bluuebunny/crossref_metadata_2025_split huggingface dataset:
Angiotensin receptor blockers and severe diarrhea and/or enterocolitis induced by CAPOX in patients with colorectal cancer: A multicentric cohort.
Authors: Fernandes Teixeira Adriano Fernandes , Felismino Tiago Cordeiro , Donadio Mauro Daniel Spina , Catani Greta , Da Silva Ana Luiza Mattos , Weschenfelder Rui Fernando , O'Connor Juan Manuel , Coutinho Anelisa Kruschewsky , Riechelmann Rachel 
Published: January 2024

88 Background: While patients (pts) with colorectal cancer (CRC) treated with CAPOX (capecitabine and oxaliplatin) may experience severe diarrhea, risk factors for this toxicity remain undetermined. We have previously shown that concurrent use of angiotensin receptors blockers (ARB), a known inhibitor of TGF-B which is important for gut mucosa proliferation, significantly increased the risk of severe diarrhea and/or enterocolitis. Here we conducted a larger and multicenter study to validate this finding, adjusting for other risk factors. Methods: Multicenter retrospective cohort of CRC pts who received ≥ 1 cycle of CAPOX. The primary endpoint was grade (G) ≥ 3 diarrhea and/or enterocolitis as described by Common Terminology Criteria for Adverse Events version 5.0. Clinical data were retrieved from medical charts. Unadjusted logistic regression was used to evaluate risk factors for ≥ G3 diarrhea/enterocolitis (use of ARBs or angiotensin-converting enzyme inhibitors [ACEi], age, ECOG, Age-adjusted Charlson Comorbidity Index [A-CCI], sidedness, presence of ileostomy, treatment intent [curative vs palliative], use of proton pump inhibitors or antiacid, and center). A multivariable analysis was performed with variables with P < 0.05 deemed significant. Results: From April/2010 to December/2023, 348 pts were included: 175 (50.3%) were female, median age was 61 years (28 - 87), 259 (74.4%) had stage III and 76 pts (21.9%), stage IV. 58 pts (16%) had G3 ≥ diarrhea/ enterocolitis, mostly before 3rd cycle. Age ≥ 65 years (Odds ratio [OR] 3.18; P < 0,0001; 95% CI, 1.78 to 5.68 ); right-sided tumors (OR 1.73; P=0.075; 95% CI, 0.95 to 3.17); use of ARBs or ACEi (OR 1.57; P=0.127; 95% CI, 0.88 to 2.79); A-CCI (OR 1.12; P=0.042; 95% CI, 1.004 to 1.23) were associated with ≥ G3 diarrhea/enterocolitis in univariate analyses. In the multivariable analysis, age ≥ 65 years was significant (OR 3.13; P=0.001; 95% CI, 1.58 to 6.20), but use of ARBs or ACEi was not significant (OR 1.16; P=0.635; 95% CI, 0.62 to 2.13). Five out of 9 pts who used Olmesartan had ≥ G3 diarrhea/enterocolitis. Conclusions: Among pts treated with CAPOX, ≥ 65 years, but not use of ARBs or ACEi, was an independent risk factor for ≥ G3 diarrhea/enterocolitis. Concurrent Olmesartan and CAPOX should be used with caution.
Oxaliplatin desensitization in patients with GI malignancies: Experience from a tertiary cancer center.
Authors: Connell Jacqueline , Vlachostergios Panagiotis J. , Williams Joseph Thomas David , Hassan Jurgees , Mansoor Wasat , Mullamitha Saifee , Hubner Richard , Braun Michael , Saunders Mark , Barriuso Jorge , Waddell Tom , Alam Nooreen , Kamposioras Konstantinos 
Published: January 2024

89 Background: Oxaliplatin hypersensitivity is not uncommon in patients with gastrointestinal (GI) cancers receiving chemotherapy. The use of oral premeditations (dexamethasone, cetirizine and famotidine) starting 24 hours before treatment and continuing for a total of three days, further intravenous premedication (dexamethasone, chlorphenamine and famotidine) 30 minutes before treatment and the gradual administration of oxaliplatin over 6.5 hours in four separate escalating doses (desensitisation protocol) is commonly used in such cases. While desensitisation is an option, especially in severe cases, responses and survival outcomes upon rechallenge are not well described. Methods: A retrospective chart review of patients with various GI malignancies who received oxaliplatin-based desensitisation chemotherapy after a severe drug reaction between October 2019 and October 2022 at a single cancer centre was performed. Clinicopathological characteristics and oncological outcomes were assessed. Results: Forty-four patients with a median age of 61 years (range 38-81) were studied. The majority had a diagnosis of CRC (n=22; 50%), followed by oesophago-gastric (n=19; 4%), appendiceal (n=1), cholangiocarcinoma (n=1), and cancer of unknown primary (n=1). More than two thirds of patients (n=32, 73%) were treated with palliative intent. The most common regimens associated with oxaliplatin hypersensitivity reactions after a median of 3 cycles (range 1-10) were FOLFOX (n=24, 55%), CAPOX (n=18, 41%), FLOT (n=1) and FOLFOXIRI (n=1). Seven patients (16%) had another reaction after desensitisation, leading to discontinuation of treatment. Thirty-seven patients (84%) completed treatment as planned. Treatment outcomes after desensitisation included 5 (11%) patients with no evidence of disease (NED) after adjuvant treatment, 16 (37%) patients with disease control, including 3 (7%) partial responders (PR) and 13 (30%) patients with stable disease (SD), and 23 (52%) patients with progressive disease (PD). Conclusions: Oxaliplatin desensitisation is feasible with low discontinuation rates and leads to acceptable oncological outcomes. All patients should be offered desensitisation to allow continuation of active systemic therapy.
Real-world assessment of capecitabine and oxaliplatin (CAPOX) tolerability in patients with localized colorectal cancer undergoing curative-intent therapy: A comprehensive single institution analysis.
Authors: Mears Veronica , Naleid Nikolas , Kakish Hanna , Selfridge J. Eva , Conces Madison , Lumish Melissa Amy , Bajor David L , Mahipal Amit , Chakrabarti Sakti 
Published: January 2024

90 Background: The combination of capecitabine and oxaliplatin (CAPOX) is commonly used in patients with localized colorectal cancer (CRC) receiving curative-intent treatment. However, real-world data on the tolerability of CAPOX in this patient population are limited. This study aimed to assess the tolerability of CAPOX in a single-institution cohort of patients with localized CRC. Methods: A retrospective analysis was conducted using our institutional pharmacy database to identify patients with localized CRC who received neoadjuvant or adjuvant CAPOX. Demographic information, clinical characteristics, and treatment details were extracted from electronic health records. The primary endpoint was the rate of treatment completion, defined as the receipt of all planned chemotherapy cycles at full dosage, for both the overall cohort and patients aged 65 and above. Secondary outcome measures included the rate of grade 3 or higher adverse events, the frequency of hospital admissions due to CAPOX-related toxicities, and dose reductions. Results: A total of 153 patients were included in the analysis, with a median age of 61 years (range 32-84). Among them, 49% were female, 78.4% had stage III CRC, and the remaining had stage II disease. The racial distribution was 81% White and 15.7% Black. The proportion of patients who completed all planned CAPOX doses was 55.5% (85/153) in the entire cohort and 38% (23/60) in patients aged 65 and above (p = 0.22). Among patients intended to receive 4 cycles of CAPOX, only 57% (37/65) completed all 4 cycles. Female patients were less likely to complete treatment than male patients (p = 0.01). Dose reductions for oxaliplatin and capecitabine were observed in 37% (57/153) and 39% (59/153) of patients, respectively. Hospitalizations related to CAPOX-induced toxicities occurred in 18% (27/153) of patients, and 31% (47/153) experienced grade 3 or higher adverse events. A switch to FOLFOX was observed in 5% (8/153) of patients. Conclusions: This study highlights that a substantial number of patients with localized CRC undergoing curative-intent treatment with CAPOX do not complete the planned courses, potentially impacting their overall survival. Moreover, a significant proportion of patients experience grade 3 or higher toxicities with CAPOX, necessitating hospital admissions. These findings underscore the need for careful patient selection and management strategies to optimize the therapeutic benefits of CAPOX in this setting.
Efficacy and safety of LY3537982, a potent and highly selective KRAS G12C inhibitor in KRAS G12C-mutant GI cancers: Results from a phase 1 study.
Authors: Hollebecque Antoine , Kuboki Yasutoshi , Murciano-Goroff Yonina R. , Yaeger Rona , Cassier Philippe Alexandre , Heist Rebecca Suk , Fujiwara Yutaka , Deming Dustin A. , Ammakkanavar Natraj , Patnaik Amita , Shimizu Toshio , Call Justin , Han Sae-Won , Fink Aaron Alan , Chen Aaron , Willard Melinda D , Balar Arjun Vasant , Koyama Takafumi 
Published: January 2024

94 Background: LY3537982 is an oral, potent, and highly selective inhibitor of GDP-bound KRAS G12C with unique pharmacologic properties that achieve high target occupancy at low absolute exposures. Here we present results of GI tumors treated on LOXO-RAS-20001, a phase 1 study of LY3537982 in patients (pts) with a KRAS G12C mutation. Methods: Dose escalation followed a mTPI-2 method. Dose expansion included a combination with cetuximab in colorectal cancer (CRC). All pts were KRAS G12C inhibitor naïve. Key objectives were to determine the RP2D, safety, PK, and antitumor activity per RECIST v1.1. Results: As of 24 July 2023, 73 pts with CRC (32), PANC (24), BTC (10), and other GI tumors (7) were treated with 50-200 mg BID LY3537982. Median age was 62 yrs (range, 36-85) and median number of prior lines of therapies was 3 (range, 0-11). No DLTs were observed. Grade 1 diarrhea was the highest frequency TEAE regardless of attribution (33%). At a median time on treatment of 4 months (range, 0.1-18), 20 pts are ongoing and 53 discontinued treatment. In the combination cohort, 46 pts with CRC were treated with 100 or 150 mg BID LY3537982 and cetuximab. Median age was 57 yrs (range, 35-77) and median number of lines of prior therapies was 3 (range, 1-8). 1 pt at 100 mg BID had a DLT (ALT/AST increased) and required a dose reduction. TEAEs ≥30% were dermatitis acneiform (59%), diarrhea (44%), dry skin (44%), hypomagnesemia (33%), and fatigue (30%). Vomiting, pruritus, skin fissures, headache, nausea, pyrexia, and rash were mostly grade 1 with 20-24% occurrence. At a median time on treatment of 6 months (range, 0.6-11), 37 pts are ongoing and 9 discontinued treatment (none due to AE). Table shows efficacy data. Conclusions: In pts with GI tumors, LY3537982 alone or in combination with cetuximab demonstrated preliminary efficacy and a favorable safety profile. Clinical trial information: NCT04956640 . [Table: see text]
Risk of relapse and patient selection for metastatic colorectal cancer liver surgery.
Authors: Machete Madalena , Azevedo Pedro , Lopes Francisco , Baptista Carlota , Margarido Inês , Branco Carlota , Correia Jorge , Pinto João Moreira , Pereira José António , Simões Pedro , Faria Harrison Ana , Rodrigues Tânia Abreu , Teixeira Jose N. , Coelho Jose Luis P. 
Published: January 2024

96 Background: Previous data on surgery for colorectal cancer (CRC) liver metastases (CRLM) documented improvement in overall survival (OS) and low perioperative mortality, but patient (pt) selection requires complex multidisciplinary work. Predictive scores such as the Comprehensive Evaluation of Relapse Risk (CERR) estimate relapse risk after surgery and help in the pre-operative decision. Objectives: This study aims to evaluate OS and progression-free survival (PFS) in a population of pts who had surgery for CRLM, and to analyse survival outcomes by risk groups, according to the CERR score. We identified individual, anatomic and biological factors with potential prognostic impact. Methods: We retrospectively analysed the medical records of pts who had CRLM surgery between January 2012 and December 2021 in two Portuguese reference centres. Outcomes for CRLM surgery were analysed by risk groups according to the CERR score of each pt (based on nodal status, preoperative CEA/CA 19.9 values, KRAS/BRAF status, presence of extrahepatic disease and modified tumour burden score). Univariate and multivariate survival analyses were performed with the log-rank test and Cox proportional-hazards regression models. Results: A total of 174 pts were included: 66,1% (n=115) male, mean age at CRLM diagnosis 62,1 (±11,5) years, 80,5% (n=140) with isolated liver metastases. Thirty-three pts (19%) had a second surgery, independently of the CERR score (chi-square p = 0,60). Eighteen (10,3%) pts had a CERR score of 0-1 (low-risk, LR), 96 (55,2%) of 2-3 (medium-risk, MR) and 60 (34,5%) of 4-5 (high-risk, HiR). With a median (MED) follow-up of 85,1 (15,6-186,5) months (mo), 100 (57.5%) pts have died. MED OS was 88,0 mo (95% confidence interval [CI] 40,6-135,4) for LR, 46,4 mo (95% CI 38,7-54,1) for MR and 30,7 mo (95% CI 23,1-38,4) for HiR pts (p=0,02); ECOG performance status was an independent prognostic factor (p=0,002) for OS. Median PFS was 88,0 mo (95% CI 6,9-169,0) for LR, 12,9 mo (95% CI 9,1-16,7) for MR and 7,7 mo (95% CI 5,9-9,4) for HiR pts (p<0,001); positive resection margins and prior induction chemotherapy (CT) were additional independent negative prognostic factors for PFS (p<0,001). Conclusions: These results suggest a significant association between relapse risk after surgery for CRLM and both OS and PFS. The CERR score can be used to select potential candidates for CRLM surgery and improve the impact of this intervention in pts with CRC. The link between induction CT and worse survival may reflect selection bias as these pts possibly had a higher volume of disease and therefore received initial systemic therapy. Prospective studies are required to confirm these results.
Combination of hSTC810 and capecitabine therapy in metastatic colorectal cancer with resistance or intolerance to oxaliplatin and irinotecan-based chemotherapy: A single arm, phase 1b/2, multicenter study.
Authors: Lee Jiwon , Lee Soohyeon , Kim Jwa Hoon 
Published: January 2024

TPS223 Background: hSTC810 is a humanized anti-BTN1A1 monoclonal antibody of the IgG4 isotype that binds to human BTN1A1 and blocks the interaction between BTN1A1 and its ligands. Butyrophilin 1A1 (BTN1A1) is a novel immune checkpoint protein that exhibits an expression pattern mutually exclusive to that of PD-1/PD-L1. BTN1A1 has been shown to inhibit anti-CD3-induced cytokine production and T-cell proliferation and also inhibit anti-CD3-induced p38 mitogen-activated protein kinase (MAPK), cAMP response element-binding protein (CREB) and target of rapamycin (TOR) phosphorylation in human T-cells. Mouse studies demonstrated that an anti-BTN1A1 antibody exhibited antitumor activity both as a single agent and in combination with anti-PD-1/PD-L1 or radiation therapy. In the first in human phase 1 study, investigating the safety and efficacy of hSTC810 in solid tumors, hSTC810 showed acceptable safety profile and the disease control rate (DCR) was 39.3%, which indicates its potential efficacy. Methods: This multi-center, open label phase 1b/2 study evaluates the safety, tolerability, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of hSTC810 combined with capecitabine in patients with metastasis/recurrent colorectal cancer. The trial is enrolling adults who are (1) histologically or cytologically confirmed colorectal adenocarcinoma (2) resistant or intolerant to oxaliplatin and irinotecan-based chemotherapy (3) adequate hematologic, hepatic, renal function (4) measurable or non-measurable disease by RECIST 1.1 (5) ECOG PS 0~2 (6) resolved acute effects of any prior therapy. Treatment will continue until disease progression or unacceptable toxicity, whichever occurs first. The primary endpoint of phase 1b is to determine dose-limiting toxicity (DLT), and recommended phase 2 dose (RP2D) of hSTC810 combined with capecitabine, each in 21-day cycles. Phase 1 comprises 3 escalation arms, and if the initial dose is deemed unsafe, 2 deescalation arms will be initiated. Once the RP2D is determined, the Phase 2 will enroll up to 39 patients. The primary endpoint of phase 2 is progression free survival (PFS); secondary endpoints include objective response rate, overall survival, disease control rate, duration of response and quality of life. The study began in Q4 2023 and is recruiting patients. AEs are assessed according to CTCAE v5. Tumor response is determined according to RECIST 1.1 criteria. An exploratory study is underway to investigate the impact of hSTC810 on the tumor microenvironment and cytokines, utilizing both tissue biopsies and blood sampling. Clinical trial information: NCT05990543 .
Phase 1/2 evaluation of revumenib in patients with advanced colorectal cancer and other solid tumors.
Authors: Parikh Aparna Raj , Radojcic Vedran , Clancy Myles , Brouwer Susan , Kushwaha Shaliny , Huang Yifan , Gabrail Nashat 
Published: January 2024

TPS227 Background: Aberrant transcription in cancer can be reversed by targeting critical epigenetic regulators. For example, in acute leukemias driven by increased HOX gene expression, inhibition of the menin-KMT2A interaction by revumenib induced remission in patients with heavily pretreated disease (Issa et al 2023). In solid tumors promoted by the aberrant activation of the Wnt/β-catenin pathway, in vitro data and in vivo studies have shown that small molecule inhibition of the menin-KMT2A interaction restricts growth, with potential therapeutic benefit in colorectal cancer (CRC), castration-resistant prostate cancer, estrogen receptor–positive breast cancer, gastrointestinal stromal tumors, and Ewing sarcoma. To test the therapeutic strategy of inhibiting the menin-KMT2A interaction in solid tumor malignancies, this study (NCT05731947) will evaluate revumenib in patients with CRC and other solid tumors. Revumenib is an oral, potent, selective inhibitor of the menin-KMT2A interaction. Methods: This phase 1/2 study is evaluating revumenib in adults aged ≥18 years with locally recurrent or metastatic CRC who have failed ≥1 prior line of therapy and in patients with other solid tumors who have failed available standard therapies. Inclusion criteria include diagnosis of microsatellite stable/proficient mismatch repair CRC or other solid tumors. Patients with CRC must be unable to receive or have disease that progressed on oxaliplatin, irinotecan, and bevacizumab; if left-sided RAS wild-type CRC, the patient must have received anti–epidermal growth factor receptor therapy. The primary phase 1 objectives are to determine the safety, tolerability, maximum tolerated dose, and recommended phase 2 dose of revumenib in patients with CRC and other solid tumors and to assess its antitumor effects. The phase 2 primary objective is to assess the antitumor effects of revumenib by blinded radiographic review. Phase 1 consists of all-comers’ dose escalation (phase 1a), and signal-seeking expansion in CRC (phase 1b). Using a rolling 6 design, the revumenib starting dose will be 163 mg 3 times daily in 28-day cycles. Up to 6 patients will be enrolled in a dose cohort. Dose escalation cohorts may be expanded and used for signal seeking in non-CRC tumor types. Phase 1b in CRC will begin when a potential phase 2 dose has been identified. The disease control rate at 6 cycles and overall response rate will be used to assess antitumor activity and will determine initiation of phase 2. In phase 2, patients with advanced CRC will be randomized 2:1 to revumenib or investigator's choice of 1 of 2 standard-of-care therapies. Patients will be followed for progression-free survival, with response assessments evaluated locally and confirmed by blinded radiographic review. As of September 5, 2023, 13 patients were enrolled in phase 1a of this study. Clinical trial information: NCT05731947 .
An open-label clinical trial of RP2 and RP3 oncolytic immunotherapy in combination with atezolizumab plus bevacizumab for the treatment of patients with advanced colorectal carcinoma.
Authors: Lenz Heinz-Josef , Somasundaram Ashwin , Lee Michael Sangmin , Sohal Davendra , Safyan Rachael A , Zhu Mojun , Jones Jeremy Clifton , Bhansali Aditya , Kalwar Roza , Cho May , Grothey Axel 
Published: January 2024

TPS228 Background: Colorectal cancer (CRC) is the third most frequently diagnosed cancer and the second leading cause of cancer-related mortality worldwide. PD-1/PD-L1 inhibition, in combination with other modalities, has demonstrated significant benefit in patients (pts) with microsatellite instability-high or mismatch repair–deficient CRC. However, these agents have limited, if any, clinical benefit in pts with microsatellite stable (MSS) or mismatch repair–proficient (pMMR) CRC. RP2 is an enhanced potency oncolytic herpes simplex virus type 1 which expresses the fusogenic gibbon ape leukemia virus glycoprotein with the R sequence deleted (GALV-GP-R–), granulocyte-macrophage colony-stimulating factor (GM-CSF), and an anti–CTLA-4 antibody-like molecule; RP3 additionally expresses 4-1BB and CD40 activating ligands but does not express GM-CSF. Both agents have demonstrated preliminary safety and antitumor activity in pts with solid tumors. This study will evaluate the safety and activity of RP2 and RP3 in combination with atezolizumab (Atezo) plus bevacizumab (Bev) in pts with advanced MSS/pMMR CRC (NCT05733611). Methods: Pts with a histologic diagnosis of unresectable and/or metastatic CRC, with documented MSS or pMMR status, and previously treated with up to 3 standard-of-care systemic regimens will be enrolled in the RP2 + Atezo + Bev or RP3 + Atezo + Bev treatment groups (30 pts per group). Further key inclusion criteria include Eastern Cooperative Oncology Group performance status 0 to 1 and adequate hepatic, renal, and hematologic function. RP2/RP3 will be injected into tumors by direct or image-guided injection. Pts will receive 8 total doses of up to 10 mL of RP2 or RP3, with a first dose concentration of 1 × 106 plaque-forming units (PFU)/mL, followed by 3 doses of 1 × 107 PFU/mL every 2 weeks, and then 4 doses of 1 × 107 PFU/mL every 3 weeks. Pts may receive a second course of up to 8 injections of RP2/RP3 if study criteria are met. Bev will be administered starting on week 1; Atezo will be administered starting week 7. The primary endpoint is objective response rate; secondary endpoints are safety, overall survival, progression-free survival, duration of response, and complete response rate. Antitumor activity will be evaluated using Response Evaluation Criteria in Solid Tumors version 1.1 as modified for this study. Safety will be assessed by physical examination, clinical laboratory evaluations, vital signs, and monitoring for adverse events (AEs; including serious AEs). Clinical trial information: NCT05733611 .