Bi-weekly irinotecan is an effective and convenient regimen in the treatment of relapsed or refractory small cell lung cancer.

BACKGROUND: Despite initial dramatic responses, metastatic small cell lung cancer (SCLC) invariably recurs. Irinotecan is one of the active agents for patients with recurrent SCLC. In the second line, weekly or three-weekly irinotecan regimens have been adopted, however, the optimal dose and schedule is not defined. In our institution, we use a bi-weekly regimen of irinotecan. In this study, we aimed to investigate the safety and efficacy of the bi-weekly irinotecan in the second- or third-line treatment of SCLC patients. METHODS: The study population consisted of advanced stage SCLC patients who were followed at Hacettepe University Cancer Institute between January 2007 and March 2021 and received salvage irinotecan 180 mg/m2 every two weeks, following progression after platinum-etoposide treatment. RESULTS: One hundred patients were included. At diagnosis, nineteen patients (19%) had limited stage and 81 patients (81%) had extensive stage SCLC. Objective response rates (ORR) were 44.6% and 46.2% for patients who received irinotecan treatment in second line, and in third line, respectively. Seventeen percent of all the patients had grade 3 and above adverse events during irinotecan treatment. In our study, 45.8% of patients were able to complete at least 6 cycles of irinotecan treatment and 69.8% were able to receive at least 3 cycles of irinotecan treatment without any dose interruption or reduction. CONCLUSIONS: Irinotecan 180 mg/m2 every two weeks appears to be safe and effective in the 2nd- and 3rd-line treatment of advanced stage SCLC. Bi-weekly administration allows G-CSF prophylaxis in between doses, leading to an uninterrupted administration.

Exploring the Effects and Potential Mechanisms of Hesperidin for the Treatment of CPT-11-Induced Diarrhea: Network Pharmacology, Molecular Docking, and Experimental Validation.

Chemotherapy-induced diarrhea (CID) is a potentially serious side effect that often occurs during anticancer therapy and is caused by the toxic effects of chemotherapeutic drugs on the gastrointestinal tract, resulting in increased frequency of bowel movements and fluid contents. Among these agents, irinotecan (CPT-11) is most commonly associated with CID. Hesperidin (HPD), a flavonoid glycoside found predominantly in citrus fruits, has anti-oxidation properties and anti-inflammation properties that may benefit CID management. Nevertheless, its potential mechanism is still uncertain. In this study, we firstly evaluated the pharmacodynamics of HPD for the treatment of CID in a mouse model, then used network pharmacology and molecular docking methods to excavate the mechanism of HPD in relieving CID, and finally further proved the predicted mechanism through molecular biology experiments. The results demonstrate that HPD significantly alleviated diarrhea, weight loss, colonic pathological damage, oxidative stress, and inflammation in CID mice. In addition, 74 potential targets for HPD intervention in CID were verified by network pharmacology, with the top 10 key targets being AKT1, CASP3, ALB, EGFR, HSP90AA1, MMP9, ESR1, ANXA5, PPARG, and IGF1. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that the PI3K-Akt pathway, FoxO pathway, MAPK pathway, TNF pathway, and Ras pathway were most relevant to the HPD potential treatment of CID genes. The molecular docking results showed that HPD had good binding to seven apoptosis-related targets, including AKT1, ANXA5, CASP3, HSP90AA1, IGF1, MMP9, and PPARG. Moreover, we verified apoptosis by TdT-mediated dUTP nick-end labeling (TUNEL) staining and immunohistochemistry, and the hypothesis about the proteins above was further verified by Western blotting in vivo experiments. Overall, this study elucidates the potential and underlying mechanisms of HPD in alleviating CID.

Phase Ib/II study on the safety, tolerability, and preliminary efficacy of pegylated irinotecan (JK1201I) as second-line monotherapy for patients with small-cell lung cancer.

PURPOSE: To evaluate the safety, tolerability, and preliminary efficacy of multiple doses of pegylated irinotecan (JK1201I) as a second-line monotherapy for treating small-cell lung cancer (SCLC) patients. METHODS: According to the "3 + 3" dose-escalation principle, patients received intravenous JK1201I at 180 or 220 mg/m2 once every 3 weeks for four cycles. Progression-free survival (PFS), overall survival (OS), median progression-free survival (mPFS), and median overall survival (mOS) were evaluated. The Kaplan-Meier method was used to analyze PFS and overall OS. Brookmeyer and Crowley's method was used for mPFS and mOS. RESULTS: This study included 29 patients with stage III-IV SCLC (stage IIIa, n = 1; stage IIIb, n = 1; and stage IV, n = 27). Of these, 26 patients were enrolled in the 180 mg/m2 dose group, and 3 patients were enrolled in the 220 mg/m2 dose group. No dose-limiting toxicity (DLT) was noted during the first 28 days of treatment. Grade 3 or higher adverse events were recorded in the 180 mg/m2 group, including diarrhea (11.5%, 3/26), neutropenia (7.7%, 2/26), and leukopenia (7.7%, 2/26). In the 220 mg/m2 group, one patient (33.3%, 1/3) experienced neutropenia or leukopenia. In the 180 mg/m2 group, 38.5% (10/26) of patients achieved an objective response rate (ORR), with a disease control rate (DCR) of 73.1% (19/26). The mPFS and mOS were 3.4 and 12.1 months, respectively. In the 220 mg/m2 group, one patient had stable disease, and one had progressive disease (PD). The ORR, DCR, mPFS, and mOS were 0% (0/3) and 33.3% (1/3), 2.7 months and 2.7 months, respectively. CONCLUSION: JK1201I exhibits promising efficacy and relatively low toxicities as a second-line monotherapy for SCLC, warranting further large-scale clinical studies to evaluate its efficacy in greater detail.

Fecal SN-38 Content as a Surrogate Predictor of Intestinal SN-38 Exposure and Associated Irinotecan-induced Severe Delayed-Onset Diarrhea by a Novel Use of the Spectrofluorimetric Method.

BACKGROUND: Irinotecan administration can lead to severe delayed-onset diarrhea (SDOD) in clinical practice. Currently, there is no reliable surrogate predictor of intestinal exposure to SN-38 and subsequent diarrhea incidence. METHODS: The relationship between fecal 7-ethyl-10-hydroxycamptothecin (SN-38) content and SDOD was investigated in Fisher 344 rats using a novel spectrofluorimetric method. Additionally, a pharmacokinetic study of irinotecan was performed to evaluate the biodistribution of SN-38 to establish the relationship between tissue and fecal SN-38 exposure. RESULTS: The spectrofluorimetric method was successfully employed to measure fecal SN-38 and CPT-11 content from Day 3 to Day 6 post-irinotecan administration. Only fecal SN-38 content on Day 3 exhibited a significantly positive correlation with SDOD incidence on Days 4 and 5. A cutoff value of SN-38 ≥ 0.066 mg/g in feces was identified, predicting severe diarrhea incidence with 81% accuracy and 80% specificity. The positive correlation between fecal SN-38 content and SN-38 exposure in the ileum on Day 3 was also reflected in the changes of indicators during intestinal injury, such as prostaglandin E2 level and antioxidant activity. CONCLUSION: Fecal SN-38 content proves to be representative of intestinal exposure to SN-38, indicative of intestinal injury, and predictive of SDOD incidence in rats, while the spectrofluorimetric method demonstrates the translational potential.

A multicenter, prospective, non-interventional real-world study to assess the effectiveness of mecapegfilgrastim in preventing neutropenia in patients with gastrointestinal cancer.

BACKGROUND: Mecapegfilgrastim, a long-acting granulocyte-colony stimulating factor has been approved for reducing the incidence of infection, particularly febrile neutropenia (FN), in China. OBJECTIVE: We conducted a multicenter prospective observational study to examine the safety and effectiveness of mecapegfilgrastim in preventing neutropenia in gastrointestinal patients receiving the chemotherapy, including S-1/capecitabine-based regimens or the fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI)/fluorouracil, leucovorin, and oxaliplatin (FOLFOX)/fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX) regimens. METHOD: Five hundred and sixty-one gastrointestinal patients from 40 sites across China, between May 2019 and November 2021, were included. The administration of mecapegfilgrastim was prescribed at the discretion of local physicians. RESULTS: The most common adverse drug reactions (ADRs) of any grade for all patients was increased white blood cells (2.9%). Grade 3/4 ADRs were observed for anemia (0.2%), decreased white blood cells (0.2%), and decreased neutrophil count (0.2%). Among the 116 patients who received S-1/capecitabine-based chemotherapy throughout all cycles, ADRs of any grade included anemia (1.7%), myalgia (0.9%), and increased alanine aminotransferase (0.9%). No grade 3/4 ADRs were observed. In 414 cycles of patients who underwent S-1/capecitabine-based regimens, only one (0.2%) cycle experienced grade 4 neutropenia. In the FOLFIRINOX, FOLFOXIRI, and FOLFOX chemotherapy regimens, grade 4 neutropenia occurred in one (2.7%) of 37 cycles, four (4.7%) of 85 cycles, and two (1.2%) of 167 cycles, respectively. CONCLUSION: In a real-world setting, mecapegfilgrastim has proven effective in preventing severe neutropenia in gastrointestinal patients following chemotherapy. This includes commonly used moderate or high-risk FN regimens or regimens containing S1/capecitabine, all of which have demonstrated favorable efficacy and safety profiles.

Meta-analysis revisiting the influence of UGT1A1*28 and UGT1A1*6 on irinotecan safety in colorectal cancer patients.

Aim: To evaluate the association between irinotecan safety and the UGT1A1 gene polymorphism in colorectal cancer (CRC) patients.Materials & methods: The studies were systematically searched and identified from three databases (PubMed, Embase and The Cochrane Library) until 28 February 2023. The relationships were evaluated using pooled odds ratio (OR).Results: A total of 30 studies out of 600 were included, comprising 4471 patients. UGT1A1*28 was associated with a statistically significant increase in the OR for diarrhea (OR: 1.59, 95% CI = 1.24-2.06 in the additive model; OR = 3.24, 95% CI = 2.01-5.21 in the recessive model; and OR = 1.95, 95% CI = 1.42-2.69 in the dominant model) and neutropenia (OR = 1.70, 95% CI = 1.40-2.06 in the additive model; OR = 4.10, 95%CI = 2.69-6.23 in the recessive model; and OR = 1.93, 95% CI = 1.61-2.31 in the dominant model). Subgroup analysis indicated consistent associations in both Asian and non-Asian populations. UGT1A1*6 was associated with a statistically significant elevation in the OR for diarrhea (only in the recessive model, OR = 2.42; 95% CI = 1.14-5.11) and neutropenia (across all genetic models).Conclusion: The UGT1A1*28 and UGT1A1*6 alleles might be a crucial indicator for predicting irinotecan safety in CRC.

[Box: see text].

Regorafenib plus FOLFIRINOX as first-line treatment for patients with RAS-mutant metastatic colorectal cancer (FOLFIRINOX-R trial): a dose-escalation study.

PURPOSE: The combination of bevacizumab and FOLFIRINOX is used in patients with RAS-mutant metastatic colorectal cancer (RASm-mCRC). Regorafenib, an oral multi-tyrosine kinase inhibitor, has antiangiogenic properties, cytostatic effects and also true cytotoxic effects, unlike bevacizumab. The aim of this study was to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of the regorafenib-FOLFIRINOX combination in patients with RASm-mCRC. METHODS: The FOLFIRINOX-R trial was a phase 1/2 study where the dose-escalation part (3 + 3 design with three dose levels, DLs) was completed before its early termination. FOLFIRINOX (14-day cycle) included oxaliplatin (standard dose), folinic acid, fluorouracil and irinotecan (150 or 180 mg/m²). Regorafenib (120 or 160 mg daily) was given from day 4 to day 10 of each cycle. Dose-limiting toxicity (DLT) was studied in the first three cycles. Eligibility criteria included ECOG performance status ≤ 1 and not previously treated RASm-mCRC. RESULTS: Thirteen patients (median age: 65 years; min-max: 40-76) were enrolled. DLT could not be evaluated in one patient (DL3) due to poor observance. The median treatment duration and median follow-up were 6.2 (min-max: 2.3-10) and 13.4 (min-max: 3.8-18.0) months, respectively. Dose was modified in 12/13 (92%) patients. One grade 3 hypokalemia occurred at DL2. MTD was not reached at DL3. Grade 3 diarrhea was recorded in 7/13 patients (13 events) equally distributed in all DLs. CONCLUSION: The RP2D for this regorafenib-FFX combination could not be determined due to a high prevalence of grade 3 diarrhea related to treatment as advised by our Independent Data Monitoring Committee. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov : NCT03828799.

Liposomal irinotecan (HR070803) in combination with 5-fluorouracil and leucovorin in patients with advanced solid tumors: a phase 1b dose-escalation and expansion study.

This phase 1b study aimed to evaluate the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetics, and preliminary efficacy of HR070803, a novel nanoliposomal formulation of irinotecan, in combination with 5-fluorouracil and leucovorin in patients with pretreated advanced solid tumors. This study consisted of dose-escalation and expansion stages. Dose escalation was performed with a traditional 3 + 3 design; patients received intravenous infusion of HR070803 from 60 to 80 mg/m2, followed by leucovorin (200 mg/m2) and 5-fluorouracil (2000 mg/m2) every 2 weeks. In the expansion stage, patients received treatments at selected tolerable dose. Fifteen patients received treatments at 60 mg/m2 (n = 12) and 80 mg/m2 (n = 3). DLTs occurred in 2 patients at 80 mg/m2 (grade 2 neutropenia that resulted in a dose delay of ≥ 7 days, n = 1; grade 3 febrile neutropenia, n = 1). The MTD was determined to be 60 mg/m2. The most frequent HR070803related adverse events included anorexia, leukopenia, neutropenia, nausea, fatigue, and diarrhea. SN-38, the active metabolite of irinotecan, exhibited lower maximum plasma concentrations and a prolonged terminal half-life when irinotecan was administered via nanoliposome compared to conventional injection. Overall, 4 patients achieved a partial response (confirmed, n = 2), and 9 had stable disease. The MTD of HR070803 was 60 mg/m2 when infused with 5-fluorouracil and leucovorin. Nanoliposomal encapsulation modified the pharmacokinetics of irinotecan and SN-38. HR070803 with 5-fluorouracil and leucovorin demonstrated a manageable safety profile and promising antitumor efficacy in advanced solid tumors. TRIAL REGISTRATION: Clinicaltrials.gov, NCT05086848. Retrospectively registered on Oct. 12, 2021.

Phase I study of trifluridine/tipiracil (TAS-102) plus irinotecan in combination with bevacizumab as a second-line therapy for patients with metastatic colorectal cancer.

PURPOSE: This phase I trial is to determine the recommended dose of the TAS-102, irinotecan plus bevacizumab regimen and assess its safety and efficacy in patients with metastatic colorectal cancer refractory to fluoropyrimidine and oxaliplatin treatment. METHODS: A 3 + 3 designed dose escalation was performed. Patients were administered TAS-102 (30-35 mg/m2 twice daily on days 1-5) and irinotecan (150-165 mg/m2 on day 1) combined with a fixed dose of bevacizumab (5 mg/kg on day 1) every two weeks. The primary endpoint was the determination of the recommended phase II dose. RESULTS: Eighteen patients were enrolled: 6 at the Level 1 (TAS-102 30 mg/m2 twice daily, irinotecan 150 mg/m2 plus bevacizumab 5 mg/kg), six at the Level 2 (TAS-102 35 mg/m2 twice daily, irinotecan 150 mg/m2 plus bevacizumab 5 mg/kg), and six at the Level 3 (TAS-102 30 mg/m2 twice daily, irinotecan 165 mg/m2 plus bevacizumab 5 mg/kg). Five dose-limiting toxicities occurred: one observed at Level 1 (thrombocytopenia), two at Level 2 (neutropenia and diarrhea), and two at Level 3 (fatigue and neutropenia). The RP2D was established as TAS-102 30 mg/m2 twice daily and irinotecan 150 mg/m2 plus bevacizumab 5 mg/kg. The most frequent grade 3/4 treatment-related adverse events were neutropenia (33.3%), diarrhea (16.7%), and thrombocytopenia (11.1%). No treatment-related death occurred. Two patients (11.1%) experienced partial responses and 14 (77.8%) had stable disease. CONCLUSION: The regimen of TAS-102, irinotecan, and bevacizumab is tolerable with antitumor activity for metastatic colorectal cancer patients refractory to first-line fluoropyrimidines and oxaliplatin treatment.

Nanoliposomal Irinotecan With Fluorouracil and Leucovorin or Gemcitabine Plus Cisplatin in Advanced Cholangiocarcinoma: A Phase II Study of the AIO Hepatobiliary-YMO Cancer Groups (NIFE-AIO-YMO HEP-0315).

PURPOSE: First-line therapy options in advanced cholangiocarcinoma (CCA) are based on the ABC-02 trial regimen (gemcitabine/cisplatin [G/C]). The NIFE trial examined nanoliposomal irinotecan/fluorouracil/leucovorin (nal-IRI/FU/LV) as alternative first-line therapy in advanced CCA. METHODS: NIFE is a prospective, open-label, randomized, multicenter phase II study that aimed at detecting efficacy comparable with the standard treatment. Patients with advanced CCA were randomly assigned (1:1) to receive nal-IRI/FU/LV (arm A) or G/C (arm B). Stratification parameters were intrahepatic versus extrahepatic CCA, sex, and Eastern Cooperative Oncology Group (ECOG; 0/1). Arm A was designed as a Simon's optimal two-stage design and arm B served as a randomized control group. The primary goal was to exclude an inferior progression-free survival (PFS) at 4 months of only 40%, while assuming a rate of 60% on G/C population. RESULTS: Between 2018 and 2020, overall 91 patients were randomly assigned to receive nal-IRI/FU/LV (n = 49) or G/C (n = 42). The NIFE trial formally met its primary end point with a 4-month PFS rate of 51% in patients receiving nal-IRI/FU/LV. The median PFS was 6 months (2.4-9.6) in arm A and 6.9 months (2.5-7.9) in arm B. Median overall survival (OS) was 15.9 months (10.6-20.3) in arm A and 13.6 months (6.5-17.7) in arm B. The exploratory comparison of study arms suggested a numerical but statistically not significant advantage for nal-IRI/FU/LV (hazard ratio for PFS, 0.85 [95% CI, 0.53 to 1.38] and for OS, 0.94 [95% CI, 0.58 to 1.50]). Analysis for stratification parameters revealed no differences for sex and ECOG, but for tumor localization. The objective response rate was 24.5% with nal-IRI/FU/LV and 11.9% with G/C. No unexpected toxicities occurred. AEs related to nal-IRI/FU/LV were mainly GI and to G/C hematologic. CONCLUSION: Treatment of advanced CCA with nal-IRI/FU/LV demonstrated efficacy in first-line therapy without new safety findings and merits further validation.

A Phase I/II Study of Valemetostat (DS-3201b), an EZH1/2 Inhibitor, in Combination with Irinotecan in Patients with Recurrent Small-Cell Lung Cancer.

PURPOSE: Recurrent small-cell lung cancer (SCLC) has few effective treatments. The EZH2-SLFN11 pathway is a driver of acquired chemoresistance that may be targeted. PATIENTS AND METHODS: This phase I/II trial investigated valemetostat, an EZH1/2 inhibitor, with fixed-dose irinotecan in patients with recurrent SCLC. Phase I primary objectives were to assess safety, tolerability, and a recommended phase II dose (RP2D). The phase II primary objective was overall response rate (ORR), with secondary objectives of determining duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Correlative analyses included immunohistochemistry of pretreatment and on-treatment tumor biopsies and pharmacokinetics analysis. RESULTS: Twenty-two patients were enrolled (phase I, n = 12; phase II, n = 10); one withdrew consent prior to treatment. Three dose-limiting toxicities (DLT) in dose-escalation resulted in valemetostat 100 mg orally daily selected as RP2D. Among 21 evaluable patients, the most frequent (≥20%) treatment-related adverse events were diarrhea, fatigue, nausea, and rash; three patients discontinued treatment for toxicity. Three of the first 10 patients in phase II experienced DLTs triggering a stopping rule. The ORR was 4/19 or 21% [95% confidence interval (CI), 6%-46%]. The median DoR, PFS, and OS were 4.6 months, 2.2 months (95% CI, 1.3-7.6 months), and 6.6 months (95% CI, 4.3 to not reached), respectively. SLFN11/EZH2 expression and SCLC subtyping markers did not correlate with response, but MHC-I expression did increase with treatment. Two responders demonstrated subtype switching on treatment. CONCLUSIONS: Combination valemetostat and irinotecan was not tolerated but demonstrated efficacy in recurrent SCLC. Valemetostat, combined with agents without overlapping toxicity, warrants further investigation in SCLC.

QUATTRO-II randomized trial: CAPOXIRI+bevacizumab vs. FOLFOXIRI+bevacizumab as first-line treatment in patients with mCRC.

BACKGROUND: The QUATTRO-II trial examined the efficacy and safety of capecitabine+oxaliplatin+irinotecan (CAPOXIRI)+bevacizumab (BEV) vs. 5-fluorouracil+folinic acid+oxaliplatin+irinotecan (FOLFOXIRI)+BEV in metastatic colorectal cancer (mCRC). METHODS: In this phase II study (ClinicalTrials.gov: NCT04097444; jRCTs041190072), patients were randomized (1:1) to FOLFOXIRI+BEV or CAPOXIRI+BEV. The induction treatment in the FOLFOXIRI+BEV/CAPOXIRI+BEV arms was continued for 8/6 cycles (maximum 12/8 cycles if feasible), and the maintenance treatment was 5-fluorouracil/leucovorin+BEV or capecitabine+BEV at the investigators' discretion. The primary endpoint was progression-free survival (PFS), with the two arms deemed equivalent if the hazard ratio (HR) of the point estimate was 0.80 < HR < 1.25. Secondary endpoints were overall response rate (ORR), overall survival (OS), incidence of adverse events (AEs), and patient-reported outcomes. FINDINGS: Overall, 51 and 52 patients were randomized to FOLFOXIRI+BEV and CAPOXIRI+BEV, respectively. The study met its primary endpoint; PFS at median follow-up of 23.7 months was 10.6 months (95% confidence interval [CI], 7.7-13.3) in the FOLFOXIRI+BEV arm vs. 10.9 months (95% CI, 9.3-14.3) in the CAPOXIRI+BEV arm (HR 1.114 [0.80 < HR < 1.25], p = 0.654). In the FOLFOXIRI+BEV vs. CAPOXIRI+BEV arms, the 2-year OS rate (95% CI) was 65.5% (49.5%-77.6%) vs. 74.3% (59.8%-84.2%), and the ORR (95% CI) was 76.5% (62.5%-87.2%) vs. 84.6% (71.9%-93.1%). Major (grade ≥3) AEs in the FOLFOXIRI+BEV vs. CAPOXIRI+BEV arms were neutropenia (68.6% vs. 40.4%), febrile neutropenia (9.8% vs. 11.5%), diarrhea (7.8% vs. 17.3%), and appetite loss (7.8% vs. 17.3%). CONCLUSION: CAPOXIRI+BEV was well tolerated with reduced hematological toxicity and efficacy comparable to those of FOLFOXIRI+BEV, providing a potentially convenient first-line treatment alternative to FOLFOXIRI+BEV in patients with mCRC. FUNDING: Chugai Pharmaceutical Co., Ltd.

Banxia Xiexin decoction combined with 5-ASA protects against CPT-11-induced intestinal dysfunction in rats via inhibiting TLR4/NF-κB signaling pathway.

BACKGROUND: Banxia Xiexin decoction (BXD) can control irinotecan (CPT-11)-caused delayed diarrhea, but the corresponding mechanism remains undefined. AIMS: This paper aimed to uncover the mechanism of BXD in regulating CPT-11-caused delayed diarrhea. MATERIALS & METHODS: Sprague-Dawley (SD) rats were assigned into the control, model, BXD low-dose (BXD-L, 5 g/kg), BXD medium-dose (BXD-M, 10 g/kg), BXD high-dose (BXD-H, 15 g/kg), 5-aminosalicylic acid (5-ASA, 10 mL/kg), and BXD-M + 5-ASA groups. Rats were injected intraperitoneally with 150 mg/kg CPT-11 at Day 4 and Day 5 to induce delayed diarrhea, and later treated with various doses (low, medium, and high) of BXD and 5-ASA for 9 days, except for rats in control group. The body weight of rats was measured. The rat colon tissue injury, inflammatory cytokine levels, and the activation of toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) signaling pathway were detected. RESULTS: BXD (5, 10, or 15 g/kg) or 5-ASA (10 mL/kg) alleviated body weight loss and colon tissue injury, decreased levels of inflammatory cytokines, and inactivated TLR4/NF-κB signaling pathway in CPT-11-induced model rats. BXD at 10 g/kg (the optimal concentration) could better treat CPT-11-induced intestinal dysfunction, as evidenced by the resulting approximately 50% reduction on injury score of model rats. Moreover, BXD-M (10 g/kg) synergistic with 5-ASA (10 mL/kg) further strengthened the inhibition on rat body weight loss, colon tissue injury, inflammatory cytokine levels, and TLR4/NF-κB signaling pathway. CONCLUSION: To sum up, BXD has a protective effect against CPT-11-induced intestinal dysfunction by inhibiting inflammation through inactivation TLR4/NF-κB signaling pathway. In particular, the combined use of BXD and 5-ASA holds great promise for treating CPT-11-induced delayed diarrhea.

Nanoliposomal irinotecan and fluorouracil plus leucovorin versus fluorouracil plus leucovorin in patients with cholangiocarcinoma and gallbladder carcinoma previously treated with gemcitabine-based therapies (AIO NALIRICC): a multicentre, open-label, randomised, phase 2 trial.

BACKGROUND: There is an unmet need for effective therapies in pretreated advanced biliary tract cancer. We aimed to evaluate the efficacy of nanoliposomal irinotecan and fluorouracil plus leucovorin compared with fluorouracil plus leucovorin as second-line treatment for biliary tract cancer. METHODS: NALIRICC was a multicentre, open-label, randomised, phase 2 trial done in 17 German centres for patients aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0-1, metastatic biliary tract cancer, and progression on gemcitabine-based therapy. Patients were randomly assigned (1:1) to receive intravenous infusions of nanoliposomal irinotecan (70 mg/m2), fluorouracil (2400 mg/m2), and leucovorin (400 mg/m2) every 2 weeks (nanoliposomal irinotecan group) or fluorouracil (2400 mg/m2) plus leucovorin (400 mg/m2) every 2 weeks (control group). Randomisation was by permutated block randomisation in block sizes of four, stratified by primary tumour site. Investigator-assessed progression-free survival was the primary endpoint, which was evaluated in all randomly assigned patients. Secondary efficacy outcomes were overall survival, objective response rate, and quality of life. Safety was assessed in all randomly assigned patients who received at least one dose of the study treatment. Enrolment for this trial has been completed, and it is registered with ClinicalTrials.gov, NCT03043547. FINDING: Between Dec 4, 2017, and Aug 2, 2021, 49 patients were randomly assigned to the nanoliposomal irinotecan group and 51 patients to the control group. Median age was 65 years (IQR 59-71); 45 (45%) of 100 patients were female. Median progression-free survival was 2·6 months (95% CI 1·7-3·6) in the nanoliposomal irinotecan group and 2·3 months (1·6-3·4) in the control group (hazard ratio [HR] 0·87 [0·56-1·35]). Median overall survival was 6·9 months (95% CI 5·3-10·6) in the nanoliposomal irinotecan group and 8·2 months (5·4-11·9) in the control group (HR 1·08 [0·68-1·72]). The objective response rate was 14% (95% CI 6-27; seven patients) in the nanoliposomal irinotecan group and 4% (1-14; two patients) in the control group. The most common grade 3 or worse adverse events in the nanoliposomal irinotecan group were neutropenia (eight [17%] of 48 vs none in the control group), diarrhoea (seven [15%] vs one [2%]), and nausea (four [8%] vs none). In the control group, the most common grade 3 or worse adverse events were cholangitis (four [8%] patients vs none in the nanoliposomal irinotecan group) and bile duct stenosis (four [8%] vs three [6%]). Treatment-related serious adverse events occurred in 16 (33%) patients in the nanoliposomal irinotecan group (grade 2-3 diarrhoea in five patients; one case each of abdominal infection, acute kidney injury, pancytopenia, increased blood bilirubin, colitis, dehydration, dyspnoea, infectious enterocolitis, ileus, oral mucositis, and nausea). One (2%) treatment-related serious adverse event occurred in the control group (worsening of general condition). Median duration until deterioration of global health status, characterised by the time from randomisation to the initial observation of a score decline exceeding 10 points, was 4·0 months (95% CI 2·2-not reached) in the nanoliposomal irinotecan group and 3·7 months (2·7-not reached) in the control group. INTERPRETATION: The addition of nanoliposomal irinotecan to fluorouracil plus leucovorin did not improve progression-free survival or overall survival and was associated with higher toxicity compared with fluorouracil plus leucovorin. Further research is necessary to define the role of irinotecan-based combinations in second-line treatment of biliary tract cancer. FUNDING: Servier and AIO-Studien.

A phase II trial of UGT1A1 genotype-guided FOLFIRI plus bevacizumab as first-line therapy for advanced, unresectable colorectal cancer.

BACKGROUND: FOLFIRI is a standard regimen for metastatic colorectal cancer (mCRC). We hypothesized that a pharmacogenomic-directed strategy where more efficient irinotecan metabolizers (UGT1A1 *1/*1 homozygotes and *1/*28 heterozygotes) receive higher-than-standard irinotecan doses would improve progression-free survival (PFS) compared to non-genotype selected historical controls with acceptable toxicity. METHODS: In this phase II multicenter study irinotecan dosing in first-line FOLFIRI and bevacizumab for mCRC was based on UGT1A1 genotype with *1/*1, *1/*28, and *28/*28 patients receiving 310 mg/m2, 260 mg/m2, and 180 mg/m2, respectively. Primary endpoint was PFS. Secondary endpoints were investigator and patient-reported adverse events, and estimation of overall survival (OS). RESULTS: One-hundred patients were enrolled with 91 evaluable for PFS and 83 evaluable for best response. Median PFS was 12.5 months (90% CI 10.9, 15.4), shorter than the anticipated alternative hypothesis of 14 months. PFS by genotype was 12.5 months (90% CI 10.9, 17.4) for *1/*1, 14.6 months (90% CI 11.8, 17.5) for *1/*28, and 6 months (90% CI 2.3, 7.7) for *28/28, respectively. OS was 24.5 months (90% CI 19.1, 30.7) and by genotype was 26.5 (90% CI 19.1, 32.9), 25.9 (90% CI 17.6, 37.7), and 13.4 (90% CI 2.3, 20.5) months for *1/*1, *1/*28, and *28/*28, respectively. G3/4 toxicity was similar between all subgroups, including diarrhea and neutropenia. CONCLUSIONS: A pharmacogenomic-directed irinotecan strategy improved PFS in the *1/*1 and *1/*28 genotypes with higher rates of neutropenia and similar rates of diarrhea compared to expected with standard FOLFIRI dosing. However, improvements in response rate and PFS were modest. This strategy should not change standard practice for mCRC patients in the first-line setting.

Pembrolizumab Plus mFOLFOX7 or FOLFIRI for Microsatellite Stable/Mismatch Repair-Proficient Metastatic Colorectal Cancer: KEYNOTE-651 Cohorts B and D.

BACKGROUND: The phase 1b KEYNOTE-651 study evaluated pembrolizumab plus chemotherapy in microsatellite stable or mismatch repair-proficient metastatic colorectal cancer. PATIENTS AND METHODS: Patients with microsatellite stable or mismatch repair-proficient metastatic colorectal cancer received pembrolizumab 200 mg every 3 weeks plus 5-fluorouracil, leucovorin, oxaliplatin (previously untreated; cohort B) or 5-fluorouracil, leucovorin, irinotecan (previously treated with fluoropyrimidine plus oxaliplatin; cohort D) every 2 weeks. Primary end point was safety; investigator-assessed objective response rate per RECIST v1.1 was secondary and biomarker analysis was exploratory. RESULTS: Thirty-one patients were enrolled in cohort B and 32 in cohort D; median follow-up was 30.2 and 33.5 months, respectively. One dose-limiting toxicity (grade 3 small intestine obstruction) occurred in cohort D. In cohort B, grade 3 or 4 treatment-related adverse events (AEs) occurred in 18 patients (58%), most commonly neutropenia and decreased neutrophil count (n = 5 each). In cohort D, grade 3 or 4 treatment-related AEs occurred in 17 patients (53%), most commonly neutropenia (n = 7). No grade 5 treatment-related AEs occurred. Objective response rate was 61% in cohort B (KRAS wildtype: 71%; KRAS mutant: 53%) and 25% in cohort D (KRAS wildtype: 47%; KRAS mutant: 6%). In both cohorts, PD-L1 combined positive score and T-cell-inflamed gene expression profiles were higher and HER2 expression was lower in responders than nonresponders. No association between tumor mutational burden and response was observed. CONCLUSION: Pembrolizumab plus 5-fluorouracil, leucovorin, oxaliplatin/5-fluorouracil, leucovorin, irinotecan demonstrated an acceptable AE profile. Efficacy data appeared comparable with current standard of care (including by KRAS mutation status). Biomarker analyses were hypothesis-generating, warranting further exploration. GOV IDENTIFIER: ClinicalTrials.gov; NCT03374254.

A multicenter retrospective observational NAPOLEON2 study of nanoliposomal irinotecan with fluorouracil and folinic acid in patients with unresectable pancreatic cancer.

Nanoliposomal irinotecan with fluorouracil and folinic acid (NFF) is a standard regimen after gemcitabine-based therapy for patients with unresectable or recurrent pancreatic cancer. However, there are limited clinical data on its efficacy and safety in the real-world. We therefore initiated a retrospective and prospective observational study (NAPOLEON-2). The results of the retrospective part were reported herein. In this retrospective study, we evaluated 161 consecutive patients who received NFF as second-or-later-line regimen. The main endpoint was overall survival (OS), and the other endpoints were response rate, disease control rate, progression-free survival (PFS), dose intensity, and adverse events (AEs). The median age was 67 years (range, 38-85 years). The median OS and PFS were 8.1 and 3.4 months, respectively. The objective response and disease control rates were 5% and 52%, respectively. The median relative dose intensity was 81.6% for nanoliposomal irinotecan and 82.9% for fluorouracil. Grade 3 or 4 hematological and nonhematological AEs occurred in 47 and 42 patients, respectively. Common grade 3 or 4 AEs included neutropenia (24%), anorexia (12%), and leukocytopenia (12%). Subanalysis of patients treated with second-line and third-or-later-line demonstrated no statistical significant difference in OS (7.6 months vs. 9.1 months, respectively; hazard ratio, 0.92; 95% confidence interval, 0.64-1.35; p = 0.68). In conclusion, NFF has acceptable efficacy and safety profile even in real-world clinical settings. The prospective study is in progress to validate these findings.

A prospective randomized controlled clinical trial investigating the efficacy of low-dose olanzapine in preventing nausea and vomiting associated with oxaliplatin-based and irinotecan-based chemotherapy.

OBJECTIVE: The aim of this study is to assess the clinical efficacy of a 5 mg dosage of olanzapine in preventing chemotherapy-induced nausea and vomiting (CINV) associated with moderately emetogenic chemotherapy (MEC) among female patients diagnosed with gastrointestinal tract tumors. METHODS: Patients undergoing the oxaliplatin/irinotecan chemotherapy regimen were enrolled in this prospective controlled study. The olanzapine group received a 5 mg dosage of olanzapine along with palonosetron and dexamethasone, while the control group received a standard two-combination regimen consisting of dexamethasone and palonosetron. The primary endpoints included the total protection (TP) rates for the entire age group and the subgroup aged 60 years and above. Secondary endpoints encompassed the total protection rates during the acute and delayed phases within the two age brackets, as well as the total control (TC) rates and complete remission (CR) rates across all three phases (total, acute, and delayed). Additionally, the study involved the assessment of quality of life and the collection of adverse events associated with the interventions. RESULTS: 1) Regarding the primary endpoint, the total phase TP rates within both the entire age group and the age group exceeding 60 years demonstrated superiority in the olanzapine group when compared to the control group (66.7% vs 37.25%, P = 0.003; 68.8% vs 44.4%, P = 0.044). 2) In terms of secondary endpoints, the olanzapine group exhibited superior acute phase TP rates in both age brackets when compared to the control group (P < 0.05). The olanzapine group also demonstrated higher delayed-phase TP rates, TC rates across all three phases, and CR rates within the two age brackets, although the differences were not statistically significant (P > 0.05). Furthermore, the quality of life in the olanzapine group surpassed that of the control group for both age brackets (P < 0.05), characterized by enhanced appetite and a higher incidence of drowsiness in the patients treated with olanzapine when compared to those in the control group (P < 0.05). CONCLUSION: Olanzapine can enhance CINV induced by MEC regimen in female patients across all age groups, including the elderly, and therefore improve the quality of life for these patients. CLINICAL TRIAL REGISTRATION: https://www.chictr.org.cn/index.html , identifier: ChiCTR20000368269, 25/08/2020.

Safety and efficacy of liposomal irinotecan as the second-line treatment for advanced pancreatic cancer: A systematic review and meta-analysis.

INTRODUCTION: Nanoliposomal irinotecan (nal-IRI) is a novel regimen for pancreatic cancer, featuring a longer half-life and an increased area under the concentration-time curve. This study aims to assess the safety and efficacy of nal-IRI as a second-line treatment for advanced pancreatic cancer. METHODS: A systemic literature search was conducted based on articles published before September 26th, 2023 in databases, including PubMed, Cochrane Library, EMBASE and Web of Science. The fixed effects model was used to calculate the pooled mean difference for overall survival (OS) and progression-free survival (PFS), as well as the pooled odds ratio for the overall response rate (ORR) and the risk of adverse events. RESULTS: A total of 21 studies, including 3044 patients with locally advanced unresectable or metastatic pancreatic cancers, were considered eligible. The use of nal-IRI, combined with 5-fluorouracil and leucovorin, resulted in significantly improved PFS (pooled mean difference=1.01 months, 95 % confidence interval [CI]=0.97-1.05, p<0.01) and OS (pooled mean difference=0.29 months, 95 %CI=0.18-0.39, p<0.01), as well as significantly better ORR (pooled odds ratio=2.06, 95 %CI=1.30-3.27, p=0.002) compared to other second-line regimens. Nonetheless, an increased risk of grade 3 or greater neutropenia, anemia, hypokalemia, diarrhea, and vomiting was also noted. CONCLUSION: Second-line treatments based on nal-IRI exhibited significantly improved PFS, OS, and ORR compared to other available treatments in advanced pancreatic cancer. Further research is necessary to corroborate these findings and define the role of nal-IRI in both first and later lines of therapy.