Explore the vast range of titles available.

Adjuvant chemotherapy has reduced the risk of tumor recurrence and improved survival in patients with resected colorectal cancer. Potential utility of circulating tumor DNA (ctDNA) prior to and post surgery has been reported across various solid tumors. We initiated a new type of adaptive platform trials to evaluate the clinical benefits of ctDNA analysis and refine precision adjuvant therapy for resectable colorectal cancer, named CIRCULATE‐Japan including three clinical trials. The GALAXY study is a prospectively conducted large‐scale registry designed to monitor ctDNA for patients with clinical stage II to IV or recurrent colorectal cancer who can undergo complete surgical resection. The VEGA trial is a randomized phase III study designed to test whether postoperative surgery alone is noninferior to the standard therapy with capecitabine plus oxaliplatin for 3 months in patients with high‐risk stage II or low‐risk stage III colon cancer if ctDNA status is negative at week 4 after curative surgery in the GALAXY study. The ALTAIR trial is a double‐blind, phase III study designed to establish the superiority of trifluridine/tipiracil as compared with placebo in patients with resected colorectal cancer who show circulating tumor–positive status in the GALAXY study. Therefore, CIRCULATE‐Japan encompasses both “de‐escalation” and “escalation” trials for ctDNA‐negative and ‐positive patients, respectively, and helps to answer whether measuring ctDNA postoperatively has prognostic and/or predictive value. Our ctDNA‐guided adaptive platform trials will accelerate clinical development toward further precision oncology in the field of adjuvant therapy. Analysis of ctDNA status could be utilized as a predictor of risk stratification for recurrence and to monitor the effectiveness of adjuvant chemotherapy. ctDNA is a promising, noninvasive tumor biomarker that can aid in tumor monitoring throughout disease management. CIRCULATE‐Japan encompasses both “de‐escalation” and “escalation” trials for circulating tumor DNA–negative and –positive patients, respectively, and helps to answer whether measuring circulating tumor DNA postoperatively has prognostic and/or predictive value. Our circulating tumor DNA–guided adaptive platform trials will accelerate clinical development toward further precision oncology in the field of adjuvant therapy.

Summary Background Trifluridine, a thymidine-based chemotherapeutic, has limited bioavailability after clinical administration as it is rapidly degraded via thymidine phosphorylase. An oral combination tablet combines trifluridine with a potent thymidine phosphorylase inhibitor, tipiracil hydrochloride. This study’s objective was to evaluate whether trifluridine/tipiracil (TAS-102) administration increases trifluridine exposure vs trifluridine alone. Methods This open-label pharmacokinetic study randomly assigned patients with advanced solid tumors into two groups. On the morning of day 1, one group received a single 35 mg/m 2 dose of trifluridine/tipiracil and the other group received a single 35-mg/m 2 dose of trifluridine. Both groups received trifluridine/tipiracil 35 mg/m 2 on the evening of day 1, then twice daily on days 2–5 and 8–12 in a 28-day cycle. Results Twenty patients received an initial one-time dose of trifluridine alone and 19 other patients received an initial dose of trifluridine/tipiracil. Trifluridine area under the curve (AUC 0-last ) and maximum observed plasma concentrations (C max ) were approximately 37- and 22-fold higher, respectively, with trifluridine/tipiracil vs trifluridine alone. Plasma concentrations of the major metabolite of trifluridine were lower following the administration of trifluridine/tipiracil vs trifluridine alone. Conclusion Tipiracil administered in combination with trifluridine significantly increased exposure to trifluridine compared with trifluridine alone.

Trifluridine/tipiracil (Lonsurf ® ) is a novel, orally active, antimetabolite agent comprised of trifluridine, a thymidine-based nucleoside analogue, and tipiracil, a potent thymidine phosphorylase inhibitor. Trifluridine is incorporated into DNA via phosphorylation, ultimately inhibiting cell proliferation. Tipiracil increases systemic exposure of trifluridine when coadministered. Trifluridine/tipiracil has recently been approved for the treatment of adult patients with metastatic colorectal cancer (mCRC) who are refractory to or are not considered candidates for, current standard chemotherapy and biological therapy in the EU and USA and in unresectable advanced or recurrent CRC in Japan. The approved regimen of oral twice-daily trifluridine/tipiracil (35 mg/m 2 twice daily on days 1–5 and 8–12 of each 28-day cycle) significantly improved overall survival and progression-free survival and was associated with a significantly higher disease control rate than placebo when added to best supportive care in the multinational, pivotal phase III trial (RECOURSE) and a phase II Japanese trial. Trifluridine/tipiracil was associated with an acceptable tolerability profile, with adverse events generally being managed with dose reductions, temporary interruptions in treatment or administration of granulocyte-colony stimulating factor. The most common grade 3–4 adverse events (≥10 %) were anaemia, neutropenia, thrombocytopenia and leukopenia. In conclusion, trifluridine/tipiracil is a useful additional treatment option for the management of mCRC in patients who are refractory to, or are not considered candidates for, currently available therapies.

In the tumour microenvironment, IL-1α promotes neoangiogenesis, matrix remodelling, tumour proliferation, chemoresistance, and metastases. Highly expressed in human colorectal cancers, IL-1α is associated with poor prognosis. XB2001, a fully human monoclonal antibody neutralizing IL-1α, was evaluated for safety and preliminary efficacy with trifluridine/tipiracil (FTD/TPI) and bevacizumab in metastatic colorectal cancer patients previously treated with oxaliplatin- and irinotecan-based chemotherapies. This single institution, phase 1 study used a 3 + 3 design to assess XB2001 at doses of 250 mg, 500 mg and 1000 mg every 14 days, associated with FTD/TPI 35 mg/m² (days 1–5 and 8-12, every 28 days) (NCT05201352). The Maximum Tolerated Dose of XB2001 + FTD/TPI was then associated in combination with bevacizumab (5 mg/kg, days 1 and 15). Safety, efficacy, pharmacokinetics and pharmacodynamics were assessed. Seventeen patients (median age: 67.4 years) were enroled. No patient exhibited dose-limiting toxicity at any dose. The most common treatment-related adverse events (TRAE) of any grade (G) were diarrhoea (35.3%), nausea (47.1%) and anaemia (35.3%). G3-4 TRAE were neutropenia (17.6%) hypertension and infection (5.9% each). The RP2D (recommended phase 2 dose) of XB2001 was 1000 mg. The disease control rate was 76%, with 23% of patients achieving an objective response, including one complete response. Response and longer progression-free survival were associated with a decrease in serum IL-6 levels during therapy. High intratumoral IL-1α expression at baseline and CD8/PD-L1 infiltration are associated with a better progression-free survival. The combination of XB2001 with FTD/TPI and bevacizumab is feasible and safe, and showed encouraging clinical activity in chemotherapy-resistant mCRC.

Abstract Background Ramucirumab plus paclitaxel after progression on fluoropyrimidine/platinum in metastatic gastric (GA) and gastroesophageal junction adenocarcinoma (GEJC) has shown improvement in overall survival over paclitaxel alone. However, the incidence of neuropathy was 46%. Therefore, there is an unmet need for novel treatment to minimize the long-term toxicity of neuropathy. We conducted a single arm phase II study of ramucirumab and trifluridine/tipiracil (FTD/TPI) in metastatic GA/GEJC. Methods Patients received ramucirumab at 8 mg/kg intravenously on day 1 and 15, and FTD/TPI at 35 mg/m2 orally twice daily on days 1-5 and days 8-12 on every 28-days cycle. The primary endpoint was 6-months overall survival (OS) rate and secondary endpoints were progression free survival (PFS), objective response rate and safety. Results At data cut-off of August 15, 2021, 23 pts were enrolled. The median age was 62 years. Most common treatment-related toxicities were diarrhea (39%), fatigue (39%), hypertension (39%), and nausea (35%). Most common treatment related Grade 3 or 4 adverse events were neutropenia (17%) and anemia (13%). The median PFS and OS was 4.8 and 6.1 months, respectively. The 6-month OS rate was 57% (95% CI: 36.4%-79.8%). Of the 18 evaluable patients with at least one post-baseline imaging, 2 (11%) patients demonstrated objective partial response, and 15 (83%) had stable disease. Conclusion The combination of ramucirumab and FTD/TPI demonstrated well-manageable safety profile. Our study did not meet primary endpoint. Ongoing clinical trials will help us understand if ramucirumab plus FTD/TPI is noninferior to ramucirumab/paclitaxel. The trial was registered at www.clinicaltrials.gov (NCT03686488).

Abstract Background Trifluridine-tipiracil (TAS-102) is approved as monotherapy and in combination with bevacizumab for refractory unresectable metastatic colorectal cancer (mCRC). The recommended dose is 35 mg/m2 twice daily on days 1-5 and days 8-12 of 28-day cycles commonly resulting in grade 3-4 neutropenia, dose delays/reductions, and requiring GCSF support. To maintain efficacy and reduce toxicity, we analyzed a biweekly dosing schedule (days 1-5 and days 15-19 q28 days). Patients and Methods A retrospective analysis was performed in patients with mCRC and appendiceal cancer who completed >12 days of TAS-102 therapy and underwent surveillance imaging every 8-12 weeks. ECOG performance status (PS), prior lines of therapy, use of bevacizumab, CTCAE grade of treatment-related myelotoxicity, dose reductions/delays, and use of GCSF were assessed. Among patients with mCRC, survival analyses were performed. Results 61 patients met inclusion criteria, with mCRC:appendiceal CA ratio of 56:5. Median ECOG PS = 1; median number of prior therapies = 3; Reduction in grade ≥3 neutropenia (16.3%, 1 patient with grade 4) and grade ≥3 anemia (8.2%) relative to the historic controls of the RECOURSE and SUNLIGHT trials. No neutropenic fever was noted; GCSF was not required. Eight patients required a dose delay. In the mCRC patients, the median progression-free survival (PFS) was 4.2 months, with a median overall survival (OS) of 9.2 months. Conclusions Biweekly dosing of TAS-102 demonstrated a reduction in myelosuppression, with similar PFS and OS. With an improved toxicity profile, this alternative dosing schedule may potentially broaden the utilization of TAS-102 in patients with borderline PS and provide a favorable option for future combination studies.

Abstract Background Trifluridine/tipiracil (FTD/TPI), an oral fluoropyrimidine (FP) from the class of antimetabolites, approved for refractory metastatic colorectal cancer, is thought, to have no cardiac toxicity. The aim of this observational, prospective, multicenter study was to identify the incidence of cardiotoxicity of FTD/TPI; secondary objectives were to evaluate whether patients with previous heart diseases or cardiovascular risk factors, who were treated with FTD/TPI, were more susceptible to cardiotoxicity. Materials and Methods Patients received FTD/TPI according to clinical practice and provided informed consent to participate in this prospective study. Any symptoms that occurred during the treatment were reported by patients using a daily questionnaire (patient-reported outcome). In the case of symptoms suspected of cardiotoxicity patients were investigated with an ECG, enzymes, and a cardiology examination. Quality of life (QoL) was analyzed using a GF7 item of the FACT-G questionnaire. Univariate and multivariate logistic regression models were used to test associations between covariates and cardiotoxicity. Changes in QoL were evaluated during treatment. Results Four out of seventy-seven patients had cardiotoxicity ≥ G3 according to the common terminology criteria for adverse events during FTD/TPI treatment. There was: chest pain in 3 cases, and heart failure in one case. The overall incidence of cardiotoxicity was 5.19%. By univariate analysis, obesity, and anemia were demonstrated to be risk factors of cardiotoxicity, while with multivariate analysis, only hemoglobin levels were statistically associated with cardiotoxicity. Average QoL after treatment was not significantly decreased as compared to average basal QoL. Conclusions The risk of developing cardiotoxicity with FTD/TPI is lower than with other FP but it is not negligible. Previous heart diseases or cardiovascular risk factors do not represent an increased risk of cardiotoxicity of FTD/TPI. Further studies are needed to investigate this topic.

Abstract Background Patients with metastatic colorectal cancer often have poor or short responses to currently available therapies. Drug repurposing with alternative dosing schedules may offer unexpected clinical benefit, even for agents that previously failed for this indication. Methods We explored a high-dose treatment strategy for sunitinib, assessing its potential for both cancer cell killing and inducing immunogenic cell death in patient-derived tumor organoids (PDTOs) of metastatic colorectal cancer (mCRC). In a randomized clinical trial, we studied the efficacy of high-dose intermittent sunitinib (700 mg once every 2 weeks) in patients with advanced CRC compared to standard therapy with trifluridine/tipiracil. The primary outcome measure was progression-free survival (PFS); secondary outcomes included overall survival, safety and tolerability, quality of life, and exploratory biomarker analyses. Results While high, intermittent dosing was found to effectively kill PDTOs in vitro, no support for immunogenic cell death was found. In our clinical trial, among a total of 63 evaluable patients, median PFS was 2.8 months (95% CI 0.9-4.7) for the investigation arm compared to 1.9 months (95% CI 1.6-2.3) for the trifluridine/tipiracil group (P = .78, HR 1.22; 95% CI 0.73-2.04). The trial was halted prematurely due to toxicities: in particular, hemorrhage, fever and gastrointestinal adverse events. Conclusion High-dose intermittent sunitinib treatment did not improve PFS for patients with heavily pretreated mCRC compared to standard 3rd or 4th-line treatment with trifluridine/tipiracil, whereas significant toxicity was observed. In addition, this approach provoked no relevant immunological responses in vitro, discouraging further research for potential combinations with immunotherapeutics. Identifier NCT03909724

Background Metastatic colorectal cancer (mCRC) remains an incurable disease with a poor prognosis. Recently, the global phase 3 SUNLIGHT study demonstrated that adding bevacizumab to trifluridine/tipiracil (FTD/TPI) in refractory disease significantly improves overall survival (OS). As a result, this combination is set to become the new standard of care for refractory mCRC. Immune checkpoint inhibitors (ICIs), including Pembrolizumab, have shown excellent results in mCRC patients with mismatch-repair deficiency (dMMR) or high microsatellite instability (MSI-H) mCRC. Additionally, recent trials evaluating both concomitant and sequential chemoimmunotherapy in mismatch-repair-proficient (pMMR) and microsatellite-stable (MSS) mCRC have yielded promising outcomes. Dendritic cell (DC) vaccines, though historically limited in effectiveness, show potential when combined with ICIs. Preliminary studies suggest they enhance chemotherapy response while maintaining favorable safety profiles. These evidences support the exploration of immunotherapy and FTD/TPI plus Bevacizumab in pMMR/MSS mCRC patients. Methods This is a single-arm, open-label, multicenter, phase 2 clinical trial evaluating the clinical and immunological activity of an innovative approach combining induction immunotherapy (Pembrolizumab plus DC vaccine) followed by maintenance chemotherapy (FTD/TPI plus Bevacizumab) in patients with refractory MSS/pMMR mCRC. The primary endpoint is the objective response rate (ORR). Secondary endpoints include progression-free survival (PFS), safety, and overall survival (OS). Discussion This study explores a novel sequential immunochemotherapy approach combining a DC-based vaccine with anti-PD-1 immunotherapy and standard chemotherapy in patients with refractory pMMR/MSS mCRC. By integrating cellular immunotherapy without omitting the current standard of care (FTD/TPI plus bevacizumab), the trial aims to enhance treatment efficacy in a setting traditionally resistant to immunological strategies. To the best of our knowledge, this is the only ongoing trial investigating this therapeutic combination in this specific patient population. Trial registration This study, acronym CombiCoR-Vax, has been registered on clinicaltrials.gov registry with identifier NCT06522919, on July 9, 2024.

PurposeThe current study aimed to determine the efficacy of trifluridine/tipiracil for elderly patients with advanced colorectal cancer.MethodsThis single-arm, open-label, multicenter, phase II study included elderly patients aged 65 years or more who had fluoropyrimidine-refractory advanced colorectal cancer and received trifluridine/tipiracil (70 mg/m2, days 1–5 and 8–12, every 4 weeks). The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival (OS), overall response rate (ORR), toxicities, association between efficacy and geriatric assessment scores, and association between toxicity and plasma drug concentrations.ResultsA total of 30 patients with a mean age of 73 years were enrolled. Median PFS was 2.3 months (95% confidence interval, 1.9–4.3 months), while median OS was 5.7 months (95% confidence interval, 3.7–8.9 months). Patients had an ORR of 0%, with 57% having stable disease. Grade 4 neutropenia was observed in 13% of the patients. Patients with a higher G8 score (15 or more) showed longer PFS than those with a lower G8 score (median 4.6 vs. 2.0 months; p = 0.047). Moreover, patients with grade 3 or 4 neutropenia showed higher maximum trifluridine concentrations than those with grade 1 or 2 neutropenia (mean 2945 vs. 2107 ng/mL; p = 0.036).DiscussionThe current phase II trial demonstrated that trifluridine/tipiracil was an effective and well-tolerated option for elderly patients with advanced colorectal cancer. Moreover, geriatric assessment tools and/or plasma drug concentration monitoring might be helpful in predicting the efficacy and toxicities in elderly patients receiving this drug.Trial registration numberUMIN000017589, 15/May/2015 (The University Hospital Medical Information Network)