bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alternative biweekly dosing schedule of trifluridine-tipiracil (TAS-102) reduces rates of myelosuppression while maintaining therapeutic efficacy in patients (pts) with previously treated metastatic colorectal cancer (mCRC).
Authors: Cann Christopher G , Cimino Sarah , Grieb Brian , Ciombor Kristen Keon , Agarwal Rajiv , Das Satya , Goff Laura Williams , Cardin Dana Backlund , Davis Shemeka , Fletcher Casey , Berlin Jordan , Eng Cathy 
Published: June 2022

3559 Background: Colorectal cancer remains a significant source of morbidity and mortality within the United States, causing nearly 53,000 deaths in 2021. For unresectable pts, the estimated 5-year survival rate is 14%. Given recent advances in treatment, 50% of pts with mCRC will receive third-line therapy or greater, making optimization of therapy in these settings pivotal. Trifluridine-tipiracil (TAS-102) is FDA approved for third-line or greater in mCRC per the RECOURSE Trial. Standard dosing is 35 mg/m2 twice daily (maximum = 80 mg/day) on Days 1-5 and Days 8-12 of 28-day cycles. This dosing schedule is associated with Grade 3-4 neutropenia (38%), requiring treatment delays (53%), dose reductions (14%) and G-CSF support (9%). To reduce this toxicity while maintaining efficacy, we studied an alternative biweekly dosing (Days 1-5 and Days 15-19 of 28-day cycles). Methods: A retrospective analysis was completed (2019-2021) at Vanderbilt-Ingram Cancer Center in pts with refractory mCRC and appendiceal cancer (CA) who completed > 12 days of TAS-102 therapy. Diagnostic imaging was completed every 8-12 weeks. Patient data was evaluated for lines of prior therapy, ECOG performance status (PS), the addition of bevacizumab, and CTCAE grade of treatment-related myelotoxicity. Evaluation of progression-free survival (PFS) was performed only in mCRC pts. Results: 24 pts met the criteria, with a mCRC:appendiceal CA ratio of 20:4 and Male:Female 13:11. Median age 61.5 yrs (range 31-80); median number of prior therapies 3; median ECOG PS of 1; and median duration of therapy 73.5 days. Hematologic toxicities: Neutropenia 30% [Grade 3 (13%), Grade 4 (0%)]; anemia 17.4% [Grade 3 (8.7%), Grade 4 (0%)]; thrombocytopenia 4.3% [Grade 3/4 (0%)]. No pts required G-CSF. One patient required a treatment-related dose delay (neutropenia), and 2 pts required dose reductions (fatigue). In mCRC pts, the median PFS was 2.3 months. To date, 7 mCRC pts remain on treatment (range: 38-385). Conclusions: In our retrospective cohort analysis, TAS-102 biweekly dosing schedule (35 mg/m2 twice daily; Days 1-5 and Days 15-19 of 28-day cycles) for pts with refractory mCRC and appendiceal CA reduced Grade 3 myelotoxicity without Grade 4 toxicities, while preserving PFS in pts with mCRC. With an improved toxicity profile, this alternative TAS -102 dosing schedule may be a more favorable option for future combination studies. Additional prospective data are needed to validate these findings. To our knowledge, this is the first analysis of biweekly TAS-102 in a US patient population.
Efficacy and safety of tislelizumab plus cetuximab and irinotecan in patients with previously treated RAS wild-type advanced colorectal cancer: Preliminary findings of a phase II, single-arm study.
Authors: Xu Xiaojing , Yu Yiyi , Wang Yan , Cui Yuehong , Li Wei , Liang Li , Li Qian , Yu Shan , Feng Yi , Liu Qing , Zhang Pengfei , Lv Minzhi , Liu Tianshu 
Published: June 2022

3566 Background: For adequately treated patients (pts) with advanced colorectal cancer, the current third-line treatment standard of TKIs or TAS-102 administration has a low clinical objective response rate and its effectiveness seems to be limited. Preclinical studies have suggested that EGFR pathway blockage and immune checkpoint inhibition have synergistic therapeutic effects in these pts. The purpose of this study was to examine the efficacy and safety of tislelizumab (anti-PD-1 antibody) plus cetuximab and irinotecan in pts with previously treated RAS wild-type advanced colorectal cancer. Methods: This is an open-label, single-arm, phase II study. RAS wild-type advanced colorectal cancer pts with at least two previous lines of therapy were included in this study and administered with tislelizumab plus cetuximab and irinotecan until disease progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) (RESCIT 1.1). Secondary endpoints included DCR, PFS, OS and safety. Results: In total, 35 eligible RAS wild-type advanced colorectal cancer pts were enrolled from March 2021 to September 2021. The median age was 58 years. All 35 pts were identified as BRAF/RAS wild-type, and 33 (94%) had left-sided colon cancer. The percentages of pts with second-line, third-line and ≥fourth-line previous treatments were 37%, 49%, and 14%, respectively. Thirty-four pts (97%) had received targeted therapies previously, including 29 (83%) with anti-EGFR therapy. By December 31, 2021, 2 pts had withdrawn from the study for personal reasons, and the remaining 33 were evaluated for efficacy. Twelve of the 33 (36.4%) pts achieved clinical partial remission and 14 (42.4%) achieved stable disease; disease progression occurred in 6 pts and 1 patient died. The ORR was 36.4% and the DCR was 78.8%. Until December 31, 2021, 23 pts continued treatments, and the median PFS was not reached. Among the 33 treated pts, 32 (97.0%) had treatment-related adverse events (AEs). Common AEs included rash (n = 32), fatigue (n = 29), decreased appetite (n = 24), nausea (n = 24), diarrhea (n = 13), liver dysfunction (n = 10), vomiting (n = 7), leukopenia (n = 7), anemia (n = 6), paronychia (n = 5), oral mucositis (n = 4), and neutropenia (n = 4). Four (12%) of the 33 pts reported grade ≥3 AEs, including rash (n = 1), neutropenia (n = 2) and vomiting (n = 1). Conclusions: Tislelizumab plus cetuximab and irinotecan shows an encouraging clinical efficacy and tolerable safety in previously treated pts with RAS wide-type advanced colorectal cancer. Clinical trial information: NCT05143099.
Clinical and radiological predictors of organ preservation in patients with rectal cancer treated with total neoadjuvant therapy.
Authors: Yuval Jonathan B , Verheij Floris S , Lin Sabrina T. , Thompson Hannah M , Omer Dana M , Kim Jin K , Smith Jesse Joshua , Gollub Marc J , Qin Li-Xuan , Garcia-Aguilar Julio ,   On behalf of the OPRA consortium
Published: June 2022

3619 Background: Baseline rectal MRI is routinely used for tumor staging, selecting the initial treatment and prognostication of patients with rectal adenocarcinoma. However, associations of baseline clinical and MRI variables with organ preservation (OP) in a prospective randomized trial have not been reported. Methods: Patients with MRI staged clinical stage II or III rectal adenocarcinoma treated in a prospective phase II clinical trial were randomized to either induction chemotherapy (FOLFOX or CAPEOX) followed by chemoradiation or chemoradiation followed by consolidation chemotherapy (FOLFOX or CAPEOX) and recommended total mesorectal excision (TME) or watch-and-wait (WW) based on clinical response. The primary outcome was OP, defined as the time from randomization to the clinical decision of TME or last follow-up, whichever occurred first. Clinical variables included: age, sex, race, tumor grade, radiation dose and treatment arm. Radiological variables (evaluated by baseline MRI prior to randomization) included: distance from the anal verge, tumor length, clinical T stage, clinical N stage, relationship to the mesorectal fascia, presence of extramural vascular invasion (EMVI) and mucinous radiographic findings (>50%). Associations of OP with clinical and radiological variables were assessed utilizing the Cox regression model in univariate and multivariate settings. The final multivariate model was chosen using backward selection. Results were analyzed by intention to treat. Results: Case report forms (CRFs) from baseline MRI were available for 289 of 324 randomized patients (89%). Patients with CRFs differed from those without CRFs in race, distance of the tumor from the anal verge and clinical T stage. Median follow-up was 3.4 years. A total of 156 of 324 patients were recommended TME during the study period. The 3-year OP rate was 47%. Independent predictors of OP in the multivariate analysis can be seen in the table. Conclusions: Although the patients included in this analysis may not be fully representative of the entire cohort, our data shows that several radiological variables associated with unfavorable tumor biology – tumor involvement of the mesorectal fascia, presence of EMVI and involved mesorectal nodes – were negatively associated with organ preservation. This information will be useful in selecting rectal cancer patients for WW and should be used for patient stratification in future clinical trials. Clinical trial information: NCT02008656. [Table: see text]
Validation of a multi-modal blood-based test for the detection of colorectal cancer with sub single molecule sensitivity.
Authors: D'Auria Kevin , Chang Yunpei , Multhaup Michael , Axelrod Haley , Zheng Lu , Burke Jordan , Young Greenwald William , He Yupeng , Pendleton Kathryn , McDonald Nathan , Raymond Victoria M. , Hartwig Anna , Duenwald Sven , Chudova Darya , Talasaz AmirAli 
Published: June 2022

3627 Background: Blood-based colorectal cancer (CRC) screening tests can improve adherence to screening guidelines. Yet, current commercially available options have poor sensitivity and specificity inhibiting incorporation into routine clinical care. Here we report the validation of a blood-based test for the detection of colorectal cancer and advanced neoplasia. Methods: This blood-based test aims to detect colorectal neoplasia by identifying tumor-associated biomarkers including genomic or epigenomic (methylation and fragmentomics) signatures in cell-free DNA (cfDNA). cfDNA is partitioned based on methylation level, enriched for informative genomic regions, and sequenced. This novel workflow enables high-fidelity analysis of multi-modal information in majority of extracted cfDNA molecules. Results are integrated into a binary “detected” versus “not-detected” result using a proprietary bioinformatic pipeline (Guardant Health, USA). The assay was trained on samples obtained from >6,000 unique individuals (2,685 cancer-free and 1,698 with advanced colorectal neoplasia (ACN) for training, 1,072 cancer-free and 551 with ACN for threshold setting). The thresholds were frozen prior to validation targeting a specificity of > 91.5%. Each aspect of the validation study followed Nex-StoCT CLIA working group and CLSI guidelines. Results: Limit of detection (LoD) was established across six dilutions. Even for low cfDNA mass inputs of less than 4ng, the 95% LoD was determined to be less than 1 tumor-derived genomic equivalent (0.5), indicating over at least 10-fold increase in assay sensitivity compared to best-in-class assays for somatic mutation detection. Precision studies in 60 positive and negative replicates from clinical samples yielded >90% average positive and negative percent agreement both within and between batches. Endogenous interference studies yielded > 90% positive and negative percent agreement between reference control and common endogenous substances, including albumin, bilirubin, hemoglobin, triglycerides, and genomic DNA, in clinical positive and negative samples and minimally manipulated samples. The clinical validation of the test was conducted in > 300 cases (biobanked pre-operative cohort for CRC cases and screening cohort for advanced adenoma and negative cases). Conclusions: Here we present the validation of a multi-modal blood-based test for the detection of colorectal cancer. This test is currently being evaluated in a registrational study (ECLIPSE: NCT04136002).
Sequential nab-paclitaxel/gemcitabine followed by modified FOLFOX for first-line metastatic pancreatic cancer: The SEQUENCE trial.
Authors: Carrato Alfredo , Pazo-Cid Roberto , Macarulla Teresa , Gallego Javier , Jiménez-Fonseca Paula , Rivera Fernando , Cano Maria Teresa , Rodríguez Garrote Mercedes , Pericay Carles , Diaz Inmaculada , Layos Laura , Graña Begoña , Iranzo Vega , Gallego-Jimenez Inmaculada , Garcia-Carbonero Rocio , Alvarez Alejandro Maria , Ruiz de Mena Inmaculada , GUILLEN PONCE CARMEN , Aranda Enrique 
Published: June 2022

4022 Background: Sequential treatment with nab-paclitaxel, gemcitabine followed by oxaliplatin, leucovorin and 5-fluorouracil ( nab-P/Gem-mFOLFOX) have shown a good safety profile and clinical activity in metastatic pancreatic ductal adenocarcinoma (mPDAC) in a previously published phase I SEQUENCE trial. Methods: We have compared nab-P/Gem-mFOLFOX to the standard nab-P/Gem in first-line treatment, in an open-label multi-institutional prospective randomised phase II trial in patients with untreated mPDAC from 14 Spanish hospitals. Patients were allocated 1:1 to nab-paclitaxel (125 mg/m2) plus gemcitabine (1000 mg/m2) on days 1, 8 and 15, followed by modified FOLFOX-6 (oxaliplatin [85 mg/m2], L-leucovorin [200 mg/m2] or racemic leucovorin [400 mg/m2], 5-fluorouracil bolus [400 mg/m2], and 5-fluorouracil 48-hour continuous infusion [2400 mg/m2]) on day 29 of a 6-week cycle or nab-paclitaxel (125 mg/m2) plus gemcitabine (1000 mg/m2) on days 1, 8 and 15 of a 4-week cycle. The primary endpoint was the 12-month overall survival rate (OS) in randomised patients. EudraCT number 2014-005350-19; ClinicalTrial.gov identifier NCT02504333. Results: Between July 27, 2017, and April 16, 2019, 182 patients were screened and 157 randomised: 78 to nab-P/Gem-mFOLFOX and 79 to nab-P/Gem. Patients receiving nab-P/Gem-mFOLFOX showed a significantly higher 12-month, and 24-month OS (95% CI): 55.3% (44.2-66.5%) versus 35.4% (24.9-46.0%) (p = 0.016), and 22.4% (13.0-31.8%) versus 7.6% (1.8-13.4%) (p = 0.012), respectively. The median OS (95% CI) reached 13.2 (10.1-16.2) months with nab-P/Gem-mFOLFOX and 9.7 (7.5-12.0) months with nab-P/Gem (HR = 0.676, 95% CI 0.483-0.947, p = 0.023). 39.7% patients in the nab-P/Gem-mFOLFOX group and 54.4% in nab-P/Gem group received subsequent anticancer treatments. Safety was comparable except for grade ≥3 neutropenia (46.1% versus 24.1%, p = 0.004) and grade ≥3 thrombocytopenia (23.7% versus 7.6%, p = 0.007) that were higher in the nab-P/Gem-mFOLFOX regimen. Two (2.6%) patients died due to adverse events in the nab-P/Gem-mFOLFOX arm. Conclusions: Nab-P/Gem-mFOLFOX showed significantly higher clinical activity than the standard nab-P/Gem treatment, with a manageable safety profile. This regimen represents a feasible and efficient new option for first-line treatment of mPDAC. Clinical trial information: NCT02504333.
Phase 3, multicenter, randomized study of CPI-613 with modified FOLFIRINOX (mFFX) versus FOLFIRINOX (FFX) as first-line therapy for patients with metastatic adenocarcinoma of the pancreas (AVENGER500).
Authors: Philip Philip Agop , Bahary Nathan , Mahipal Amit , Kasi Anup , Rocha Lima Caio Max Sao Pedro , Alistar Angela Tatiana , Oberstein Paul Eliezer , Golan Talia , Sahai Vaibhav , Metges Jean Philippe , Lacy Jill , Fountzilas Christos , Lopez Charles D. , Ducreux Michel , Hammel Pascal , Salem Mohamed E. , Bajor David Lawrence , Benson Al Bowen , Buyse Marc E. , Van Cutsem Eric 
Published: June 2022

4023 Background: Metastatic pancreatic cancer (mPC) remains a deadly disease with very limited treatment options. FFX is a standard first-line therapy for mPC with a median overall survival (mOS) of 11.1 months. CPI-613 is a stable intermediate of a lipoate analog that inhibits pyruvate dehydrogenase and α-ketoglutarate dehydrogenase enzymes of the tricarboxylic cycle preferentially within the mitochondria of cancer cells. In a phase I study, CPI-613+mFFX was safe and exhibited promising signal of efficacy. Methods: A global, randomized phase 3 trial was conducted across 73 sites to investigate the efficacy and safety of CPI-613 in combination with mFFX compared to standard dose FFX in treatment-naïve patients with mPC. Treatment was administered in 2-weekly cycles until progression or intolerable toxicity. In the experimental arm, CPI-613 at 500 mg/m2 was given intravenously on days 1 and 3. The doses of irinotecan, oxaliplatin, and 5-fluorouracil in the experimental arm were 65 mg/m2, 140 mg/m2, and 2,400 mg/2, respectively. Primary endpoint was OS. Secondary endpoints were progression-free survival (PFS), overall response rate (ORR), duration of response, pharmacokinetics, patient reported outcomes and safety. Results: 528 patients were randomly assigned (266 in test and 262 in control arm). There were 362 deaths, with a mOS of 11.1 months for CPI-613+mFFX vs. 11.7 months for FFX [hazard ratio (HR), 0.95; 95% CI, 0.77 to 1.18; P = 0.655]; mPFS was 7.8 months vs. 8.0 months respectively [HR, 0.99; 95% CI, 0.76 to 1.29; P = 0.94]; ORR was 39% in the test arm vs. 34% in the control arm [ORR ratio, 1.23 (95% CI, 0.86 to 1.75)]. Grade ≥ 3 treatment-emergent adverse events with ≥ 10% frequency in CPI-613 plus mFFX vs. FFX arm were diarrhea (11.2% vs. 19.6%), hypokalemia (13.1% vs. 14.9%), anemia (13.9% vs. 13.6%), neutropenia (11.2% vs. 14.0%), thrombocytopenia (11.6% vs. 13.6%) and fatigue (10.8% vs. 11.5%). Conclusions: The addition of CPI-613 to mFFX failed to show significant improvements of ORR, PFS or OS. The mFFX in the test arm that had the lowest prospectively tested doses of FFX was without compromise on PFS or OS and may be considered as a reference for future FFX administration. Clinical trial information: NCT03504423.
Combination of oligo-fractionated irradiation with nivolumab can induce immune modulation and replacement of T cell clones in patients with gastric cancer (phase I/II clinical study).
Authors: Kono Koji , Mimura Kousaku , Ogata Takashi , Yoshimoto Yuya , Yoshida Daisaku , Nakajima Shotaro , Sato Hisashi , Machida Nozomu , Yamada Takanobu , Watanabe Yohei , Tamaki Tomoaki , Fujikawa Hirohito , Inokuchi Yasuhiro , Hayase Suguru , Hanayama Hiroyuki , Saze Zenichiro , Katoh Hiroyuki , Oshima Takashi , Suzuki Yoshiyuki , Nardin Alessandra 
Published: June 2022

4027 Background: Although basic, translational and clinical research suggest a possibility of synergistic effect of radiation-induced immunogenic cell death with immune checkpoint inhibitors, the effectiveness of the combination therapy is not fully established. Therefore, we conducted a single-arm, phase 1/2 trial (ClinicalTrials.gov, NCT03453164) in gastric cancer (GC) patients treated with a combination of nivolumab and oligo-fractionated irradiation (22.5 Gy/5 fractions/5 days). Methods: Eligible patients (n = 40) had un-resectable advanced or recurrent GC which progressed after primary and secondary chemotherapy with more than one lesion assessable in diagnostic imaging (one lesion must be ≥2cm). PBMCs from enrolled patients underwent high-dimensional flow cytometry-based, multiplexed MHC multimer analysis using a total of 46 tumor-associated antigens (TAA) and 10 virus epitopes and next-generation sequencing-based repertoire analysis of TCR β-chain. Results: The disease control rate (DCR) for the non-irradiated target as abscopal effect as the primary endpoint was 22.5%, and the DCR for the irradiated lesion was 40.0%. The median survival time was 230 days (157-330 days, 95%CI) and probability of 1-year survival rate was 28.6%. Although most TAA-specific T cells could be tracked longitudinally pre- and post-treatment, some several novel TAA-specific CD8 T cells were detected de novo after irradiation, indicating that potential irradiation-driven antigen spreading. Moreover, irradiation was associated with phenotypical changes of TAA-specific CD8 T cells towards higher expressions of KLRG1, HLA-DR, TIGIT and CD160 and lower expression of CD27 and CD127. Furthermore, the T cell clonality evaluated by the inverted Pielou’s evenness indicated that longer survival patients had more diverse TCR beta repertoire during treatment in comparison to shorter survivors. Also, we confirmed several new sequence-reads after radiation and nivolumab treatment in the top 30 most frequent clonotypes. Conclusions: Taken together, our results suggest that irradiation may induce, through immunogenic cell death, an immune-modulating effect with potential antigen spreading and a more diverse TCR repertoire, ultimately resulting in better survival during combination therapy of radiation with nivolumab. Clinical trial information: NCT03453164.
SOURCE beyond first-line: A survival prediction model for patients with metastatic esophagogastric adenocarcinoma after failure of first-line palliative systemic therapy.
Authors: Kuijper Steven C. , Pape Marieke , Haj Mohammad Nadia , Van Voorthuizen Thymen , Zwinderman Aeilko H. , Verhoeven Rob , Van Laarhoven Hanneke W.M. 
Published: June 2022

4037 Background: Prediction models for survival may aid shared decision making between physicians and patients. Prior models have been developed that predict survival for patients with potentially curable esophagogastric cancer and patients with metastatic esophageal cancer who start first-line therapy (the SOURCE models). The aim of this study was to develop and internally validate a registry-based clinical prediction model, called SOURCE beyond first-line, for survival of patients with metastatic esophagogastric cancer after failure of first-line palliative systemic therapy. Methods: Patients with unresectable or metastatic (synchronous or metachronous) esophageal or gastric cancer who received first-line systemic therapy (N = 1067) between 2015-2017 were selected from the Netherlands Cancer Registry. Follow-up data were retrieved in 2019. Patient, tumor and treatment characteristics at primary diagnosis and at progression of disease, were used to develop the prediction model. A Cox proportional hazards regression prediction model was developed through forward and backward selection using Akaike’s Information Criterion. The model was internally validated through 10-fold cross-validations to assess performance on unseen data. Model discrimination (C-index) and calibration (slope and intercept) were used to evaluate performance of the complete and cross-validated models. Results: The final model consisted of 10 patient, tumor and treatment characteristics. The C-index was 0.75 (0.74-0.77), the calibration slope 0.99 (0.98-0.99) and the calibration intercept 0.02 (0.01-0.02). Internal cross-validation of the model showed that the model performed adequately on unseen data: C-index 0.79 (0.76-0.80), calibration slope 1.02 (1.00-1.04) and calibration intercept -0.01 (-0.01-0.02). Conclusions: The SOURCE beyond first-line model predicted survival with fair discriminatory ability and good calibration, and is a valuable addition to the existing SOURCE prediction models. In the future this model will be integrated in an online decision support tool that can be used in clinical practice to aid personalized treatment.