bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinicopathological features of post-colonoscopy colorectal cancer in patients with Japanese Lynch syndrome: A multicentric retrospective observational study.
Authors: Takao Akinari , Iizuka Toshiro , Takao Misato , Chino Akiko , Akagi Kiwamu , Yamada Masayoshi , Tanakaya Kohji , Ishida Hideyuki , Komori Koji , Sasaki Kazuhito , Miguchi Masashi , Hirata Keiji , Sudo Tomoya , Miyakura Yasuyuki , Ishikawa Toshiaki , Yamaguchi Tatsuro , Tomita Naohiro , Ajioka Yoichi
Published: January 2024

79

Background: Due to the high incidence of heterochronic and concurrent colorectal cancer in Lynch syndrome (LS), colonoscopic surveillance is recommended in Japan every 1-2 years. Even with regular colonoscopic surveillance, post-colonoscopy colorectal cancer (PCCRC) often occurs in the intervals between surveillance, but there are currently no reports of the details of PCCRC in LS in Japan. Methods: Of 1756 colonoscopies performed between 2009 and 2018 in 316 patients with a diagnosis of LS confirmed by genetic testing who were enrolled in a nationwide, Japanese, multicentric study conducted by the Committee of Hereditary Colorectal Cancer of the Japanese Society for Cancer and Rectum, 1203 colonoscopies in 256 patients were assessed to determine the clinicopathological characteristics of PCCRC, after including cases of first-time surveillance, previously untreated lesions, and inadequate pretreatment. Then, the incidence of PCCRC was compared between patients with a median surveillance colonoscopy interval < 12 months (group A) and > 12 months (group B). Results: There were 49 cases of PCCRC with a total of 84 lesions. The number of lesions per tumor depth was 66, one, five, seven, four, and one for pTis, pT1, pT1a, pT1b, pT2, and pT3, respectively. Two (2.4%), 20 (23.8%), 21 (25%), four (4.8%), 18 (21.4%), and 19 (22.6%) lesions were localized in the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum, respectively. In pTis-pT1b, the macroscopic type was 0-IIa in 33 lesions (41.8%), 0-IIc in four lesions (5.1%), 0-IIa+IIc in five lesions (6.3%), 0-IIb in one lesion (1.3%), 0-Is in 15 lesions (19%), 0-Ip in one lesion (1.3%), 0-Isp in 16 lesions (20.3%), and unknown in four lesions. In pT1b-pT3, seven lesions (63.6%) were smaller than 20 mm. In terms of the median interval between surveillance colonoscopies, 130 patients had a median interval < 12 months (group A), and 126 patients had a median interval > 12 months (group B). In groups A and B, PCCRC, metachronous cases, simultaneous cases, and depths than pT1b were observed in 29 (22%) and 20 (16%) cases (p=0.21); 14 (11%) and two (1.6%) cases (p=0.006); six (4.6%) and one (0.8%) case (p=0.22), and six (4.6%) and four (3.2%) cases (p=1), respectively. Conclusions: In PCCRC in Lynch syndrome, invasive carcinomas < 2 cm should be noted. In addition, a surveillance interval of 12 months may be insufficient in patients with LS. Thus, further investigation is warranted.
Impact of the COVID-19 pandemic on colorectal cancer stage at presentation.
Authors: Squires Malcolm Hart , Lindolm Nicole , Shea Reilly , Donahue Erin E. , Wallander Michelle , Salo Jonathan C.
Published: January 2024

80

Background: The primary study objective was to assess the impact of COVID-19 on the stage at presentation for patients with newly diagnosed colorectal cancer treated within a large cancer center network. Additionally, we aimed to evaluate differences in pathologic stage and treatment modality for patients diagnosed with colorectal cancer both immediately before and during the height of the COVID-19 pandemic. Methods: A retrospective analysis was performed on all subjects newly diagnosed with colorectal cancer between January 2019 and April 2021 at Levine Cancer Institute. Patients had a primary diagnosis of adenocarcinoma of the colon, rectum, or appendix. Patients were categorized into two cohorts based on date of diagnosis, with the pre-COVID-19 group diagnosed between January 2019 and February 2020 and the COVID-19 group diagnosed between March 2020 and April 2021. Chi-squared tests were used to evaluate the association between COVID-19 group and stage at presentation as well as pathologic stage. Results: A total of 1,190 patients were diagnosed with colorectal cancer within the study timeframe. Of the 613 patients diagnosed pre-COVID-19, 159 (25.9%) had metastatic disease at initial presentation. Comparatively, 577 patients were diagnosed during the COVID-19 study period, with 143 (24.8%) presenting with metastatic disease (p = 0.65).Of the 888 patients who presented with non-metastatic disease, 770 underwent primary surgical intervention for the initial treatment of their cancer, with 396 (87.2%) pre-COVID-19 and 374 (86.2%) COVID-19 patients receiving surgery (p = 0.65). Likewise, no significant difference was observed for T-classification, N-classification, or overall pathologic stage among patients undergoing surgical resection between the pre-COVID-19 and COVID-19 groups (p = 0.20; Table). Furthermore, amongst patients who presented with non-metastatic disease, chemotherapy was utilized for 200 (44.1%) patients diagnosed pre-COVID-19 and 190 (43.8%) patients diagnosed during COVID-19 (p = 0.93). Conclusions: We did not observe a significant difference in the proportion of patients presenting with metastatic colorectal cancer during COVID-19 versus those presenting pre-COVID-19. Furthermore, there was no significant difference observed among non-metastatic patients between the two groups for rates of initial surgical resection, pathologic stage, and treatment with chemotherapy. [Table: see text]
COLONTOWN Searching Safari: Education to remove barriers to pursue clinical trials for patients with metastatic colorectal cancer (mCRC).
Authors: Clauer Julie , Seybold Nancy , George Manju
Published: January 2024

82

Background: Clinical trials can expand otherwise limited treatment options for patients with metastatic cancer. Yet, the complexity of the trial landscape can prevent patients from pursuing trials. Even in mCRC patients motivated to participate in trials, 79% described trial search negatively, mainly ‘overwhelming.’ We hypothesized that “clinical trial-literacy” and familiarity with the tools/process of pursuing trials were critical precursors for patients to incorporate trials into their treatment plan. To test this, we, as managers of COLONTOWN, a large, online CRC patient/caregiver community, developed an interactive course. Methods: We reviewed many posts from the COLONTOWN clinical trial groups to identify gaps between the desire to participate in a trial and the knowledge/tools needed to do so. We then determined those most likely to benefit as mCRC MSS patients interested in, but not in urgent need of, trials. We developed a 4-week long course with 5 hours of live online sessions and 5 hours of homework. Participants built fluency in the language of clinical trials, learned about available tools, and identified and assessed trials in the context of their personal needs and disease dynamics. Unlike most other trial resources, the focus was on informed patient-centered decision-making, not on the science or mechanics of trials. The course was offered 3 times in 2022/23 with iterative improvements after each session. Participants (n=48) were assessed for their attitudes around trials before and after the course to measure impact. Results: We found that our repeatable, scalable course improves mCRC patient perceptions of and skills to pursue trials as evidenced by pre-course vs. post-course surveys. This included average response to “How prepared do you feel to find a clinical trial?” increasing from 2.1 to 3.8 on a 5-pt scale and positive sentiment about the process rising from 7% to 71% (table). Positive feedback on meeting course objectives and amount of coursework being ‘just right’ (96% and 92% of responses, respectively) support the material’s value for time invested. Conclusions: Through systematic skill building, self reflection, and practical tools, our guided course can build confidence and empower patients and caregivers to take the next step to pursue clinical trials. Patient education can indeed help overcome often-overlooked emotional and knowledge barriers to pursuing clinical trials present even in a motivated patient population. Next, we plan to create and assess the benefit of an additional on-demand e-learning course and to expand to other patient groups. [Table: see text]
Associations of postdiagnosis changes in physical activity with all-cause mortality among patients with stage I-IIA colorectal cancer.
Authors: Smit Karel , Derksen Jeroen W.G. , van Lanen Anne-Sophie , Wesselink Evertine , Kok Dieuwertje E. , Kampman Ellen , van Duijnhoven Fränzel J.B. , Koopman Miriam , May Anne M.
Published: January 2024

87

Background: Several observational studies show an association between physical activity (PA) at diagnosis and reduced risk of mortality among colorectal cancer (CRC) patients, but there has been limited research examining the potential benefit of changes in PA levels after CRC diagnosis. Here we investigate the association between change of PA and all-cause mortality in patients with stage I-IIA CRC receiving resection with curative intent. Methods: Data were used from two large Dutch CRC cohort studies (PLCRC & COLON), which assessed PA at diagnosis (T0), six (T6) and twelve (T12) months after diagnosis, using the SQUASH questionnaire. A total of 2540 stage I-IIA CRC patients with repeated PA measures (i.e. a T0 and at least a T6 or T12 questionnaire) were used for this analysis. Total PA was quantified by calculating Metabolic Equivalent Task (MET) hours per week and categorized as low, moderate, and high PA, based on tertiles of an age- and sex-matched sample of the general population. PA changes were evaluated at T6 and T12 relative to T0. Being active was defined per timepoint as being in the moderate or high total PA group, or adhering to the PA guideline (minimum of 150 minutes per week of moderate-intensity PA). Cox proportional hazards models were used to study the association between PA variables and all-cause mortality, adjusted for age, sex, BMI, and tumor location (colon vs rectum). Results: Median follow-up time was 35 months (interquartile range 19 – 55) during which a total of 133 deaths occurred. Being active at both T0 and T6 compared to being inactive at these timepoints, was associated with a lower rate of all-cause mortality for both PA variables (adjusted hazard ratio (HR) 0.39 [95% confidence interval 0.24-0.63] and 0.41 [0.23-0.72] for total PA and guideline adherence, respectively). Similar results were found when comparing T12 to T0 (being active according to total PA HR 0.20 [0.09-0.42] and guideline adherence HR 0.31 [0.14-0.72]). Changing to either activity or inactivity at T6 or T12 was not significantly associated with all-cause mortality (Table). Conclusions: Maintaining a physically active lifestyle following surgery for stage I to IIA CRC is associated with longer overall survival, reinforcing the recommendations for physical activity. [Table: see text]
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 .
Node-sparing modified short-course radiotherapy combined with CAPOX and tislelizumab for locally advanced MSS of middle and low rectal cancer (mRCAT): An open-label, single-arm, prospective, multicentre clinical trial.
Authors: Song Zhangfa , CAI CHENG , Sun Xiaonan
Published: January 2024

TPS233

Background: Neoadjuvant chemoradiotherapy followed by total mesorectal excision is a standard treatment for locally advanced rectal cancer. Mismatch repair-deficient locally advanced rectal cancer was highly sensitive to PD-1 blockade. However, most rectal cancers are mismatch repair-proficient or microsatellite stable subtypes for which PD-1 blockade is ineffective. Radiation can trigger the activation of CD8+ T cells, further enhancing the responses of microsatellite stable rectal cancer to PD-1 blockade. Radioimmunotherapy offers a promising therapeutic modality for rectal cancer. Progenitor T exhausted cells are abundant in tumour-draining lymph nodes and play an important role in immunotherapy. Conventional irradiation fields include the mesorectum and regional lymph nodes, which might cause considerable damage to T lymphocytes and radiation-induced fibrosis, ultimately leading to a poor response to immunotherapy and rectal fibrosis. This study investigated whether node-sparing modified short-course irradiation combined with chemotherapy and PD-1 blockade could be effective in patients with microsatellite stable locally advanced rectal cancer. Methods: Our clinical trial investigates the safety and efficacy of node-sparing modified short-course radiotherapy combined with CAPOX and tislelizumab for microsatellite stable locally advanced middle and low rectal cancer. This phase II study will recruit 32 patients to receive node-sparing modified short-course radiotherapy (the irradiated planned target volume only included the primary tumour bed but not the tumour-draining lymph nodes, 25 Gy/5f, 5 Gy/f) followed by CAPOX and tislelizumab. 2 of planned 32 patients have been enrolled. CAPOX and tislelizumab will be started two days after the completion of radiotherapy: oxaliplatin 130 mg/m2 intravenous infusion, day 1; capecitabine 1000 mg/m2 oral administration, days 1-14; and tislelizumab 200 mg, intravenous infusion, day 1. There will be three 21-day cycles. TME will be performed at weeks 11-12. We will collect blood, tumour, and lymphoid specimens; perform flow cytometry and in situ multiplexed immunofluorescence detection; and analyse the changes in various lymphocyte subsets. The primary endpoint is the rate of pathological complete response. The organ preservation rate, tumour regression grade, local recurrence rate, disease-free survival, overall survival, adverse effects, and quality of life will also be analysed. Clinical trial information: NCT05972655 .
MRD assay to evaluate recurrence and response via a tumor informed assessment: MARIA-Colorectal Cancer Observational trial.
Authors: Esplin Edward D. , Swan Kelli , Ifhar Lee , Heald Brandie , Nielsen Sarah M. , Pineda Alvarez Daniel Esteban , O'Callaghan William D. , Daber Robert , Ross Darrel , Vieira Carlos , Korn W. Michael , Chaudhuri Aadel A.
Published: January 2024

TPS242

Background: The detection of ctDNA in patients with colorectal cancer (CRC) is emerging as a potential biomarker to identify patients at high risk of relapse, assess treatment response and monitor for recurrence. Solid tumors are currently monitored by imaging studies, tumor markers and clinical symptoms and recent studies suggest tumor-informed molecular residual disease (MRD) testing may outperform these current methods and may serve as a prognostic biomarker to aid in the identification of patients at high risk of relapse (Reinert et al, 2019; Christensen et al, 2019; Coombes et al, 2019). Recent studies have demonstrated that tumor-informed MRD testing can detect relapse prior to detection with imaging in CRC and while interventional trials are needed, this may provide an opportunity for therapeutic intervention (Reinert et al, 2019; Kotani et al, 2023). This study utilizes the Invitae Personalized MonitoringTM (PCM) test, a highly sensitive tumor-informed MRD test (Zhao et al, 2023), to monitor early stage CRC patients. Methods: MARIA is a multi-site, prospective, observational trial in the United States of 200 newly diagnosed patients with early stage (high risk stage II, stage III and stage IV oligometastases) CRC undergoing curative intent treatment. Formalin fixed paraffin embedded (FFPE) tissue from the biopsy or surgical specimen is utilized to create the PCM test. Tumor tissue and a matched normal blood sample will undergo whole exome sequencing to identify 18-50 unique tumor variants to create a patient specific panel (PSP) for ctDNA analysis. Participants are asked to provide serial plasma specimens for ctDNA analysis at baseline, post surgical landmark and surveillance time points. A clinical report will be provided to the ordering physician. Physicians will be asked to complete a case report form for each participant when the first result is reported and every 6 months. The primary endpoint is to evaluate the correlation between the PCM test result at the landmark timepoint and the patient’s 24 month recurrence risk. Secondary endpoints include evaluating the impact on patient outcomes attributable to MRD result-based changes to treatment or clinical management, correlating between the PCM result at the baseline time point and patient recurrence risk and outcomes and investigating the lead time of PCM positivity over clinical/imaging based evidence of recurrence. Active enrollment started in March, 2022. Clinical trial information: NCT05219734 .
Cohort expansion from the phase 1 JEWEL-101 study investigating the tissue factor-targeting antibody-drug conjugate XB002 in patients with advanced solid tumors: Pancreatic and esophageal cancer cohorts.
Authors: Ulahannan Susanna Varkey , Johnson Melissa Lynne , Weiss Mia C. , Vandross Andrae L. , Vidal-Cardenas Sofia Luz , Syed Mustafa , Tolcher Anthony W.
Published: January 2024

TPS421

Background: Patients (pts) with metastatic pancreatic and esophageal cancers have poor prognosis, with 5-year survival rates of 3% and 6%, respectively (SEER 22). Tissue factor (TF), a factor VIIa receptor involved in initiation of the extrinsic coagulation cascade, is overexpressed in these tumors and has been associated with poor outcomes. XB002 is a novel antibody-drug conjugate (ADC) composed of a high-affinity TF-directed human monoclonal antibody conjugated to the linker-payload zovodotin. Zovodotin consists of an auristatin-based payload with a stable protease-cleavable linker; it is designed to have lower off-target payload deconjugation and improved tolerability versus other auristatin-based ADCs. In preclinical studies, XB002 showed encouraging safety and antitumor activity without affecting coagulation. JEWEL-101 (NCT04925284) is a phase 1, dose-escalation and multi-cohort expansion study evaluating XB002 alone and in combination with nivolumab or bevacizumab in pts with advanced solid tumors. Preliminary results from the dose-escalation stage showed XB002 was well tolerated at multiple dose levels, with low-grade ocular toxicity and no bleeding events or treatment-related peripheral neuropathy (PN).1 Presented here is the design of the expansion cohorts for pancreatic and esophageal cancers. Methods: Eligible pts must have an inoperable, locally advanced, metastatic, or recurrent solid tumor. Pts with pancreatic adenocarcinoma will receive XB002 single agent. Pts enrolled with esophageal squamous cell carcinoma (ESCC) will be randomized between 2 cohorts to receive either XB002 single agent or XB002 plus nivolumab. All pts in the pancreatic cancer and ESCC cohorts must have ECOG performance status of 0–1, measurable disease per RECIST v1.1, and have received 1–2 prior lines of systemic anticancer therapy, and radiographically progressed during or after their last therapy. Prior immunotherapy is allowed for pancreatic cancer and required for ESCC if locally considered standard of care and pts are eligible. Key exclusion criteria include prior treatment with TF-targeting or auristatin-based ADCs, and significant ocular disorders. Concomitant anticoagulants are permitted, and pts with PN are eligible, provided it is not impacting activities of daily living. The primary objective is objective response rate per RECIST v1.1 by investigator. Secondary objectives include safety, pharmacokinetics, immunogenicity, progression-free survival, duration of response, and overall survival. Enrollment is ongoing in the United States, Europe, and the Asia-Pacific region. 1. Ulahannan et al. ENA 2022. Clinical trial information: NCT04925284 .
A modified triplet combination of docetaxel, oxaliplatin, and fluorouracil for gastric cancer (GC) with peritoneal carcinomatosis (PC) and inoperable malignant bowel obstruction (MBO): A multi-center, non-randomized, three-cohort, phase II trial (Zhen Jing).
Authors: Xiao Jian , Li Shanshan , Zhai Xiaohui , Hong Wanjia , Cao Taiyuan , Lin Xiaoru , Shi Lishuo , Hu Meiyu , Zhang Rongqin
Published: January 2024

TPS426

Background: For GC, PC is ranked as the most common in relapse and the second common in metastasis. MBO is a frequent and preterminal complication of PC, which has been reported to have a poor overall survival (OS) of only 3 months without effective treatment. Medical therapy of gastroenteric drainage and symptomatic drugs is the cornerstone management for MBO, just alleviating symptoms. Interventional therapy and surgery are effective but indicated in limited patients (pts) with strict selection. Chemotherapy is the mainstay treatment for metastatic GC but its role in MBO is poorly defined. Only a few retrospective studies are available, showing conflicting results on obstruction clearance (OC) and OS. Methods: We are conducting the Zhen Jing trial in five Chinese centers to investigate the tolerability and efficacy of a dose-sense regimen of docetaxel, oxaliplatin and fluorouracil in MBO from GC. Cohort A is for pts in first-line setting. Cohort B is for second-line setting. Cohort C is for pts who have failed to two or more regimens. Eligible pts will receive the same experimental regimen every 28 days: docetaxel 25 mg/m2 on days 1, 8, 15; oxaliplatin 85 mg/m2 on days 1, 15; fluorouracil 1200 mg/m2 24-hour infusion on days 1, 8, 15. A Simon's two-stage optimal design is applied (table below). The primary endpoint is 60-day OC rate. Secondary endpoints are 30-day OC rate, time to OC, OC duration, safety, overall survival and quality of life. Till July 2023, a total of 34 pts has been enrolled (16 in cohort A, 9 in cohort B, 9 in cohort C). Inclusion Criteria: 18-75 years old; Eastern Cooperative Oncology Group performance status ≤ 3; adenocarcinoma of stomach or gastroesophageal junction; peritoneal carcinomatosis established by imaging data or pathological evidence; MBO below the Treitz ligament based on clinical grounds or radiological findings; inappropriate for operation judged independently by two surgeons; written informed consent. Exclusion Criteria: Treated by a combination regimen containing all the study drugs; allergy to any of the study drugs; HER-2 gene overexpression; high microsatellite instability or mismatch repair deficiency; strangulated obstruction; active gastrointestinal bleeding; uncontrolled active infection; unstable heart diseases; severe lung diseases; central nervous system diseases; concomitant cerebral or meningeal metastasis; surgery or stent are required. Clinical trial information: NCT04840264 . [Table: see text]
A phase I study of EO-3021 in adult patients with solid tumors likely to express CLDN18.2.
Authors: Pelster Meredith , Perez Cesar Augusto , Chandana Sreenivasa R , Uboha Nataliya Volodymyrivna , Swami Ashwin , McDonald Holly , Srivastava Jaya , Barve Minal A.
Published: January 2024

TPS429

Background: Claudin 18 isoform 2 (CLDN18.2) belongs to a family of tight junction proteins with broad expression in gastric and gastroesophageal junction (GEJ), pancreatic, esophageal, and other solid tumors. Expression of CLDN18.2 in normal tissue is limited to the gastric mucosa, making it a promising antibody-drug conjugate (ADC) therapeutic target. Currently, there are no approved therapies targeting CLDN18.2. EO-3021 (also known as SYSA1801) is an ADC comprised of a fully human CLDN18.2 monoclonal antibody (mAb) specifically conjugated at glutamine 295 with a cleavable linker and MMAE with a homogenous drug-to-antibody ratio (DAR) of 2. In preclinical models, EO-3021 selectively delivers a potent cytotoxic MMAE payload directly to cancer cells expressing CLDN18.2, retains antibody-dependent cellular toxicity (ADCC) and complement-dependent cytotoxicity (CDC) activity, and exhibits a bystander effect.1 In an ongoing Phase 1 study in China (NCT05009966), EO-3021 exhibited signs of anti-tumor activity in patients with gastric cancer and had an acceptable safety profile.2 Outside of Greater China, EO-3021 is being evaluated by Elevation Oncology for the treatment of patients with advanced or metastatic solid tumors likely to express CLDN18.2, particularly gastric and GEJ adenocarcinomas. Methods: This is a Phase I, open-label, multi-center, dose escalation and expansion study to investigate the safety, tolerability, pharmacokinetics (PK) and preliminary anti-tumor activity of EO-3021 in patients with solid tumors likely to express CLDN18.2 (NCT05980416). Patients whose tumors have progressed on or after standard therapy, or who are intolerable for available standard therapy are eligible for participation. Approximately 120 patients will be enrolled in this study. There are 4 planned dose levels in the dose finding portion of the study. Patients will receive EO-3021 intravenously (IV) once every three weeks until disease progression or unacceptable toxicity. The expansion cohort will evaluate EO-3021 in patients with gastric/GEJ adenocarcinoma. Provision of tumor samples (archived and fresh biopsy) is required for study enrollment. CLDN18.2 expression in tumor tissue via will be assessed by retrospective evaluation via central immunohistochemistry assay; results will be explored for possible correlation with tumor response. Enrollment in the dose escalation portion of the study began in August 2023. 1. Dan M, et al. Cancer Res. 83, 2023. 2. Wang Y, et al. J Clin Oncol. 41, 2023. Clinical trial information: NCT05980416 .