bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase Ia/b first-in-human, open-label, multicenter study of BI 905711, a bispecific TRAILR2 agonist, in patients with advanced gastrointestinal cancers.
Authors: Harding James J. , Hofheinz Ralf-Dieter , Elez Elena , Kuboki Yasutoshi , Rasco Drew W. , Cecchini Michael , Shen Lin , He Min , Archuadze Shorena , Chhaya Niraj , Pant Shubham 
Published: January 2023

115 Background: BI 905711 is a tetravalent bispecific antibody that cross-links TRAILR2 with CDH17. This cross-linking drives CDH17-dependent TRAILR2 oligomerization, leading to caspase activation and eventual apoptosis, inhibiting tumor growth in preclinical models of GI cancer. Methods: This Phase Ia/b study of BI 905711 in patients (pts) with advanced GI cancers (NCT04137289) aimed to determine the maximum tolerated dose (MTD) based on the proportion of pts with dose-limiting toxicities (DLT) and explore preliminary antitumor activity. In Phase Ia, pts received BI 905711 every 14 days. One pt with colorectal cancer (CRC) was enrolled at each of the 2 lowest dose levels (0.02/0.06 mg/kg) and 4 pts with CRC were enrolled at each subsequent level (0.2/0.6/1.2/2.4/3.6/4.8 mg/kg). Up to 4 pts with non-CRC GI cancers were included at the dose level below the CRC cohort. Dose escalation was guided by a Bayesian logistic regression model. Results: As of 01 August 2022, 48 pts (CRC: n = 26; non-CRC: n = 22, including 13 with pancreatic ductal adenocarcinoma [PDAC]) had received BI 905711 (dose range 0.02–4.8 mg/kg); pts had a median age of 61 years (range 27–78) and had received a median of 3 (range 1–11) prior lines of treatment. No DLTs were observed and the MTD was not reached. 41 pts had AEs (grade [G] 3–5: 14 pts; serious: 13 pts). 17 pts had treatment-related AEs (TRAEs); 4 TRAEs were G3: AST increased (2 pts), fatigue and ALT increased (1 pt each). 1 pt had serious TRAEs: G2 decreased appetite and G3 fatigue. 2 pts had G1/2 infusion-related reactions that resolved and did not prevent resumption of treatment. PD biomarker modulation on the level of plasma caspase-3/7 activity was most common at 0.6 mg/kg (4/7 pts) or 1.2 mg/kg (2/6 pts). 13 pts achieved stable disease (SD) and 8 pts were progression-free for ≥4 months (PFS4). In pts with CRC, 6 pts achieved SD and 3 had PFS4. Among non-CRC pts, 7 pts achieved SD (PDAC: n = 6) and 5 had PFS4 (PDAC: n = 4). Median duration of treatment was 30.5 days (range 15–246) overall and 71 days (range 15–211) in the 0.6 mg/kg group (n = 8, predicted therapeutic dose; of whom 3 pts had PFS4: CRC: n = 1/4 [all CDH17+]; non-CRC: n = 2/4). Conclusions: In heavily pretreated pts, BI 905711 was associated with a tolerable safety profile and early signs of disease control. BI 905711 will be further assessed in Phase Ib in 4 dose groups: 0.6/1.2/2.4 mg/kg every 14 days, and 0.6 mg/kg weekly. Clinical trial information: NCT04137289 .
Phase II evaluation of combination immunotherapy with CV301, N-803, bintrafusp alfa, and M9241 in patients with advanced small bowel and colorectal cancers.
Authors: Pastor Danielle M. , Redman Jason M. , Floudas Charalampos S. , Lamping Elizabeth , Francis Deneise C. , Cordes Lisa M. , Marte Jennifer L. , Schlom Jeffrey , Gulley James L. , Strauss Julius 
Published: January 2023

116 Background: Although immune checkpoint inhibitors (CPI) are inactive as monotherapy for microsatellite stable (MSS) mCRC, preclinical modeling suggests that addition of other immune-oncology agents can produce antitumor activity. CV301 is a poxviral vaccine against CEA and MUC1. N-803 is an IL-15 superagonist. M9241 is tumor-targeted IL-12. Bintrafusp alfa (BA) is a bifunctional anti-PD-L1/TGF-βRII fusion protein. Methods: Patients with advanced MSS or proficient mismatch repair (pMMR) small bowel or CRC were eligible (NCT04491955). Patients enrolling to Arm 1 received triple therapy with BA 1200 mg IV every 2 weeks, N-803 15 mcg/kg SC every 4 weeks, and CV301 SC on D1, D15, D29, and monthly, thereafter. Patients enrolling to Arm 2 received quadruple therapy, with M9241 (8 mcg/kg or 16.8 mcg/kg SC every 4 weeks) plus BA (300 mg or 1200 mg IV), N-803 (10 mcg/kg SC) and CV301 SC, depending on dose escalation schedule. Results: Thirty patients (2 small intestinal, 17 colon, 11 rectal) were treated. All patients had received prior 5-fluorouracil-based treatment, with 29/30 (96.7%) having received ≥ 2 lines of systemic therapy. Twelve patients received triple therapy; 18 received quadruple therapy. Grade 3 treatment-related AEs (TRAEs) occurred in 8 patients (26.7%); anemia occurred most commonly (n = 5), with grade 3 gastrointestinal hemorrhages occurring in 2 patients (on quadruple therapy). Other grade 3 TRAEs included elevated cardiac troponin, AST, and alkaline phosphatase (n = 1 each; all with triple therapy), and adrenal insufficiency (n = 1; quadruple therapy). No grade 4 or 5 TRAEs occurred. Triple therapy resulted in disease reduction in 2 patients (7.5%, 25.6%); quadruple therapy resulted in disease reduction in 2 patients (26.7%, 70.6%). Median overall survival (OS) for triple and quadruple therapy have not been reached, with 12 month survival being 66.7% (95% CI: 33.7-86.0%) for triple therapy and 77.2% (95% CI: 43.3-92.3%) for quadruple therapy. Conclusions: Combination therapies with CV301, N-803, bintrafusp alfa, and M9241 had manageable safety profiles. Preliminary clinical activity was observed in patients with advanced MSS/pMMR small bowel or CRC. Median OS was promising as compared to historical median survivals of 6-7 months following receipt of multiple lines of therapy. Clinical trial information: NCT04491955 .
BREAKWATER safety lead-in (SLI): Encorafenib (E) + cetuximab (C) + chemotherapy for BRAFV600E metastatic colorectal cancer (mCRC).
Authors: Kopetz Scott , Yoshino Takayuki , Kim Tae Won , Yaeger Rona , Desai Jayesh , Wasan Harpreet Singh , Van Cutsem Eric , Ciardiello Fortunato , Maughan Tim , Eng Cathy , Tie Jeanne , Elez Elena , Lonardi Sara , Zhang Xiaosong , Chung Chin-Hee , Usari Tiziana , Nicholz Tim , Murphy Danielle A. , Tabernero Josep 
Published: January 2023

119 Background: Based on the phase 3 BEACON study (NCT02928224), BRAF inhibitor (i) encorafenib (E) + EGFRi cetuximab (C) was approved for the treatment (tx) of previously treated patients (pts) with BRAFV600E mCRC, with mPFS of 4.3 months (mo) and ORR of 19.5%. In the phase 2 ANCHOR study (NCT03693170), mPFS was 5.8 mo and ORR was 48% for 1L EC + binimetinib in BRAFV600E mCRC. To further assess 1L approaches, the ongoing phase 3 BREAKWATER study (NCT04607421) is evaluating EC ± chemotherapy vs standard-of-care chemotherapy in BRAFV600E mCRC. Here, we present updated safety and antitumor activity data as well as biomarker data from the BREAKWATER SLI. Methods: Inclusion criteria for the SLI were BRAFV600E mCRC (blood or tumor tissue), ≤1 prior systemic tx for mCRC, and ECOG PS 0/1. Pts previously treated with BRAFi/EGFRi or both oxaliplatin and irinotecan were excluded. Pts received E 300 mg daily + C 500 mg/m2 every 2 weeks (Q2W) + either mFOLFOX6 Q2W (n=27) or FOLFIRI Q2W (n=30) in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was frequency of dose-limiting toxicities. Secondary endpoints included safety, pharmacokinetics, and antitumor activity. Exploratory endpoints included evaluation of plasma (circulating tumor DNA [ctDNA] genomic profiling) and tumor tissue (molecular profiling) biomarkers. Updated results from the BREAKWATER SLI will be presented, including overall safety and tolerability and antitumor activity. Biomarker data, including changes from baseline in BRAFV600E ctDNA following treatment (Cycle 1 Day 15, Cycle 2 Day 15 and Cycle 7 Day 1) and MSI status of pts, will also be presented. Expected conclusions will be included in the final abstract. Clinical trial information: NCT04607421 .
Phase II trial of rosuvastatin combined with chemoradiation therapy (CRT) in the treatment of high-risk locally advanced rectal cancer (STARC trial).
Authors: Monzon Jose Gerard , Joseph Kurian , Chen Eric Xueyu , Tang Patricia A. , Sinha Rishi , Dennis Kristopher , Goodwin Rachel Anne , Severin Diane , Dimitroulakos Jim , Vickers Michael M. 
Published: January 2023

131 Background: Pre-clinical evidence suggest that statins have antiproliferative, proapoptotic, and anti-invasive properties. Also, statins can sensitize cancer tissues and protect normal tissues to the effects of radiation. A standard treatment of locally advanced rectal cancer (LARC) involves neoadjuvant CRT followed by surgery and adjuvant chemotherapy. Retrospective analyses of statin use in rectal cancer patients receiving CRT suggest a higher pathological complete response rate (pCRr). Methods: Patients with clinical stage II-III rectal adenocarcinoma, within 5 cm of the anal verge (AV) or less than 12cm from the AV with threatened circumferential resection margin were treated with rosuvastatin 40 mg daily starting 2 weeks prior to the start and until 4 weeks after the end of CRT. The primary objective of the study was pCRr. Secondary objectives included, near-CRr, Ro resection rate (RR), sphincter preservation, 3-year relapse free survival (RFS), 3-year overall survival (OS), toxicity and safety. A Simon’s minimax two-stage design was used to determine significance. A pCRr of ≥25% was required to reject the null hypothesis. RFS and OS rates were calculated using the Kaplan-Meier product-limit method. Results: Forty-five patients were enrolled from 2016 to 2021. Sixty-seven percent were male with a median age of 54 (IQR 37- 61), 97.8% (44/45) had ECOG PS of 0-1, 15.6% (7/45) were cT4, 73.3% (33/45) were cN+. Of the 38 evaluable patients, 9 had a pCR (23.7%), an additional 9 had a near-pCR (23.7%). With a median follow-up of 3.26 years, the 3-year OS rate was 96.3% (95% CI (0.765, 0.995)) and the 3-year DFS rate was 77.9% (95% CI (0.604, 0.883)) in the evaluable patients. One patient elected for non-operative management and has an on-going clinical CR for the last 15 months. Surgery was sphincter sparing in 17 patients (43.6%) and an 87.2% Ro RR was observed. Toxicities attributable to rosuvastatin included: two patients with elevations in liver enzymes, grade 3. Remaining toxicities were grade 2 or less, with the most common toxicities being fatigue (n = 5) and pain (n = 3). Only 2 patients experienced CPK elevations, both grade 2. Conclusions: The addition of rosuvastatin to nCRT resulted in a considerable complete and near-complete response rate with an acceptable toxicity profile. Rosuvastatin treatment should be studied further in the total neoadjuvant and non-operative management settings for locally advanced rectal cancer. Clinical trial information: NCT02569645 .
Updated results of ALTER-C002: Anlotinib combined with CAPEOX as first-line treatment in RAS/BRAF wild-type unresectable metastatic colorectal cancer.
Authors: Ding Ke-Feng , Liu Yue , Xiao Qian , He Jinjie , Hu Hanguang , Du Jinlin , Zhu Yuping , Chen Jiaqi , Liu Zhuo , Wang Jianping , Sun Lifeng , Xu Dong , Li Jun , Liao Xiujun , Wang Jianwei , Cai Yibo , Cai Cheng , Jin Zhekang , Yuan Ying 
Published: January 2023

138 Background: Anlotinib is an oral multi-target tyrosine kinase inhibitor, mainly targeting VEGFR1-3, FGFR 1-4, PDGFR a/b and c-kit. Previous trial had demonstrated that anlotinib monotherapy was effective and safe in advanced colorectal cancer. ALTER-C002 trial is an open-label, single-arm, phase II study, aimed to evaluate the efficacy and safety of anlotinib plus CAPEOX as first-line therapy in patients with RAS/ BRAF wild-type unresectable metastatic colorectal cancer (mCRC). Preliminary results demonstrated significant antitumor activity and manageable toxicity. Here we reported the updated results at the data cutoff of August 19, 2022. Methods: RAS/BRAF wild-type unresectable mCRC patients with no prior systemic treatment received anlotinib (12 mg p.o. qd, d1-d14, q3w), capecitabine (850 mg/m2 p.o., bid, d1-d14, q3w) and oxaliplatin (130 mg/m2 i.v., d1, q3w) for 6 cycles followed by anlotinib and capecitabine as maintenance therapy until disease progression. Tumor response was assessed every 6 weeks according to RECIST v1.1 by investigator. The primary endpoint was ORR, and secondary endpoints included safety, DCR, DOR and PFS. Results: From Nov 2019 to February 2021, 30 eligible patients were enrolled, of whom, median age was 60y (range, 32-72y), 26 (86.7%) had left colon or rectal cancer, and 25 (83.3%) had liver metastases. The ORR was 76.7% (95% CI, 57.7-90.1%) with 2 patient achieved a complete response (CR); DCR was 93.3% (95% CI, 77.9-99.2%). At the data cutoff date, the median DOR was 7.9 months (95% CI, 4.3–11.4) and the median DOT was 8.38 months (95%CI, 5.9-10.9). The median OS has not reached yet, the 24-month OS rate was 72.8% (95%CI, 50.7-86.3%) and the 30-month OS rate was 58.3% (95%CI:25.5-80.8%). Grade 3-4 treatment-emergent adverse events (TEAEs) occurred in 25 (83.3%) patients; the most common grade 3 or 4 TEAEs ( > 10%) were hypertension (50%, 15/30 pts), neutropenia (26.7%, 8/30 pts) and diarrhea (13.3%, 4/30 pts). No grade 5 treatment-related events occurred. Conclusions: Anlotinib combined with CAPEOX exhibited promising ORR in the first-line treatment of mCRC compared to those of previous treatment. A longer follow-up is needed for a more complete assessment, and we launched a phase III, multicenter, open-label trial to assess the efficacy of this regimen comprehensively. Clinical trial information: NCT04080843 .
Association of transanal minimally invasive surgical approach with oncologic outcomes over conventional transanal excision for early-stage rectal cancer: An analysis of the US Rectal Cancer Consortium.
Authors: Warren Emilie , Gamboa Adriana C. , Medin Caroline , Hendren Samantha , Regenbogen Scott E. , Holder-Murray Jennifer , Kalady Matthew , Ejaz Aslam , Hawkins Alexander , Wise Paul , Silviera Matthew , Maithel Shishir K. , Balch Glen C. 
Published: January 2023

145 Background: For early-stage rectal cancer, minimally invasive surgical (MIS) approaches such as transanal endoscopic microsurgery (TEM) and transanal minimally invasive surgery (TAMIS) have not been widely adopted over conventional transanal excision (TAE). Direct comparisons are lacking. Our aim was to compare oncologic and perioperative outcomes between the two approaches. Methods: We identified patients with Tis or T1 tumors who underwent TAE or MIS (TEM or TAMIS) between 2007-2017 from the US Rectal Cancer Consortium database. Patients who received neoadjuvant therapy were excluded. Primary outcomes were rate of recurrence and recurrence-free survival (RFS). Results: Of 1881 patients, 89 met inclusion criteria: 44 TAE and 45 MIS (20 TEM, 25 TAMIS). Median age was similar between groups (63.5 years TAE vs 61 years MIS; p=0.582). Patients in each group had similar functional status and tumor size (1.86 cm TAE vs 1.79 cm MIS, p=0.837). The majority of patients had tumors ≤ 6 cm from the anal verge (75.7% TAE vs 65.5% MIS, p=0.544). The TAE group had a 10.3% margin positive rate versus 0% in the MIS group (p=0.049). There was a lower incidence of recurrence in the MIS group (4.5%) compared to TAE (26%, p=0.01); all recurred locally except for one in the TAE group. Median follow-up time was 23.7 months. On Kaplan-Meier analysis, MIS approach was associated with improved 5-year RFS (86.4%, p=0.005) and local RFS (86.4%, p=0.01), versus TAE (46.9% and 50.5%, respectively). On univariate cox regression analysis, lymphovascular invasion was associated with worse RFS (HR 4.23, p=0.033) and local RFS (HR 5.26, p=0.02), while MIS approach was associated with improved RFS (HR 0.15, p=0.015) and local RFS (HR 0.17, p=0.023). On multivariable cox regression, only MIS approach remained associated with improved RFS (HR 0.09, p=0.028) and local RFS (HR 0.11, p=0.045). Perioperative complication and readmission rates were equal between the two groups. Conclusions: In patients with Tis and T1 rectal cancers who undergo local excision, an MIS approach (TEM or TAMIS) is associated with a decreased rate of recurrence and improved RFS and local RFS compared to TAE, with no significant difference in perioperative complication rate. The MIS approach should be more frequently incorporated into standard practice. [Table: see text]
Antitumor activity of intraperitoneal (IP) paclitaxel to mucinous appendiceal adenocarcinoma in orthotopic patient-derived xenograft model.
Authors: Ito Ichiaki , Yousef Abdelrahman M.G. , Dickson Princess A , Fournier Keith F. , Fowlkes Natalie Wall , Shen John Paul Y.C. 
Published: January 2023

151 Background: Appendiceal adenocarcinomas (AAs) are a rare and heterogeneous mix of tumors for which only few preclinical models exist for drug discovery. These tumors are commonly treated with chemotherapy like those for colorectal cancer despite clear evidence that the two cancers are distinctly different in their clinical behavior and molecular profiles. Taxanes such as paclitaxel (PTX) and docetaxel have been used in the systemic treatment of gastric cancer with peritoneal metastases. IP administration of PTX has been considered a promising treatment for eliminating peritoneal metastasis, as IP delivery of PTX can attain a higher drug exposure in the peritoneal cavity with reduced systemic toxicity because of high local concentrations over a long period of time due to its hydrophobic property. The purpose of this study was to test the efficacy of IP PTX treatment in orthotopic AA PDX models. Methods: AA tumors TM00351, PMP-2 and PMCA-3 were implanted in the peritoneal cavity of NSG mice. PDX models were treated with PTX (6.25, 12.5 or 25.0 mg/kg, IP) with weekly (3 weekly treatments and 1 week off, for two cycles) or biweekly (biweekly treatments for up to 12 weeks) schedule. The peritoneal tumor burden was monitored by MRI. Solid tumor size was evaluated by modified peritoneal Response Evaluation Criteria In Solid Tumors (mpRECIST) method using ImageJ software and mucinous tumor volume was quantified by OsiriX Lite software. Results: TM00351, taken from a high-grade tumor (Grade 3), formed mucin-rich solid tumors with mucinous ascites. PDX models PMP-2 (Grade 2) and PMCA-3 (Grade 3), both with GNASR201C mutation, had a mucinous phenotype similar to GNAS mutant appendiceal tumors in humans. Weekly 25.0 mg/kg of IP PTX treatment reduced AA tumor growth of TM00351 (77.9% reduction vs. control), PMP-2 (98.6% reduction vs. control), and PMCA-3 (85.6% reduction vs. control). Similarly, biweekly 25.0 mg/kg of IP PTX treatment was effective on PMCA-3 (66.2% reduction vs. control). Survival of PMCA-3 PDX mice was significantly improved by 12.5 mg/kg (p=0.0254, log-rank test) and 25.0 mg/kg (p=0.0038) of IP PTX. At 25.0 mg/kg IP PTX treatment induced 12.0% body weight loss of PMCA-3 PDX mice 1 week after the treatment. Lower doses of IP PTX treatment, 6.25 and 12.5 mg/kg, did not induce significant body weight loss or any noticeable adverse effects on mice. Comparing the efficacy of IV to IP administration, neither 6.25 or 12.5 mg/kg of IV PTX reduced growth of PMCA-3, 25.0 mg/kg of IV PTX was lethal to mice shortly after administration. Conclusions: IP PTX is a therapeutically active for mucinous AA tumors.
Colorectal cohort analysis from the Intraperitoneal Chemotherapy After Cytoreductive Surgery for Peritoneal Metastasis (ICARuS) clinical trial.
Authors: Nash Garrett Michael , Garcia-Aguilar Julio , Paty Philip , Gonen Mithat , Foote Michael Bonner , Chung Sebastian , Mohamed Mostafa , Aguirre Nicole , Weiser Martin R. , Rassam Rachel , Guillem Jose G. , Smith Jesse Joshua , Pappou Emmanouil , Wei Iris H , Momtaz Parisa , Gollub Marc J , Vakiani Efsevia , Shia Jinru , Saltz Leonard B. , Cercek Andrea 
Published: January 2023

160 Background: ICARuS is a randomized phase II, multicenter trial to evaluate the relative efficacy of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) with mitomycin C vs. Early Postoperative Intraperitoneal Chemotherapy (EPIC) with floxuridine (FUDR), after cytoreductive surgery (CRS), for the treatment of peritoneal metastases (PM) from colorectal (CRC) or appendiceal cancer (AC). PRODIGE7 results failed to demonstrate benefit of HIPEC therapy after complete gross resection of CRC PM, prompting termination of CRC accrual and early cohort analysis. Methods: Patients with isolated, confirmed PM were eligible for 1:1 randomization to CRS plus HIPEC with mitomycin C or CRS plus EPIC with FUDR. Patients were stratified by recent systemic chemotherapy and disease (AC vs. CRC). The trial was originally powered to evaluate 212 patients for a 20% gain in a primary endpoint of 3-year progression free survival (PFS: HR = 1.75). Results: Seventy-five CRC patients were included between 4/2013 and 12/2018 for HIPEC (N = 40) or EPIC (N = 35) treatment. Baseline characteristics were well balanced. After a median follow up of 36 months, the median PFS was 7.7 months (95% CI: 6.3-11.1) in the HIPEC arm and 8.8 months (95% CI: 7.1-21.9) in the EPIC arm, HR = 0.69 (95% CI: 0.42-1.14) p = 0.14. In the 42 left-sided primary cancers, the median PFS was 8.4 months (95% CI: 6.4-17.7) in the HIPEC arm and 12.5 months (95% CI: 8.1-NR) in the EPIC arm, HR = 0.60 (95% CI: 0.29-1.22) p = 0.14. In the 33 right-sided primary cancers, the median PFS was 6.5 months (95% CI: 5.5-14.1) in the HIPEC arm and 8 months (95% CI: 5.8-24.1) in the EPIC arm, HR = 0.80 (95% CI: 0.39-1.64) p = 0.53. PFS was significantly better in the EPIC arm among patients with BRAF wildtype (WT) tumors and patients with higher PM burden (PCI > 7). There was no difference between HIPEC and EPIC in the primary toxicity endpoint of complications grade 3 or above (23 vs. 34%, p = 0.3). Conclusions: Three-year PFS did not significantly differ between treatment arms. The lack of survival benefit of HIPEC in the entire cohort and in subset analysis is consistent with the findings of PRODIGE7. ICARuS remains open to accrual for AC. These data support further investigation of the potential benefit of EPIC with CRS in carefully selected patients with CRC PM. Clinical trial information: NCT01815359 .