bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and efficacy of the HER2-derived GP2 peptide vaccine in combination with trastuzumab for breast cancer patients in the adjuvant setting.
Authors: Patil Ritesh , Clifton Guy T. , Litton Jennifer Keating , Shumway Nathan M. , Vreeland Timothy J , Berry John S. , Trappey Alfred F , Ponniah Sathibalan , Peoples George Earl , Mittendorf Elizabeth Ann 
Published: March 2020

3096 Background: GP2 is a 9 amino acid HLA-A2/A3 restricted HER2-derived peptide. GP2 + GM-CSF has been shown to be safe and effective in eliciting anti-HER2 immune response in breast cancer patients. Preclinical data has demonstrated that pretreatment of cells with trastuzumab (Tz) enhances susceptibility to lysis by GP2-specific cytotoxic T lymphocytes (CTLs). We conducted a phase Ib study to evaluate the combination of the GP2 vaccine and Tz. Methods: HLA-A2/A3 + patients with HER2 overexpressing breast cancer receiving Tz as standard therapy were enrolled. The study was designed as a 3+3 dose escalation trial with an expansion cohort evaluating 4 dose levels of the vaccine administered as 6 inoculations given every 3 weeks in combination with Tz (6mg/kg). Toxicity was graded 48-72 hr post vaccination using NCI Toxicity Criteria. Ejection fraction (EF) was monitored every 3 mo. Immunologic response was assessed in vivo by injection site local reaction (LR) and in vitro by quantifying the number of GP2-specific CTLs by HLA-A2: IgG dimer assays and their functional activity by ELISPOT. Results: 19 patients enrolled (median age 47 yr, mean tumor size 3.4 cm, 74% were grade 3, 53% ER/PR+, 63% node positive, 74% received anthracycline based therapy). Maximum local toxicities were grade 1 (77% of patients) and grade 2 (6%), and maximum systemic toxicities were grade 1 (24%) and grade 2 (5%). There were no grade 3 or 4 local or systemic toxicities. There was no significant change in EF at 3 mo (57± 1%, p=0.23) or 6 mo (59±1%, p=0.8) compared to baseline (58±0.9%). Mean post-vaccine series LR was significantly larger than initial vaccination LR (68.2 ± 8.6 mm vs 28.0 ± 10.3 mm, p=0.0004). In vitro assays demonstrated an increase in the maximal number of post- versus pre-vaccination GP2-specific CTLs by dimer assay (1.45 ± 0.19 vs 0.96 ± 0.19%, p=0.06) and increased ELISPOT activity [median 86 range (3-194) vs 34 (range 0-295) spots/106 cells]. Conclusions: GP2 vaccine in combination with Tz is both safe and immunogenic in HER2-overexpressing breast cancer patients in the adjuvant setting. Toxicity was limited to mild local and systemic reactions. There were no dose limiting toxicities or cardiac events.
A phase I trial of intratumoral administration of HF10 in patients with refractory superficial cancer: Immune correlates of virus injection.
Authors: Gildener-Leapman Neil , Ferris Robert L. , Ohr James , Argiris Athanassios , Nemunaitis John J. , Senzer Neil N. , Bedell Cindi , Gross Neil D. , Vetto John T. , Tanaka Maki , Nishiyama Yukihiro , Ungerleider Richard S. 
Published: March 2020

3099 Background: HF10 is a spontaneously occurring, oncolytic, mutant Herpes Simplex Virus type 1 (HSV-1). Several deletions/insertions in its genome render it nonpathogenic. HF10 has been tested in solid tumors accessible for injection. Methods: We report correlative studies from an open label, non-randomized, multicenter, single dose escalation phase I study in patients with refractory superficial cancer. The study was a “3 + 3” design with 4-dose cohorts at escalating doses of HF10 (1 x 105 TCID50/dose with incremental dose escalations up to 1 x 107 TCID50/dose), which has been completed. Body fluids (qPCR), peripheral blood (flow cytometry) and serum (30-plex cytokine assay) were examined for viral levels, quantitative immune cell variation, and cytokines, respectively. Results: Seventeen patients were enrolled and 15 treated (9 H/N; 4 melanoma; 1 colon; 1 sarcoma). Best response was stable disease in six patients and progressive disease in nine patients. Three of the 15 patients had an adverse event possibly related to the study therapy. These AEs were grade 1 hypotension (1) and flu-like symptoms (2): typical of treatment with oncolytic viruses. qPCR analysis transiently revealed virus in the saliva of two patients (day 2 and day 22); viral clearance was achieved after 1 and 7 days respectively. Comparing the two highest and two lowest dose HF10 cohorts, CD8+PD1+ cells were decreased with increasing HF10 dose (p=0.023). Increased monocyte population (CD14+CD11c+) appeared to correlate with increased HF10 dose (p=0.063). IL-8 increased in all samples (p=0.0078 Wilcoxon Signed rank test) post injection. Conclusions: Single dose intratumoral injection was well tolerated with mild-drug related AEs and rapid viral clearance. Six patients achieved stable disease during the study period. There appears to be a generalized IL-8 related inflammatory response coincident with increased peripheral blood monocytes after HF10 administration. Decreased CD8+PD1+ cells may indicate a shift towards a non-exhausted, functional CTL phenotype. These results justify the currently accruing study of multiple administrations of HF10 at the highest administered dose. Clinical trial information: NCT01017185.
Validation of DPYD variants DPYD*2A, I560S, and D949V as predictors of 5-fluorouracil (5-FU)-related toxicity in stage III colon cancer (CC) patients from adjuvant trial NCCTG N0147.
Authors: Lee Adam , Shi Qian , Pavey Emily S , Sargent Daniel J. , Alberts Steven R. , Sinicrope Frank A. , Berenberg Jeffrey , Goldberg Richard M. , Diasio Robert B. 
Published: March 2020

3510 Background: Prediction of 5-FU-related adverse events (5FU-AEs) continues to be problematic. Pharmacogenetic studies on the rate-limiting enzyme in 5-FU metabolism, dihydropyrimidine dehydrogenase (DPD), suggest a link between three variants and both decreased enzyme activity and increased toxicity: c.1905+1 G>A (DPYD*2A; rs3918290), c.1679 T>G (I560S; DPYD*13; rs55886062), and c.2846A>T (D949V; rs67376798). Since the adverse impact of DPYD variants on 5-FU toxicity remains controversial, we determined associations between the three known DPYD variants and 5FU-AEs in stage III CC patients receiving FOLFOX or FOLFIRI (+ cetuximab) after curative resection. Methods: 2886 patients were genotyped by multiplexed single-base extension assays using the IPLEX Gold Kit and analyzed on the Sequenom MassARRAY system. Grade 3+ AEs were recorded per CTCAE v3. Fisher’s exact test, unequal variance two-sample t-test, and Wilcoxon rank sum test were used to compare categorical variables, continuous variables, and counts between patients with wild-type and mutant status. Logistic regressions were used to assess univariate and multivariate associations. Results: Patients displayed the following characteristics: male gender 53.2%, median age 58 [19-86], proficient DNA mismatch repair status 88.6%, PS-0 76.6%, + irinotecan 8.1%, and + cetuximab 45.9%. A total of 27 (0.9%), 4 (0.1%), and 32 (1.1%) patients carried the DPYD*2A, I560S, and D949V variants, respectively. Analysis identified significant associations between DPYD*2A and D949V variants and toxicity, with grade 3+ 5FU-AEs identified in 22 DPYD*2A carriers (OR=11.9, 95% CI 4.0-32.7, p<0.0001) and 22 D949V carriers (OR=5.5, 95% CI 2.5-12.1, p< 0.0001). No interaction effect was found between DPYD*2Aand D949V on grade 3+ 5FU-AEs (p = 0.98), nor on overall grade 3+ AEs (p = 0.97). No significant association was identified between I560S and grade 3+ 5FU-AEs. Conclusions: In the largest study to date, statistically significant associations were found between DPYD*2A and D949V variants and increased incidence of grade 3+ 5FU-AEs, suggesting utility in 5-FU toxicity prediction.
Analysis of KRAS/NRAS and BRAF mutations in the phase III PRIME study of panitumumab (pmab) plus FOLFOX versus FOLFOX as first-line treatment (tx) for metastatic colorectal cancer (mCRC).
Authors: Oliner Kelly S. , Douillard Jean-Yves , Siena Salvatore , Tabernero Josep , Burkes Ronald L. , Barugel Mario Edmundo , Humblet Yves , Bodoky Gyorgy , Cunningham David , Jassem Jacek , Rivera Fernando , Kocáková Ilona , Ruff Paul , Blasinska-Morawiec Maria , Smakal Martin , Williams Richard Thomas , Rong Alan , Wiezorek Jeffrey S. , Sidhu Roger , Patterson Scott D. 
Published: March 2020

3511 Background: Analysis of a phase III pmab monotherapy study indicated that KRAS and NRAS mutations beyond KRAS exon 2 may be predictive of pmab efficacy (Peeters et al, 2013). Methods: The primary objective of this prospectively defined retrospective analysis of PRIME was to assess the effect of pmab + FOLFOX vs FOLFOX on overall survival (OS) in pts with mCRC based on RAS (KRAS or NRAS) or BRAF mutation status. "Gold standard" bidirectional Sanger sequencing and WAVE-based SURVEYOR Scan Kits from Transgenomic (conducted independently) were used to detect mutations in KRAS exon 3, exon 4; NRAS exon 2, exon 3, exon 4; and BRAF exon 15. Results: RAS ascertainment rate was 90%. Tx HRs for pts with WT RAS were 0.78 (95% CI, 0.62 - 0.99; p = 0.04) for OS (median gain of 5.8 months in the pmab arm) and 0.72 (95% CI, 0.58 - 0.90; p = < 0.01) for PFS. Tx HRs for WT KRAS exon 2/mutant (MT) other RAS were 1.29 (95% CI, 0.79 - 2.10; p = 0.31) for OS and 1.28 (95% CI, 0.79 - 2.07; p = 0.32) for PFS. Tx HRs for pts with WT or MT BRAF were inconsistent with a predictive biomarker (Table). Prognostic effects of the tested biomarkers will be presented. Conclusions: A statistically significant OS benefit was observed in pts with WT RAS mCRC treated with pmab + FOLFOX vs FOLFOX. Pmab is unlikely to benefit pts with any RAS mutations. In this analysis, BRAF mutation had no predictive value. Clinical trial information: NCT00364013. [Table: see text]
EGFR and KRAS mutations during anti-EGFR monoclonal antibody treatment in metastatic colorectal cancer: Clinically relevant?
Authors: Karayan-Tapon Lucie , Ferru Aurelie , Cortes Ulrich , Villalva Claire , Tourani Jean Marc , Silvain Christine , Levillain Pierre , Tougeron David 
Published: March 2020

3513 Background: It is well-established that only patients with wild-type KRAS metastatic colorectal cancer (mCRC) benefit from treatment with an epidermal growth factor receptor monoclonal antibody (anti-EGFR mAb). Recently, in patients with tumor progression after anti-EGFR mAb, occurrence of EGFR mutation (n=2/10) [Montagut C et al., Nat Med 2012] or KRAS mutation (n=6/10) [Misale S et al., Nature 2012] in metastases has been identified. These mutations could explain treatment resistance but still need to be confirmed with simultaneous analysis of KRAS and EGFR mutations. Methods: We analyzed 37 tumor samples after anti-EGFR mAb treatment for mCRC (34 from metastasis lesions and 3 from primary tumors). We analyzed KRAS (codons 12 and 13), BRAFV600E and EGFRS492R mutations using a highly sensitive technique, pyrosequencing (TheraScreen KRAS Pyro Kit, Qiagen). All tumors were KRAS, BRAFV600E and EGFRS492Rwild-type before anti-EGFR mAb treatment. Results: The majority of patients were treated using anti-EGFR mAb in first-line chemotherapy (70%) and combined with cytotoxic chemotherapy (96%). Cetuximab was used in 86% and panitumumab in 14% of the cases. Among the 37 tumor specimens, 8 were collected after disease progression, and the others after disease control. No EGFRS492R mutation was detected. No tumors developed BRAF mutation but one tumor acquired a KRAS mutation. Nevertheless, the KRAS mutation in this patient (G12V) was detected, after 5-fluorouracil plus cetuximab therapy, only in the primary tumor in the colon but not in the liver metastasis. Moreover, there was a disease control (partial response). Conclusions: Our results suggest that EGFRS492R and acquired KRAS mutations during anti-EGFR mAb therapy are not the only factors accounting for anti-EGFR resistance. Moreover, occurrence of KRAS mutation during anti-EGFR therapy could differ between primary tumor and metastases.
FOLFIRI plus bevacizumab (bev) as second-line therapy in patients (pts) with metastatic colorectal cancer (mCRC) who have failed first-line bev plus oxaliplatin-based therapy: The randomized phase III EAGLE study.
Authors: Tamagawa Hiroshi , Iwamoto Shigeyoshi , Takahashi Takao , Nakamura Masato , Munemoto Yoshinori , Kato Takeshi , Hata Taishi , Denda Tadamichi , Morita Yoshitaka , Inukai Michio , Kunieda Katsuyuki , Nagata Naoki , Kurachi Kiyotaka , Ina Kenji , Oshiro Takashi , Shimoyama Tatsu , Baba Hideo , Oba Koji , Sakamoto Junichi , Mishima Hideyuki 
Published: March 2020

3516 Background: The phase III ML18147 study (NCT00700102) showed a survival benefit for the continuation of bev after 1st-line bev-containing therapy in pts with mCRC. Continuation of bev beyond disease progression in this setting was approved by the FDA in Jan 2013. In the randomized, phase II SPIRITT study (NCT00418938) assessing 2nd-line treatment for mCRC, progression-free survival (PFS) was longer in the bev arm compared with the panitumumab arm, but the difference was not statistically significant. We describe the results of EAGLE, a multicenter, randomized phase III study evaluating the optimal dose of 2nd-line bev in Japan (UMIN000002557). Methods: Pts were randomized 1:1 to receive bev 5 mg/kg (Arm A) or 10 mg/kg (Arm B) plus FOLFIRI Q2W. Key eligibility criteria: age ≥20 years, mCRC, ECOG PS ≤1, and treatment failure to prior 1st-line bev plus oxaliplatin-based therapy (≥4 cycles). The primary endpoint was PFS. Secondary endpoints included time to treatment failure (TTF), PFS from 1st-line therapy, response rate (RR) and safety. The planned sample size was 370 pts to detect 30% risk reduction with 90% power assuming a two-sided significance level of 0.05. Results: 387 pts were randomized between Sep 2009 and Jan 2012; 367 pts formed the full analysis set (Arm A 179 pts; Arm B 188 pts). Baseline characteristics were well balanced between the treatment arms. Respectively for Arm A and B, PFS was 6.2 and 6.3 months (HR 1.03, 95% CI: 0.82-1.30; p=0.815), TTF 5.3 and 5.3 months (HR 1.08, 95% CI: 0.87-1.33; p=0.485), PFS from 1st-line therapy 17.6 and 17.8 months (HR 0.99, 95% CI: 0.78-1.25; p=0.919) and RR 11.7% and 10.1%. Frequently reported AEs in Arm A and B, respectively, were: hypertension (13.0%, 18.1%), proteinurea (36.8%, 35.2%), GI perforation (4.7%, 3.1%), grade 3/4 neutropenia (46.1%, 39.9%), grade 3/4 fatigue (7.8%, 10.9%), and grade 3/4 anorexia (5.7%, 5.2%). Treatment-related deaths occurred in 2 pts in each arm. Conclusions: The study did not meet its primary endpoint. PFS in Arm A was comparable to that reported in the ML18147 study. Safety in both arms was consistent with previously reported studies. Clinical trial information: UMIN000002557.
Effectiveness of bevacizumab added to gold standard chemotherapy in metastatic colorectal cancer (mCRC): Final results from the Itaca randomized clinical trial.
Authors: Passardi Alessandro , Scarpi Emanuela , Cavanna Luigi , Fontana Annalisa , Vertogen Bernadette , Ruscelli Silvia , Tamburini Emiliano , Ragazzini Angela , Frassineti Giovanni Luca , Nanni Oriana , Amadori Dino 
Published: March 2020

3517 Background: Evidence from available RCTs indicates that the addition of bevacizumab (B) to chemotherapy (CT) results into an improved survival in metastatic colorectal cancer (mCRC). However, the magnitude of this effect is different across trials, with marginal benefit observed when gold standard CT regimens are used. With these premises we performed a phase III randomized clinical study to evaluate the effectiveness of gold standard mCRC first line CT + B. This study was funded by the Italian Ministry of Health. Methods: mCRC patients candidate were randomized to receive first line CT +B or first line CT alone. CT regimens included FOLFOX4 (oxaliplatin 85 mg/m2 d1, folinic acid FA 100 mg/m2 dd1,2, 5FU 400 mg/m2 iv bolus dd 1,2 plus 5FU 600 mg/m2 22-h ic dd1,2 – Q14 days) or FOLFIRI (irinotecan 180 mg/m2d1, FA and 5FU as in FOLFOX4, Q 14 days); B 5 mg/kg was administered Q 14 days. The primary end point was Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS), Response Rate (ORR) and safety. Three hundreds ten events were required to statistically differentiate PFS between groups with 80% power. Results: Between 11/2007 and 03/2012, 376 patients were randomized. Patient characteristics were well balanced between the two arms. FOLFOX4 was used in 60% of the patients and FOLFIRI in 40%. After a median follow up of 18.4 months, 313 progressions and 179 deaths were observed. No statistically significant differences in PFS, OS and ORR were observed (see table). B containg regimens were associated with more frequent hypertension, bleeding, proteinuria and asthenia. Conclusions: The addition of B to a gold standard CT for mCRCdoes not result into an improved prognosis in terms ofPFS, ORR, OS. ITACA’s results (control arm) suggest that the chemotherapeutic schedules used in some of the previously published bevacizumab trials might be suboptimal. Clinical trial information: 2007-004539-44. [Table: see text]
Noninferiority of S-1 to UFT/LV as adjuvant chemotherapy for stage III colon cancer: A randomized phase III trial (ACTS-CC).
Authors: Nakamoto Yoshihiko , Ishiguro Megumi , Yoshida Motoki , Ikejiri Koji , Mochizuki Izumi , Mochizuki Hidetaka , Kotake Kenjiro , Kameoka Shingo , Takahashi Keiichi , Watanabe Toshiaki , Watanabe Masahiko , Boku Narikazu , Tomita Naohiro , Matsubara Yoshihiro , Sugihara Kenichi ,   ACTS-CC Study Group
Published: March 2020

3518 Background: The ACTS-CC trial is a phase III trial designed to validate non-inferiority of S-1 to UFT/LV, a standard treatment in Japan as adjuvant chemotherapy for stage III colon cancer. This is the first report which evaluated the efficacy of S-1 as adjuvant therapy for colon cancer. Methods: 20-80 aged patients with stage III colon cancer who underwent curative surgery were randomly assigned to receive S-1 (80, 100, or 120 mg/day according to BSA on days 1 to 28, followed by 14 days rest, 4 courses) or UFT/LV (UFT: 300 to 600 mg/day according to BSA and, LV: 75 mg/day on days 1 to 28, followed by 7 days rest, 5 courses). Primary endpoint was DFS. Sample size was 1,480 determined with one-sided alpha of 0.05, power of 0.80, and non-inferiority margin of hazard ratio (HR) of 1.29. Results: Among 1535 enrolled patients between Apr. 2009 and Jun. 2010, 1518 patients (758 in S-1 group, 760 in UFT/LV group) were included in the efficacy analysis. Median follow-up was 41.3 months, the mean age at enrollment was 64.5 years, wide lymph node dissection (D3) was done in 79.8%, the median number of dissected lymph nodes was 17, and stage IIIA/IIIB/IIIC were 15%/71%/14%. The 3-year DFS rate was 75.5% in S-1 group and 72.5% in UFT/LV group. The HR of DFS was 0.85 (95%CI: 0.70-1.03) and non-inferiority of S-1 was demonstrated (p<0.0001). The completion rate of the protocol treatment was 76.5% in S-1 group and 72.5% in UFT/LV group. The overall incidence of grade ≥3 adverse events (AEs) in S-1 group and UFT/LV group were 16.0% and 14.4%: 4.4% and 5.5% for diarrhea, 4.9% and 3.5% for anorexia, 0.7% and 0.4% for leucopenia, 0.9% and 0.1% for anemia, 0.1% and 0.4% for thrombocytopenia, 1.2% and 1.5% for hyperbilirubinemia, 0.8% and 2.1% for AST elevation, and 1.1% and 3.3% for ALT elevation, respectively. Conclusions: Adjuvant therapy of S-1 for stage III colon cancer was demonstrated to be non-inferior in DFS to that of UFT/LV. Although AE profiles differed between S-1 group and UFT/LV group in this trial, incidence and degree of AEs were acceptable, and the completion rate of the protocol treatment was high. Adjuvant chemotherapy using S-1 will be a treatment option for stage III colon cancer. Clinical trial information: NCT00660894.
Prognostic value of early objective tumor response (EOTR) to first-line systemic therapy in metastatic colorectal cancer (mCRC): Individual patient data (IPD) meta-analysis of randomized trials from the ARCAD database.
Authors: Sommeijer Dirkje Willemien , Shi Qian , Meyers Jeffrey P , Sjoquist Katrin Marie , Hoff Paulo Marcelo , Seymour Matthew T. , Cassidy James , Goldberg Richard M. , Douillard Jean-Yves , Hecht J. Randolph , Hurwitz Herbert , Tournigand Christophe , Tebbutt Niall C. , Aranda Enrique , Souglakos John , Kabbinavar Fairooz F. , Chibaudel Benoist , De Gramont Aimery , Sargent Daniel J. , Zalcberg John Raymond ,   for the ARCAD Group
Published: March 2020

3520 Background: EOTR has been suggested as a potential surrogate for overall survival (OS) in patients (pts) with mCRC and allows early assessment of treatment efficacy, facilitating adaptive trial design. We assessed at the individual patient level, the correlation between EOTR (complete or partial response) at 6, 8 and 12 weeks (wk), OS and progression free survival (PFS) in pts with mCRC treated with 1stline chemotherapy with or without a targeted agent as a first step in a surrogacy demonstration. Methods: IPD from 13,949 pts enrolled on 15 randomized Phase III trials in 1st line mCRC were used; 8 trials included targeted (anti-angiogenic and anti-EGFR) agents. EOTR prognostic value was assessed by landmark analyses using Cox models stratified by treatment assignment. P-values <0.01 were considered statistically significant to account for multiple comparisons. Results: Of 13,949 pts, 11,987 had sufficient response data to be included in the analysis. Median OS was 21.7 months (mo) in pts with an EOTR vs. 16.5 mo without EOTR at 6 wk (p<.0001, Hazard Ratio [HR] 0.64, 95% confidence interval [CI] 0.58-0.70, c statistic [c] 0.55). HRs were similar whether pts were treated with targeted therapies (p<.0001, HR 0.68, 95% CI 0.58-0.80, x 0.54) or non-targeted therapies (p<.0001, HR 0.61, 95% CI 0.55-0.69, x 0.55). Median PFS was 8.4 mo in pts with EOTR at 6 wk vs. 7.0 mo in pts without EOTR (p<.0001, HR 0.79, 95% CI 0.73-0.85). EOTR at 8 and 12 wks were also significantly associated with longer OS and PFS. The prognostic value of EOTR at 6, 8 and 12 wks remained significant (p<0.0001) after adjusting for age, gender, performance statusand location of metastatic disease (lung or liver). Overall tumor response (to 26 wk) however provided superior OS prediction (p<.0001, HR 0.51, 95% CI, 0.47-0.56, CS 0.61) vs. EOTR. Conclusions: Early response measured at 6, 8 or 12 wk after starting 1st line treatment was a strong and independent predictor of both OS and PFS in patient with mCRC and warrants further consideration as a potential endpoint for future trials, particularly randomized phase II trials.