Colorectal Cancer

Assuming the following hypotheses: H0: The mPFS of the test group minus the mPFS of the control group equals 0 H1: The mPFS of the test group minus the mPFS of the control group does not equal 0 Assuming an mPFS of 5.0 months for the test group and 1.8 months for the control group, with a two-sided alpha level of 0.05 and 80% power, at least 32 events need to be observed. Within a 9-month enrollment period and a total study duration of 15 months, 44 subjects need to be enrolled to achieve this. Considering an additional dropout rate of 15%, 26 subjects per group are required, totaling 52 subjects (using PASS 2023 Log-rank procedure). Enrollment sites: Beijing Friendship Hospital, Capital Medical University, Peking Union Medical College Hospital, Peking University People's Hospital. Allocation of enrollment across sites: Each site will compete for enrollment, with each site enrolling no less than 14 subjects. 1. Regorafenib: Start at 80 mg once daily, orally, taken at a fixed time for 2 consecutive weeks and then stopped for 1 week. If the patient tolerates it well, increase to 120 mg/d in Cycle 2. 2. Tislelizumab: 200 mg, iv.gtt, single infusion, 21 days as a cycle, Day 1. 3. Thymalfasin: 4.8 mg, administered subcutaneously twice weekly. Treatment will continue until disease progression or until an intolerable adverse reaction occurs that does not resolve despite dose modification.

Standard treatment for patients with locally advanced rectal cancer consists of a long course of (CRT) followed by surgical resection. Although the aim of neoadjuvant treatment in these patients is not organ preservation, but rather to provide improved local control, in the tumour disappears completely. Studies from Maastricht, the UK and Brazil have shown that in selected patients with a clinical complete response after CRT, a "wait-and-see" policy without any surgery could be a safe alternative with comparable long-term outcome and better functional outcome compared to patients who had surgery. The main objective of the study is to provide short and long term oncological and functional outcome data on organ preserving treatment in good responders after a standard indication for neoadjuvant (chemo)radiation. Additional aims are: to set up a national network with expertise centres in the 'wait-and-see' treatment of rectal cancer; to set up a national registry for organ preservation treatment that will generate more evidence on the management and oncological outcome of patients evaluated and treated with organ preservation and \[3\] to offer through this network to all patients who are considered good candidates this 'wait-and-see' approach using the most up to date tools for selection and follow-up. Study design: multicenter prospective observational cohort study and implementation study. Study population: The population will consist of patients, aged 18 years or older, with rectal cancer who after a long course of CRT or a short course of radiation with a long waiting interval have a clinical complete response (ycT0N0). The main study endpoint is 2-year non-regrowth disease-free survival. Secondary endpoints are \[1\] the number of fully operational centres who can deliver high quality organ preserving care in rectal cancer in the Netherlands, \[2\] 2-year regrowth rate, \[3\] 2-year local control, \[4\] 2-year overall survival, \[5\] determination of the optimal follow-up schedule and \[6\] quality of life. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: In the majority of patients who participate in the study, major surgery and the associated morbidity can be avoided. Although scientific proof shows "wait-and-see" only comes with a small risk with adequate selection and follow up, the exact risk is not yet well established and needs to be confirmed by this study. The benefit-risk ratio for this study is regarded as favourable.

Patients with cancer receiving systemic anti-cancer treatments have been generally assumed by many to be at a higher risk from the disease than their counterparts are who are not receiving anticancer treatment. However, their risk of morbidity and mortality from COVID-19 as a consequence of severe acute respiratory syndrome coronavirus 2 infection is not uniform across the world. The evidence to support this claim is scarce and limited to retrospective series arising from China, the epicenter of the COVID-19 pandemic, and involving small numbers of patients. However, despite these severe limitations, the promulgation of this hypothesis has led to widespread global changes to patterns of prescribing chemotherapy and anticancer treatment. In a global health emergency, oncologists, must secure evidence from a large datasets, which can then inform their risk-benefit analyses for individual patients in terms of the use of anticancer treatments. On March 18, 2020, the investigators launched the UK Coronavirus Cancer Monitoring Project (UKCCMP), with widespread support across our national cancer network. 8 Within 5 weeks, the UKCCMP had generated the largest prospective database of COVID-19 in patients with cancer that had been generated to date. the investigators aimed to describe the clinical and demographic characteristics and COVID-19 outcomes in this cohort of patients with cancer and symptomatic COVID-19, and attempted to assess how the presence of cancer and the receipt of cytotoxic chemotherapy and other anticancer treatments affects the COVID-19 disease phenotype. New Taipei City Municipal Hospital has established a special infectious pneumonia ward in May 2021 to treat patients infected with symptomatic severe acute respiratory syndrome coronavirus 2 patients. During the period, 97 patients were admitted and treated with 10 infection-related deaths. In light of the current timing of the pandemic, most published serological studies are predominantly cross-sectional, or at most, include a longitudinal follow-up of few months. Severe acute respiratory syndrome coronavirus 2 has spread globally over the past year, infecting an immunologically naive population and causing significant morbidity and mortality. Immunity to severe acute respiratory syndrome coronavirus 2 induced either through natural infection or vaccination has been shown to afford a degree of protection against reinfection and/or reduce the risk of clinically significant outcomes. Seropositive recovered subjects have been estimated to have 89% protection from reinfection, and vaccine efficacies from 50 to 95% have been reported. However, the duration of protective immunity is presently unclear, primary immune responses are inevitably waning, and there is ongoing transmission of increasingly concerning viral variants that may escape control by both vaccine-induced and convalescent immune responses. Age is considered one of the most crucial covariates that affect phenotypes. However, aging rate may vary among different populations due to genetic variation or miscellaneous environmental exposures. Chronological age is not a perfect proxy for the true biological aging status of the body. A new biological aging measure, phenotypic age (PhenoAge), has been shown to capture morbidity and mortality risk in the general US population and diverse subpopulations. However, how the phenotypic age affect host immunity is not well investigated. There are currently no effective therapies for severe acute respiratory syndrome coronavirus 2, which causes severe respiratory illness or death. Serum neutralizing antibodies rapidly appear after severe acute respiratory syndrome coronavirus 2 infection and vaccination. However, little was known about the change of protective antibody titers both to nature infection and post vaccination. And there is ongoing transmission of increasingly concerning viral variants that may escape control by both vaccine-induced and convalescent immune responses. Defining the antibody response to severe acute respiratory syndrome coronavirus 2 in patients with cancer receiving anti-cancer therapy, (including chemotherapy, targeted therapy and immunotherapy) will be essential for understanding infection progression, long-term immunity, vaccine efficacy and how phenotypic age affect associated antibodies.

Participants eligible for this trial will be randomized 1:1 into one of the two arms (Arm A and Arm B) stratified by: I) -Previous anti-angiogenic therapy (yes vs. no), II) BRAF/RAS mutation status (wildtype vs. mutation) or III) History of liver metastases (never vs. prior but treated). Patients in Arm A (experimental arm) will receive Fruquintinib (orally, 5 mg once a day, at day 1-21 of each 28-day cycle \[Q4W\]) plus Tislelizumab (i.v., 400 mg, at day 1 of each 42-day cycle \[Q6W\]). Patients in Arm B (control arm) will receive Trifluridine/tipiracil (orally, 35 mg/m2 twice a day, day 1-5 and day 8-12 of each 28-day cycle \[Q4W\]) plus Bevacizumab (i.v., 5 mg/kg, at day 1 of each 14-day cycle \[Q2W\]). The treatment will be performed until disease progression, unacceptable toxicity, patients' request, or end of protocol-defined treatment time (maximum of 15 months). All patients will be followed up for a maximum of 18 months after last patient in or until death, withdrawal of consent or loss to follow-up, whatever occurs first.

This is a first in human, Phase 0/1, open-label study of 177Lu-RAD204 consisting of an Imaging Period with 177Lu-RAD204im (imaging dose) and a Treatment Period with 177Lu-RAD204tr (treatment dose) to determine the recommended dose(s) for future exploration of 177Lu-RAD204 in participants with PDL1+ advanced solid tumors. Screening Period: Screening Period of up to 4 weeks. Phase 0 (Imaging Period): Low dose (10mCi) of 177Lu-RAD204 administered on Imaging Day 1 with a follow-up period of up to 2 weeks to assess imaging, safety and dosimetry. The dose may be increased, if needed, to improve image quality. Phase 1 (treatment Period): 177Lu-RAD204tr dose escalation * Treatment Period with each cycle lasting 6 weeks. Extension of the planned dose intervals are possible following discussion and agreement between the Sponsor and Investigator. * Participants may be treated with multiple cycles, as long as they appear to derive clinical benefit as determined by the Investigator and provided there is adequate clinical safety and organ dosimetry data. * Dose Limiting Toxicity (DLT) observation period for 177Lu-RAD204tr is 6 weeks following the first injection of 177Lu-RAD204tr. * Should an alternative treatment schedule be explored, the DLT observation period for 177Lu-RAD204tr at that dose level will be the proposed cycle duration.

The purpose of this study is to establish the safety profile, biodistribution, pharmacokinetics (pk), and radiation dosimetry of 177Lu-BetaBart, to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D), and to evaluate preliminary anti-tumor activity in select patient populations. The study is divided into 2 phases. Phase 1 is the dose escalation phase to establish the safety profile of 177Lu-BetaBart and to determine the MTD and/or RP2D of 177Lu-BetaBart using a Bayesian Optimal Interval (BOIN) design. Phase 2a is the dose expansion phase at the RP2D to confirm the safety of the MTD and/or RP2D and to evaluate preliminary anti-tumor activity of 177Lu-BetaBart in select patient populations using a probability of success design for the objective response rate (ORR) based on a Bayesian beta-binomial design. Participants ≥ 18 years of age with castration-resistant prostate cancer (CRPC), colorectal cancer (CRC), non-small-cell lung cancer (NSCLC), small-cell lung cancer (SCLC), head and neck squamous cell carcinoma (HNSCC), ovarian cancer, cervical cancer, endometrial cancer, triple negative breast cancer (TNBC), or esophageal squamous cell carcinoma (ESCC) who have documented disease progression during or after their most recent line of anticancer therapy will be eligible to enroll. CRC will be capped at 33% of enrollment per cohort. Each phase consists of a Screening Period, a Treatment and Imaging Period, and a Safety and Long-term Follow-up Period.

Subjects with various types of cancer underwent 18F-FAPI-04 PET/CT and PET/MR imaging either for an initial assessment, recurrence detection or assessment of pathologic response. Tumor uptake was quantified by the maximum standard uptake value (SUVmax) and tumor to background (TBR). Using histopathology and follow-up as gold standard, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of 18F-FAPI-04 PET/CT and PET/MR were calculated.

This is a non-inferiority randomized phase II trial investigating the efficacy and safety of 5FU/LV in combination with regorafenib for patients with metastatic colorectal cancer in the third-line setting. Patients will be randomly assigned in a 2:1 ratio between 5FU/LV combined with regorafenib or trifluridine-tipiracil (FTD-TPI) plus bevacizumab. Arm 1 (Treatment Arm) will consist of the 5FU/LV administered to 38 patients as (LV \[400 mg/m² IV over 120 minutes\], followed by 5FU \[400 mg/m² IV bolus then 2400 mg/m² IV infusion over 46 hours\] in 2-week cycles) and regorafenib will be administered dose of 80-120 mg per day with weekly 40 mg per day increases to a maximum of 120 mg per day for 3 weeks on /1 week off until disease progression, up to 12 cycles of treatment. Arm 2 (Control Arm) received by an additional 19 patients, will be given as FTD-TPI, administered orally, BID, at a starting dose of 35 mg/m2 of body-surface area, on days 1 through 5 and on days 8 through 12 every 28 days. Bevacizumab, at a dose of 5 mg per kilogram of body weight, will be administered intravenously on days 1 and 15. The 28-day treatment cycle continued until disease progression or unacceptable toxic effects occurred or consent was withdrawn, up to 12 cycles of treatment.

An upfront-intensified treatment combining all the three active cytotoxic agents in mCRC including fluoropyrimidines, oxaliplatin, irinotecan (FOLFOXIRI) plus antiangiogenic blockade with bevacizumab significantly improved progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) compared to standard FOLFIRI and bevacizumab irrespective to RAS/BRAF status, at price of higher rate of specific toxicities. Advantages of an intensified regimen include: 1) exposure to all active available drugs, since more than 10-15% of patients would not receive any second-line therapy due to early performance status deterioration; 2) the chance of achieving a high rate (around 36%) of secondary R0/R1 resection of metastases in patients with liver-limited and initially unresectable liver metastases. Furthermore, results from the phase 3 TRIBE2 study showed that the intensified upfront regimen FOLFOXIRI-bevacizumab followed by the pre-planned reintroduction of the same agents after progressive disease provided a statistically significant and clinically relevant survival benefit when compared with the pre-planned sequential administration of FOLFOX-bevacizumab and FOLFIRI-bevacizumab in unresectable patients with mCRC. Therefore, FOLFOXIRI-bevacizumab regimen is recommended by all major guidelines as one of the possible upfront treatment options for mCRC, and is used in the clinical practice mainly for patients with highly aggressive disease (such as those with right sided and/or RAS or BRAF mutated). Notably, since no biomarkers are available for predicting sensitivity/resistance to single chemotherapeutic drugs, the simultaneous delivery of all active chemotherapeutic agents might overcome resistance to single drugs. MGMT promoter methylation is found in about 40% of colorectal tumors. MGMT deficiency impairs DNA repair following administration of several alkylating agents, including temozolomide. Temozolomide has limited single-agent activity (around 10%) in patients with pretreated MGMT methylated mCRC. Promising activity has been reported for temozolomide in combination with the potentially synergic drug irinotecan (TEMIRI regimen) in clinically and molecularly selected patients. In a recent phase 2 randomized trial, capecitabine in combination with temozolomide (CAPTEM regimen) displayed similar activity and efficacy with respect to standard FOLFIRI as second-line therapy for MGMT methylated RAS mutated mCRC. Heterogeneity of MGMT promoter methylation and residual MGMT protein expression might account for lack of activity of temozolomide in patients with MGMT promoter methylation assessed by means of a qualitative-only assay, i.e. methylation-specific PCR (MSP), which has been used as selection assay for patients' enrollment in published trials. Exploratory analyses have consistently shown the role of quantitative assessment of MGMT promoter methylation by means of digital PCR (methylBEAMing) and MGMT protein expression by immunohistochemistry (IHC) as potential predictive factors in mCRC patients treated with temozolomide. In the randomized phase 2 CAPTEM versus FOLFIRI second-line trial, patients with retained MGMT positivity by IHC had poorer outcomes in terms of PFS, OS and disease control rate (DCR: interaction test with arm: P=0.028). Any residual MGMT protein expression has been associated with lack of response to temozolomide across different trials, further supporting the restriction of temozolomide-based therapies for patients with MGMT IHC negativity coupled with gene methylation (MGMT silencing). Mismatch repair deficiency/microsatellite instability (MSI) has been linked to innate resistance to several alkylating chemotherapeutic agents, including temozolomide, since cytotoxicity of these agents strictly relies on functional mismatch repair. Therefore, patients with MSI-high mCRC are excluded from temozolomide-based therapy. Temozolomide could be regarded as a "targeted" chemotherapy for patients with MSS and MGMT silenced tumors. In this subgroup of patients, an intensified triplet upfront regimen including temozolomide, fluoropyrimidines, irinotecan, associated with bevacizumab, could be a novel combination in molecularly hyperselected mCRC patients. Moving from this rationale the investigators designed this phase 1b trial assessing safety, recommended dose and preliminary activity of 5-fluoruracil, irinotecan, temozolomide and bevacizumab (FLIRT-bevacizumab) as a biomarker-guided initial therapy for patients with MGMT silenced and MSS mCRC. The study will consist in a dose-escalation assessment of the safety of the treatment in subjects with previously untreated MGMT silenced, MSS mCRC. A 3 + 3 design will be used to assess the maximum tolerated dose (MTD) or maximum tested dose of the combination FLIRT-bevacizumab. The MTD will be defined as the dose level at which ≥2/3 or ≥2/6 subjects experience a dose-limiting toxicity (DLT). When the MTD or maximum tested dose has been determined or reached, the RP2D to be tested in a future phase II trial will be one dose level below the MTD or the maximum tested dose if MTD will not be reached. At least 6 patients should be treated at the RD during the dose escalation. The treatment will consist of an induction period of four 28-day cycles of FLIRT- bevacizumab followed by maintenance regimen of 5-FU/LV-bevacizumab administered every 14 days in combination with per os temozolomide according to dose level over days 1-5 every 28 days in patients without progressive disease at the end of the induction period. Patients will undergo tumor assessment at baseline and every 8 ± 1 weeks until confirmed disease progression, unacceptable toxicity, withdrawal of consent, death, whichever occurs first. The treatment will continue until progressive disease, unacceptable toxicities, or consent withdrawal. The phase 1b part of the study has been completed and the RP2D of temozolomide is 150 mg/sqm on days 1-5 every 28 days. The phase 2 part is ongoing.

Colorectal cancer (CRC) is a common malignancy of the digestive tract, which constitutes a major public health burden. Almost 90% of CRC cases progress from precursor adenomatous polyps through adenoma-carcinoma sequence. Endoscopic detection and removal of colorectal adenoma (CRA) could reduce the incidence and mortality risk of CRC, but the recurrence rate is still high. Therefore, chemoprevention is quite important, not only solve the urgent public health problem, but also be cost-effective. In 2020, the investigators published a multicenter, randomized, double-blind, placebo-controlled clinical study (NCT02226185) in the Lancet Gastroenterology \& Hepatology. The result concluded that oral BBR for 2 years significantly reduced recurrence after endoscopic removal of CRA (RR 0.77, 95%CI 0.66-0.91; p=0.001). BBR also has a significant preventive effect on all polypoid lesions, including adenomas and serrated lesions (adjusted RR 0.78, 95%CI 0.66-0.91; p=0.002) . Does BBR still have a long-term protective effect on the recurrence of CRA after discontinuation? That's what the investigators concerned. The present study is performed to observe and compare retrospectively the recurrence rate of CRAs in patients of the original BBR RCT study (NCT02226185) within 6 years after discontinuation of medication, including the overall recurrence rate of traditional adenomas within the first year, 1-3 years, 3-6 years, and the entire follow-up period of 6 years. The aim is to evaluate the long-term efficacy of BBR in preventing recurrence and carcinogenesis after endoscopic resection of CRAs.