bluuebunny/crossref_metadata_2025_split huggingface dataset:
First-in-human phase I dose-escalation study of the oral selective C-met inhibitor EMD 1204831 in patients with advanced solid tumors.
Authors: Amin Hesham M. , Falchook Gerald Steven , Fu Siqing , Hong David S. , Tsimberidou Apostolia Maria , Naing Aung , Wheler Jennifer J. , Piha-Paul Sarina Anne , Janku Filip , Klevesath Manfred B , Jego Virginie , Johne Andreas , Kurzrock Razelle 
Published: March 2020

3107^ Background: The cell surface receptor tyrosine kinase c-Met and its ligand, the hepatocyte growth factor, are implicated in tumor cell migration, invasion, survival, and proliferation. EMD 1204831 is a novel potent and highly selective reversible, ATP-competitive small molecule c-Met inhibitor. Methods: This is a phase I, first-in-human clinical trial with escalating doses of EMD 1204831 (NCT01110083). The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included evaluation of safety, pharmacokinetics (PK), pharmacodynamics (Pd), and preliminary anti-tumor activity. Eligible patients had advanced solid tumors not amenable to standard therapies. Following a classical 3+3 dose-escalation scheme, successive cohorts of patients were treated with twice daily (BID) oral EMD 1204831 in 21-day cycles. Pd markers were evaluated in paired tumor biopsies (phospho-c-Met). Results: Until 31 December 2011, 30 patients were enrolled and treated. The dose was escalated in successive cohorts starting from 50 mg BID up to 1400 mg BID. After first (single) administration, median Cmax and AUC0–12 values increased with dose. At higher doses, a decrease in exposure of EMD 1204831 was noted after multiple dosing, potentially caused by autoinduction of the compound’s metabolism. Further dose escalation was discontinued, and no further patients were enrolled. One dose-limiting toxicity (DLT) of grade (G) 3 pancreatitis, considered as a serious adverse event (AE), was observed at 400 mg BID. No other DLTs or treatment-related serious AEs were observed. The remaining treatment-related AEs of G2 or higher included G3 and G2 lipase elevation (n=1 for each grade), G2 upper abdominal pain (n=2), G2 gastroesophageal reflux disease (n=2), and G2 constipation (n=1). Twenty-five patients (83%) had no drug-related toxicity greater than G1. Of 29 patients evaluable for anti-tumor activity, 3 had stable disease lasting for at least 4 months. Conclusions: Due to potential autoinduction of the compound’s metabolism, dose escalation was discontinued before an MTD was reached. Final safety, PK, and clinical tumor response results will be presented.
Phase I trials of PS-341 (bortezomib, B) in combination with topotecan (T) in advanced solid tumors: A potential pharmacokinetic (PK) interaction.
Authors: Morgan Robert , Valdes Frances , Synold Timothy W. , Frankel Paul Henry , Ruel Christopher , Carroll Mary I. , Lim Dean , Cristea Mihaela C. , Koczywas Marianna , Leong Lucille A. , Chung Vincent M. , Reckamp Karen L. , Shibata Stephen , Portnow Jana , Chow Warren Allen , Twardowski Przemyslaw , Luu Thehang H. , Somlo George 
Published: March 2020

3108 Background: Preclinical data has demonstrated that B when combined with camptothecins enhances apoptotic effects which may be independent of NF-κB status and dependent on the sequence of exposure to the proteasome inhibitor. Other data suggests PK interactions of B with some chemotherapeutic agents. It is hypothesized that B will act synergistically with T and enhance the apoptotic effects of T. Conflicting data exists regarding schedule dependent synergistic cytotoxicity of the combination. This study examined both sequences of administration and determined the PK of each sequence. Methods: A standard 3 + 3 schedule was used in both sequences (S). The dose of B was fixed with escalating doses of T. S1: B 1.3 mg/m2 on days 1, 4, 8, and 11. T 2 to 3.5 mg/m2 on days 1 and 8 was given 6 h before B. S2: B 1.3 mg/m2 on days 1, 4, 8, 11 followed by T 2 to 3 mg/m2 given 6 h after B. Cycle length was q28 days. PK sampling for both sequences was performed. Results: 54 pts (S1: 27, S2: 27) received a median of 2 cycles (range 1-7) of therapy. Pts were heavily pre-treated. For S1, the maximum tolerated dose (MTD) of B and T were 1.3 and 3 mg/m2 respectively. For S2, the MTD of B and T were 1.3 and 2.5 mg/m2 respectively. Dose-limiting toxicities (2 pt in each sequence) were gr 3 thrombocytopenia in S1, and gr 4 thrombocytopenia in S2. Stable disease was seen in 6/27 pts in S1, and 6/27 in S2. PK results for S2 show no significant difference between the day 1 and day 8 PKs. However, the mean AUC (454±150 mg/Lxhr) and Cmax (123±51 mg/L) at the MTD of 2.5 mg/m2 reached on this trial is similar to those reported with single agent doses of 4 mg/m2 given over 30 minutes weekly x 3. As a result, the estimated topotecan clearance (11.3±5 L/hr) when given following bortezomib is approximately one half of the reported clearance for the single agent. (Curtis et al, J Clin Pharmacol, 50:268, 2010). Conclusions: The tolerability and toxicity of both sequences was similar. MTD differs with S2 having a lower tolerated dose of T. PK results suggest a possible drug-drug interaction with decreased clearance of T with S2. PK results for S1 are pending. Supported by CCSG CA62505.
Validation of the 12-gene colon cancer recurrence score (RS) in NSABP C07 as a predictor of recurrence in stage II and III colon cancer patients treated with 5FU/LV (FU) and 5FU/LV+oxaliplatin (FU+Ox).
Authors: O'Connell Michael , Lee Mark , Lopatin Margarita , Yothers Greg , Clark-Langone Kim , Millward Carl , Paik Soonmyung , Sharif Saima , Shak Steven , Wolmark Norman 
Published: March 2020

3512 Background: Standardized clinical tools which accurately quantify recurrence risk are needed for optimal adjuvant treatment of colon cancer. The 12-gene RS has been validated in stage II colon cancer pts from QUASAR and CALGB 9581. We conducted a large prospectively-designed clinical validation study of RS, w/ pre-specified endpoints, methods, and analysis plan, in stage II and III colon cancer pts randomized to FU or FU+Ox in NSABP C-07. Methods: 50% of C-07 pts w/ tissue were randomly selected, stratified on stage (AJCC 6th) and recurrence. Gene expression was quantitated by RT-PCR on 25 µm manually microdissected fixed colon tumor tissue. Data were analyzed by Cox regression controlling for stage and treatment (TRT). Results: RT-PCR was successful in 892/921 pts (97%): 449 FU, 443 FU + Ox; 264 st II, 409 st IIIA/B, 219 st IIIC. The primary endpoint was met: RS predicted recurrence (HR/25 units=1.96, 95% CI 1.50-2.55 p<.001). RS also predicted disease-free survival (p<.001) and overall survival (p<.001). RS predicted recurrence (p=.001) independent of T and N stage, MMR, nodes examined, grade, and TRT. Predefined high RS group (26% of pts) had higher recurrence risk than low RS group (39% of pts): HR=2.11, p<.001. Cox model 5 yr recurrence risk (95%CI) in FU treated pts by RS group (low, int, high): st II 9% (6-13%), 13% (8-17%), 18% (12-25%); st IIIA/B 21% (16-26%), 29% (24-34%), 38% (30-46%); st IIIC 40% (32-48%), 51% (43-59%), 64% (55-74%). RS did not have significant interaction w/ stage (p=0.90) or age (p=0.76). Relative benefit of Ox was similar across range of RS (interaction p=0.48); accordingly, in Cox model and Kaplan-Meier analyses, absolute benefit of Ox increased w/ higher RS. Conclusions: RS predicts recurrence risk in stage II and III colon cancer, capturing underlying biology and providing risk information beyond conventional factors. RS is not predictive of relative benefit of Ox added to adjuvant FU but enables better discrimination of absolute Ox benefit as a function of risk. Incorporating RS into the clinical context may better inform adjuvant therapy decisions for pts w/ stage III as well as stage II colon cancer.
Prospective evaluation of candidate SNPs of VEGF/VEGFR pathway in metastatic colorectal cancer (mCRC) patients (pts) treated with first-line FOLFIRI plus bevacizumab (BV).
Authors: Cremolini Chiara , Loupakis Fotios , Yang Dongyun , Salvatore Lisa , Zhang Wu , Wakatsuki Takeru , Schirripa Marta , Lonardi Sara , Antoniotti Carlotta , Aprile Giuseppe , Masi Gianluca , Graziano Francesco , Ruzzo Annamaria , Lucchesi Sara , Ronzoni Monica , Maus Martin Karl Herbert , Bocci Guido , Tonini Giuseppe , Falcone Alfredo , Lenz Heinz-Josef 
Published: March 2020

3518 Background: Despite several attempts, no predictors of benefit from BV have been so far identified. We reported the association of VEGF rs833061 T/T to a worse outcome in mCRC pts treated with first-line FOLFIRI+BV, but not in a historical cohort treated with FOLFIRI. Recent post-hoc analyses on randomized trials suggested the potential prognostic and/or predictive role of other VEGF and VEGFR1/2 SNPs. Methods: Moving from our retrospective finding, we designed a prospective validation trial in mCRC pts treated with first-line FOLFIRI+ BV to detect a HR for PFS of 1.7 for VEGF rs833061 T/T compared to C- variants. With two-sided a=0.05 and b=0.20, 199 events were required. Accrual was faster than expected and in the meanwhile promising results about other SNPs were reported and we therefore included a confirmatory analysis of VEGF rs699946 A/G, VEGFR1 rs9582036 A/C and rs7993418 A/G, VEGFR2 rs11133360 C/T, rs12505758 C/T and rs2305948 C/T and EPAS rs4145836 A/G SNPs. Germ-line DNA was extracted from peripheral blood. SNPs were analyzed by PCR and sequencing. Results: Four-hundred-twenty-four pts were included. At a median follow up of 24 months, median PFS was 10.5 months. At the univariate analysis, no differences in PFS according to VEGF rs833061 C/T variants were observed (p=0.38). Among analyzed SNPs, only VEGFR2 rs12505758 C- variants (n=118) were associated to shorter PFS compared to TT (n=306) (HR: 1.40 [95%CI: 1.07-1.84], p=0.015). In the multivariate model, this association retained significance (HR: 1.402 [95%CI:1.079-1.822], p=0.012), that was lost by applying multiple testing correction. Conclusions: This prospective experience failed to validate the hypothesized predictive impact of VEGF rs833061 variants. Also other previous retrospective findings on different candidate SNPs were not confirmed. Only VEGFR2 rs12505758 variants, whose prognostic rather than predictive impact was previously reported, correlated with PFS. We suggest that future studies on biomarkers of benefit from BV should look at the complexity of tumoral angiogenesis at different levels and not only from the genetic perspective.
Ligand expression of the EGFR ligands amphiregulin, epiregulin, and amplification of the EGFR gene to predict for treatment efficacy in KRAS wild-type mCRC patients treated with cetuximab plus CAPIRI and CAPOX: Analysis of the randomized AIO CRC-0104 trial.
Authors: Stintzing Sebastian , Jung Andreas , Kapaun Christine , Reiche Jana , Modest Dominik Paul , Giessen Clemens Albrecht , Vehling-Kaiser Ursula , Stauch Martina , Hass Holger , Fischer von Weikersthal Ludwig , Kirchner Thomas , Heinemann Volker 
Published: March 2020

3519^ Background: We investigated the expression of the EGFR ligands amphiregulin (AREG) and epiregulin (EREG) as well as the amplification of the EGFR-gene in tumor specimens of mCRC patients (pts) treated first-line with anti-EGFR targeted cetuximab together with CAPOX or CAPIRI. Expression levels were correlated with overall response rate (ORR), progression free survival (PFS) and overall survival (OS) to determine their relationship with effectiveness in this setting. Methods: A total of 185 mCRC pts were randomized to cetuximab (400mg/m² day 1, followed by 250mg/m² weekly) plus CAPIRI (irinotecan 200mg/m², day 1; capecitabine 800mg/m² twice daily days 1-14, every 3 weeks; 20% dose reduction of both agents for pts older than 65 years) or plus CAPOX (oxaliplatin 130mg/m² day 1; capecitabine 1000mg/m² twice daily days 1-14, every three weeks). The primary study endpoint was ORR. KRAS mutational status did not correlate with treatment outcome. The cut-offs for EGFR-amplification using FISH, AREG and EREG levels determined by RT-qPCR were calculated using ROC analysis for ORR. Results: Within the subgroup of KRAS wildtype tumors, analysis of EREG- and AREG-expression was possible in 99 pts and of EGFR-amplification in 63 pts. Higher AREG levels correlated significantly with higher ORR (83% vs 46%, p=0.006, OR 0.31), longer PFS (9.6mo vs 4.9, p<0.001, HR 0.35) and longer OS (39.9mo vs 17.2mo, p<0.001, HR 0.36). Higher EREG levels showed a significant correlation with ORR (74% vs 47%, p=0.036, OR 0.54), longer PFS (7.9mo vs 4.9mo, p=0.026, HR 0.57) and OS (33.0mo vs 20.2mo, p=0.041, HR 0.57). EGFR-amplification correlated significantly with higher ORR (71% vs 33%, p=0.004, OR 0.49), longer PFS (8.4mo vs 4.6mo, p=0.004, HR 0.50) and longer OS (30.5mo vs 15.2mo, p=0.001, HR 0.44). Conclusions: In the treatment setting of cetuximab combined with CAIPIRI or CAPOX, AREG, EREG and EGFR-amplification predicted treatment efficacy. Within the subgroup of pts with KRAS wildtype tumors, EGFR-FISH and AREG expression have the strongest relationship with treatment efficacy.
Effect of low-frequency KRAS mutations on the response to anti-EGFR therapy in metastatic colorectal cancer.
Authors: Tougeron David , Lecomte Thierry , Pages jean-Christophe , Collin Christine , Villalva Claire , Ferru Aurelie , Tourani Jean Marc , Silvain Christine , Levillain Pierre , Karayan-Tapon Lucie 
Published: March 2020

3520 Background: Monoclonal antibodies against the epidermal growth factor receptor (EGFR) are standard components of treatment algorithms in metastatic colorectal cancer (mCRC). It is already well established that only patients with wild-type KRAS tumors benefit from treatment with an anti-EGFR agent. Pyrosequencing is now used for a precise determination of KRAS mutation burden and a conservative cutoff of 10% was defined as the lower limit of quantification for the assignment of mutation status. Up to now, the impact of low-signal KRAS mutations below 10% on the response to anti-EGFR therapy in mCRC has not been evaluated. Methods: All consecutive patients treated by anti-EGFR for a mCRC between January 2006 and June 2011 have been retrospectively analyzed by pyrosequencing using the therascreen KRAS Pyro Kit (Qiagen). All patients were defined wild-type (WT) for KRAS status using direct sequencing. The PFS data were plotted as Kaplan–Meier curve and compared by the log-rank test. Results: A total of 141 patients treated by anti-EGFR for a mCRC were included in the study. Mean age was 64.1 ± 14.8 years and a majority of patients had synchronous metastases (68.6%). Patients benefited from anti-EGFR in first-line chemotherapy (30.7%), second-line (22.9%), third-line (35%) or later (11.4%). Majority of patients benefited from anti-EGFR combined with cytotoxic chemotherapy (91.4%), mostly irinotecan (78.6%). Using pyrosequencing, 117 tumors had a KRAS WT status and 24 tumors had low-signal mutation, between 2 and 10% (KRAS lowMT). Response rate according RECIST criteria were 13.6% versus 35.4% partial response, 13.6% versus 37.2% stabilization and 72.7% versus 27.1% progression (p<0.01), for KRAS lowMT versus KRAS WT respectively. The PFS was respectively 2.6 ± 0.2 months for KRAS lowMT versus 6.0 ± 0.5 months for KRAS WT (p=0.024). Overall survival was not different between the two groups (27.4 months versus 33.0 months, p=0.4). Conclusions: Patients with tumors harboring KRAS lowMT benefit less of anti-EGFR therapy than patients with tumor harboring KRAS WT. While these results invite to consider low-signal tumors as positives, generalization awaits a large prospective trial.
Randomized phase III study of adjuvant chemotherapy with oral uracil and tegafur plus leucovorin versus intravenous fluorouracil and levofolinate in patients (pts) with stage III colon cancer (CC): Final results of Japan Clinical Oncology Group study (JCOG0205).
Authors: Shimada Yasuhiro , Hamaguchi Tetsuya , Moriya Yoshihiro , Saito Norio , Kanemitsu Yukihide , Takiguchi Nobuhiro , Ohue Masayuki , Kato Takeshi , Takii Yasumasa , Sato Toshihiko , Tomita Naohiro , Yamaguchi Shigeki , Akaike Makoto , Mishima Hideyuki , Kubo Yoshiro , Mizusawa Junki , Nakamura Kenichi , Fukuda Haruhiko 
Published: March 2020

3524 Background: NSABP C-06 reported the non-inferiority of oral adjuvant uracil and tegafur plus leucovorin (UFT/LV) to weekly fluorouracil and folinate (5-FU/LV) in disease-free survival (DFS) in stage II/III CC. Although adjuvant FOLFOX for stage III is standard care in US or EU, its toxicity and cost is major problem. This is the first report of JCOG0205, which compared UFT/LV to standard 5-FU/levofoloinate (l-LV) in stage III CC. Methods: Pts were randomized to 3 courses of 5-FU/l-LV (5-FU 500 mg/m2, l-LV 250 mg/m2, on days 1, 8, 15, 22, 29, 36, q8w), or 5 courses of UFT/LV (UFT 300 mg/m2/day, LV 75 mg/day, on days 1–28, q5w). Primary endpoint was DFS. Sample size was 1,100, determined with one-sided alpha of 0.05, power of 0.78, and non-inferiority margin of hazard ratio (HR) of 1.27. Owing to interim analyses, the multiplicity-adjusted alpha and confidence coefficient of CI in the final analysis were 0.0433 and 91.3%. Results: Between Feb 2003 and Nov 2006, 1,101 pts (1,092 eligible) were randomized to 5-FU/l-LV (n=550) or UFT/LV (n=551). Median follow-up was 72.0 months, median age: 61, colon/rectum: 67%/33%, number of positive nodes <3/4<: 73%/27%, stage IIIa/IIIb: 75%/25%. The HR of DFS was 1.02 (91.3% CI, 0.84–1.23) and non-inferiority of UFT/LV was demonstrated (P=0.0236). Incidences of G3/4 toxicities were 8.4% neutropenia in 5-FU/l-LV and 8.7% ALT elevation in UFT/LV. In the 2 arms (5-FU/l-LV, UFT/LV), diarrhea (9.6%, 8.5%) and anorexia (4.0%, 3.7%) were similar. G3/4 diarrhea was one-third less and G3/4 ALT elevation was three times more common than those in C-06. No treatment-related death was reported. Conclusions: Adjuvant UFT/LV is demonstrated to be non-inferior to standard 5-FU/l-LV in DFS. Five-year OS (87.5%) is favorable to 69.6% in C-06, possibly due to D3 dissection and stage migration. UFT/LV should be an oral treatment option for stage III CC. [Table: see text]
Do we need adjuvant therapy in rectal cancer with complete pathologic response (ypT0N0) after induction chemoradiation and laparoscopic mesorectal excision?
Authors: Pereira Verónica , Sosa Aarón , Reig Óscar , Victoria Iván , Féliz Luis Roberto , Ayuso Juan Ramón , Bombí Josep Antoni , Castells Antoni , Conill Carles , Cuatrecasas Miriam , Delgado Salvadora , Fernández-Esparrach Gloria , Ginés Àngels , Lacy Antonio , Miquel Rosa , Pagés Mario , Pineda Estela , Garcia-Albeniz Xabier , Gallego Rosa , Maurel Juan 
Published: March 2020

3536 Background: Neoadjuvant chemo-radiotherapy (CRT) is the standard of care for patients (pts) with u>T3 by endoscopic ultrasound (EUS) rectal cancer. Although pts with complete pathological response (ypT0N0) fare well in multiple series, there is uncertainty of whether it’s due to the induction (CRT), due to the adjuvant chemotherapy (ACT) or due to the combination of both therapies. We have evaluated long-term outcomes in CRT-treated pts. Those with ypT0N0, were not treated with ACT. Methods: Pts with u>T3 rectal cancer, received neoadjuvant chemotherapy (225mg/m2/day 5-fluorouracil (FU)) in continuous infusion (CI) per 5 weeks (wks) and concomitant radiotherapy (45 Gy). Laparoscopic surgery (LAP) was planned after an interval of 5-8 wks. Pts achieving ypT0N0 were no treated with ACT. Pts with ypT>1 or N1 were treated with 3 gr/m2 FU in 48 hour CI and LV 200 mg/m2 every 2 wks x 6 cycles. Results: From November 2000 to November 2008, a cohort of 173 pts were treated with induction CRT and 167 pts underwent total mesorectal excision (LAP, n=158, open surgery n=9). Complete pathological response was achieved in 26/167 pts (15.5%). After a median follow-up of 58.3 months, pts with ypT0N0 have a 5-year disease-free survival and overall survival rate of 96% (95% CI 76 to 99%) and 100% (95% CI not estimable) respectively. Conclusions: Using these results, a clinical trial comparing observation versus adjuvant therapy in ypT0N0 after standard CRT, would need to enroll 3088 pts to show a HR of 0.75 in favor of ACT after 5 years of follow-up (alpha=.05, beta=.2). In case that the true DFS lied in the lower bound of the 95% CI, 636 patients would be needed under the same assumptions. These results do not support the administration of ACT to ypT0N0 patients.
KSR1 gene polymorphism in mCRC patients treated with first-line FOLFIRI and bevacizumab.
Authors: Schirripa Marta , Loupakis Fotios , Cremolini Chiara , Yang Dongyun , Labonte Melissa Janae , Zhang Wu , Salvatore Lisa , Wakatsuki Takeru , El-Khoueiry Rita , Antoniotti Carlotta , Aprile Giuseppe , Maus Martin Karl Herbert , Lucchesi Sara , Allegrini Giacomo , De Vita Fernando , Zhang Hua , Giamas Georgios , Stebbing Justin , Falcone Alfredo , Lenz Heinz-Josef 
Published: March 2020

3546 Background: Kinase suppressor of Ras (KSR) 1 is a scaffolding protein regulating the Raf/Mek/ERK cascade. Preclinical data showed that KSR1 could increase estrogen receptor transcriptional activity after exposure to estrogens. Recent retrospective analyses suggested a possible role for KSR1 rs2241906 C/T polymorphism in predicting the outcome of patients with mCRC. Methods: MCRC patients receiving first-line FOLFIRI+bevacizumab prospectively enrolled in a translational research program were selected on the basis of KRAS and BRAF mutational status availability. KSR1 rs2241906 polymorphism was analyzed on DNA extracted from peripheral blood by means of PCR and direct sequencing. Taking into account the connection between estrogen pathway and KSR1, subgroup analyses according to gender were pre-planned. Results: 287 patients were included. Main patients’ characteristics were the following: M/F=175/112; median age=62 (range 26-79); ECOG-PS 0/1-2=240/47; synchronous/metachronous disease=213/74; Köhne score (low/intermediate/high/data missing)=122/129/22/14; KRAS-BRAF mutational status (wt-wt/mut-wt/wt-mut)= 123/146/18. In the overall KRAS-BRAF wt population, KSR1 polymorphism did not affect the outcome. The analysis performed according to gender showed that in the KRAS-BRAF wt population females with KSR1 rs2241906 T/- achieved a significantly better PFS (median 15.9 mos) in comparison to C/C variant carriers (median 8.8 mos) (HR=0.44 [95%CI 0.21-0.91], p=0.010); meanwhile males with T/- showed a worse PFS in comparison to those carrying the C/C variant (HR=1.92 [95%CI 1.05-3.53], p=0.021). These results were significant also in a multivariate model and a significant interaction of gender with PFS according to KSR1 allelic variants was demonstrated (p=0.004). Conclusions: This prospectively conceived pharmacogenetic study confims the role of KSR1 polymorphisms in affecting the outcome of mCRC KRAS-BRAF wt patients. In particular, these results indirectly indicate that estrogenic stimulation could affect the proliferation of KRAS-BRAF wt CRC cells through an interaction with KSR1. Preclinical investigations to further explore this preliminary hypothesis are ongoing.