of RO4929097, so pharmacokinetic (PK) evaluation of RO4929097 and cape was planned. Methods: Adult patients with refractory solid tumors were eligible and received RO4929097 and cape at a fixed dose of 1000 mg/m2 BID with escalating doses of RO4929097 on a 21-day cycle according to a 3+3 design. Cape was administered for 14 days and the RO49029097 once daily, 3 days per week. RO4929097 plasma concentrations were evaluated by LC/MS/MS on days 3 and 10 of cycle 1, and PK parameters analyzed with WinNonLin version 5.2. Results: 4 dose levels have been completed (20, 30, 45 and 68 mg); 18 of 19 patients are evaluable for toxicity and PK data is available for 11 patients. One DLT has been observed (intolerable grade 2 fatigue) at 68 mg. There have been 2 confirmed partial responses: fluoropyrimide-refractory colon cancer (for 12 cycles) and cervical cancer (for 6 cycles). The half-life, Cmax and AUC of RO4929097 all significantly decreased on day 10 compared to day 3, with an increase in clearance for all doses. The half-life was significantly shorter in dose level 3 (p=0.0012) and dose level 4 (p=0.0126) compared to dose level 1. Conclusions: RO4929097 plus cape was well tolerated. Activity was seen in cervical and colon cancer. Autoinduction of RO4929097 was seen both with increasing cycle number and increasing dose. However, all plasma concentrations of RO4929097 were above those needed for Notch inhibition (1.9 ng/mL based on prior studies). Dose level 1 (cape 1000 mg/m2 BID and RO4929097 20 mg daily) is the recommended phase II dose. [Table: see text]
Phase I trial to assess the safety and pharmacokinetics of afatinib and weekly vinorelbine in patients with advanced solid tumors.
Authors: Hollebecque Antoine , Bahleda Rastislav , Berge Yann , Massard Christophe , Uttenreuther-Fischer Martina Maria , De-Montserrat Helene , Tschoepe Inga , Soria Jean-Charles , Delord Jean-Pierre 
Published: March 2020

3104 Background: Afatinib (A) is an oral, irreversible ErbB Family Blocker with activity in a wide range of tumor cell lines dependent on ErbB signaling. Vinorelbine (VNR) interferes with tubulin polymerization and spindle formation during metaphase. Additive or supra-additive activity of A or EGFR TKI with VNR has been demonstrated in preclinical models. Methods: This dose-escalation Phase I study established the safety profile, MTD and PK of A with i.v. and p.o. VNR using a modified 3+3 design. Eligible patients (pts) were ≥18 years with refractory advanced or metastatic tumors, an ECOG PS 0–1, and adequate organ and bone marrow function. VNR i.v. (25 mg/m2)/oral (60 mg/m2 with escalation to 80 mg/m2 after 3 weeks) was administered weekly on Days 1, 8, 15 and 22 with escalating oral daily doses of A 20 mg, 40 mg and 50 mg in 28-day treatment courses. Results: The study treated 55 pts: 30 pts for MTD determination and 25 pts in the PK expansion cohort (24 M/31 F), median age 54 years (range 34–72). 28/27 pts were included in the VNR i.v./p.o. cohorts, respectively. Patients had NSCLC, breast, pancreatic (n=13/5/3), head and neck, stomach or colorectal cancer (n=2 each group); 28 pts had other cancers. At 20 mg A, no DLTs occurred in the VNR i.v./p.o. cohorts; whereas, at 50 mg A, 4/6 pts and 3/5 pts experienced DLTs. At 40 mg A and VNR i.v./p.o., 1/6 pts included for MTD determination experienced DLT, as did 7/13 pts and 2/12 pts in the VNR i.v./p.o. PK expansion cohorts, respectively. Main DLTs were diarrhea and febrile neutropenia. Median treatment duration (snapshot date 9 Dec 2011) across all dose groups was 80 days (range 10–687), with 98 and 58 days in the MTD cohorts of VNR i.v./p.o., respectively. Related AEs observed in most patients were diarrhea, asthenia, nausea, vomiting, neutropenia, decreased appetite, mucositis and rash. Five pts had a PR, confirmed in 2 pts. Preliminary PK analyses suggest no drug–drug interaction between A and i.v. VNR. Conclusions: Afatinib in combination with weekly i.v./p.o. VNR is tolerated, with manageable, reversible, target-related side effects and promising signs of clinical activity in heavily pretreated patients. The MTD for A for both combinations is 40 mg daily.
Final analysis of the phase III randomized trial of cetuximab (CET) plus either brivanib alaninate (BRIV) or placebo in patients (pts) with chemotherapy refractory, K-RAS wild-type (WT), metastatic colorectal carcinoma (mCRC): The NCIC Clinical Trials Group and AGITG CO.20 trial.
Authors: Siu Lillian L. , Shapiro Jeremy David , Jonker Derek J. , Karapetis Christos Stelios , Zalcberg John Raymond , Simes John , Couture Felix , Moore Malcolm J. , Price Timothy Jay , Siddiqui Jehan , Nott Louise M. , Charpentier Danielle , Liauw Winston S. , Sawyer Michael B. , Jefford Michael , Magoski Nadine M , Haydon Andrew Mark , Walters Ian B. , Tu Dongsheng , O'Callaghan Christopher J. 
Published: March 2020

3504 Background: The anti-EGFR monoclonal antibody CET has improved survival in pts with chemotherapy refractory, K-RAS WT mCRC. BRIV is a potent inhibitor of multiple receptor tyrosine kinases including both VEGFR and FGFR. The combination of CET and BRIV targets tumor growth and angiogenesis and demonstrated encouraging activity in an early phase clinical trial. Methods: Pts with mCRC previously treated with combination chemotherapy were randomized 1:1 to receive CET 400 mg/m2 IV loading dose followed by weekly maintenance of 250 mg/m2 plus either BRIV 800 mg PO daily (Arm A) or placebo (Arm B). Pts may have had 1 prior anti-VEGF, but no prior anti-EGFR therapy. Primary endpoint was overall survival (OS). Results: From 02/2008 to 02/2011, 750 pts were randomized (376 in Arm A and 374 in Arm B). Demographics: median age=64 (range 27-88); male=64%; ECOG 0:1:2 (%)=32:58:10; >3 prior chemotherapy regimens=92%; prior anti-VEGF therapy=41%; K-RAS WT=97%. Primary analysis was conducted per protocol after 536 deaths were observed, with median OS of 8.8 months in Arm A and 8.1 months in Arm B, hazard ratio (HR)=0.88; 95% CI=0.74 to 1.03; p=0.12. Median progression-free survival (PFS) was 5.0 months in Arm A and 3.4 months in Arm B, HR=0.72; 95% CI=0.62 to 0.84; p<0.0001. Incidence of any ≥grade 3 adverse event (AE) was 78% in Arm A and 53% in Arm B. Time to deterioration of physical function was shorter and global quality of life scores were lower in Arm A vs Arm B. Planned subgroup analyses revealed no statistically difference in treatment effects on OS based on pre-specified factors of age, gender, ECOG and race. Likewise, no difference was detected based on exploratory subgroup analyses of LDH and prior anti-VEGF therapy. Conclusions: Despite positive effects on PFS, the combination of CET+BRIV did not significantly improve OS in pts with chemotherapy refractory, K-RAS WT mCRC. Final updated results based on 20-25% additional events for a total of nearly 700 deaths, as well as further exploratory subgroup analyses, will be presented.
EORTC liver metastases intergroup randomized phase III study 40983: Long-term survival results.
Authors: Nordlinger Bernard , Sorbye Halfdan , Glimelius Bengt , Poston Graeme John , Schlag Peter M. , Rougier Philippe , Bechstein Wolf , Primrose John Neil , Walpole Euan Thomas , Mauer Murielle E. , Gruenberger Thomas ,   For the EORTC GI Group, CR UK, ALMCAO, AGITG, Nordic Group, and FFCD.
Published: March 2020

3508 Background: This study evaluates the benefit of combining peri-operative chemotherapy and surgery for patients with liver only metastases from colorectal cancer (LM) deemed resectable on pre-operative imaging. The PFS results, the primary endpoint, were reported (ASCO 2007). We now report on the secondary endpoint overall survival (OS) results, after a median follow-up of 8.5 years. Methods: Between September 2000 and July 2004, 364 patients (pts) with up to 4 LM were randomized between peri-operative FOLFOX4 (oxaliplatin 85mg/m² and LV5FU2), 6 cycles before and 6 cycles after surgery, (CT arm), and surgery alone (S arm). OS was compared between arms using a 2-sided non-stratified log-rank test at the 0.05 level of significance (intent-to-treat analysis). Results: 182 pts were randomized in each arm (CT arm and S arm) of which 171 were eligible (CT and S) and 152 underwent resection (CT and S). In the CT arm, 171 received preop CT and 115 received postop CT. At a median follow-up of 8.5 years, 221 deaths were reported (61 % of all randomized pts). Causes of death in CT arm were cancer relapse (85 pts), complication of surgery (2 pts), other causes (16 pts) and unknown cause (4 pts), and in S arm, cancer relapse (99 pts), complication of surgery (2 pts), other causes (11 pts) and unknown cause (2 pts). Observed median OS was higher in CT arm: 61 months (CT) vs. 54 months (S) in all randomized pts and 64 months (CT) vs. 55 months (S) in eligible pts. The 5 year OS rate was 51.2% (CT) vs. 47.8% (S) (all randomized) and 52.4% (CT) vs. 48.3% (S) (eligible pts). There was no significant difference in OS between arms (HR=0.88, 95% CI 0.68-1.14, p=0.34) (all randomized). After progression, second line treatment with chemotherapy was given in 59 % (CT) and 77% (S) of the pts with cancer progression and repeat surgery in 46% (CT) and 40% (S), respectively. Conclusions: Peri-operative chemotherapy with FOLFOX4 improves PFS but does not significantly improve OS over surgery alone. A potential benefit may have been diluted by second treatment lines and by more deaths unrelated to cancer in the CT arm.
Prognostic impact of BRAF and KRAS mutations and their relationship to DNA mismatch repair (MMR) status in 2,686 stage III colon cancer patients (pts) treated in a phase III study of adjuvant FOLFOX with or without cetuximab: NCCTG N0147.
Authors: Sinicrope Frank A. , Mahoney Michelle R. , Smyrk Thomas C. , Thibodeau Stephen N. , Goldberg Richard M. , Nelson Garth D. , Sargent Daniel J. , Alberts Steven R. ,   North Central Cancer Treatment Group
Published: March 2020

3514 Background: Activating mutations in the BRAF oncogene (mutBRAF) are associated with deficient MMR (dMMR) in sporadic colon cancers and are mutually exclusive with KRAS mutations (mutKRAS). We evaluated BRAF and KRAS in relation to MMR and disease-free survival (DFS) in stage III pts treated with adjuvant FOLFOX +/-cetuximab; study was amended mid-way to require prospective KRAS testing (Alberts SR, ASCO 2010). Methods: Extracted DNA from archival tumors was analyzed for BRAF exon 15 (V600E) and KRAS exon 2 mutations by allele specific RT-PCR. Tumors with loss of any MMR protein (MLH1, MSH2, MSH6) were categorized as dMMR vs proficient (pMMR). DFS was censored at 4 yrs; median follow-up was 3.1 yrs. Results: Among 2,686 pts, 12% (314/2580) of tumors were dMMR; 28% (716/2579) had mutKRAS, and 14% (346/2515) had mutBRAF of which 43% (150/346) were dMMR. mutBRAF was associated with high grade, proximal site, T3-4, >4 LNs, and dMMR (all p<0.002); mutKRAS with low grade, proximal, <3 LNs, and pMMR (all p<0.02). Among dMMR tumors, mutKRAS was more frequent in distal vs proximal cancers (28% vs. 8%, p=0.0004). Both mutKRAS (HR=1.42, p=0.0001) and mutBRAF (HR=1.34, p=0.02) were associated with worse DFS and remained significant after adjustment for treatment, MMR, grade, site, T stage and LNs. mutBRAF (p=0.003) and mutKRAS (p=0.003) were each prognostic for DFS in pMMR, but not dMMR tumors (KRAS, p=0.79; BRAF, p=0.60). While MMR was not significant univariately, proximal dMMR tumors had favorable DFS [HR 0.8, 95% CI (0.6-1)] and distal dMMR tumors had poor DFS [HR 2 (1.1-3.4)] after adjusting for KRAS, BRAF, grade, T stage and LNs (pinteraction=0.02). pMMR/mutBRAF (p=0.027) and pMMR/mutKRAS (p<0.001) had worse DFS vs pMMR/bothWT. Conclusions: mutBRAF and mutKRAS were significantly associated with worse DFS independent of treatment, covariates, and each other, with the DFS impact restricted to pMMR tumors. Prognostic impact of MMR was dependent upon tumor site after adjusting for covariates. Support: NIH Grant CA 25224, NCI K05CA 142885, Bristol-Myers Squibb, ImClone, Sanofi-Aventis, and Pfizer.
Adjuvant chemotherapy (AC) use and outcomes in stage II colon cancer (CC) with and without poor prognostic features.
Authors: Kumar Aalok , Kennecke Hagen F. , Lim Howard John , Renouf Daniel John , Woods Ryan , Speers Caroline , Cheung Winson Y. 
Published: March 2020

3527 Background: AC is frequently considered inpatients (pts) with "high risk" stage II CC, defined by the presence of >/=1 poor prognostic features, such as obstruction or perforation, T4 stage, <12 lymph nodes retrieved, positive margins, and lymphovascular or perineural invasion. However, survival benefits associated with AC use in high risk pts remain largely unproven. Our aims were to 1) examine patterns of AC use in stage II CC and 2) explore the relationship between AC use and survival in high vs low risk pts. Methods: All pts diagnosed with stage II CC in British Columbia from 1999 to 2008 and evaluated at any 1 of 5 regional centers were reviewed. Kaplan-Meier and Cox regression methods were used to correlate a) high vs low risk status and b) receipt of AC with relapse-free (RFS), disease specific (DSS) and overall survival (OS). Results: We identified 1,697 stage II CC pts: 1,236 (73%) high risk and 461 (27%) low risk among whom 363 (29%) and 61 (13%) received AC, respectively. Individuals with high risk features who received AC were younger (median 62 vs 72 years, p<0.001) and had better performance status (ECOG 0/1 47% vs 34%%, p=0.02). In the high risk group, AC was associated with improved 5-year OS, but not with RFS or DSS (Table). After adjusting for confounders, an OS advantage from AC persisted for high risk pts (HR 0.67, 95CI 0.52-0.86, p=0.002), but no significant RFS or DSS benefits were seen (HR 0.76, 95CI 0.58-0.99, p=0.05 and HR 0.75, 95CI 0.55-1.02, p=0.11, respectively). Subgroup analyses showed that individuals with T4 lesions had improved RFS (HR 0.63, 95CI 0.42-0.95, p=0.03), DSS (HR 0.59, 95CI 0.37-0.93, p=0.02), and OS (HR 0.50, 95CI 0.33-0.77, p=0.002). Conclusions: In this population-based cohort of stage II CC, AC was associated with an OS advantage in high risk pts, likely due to pt selection. RFS and DSS benefits were mainly seen in T4 lesions, suggesting a limited role for AC in pts deemed high risk based on clinical and pathological factors. Risk stratification based on molecular testing should be further explored. [Table: see text]
Impact of body mass index (BMI) and weight changes on recurrence and survival in stage III colon cancer (CC).
Authors: Vergidis Joanna , Alipour Sina , Cheung Winson Y. 
Published: March 2020

3560 Background: Research suggests that physical activity can lower the risk of relapse and mortality from CC. It is unclear if such potential benefits are mediated through an effect on weight. Our aims were to 1) evaluate the impact of pre-treatment BMI on recurrence and survival in early stage CC, 2) examine how weight gains and losses from baseline may affect outcomes, and 3) explore if the effects of different body compositions are modified by adjuvant therapy (AT). Methods: Patients (pts) diagnosed with stage III CC from 2006 to 2008, evaluated at any 1 of 5 cancer centers in British Columbia, and who had their weights measured serially throughout their AT period were reviewed. Using Cox proportional hazards models, we compared outcomes among a) BMI<25 [normal] vs. 25-30 [overweight] vs. >30 [obese] and b) weight increase or decrease of < vs. >/=5% and < vs. >/=10%, while controlling for confounders. Results: A total of 821 pts were included: median age was 65 years, 50% were men, and 83% were ECOG 0/1. At baseline, 43, 37, and 20% were normal, overweight, and obese, respectively. Compared to pts with normal BMI, those who were overweight or obese did not show an increased risk of recurrence (HR 0.81, 95%CI 0.42-1.58 and HR 1.09, 95%CI 0.48-2.51, respectively, p trend=0.74) or death (HR 0.54, 95%CI 0.26-1.13 and HR 0.62, 95%CI 0.22-1.74, respectively, p trend=0.24). A number of pts experienced weight gain or loss during their AT period, but none of these weight changes affected outcomes (Table). Receipt of AT did not modify the effects of BMI or weight change. In Cox models, advanced age and poor performance status were the main factors that consistently correlated with an increased risk of recurrence and death (p<0.05). Conclusions: Neither baseline BMI nor short-term weight changes during AT appear to affect outcomes in stage III CC. Physical activity likely exert its benefit on relapse and survival by influencing long-term weight changes or acting via other alternative mechanisms. [Table: see text]
Chemotherapy plus cetuximab in patients with liver-limited or non-liver-limited KRAS wild-type colorectal metastases: A pooled analysis of the CRYSTAL and OPUS studies.
Authors: Kohne Claus-Henning , Bokemeyer Carsten , Folprecht Gunnar , Sartorius Ute , Schlichting Michael , Rougier Philippe R , Van Cutsem Eric 
Published: March 2020

3562 Background: In the CRYSTAL and OPUS studies, adding cetuximab (cet) to first-line chemotherapy (CT) improved clinical benefit in patients (pts) with KRAS wild-type (wt) metastatic colorectal cancer. In a pooled analysis of these trials the benefit of treatment according to whether pts had liver-limited disease (LLD) or non-LLD was analyzed. Methods: Cox‘s proportional hazards model for overall survival (OS) and progression-free survival (PFS) or logistic regression model for best overall response and R0 resection were used on individual pt data, stratified by study. Likelihood ratio tests were used to explore interactions. Results: Adding cet to CT significantly improved PFS and overall response rate (ORR) in LLD pts, and OS, PFS and ORR in non-LLD pts and increased R0 resection rates (table). No treatment-by-study interactions were found. Treatment effects did not vary significantly by LLD status (PFS p=0.60, OS p=0.68, ORR p=0.0737, R0 resection p=0.71). However LLD vs non-LLD pts had improved outcome in each treatment arm: PFS, CT hazard ratio, HR=0.74, p=0.0910; CT + cet HR=0.66, p=0.0309; OS, CT HR=0.70, p=0.0091; CT + cet HR=0.74, p=0.0388; ORR, CT odds ratio=1.20, p=0.47, CT + cet odds ratio=2.32, p=0.0015; R0 resection, CT odds ratio=3.15, p=0.0496, CT + cet odds ratio=3.82, p=0.0018. Kaplan Meier survival plots will be shown. Conclusions: The OS benefit from adding cet to CT is more pronounced in non-LLD pts, thus strengthening the value of cet in palliative treatment.LLD status is associated with improved prognosis and may be predictive for response in pts receiving CT + cet, facilitating potentially curative resection. More pts (with R0 resection and longer follow-up) may be needed to confirm an OS benefit from CT + cet in LLD pts. [Table: see text]
Evaluation of FDG-PET in pretreatment staging in locally advanced rectal cancer: A prospective study.
Authors: Guillem Jose G. , Ruby Jeannine Alberts , Leibold Tobias , Akhurst Timothy J. , Larson Steven M. , Gollub Marc , Ginsberg Michelle S. , Saltz Leonard 
Published: March 2020

3563 Background: The utility of adding 18F-Fluorodeoxyglucose-Positron Emission Tomography (PET) to the pre-treatment staging of patients with locally advanced rectal cancer has not been well evaluated. Methods: Following completion of standard work-up, including physical examination, endorectal ultrasound, CT of the abdomen and pelvis, and chest CT or chest x-ray, 150 patients with primary, resectable, biopsy-proven rectal adenocarcinoma requiring neoadjuvant chemoradiation were enrolled in a prospective, single-stage, phase II study evaluating the role of PET. All patients underwent a dedicated whole-body PET prior to initiation of neoadjuvant chemoradiation. The primary endpoint of this analysis was to determine the accuracy of PET in detecting extrapelvic metastatic disease in primary rectal cancer patients considered operable on the basis of currently-standard work-up. Results: Among the 117 eligible patients found to be stage II or III by standard staging techniques, none (0%) were found by PET to have extrapelvic metastatic disease. PET yielded a false positive result in 3 patients (2.6%). PET yielded a false-negative result in 3 patients who were subsequently diagnosed with metastatic disease: 2 pre-operatively (liver, lung) and 1 intra-operatively (obturator lymph node). In 1 patient, PET did identify a previously unappreciated obturator lymph node metastasis; left pelvic sidewall dissection at the time of rectal resection confirmed metastatic adenocarcinoma in one obturator lymph node. Conclusions: Of the 117 rectal cancer patients evaluated and found to have locoregional disease by standard examination and imaging techniques, none had extrapelvic metastatic disease accurately identified by PET. PET did not improve the accuracy of pre-treatment staging. As such, consistent with current NCCN guidelines, PET does not have a role in pre-treatment staging of locally advanced rectal cancer.
The relationship between microRNA-126 and maintenance therapy with bevacizumab after bevacizumab plus chemotherapy as first-line treatment for patients with metastatic colorectal cancer: Results of the phase III Nordic ACT trial NCT00598156 translational study.
Authors: Hansen Torben , Christensen Rene dePont , Andersen Rikke Fredslund , Spindler Karen-Lise Garm , Soerensen Flemming Brandt , Johnsson Anders , Jakobsen Anders Kristian Moeller 
Published: March 2020

3573 Background: Maintenance therapy during chemotherapy free intervals is a debatable topic in metastatic colorectal cancer (mCRC). In the Nordic ACT trial patients benefitting from induction chemotherapy plus bevacizumab were randomized to bevacizumab with or without erlotinib. MicroRNA-126 (miRNA-126) is believed to influence angiogenesis in several ways, and we investigated the relationship between miRNA-126 and progression free survival (PFS) under maintenance therapy. Methods: The miRNA-126 was analysed by polymerase chain reaction on both genomic DNA (by the pri-miRNA-126 (A24G) single nucleotide polymorphism (SNP)) and paraffin embedded primary tumors, (which were classified as low or high miRNA-126 expressing tumours using the median value as cut-off). Diagnostic biopsies were not processed due to limited tumour tissue. Of the 159 randomized patients blood samples were available from 151 and primary tumours from 91. The PFS (from time of randomization) was compared using the Kaplan-Meier method and the log rank test. The Cox Regression analyses were used to test for independent contributions. Results: The A24G SNP was not related to PFS, but a significant association was seen between genotypes and miRNA-126 expression levels.Furthermore, the PFS was increased in patients with high tumor miRNA-126 expression compared to patients with low expression, hazard ratio (HR) 0.58 (95% confidence interval (CI) 0.38-0.90), p = 0.015. The median PFS was 6.2 months (95% CI 4.3-6.6 months) and 4.0 months (95% CI 2.6-4.5 months), respectively. Results did not differ between treatment arms, but the Cox Regression analysis confirmed an independent prognostic value of the tumor miRNA-126 expression, HR 0.61 (95% CI 0.39-0.95), p = 0.030. Conclusions: The miRNA-126 may be a potential marker for bevacizumab containing maintenance therapy. A similar relationship with PFS has recently been demonstrated in patients with mCRC treated with chemotherapy only. The results call for validation.