Dose Of Irinotecan Research Articles

In vivo, In vitro, and In silico Studies of Umbelliferone and Irinotecan on MDA-MB-231 Breast Cancer Cell Line and Drosophila melanogaster Larvae.

Deaths from cancer are still very common all over the world and continue to be the focus of scientific research. Chemotherapy is one of the primary treatments used to prevent deaths from cancer. Side effects of chemotherapeutic drugs and resistance of cells to drugs are essential problems that limit the treatment process. Drug combination therapy is regarded as a significant application that inhibits the growth of tumors and is anticipated to provide a solution for the issues encountered. The combination therapy aims at a synergistic effect that will limit drug resistance and cytotoxic effects with appropriate drug combinations. In this context, we aim to investigate the in vitro, in vivo, and in silico effects of single and combined doses of umbelliferone and irinotecan, known for their anticarcinogenic and curative effects, on MDA-MB-231 breast cancer cell lines and the model organism Drosophila melanogaster. Irinotecan is currently used as an anticarcinogenic drug. Anticarcinogenic effects of umbelliferone have also been detected. The in vivo, in vitro, and in silico impacts of single and combined doses use of these two agents are not yet available in the literature. This study aims to determine the anticarcinogenic effects of single and combined use of umbelliferone and irinotecan at the molecular level. It also attempts to determine the binding energies of chemicals to cancerrelated proteins through docking and molecular dynamic studies. The cytotoxic effects of individual and combinational doses of umbelliferone and irinotecan on the MDAMB- 231 cell line and D. melanogaster were calculated by XTT and probit analyses. IC50 values for the cancer cells, LC50, and LC99 values for D. melanogaster were found. Gene expression analysis was performed to determine the effects of chemical agents on miR-7, miR-11, and miR-14, and their expression levels were found. The sequences of miRNAs not found in the literature were determined, and their molecular imaging was performed. In addition, the binding energies of irinotecan and umbelliferone to Bcl-2, Bad, and Akt1 proteins, which are known to have apoptotic effects, were found by the molecular docking method. Molecular dynamics studies of Bad proteins and chemicals were also performed. The drug potential of chemicals was determined by ADME/T analysis. The cytotoxic effect on cells was calculated, and the IC50 value of umbelliferone was calculated as 158 μM, the IC50 value of irinotecan was calculated as 48,3 μM and the IC50 value was calculated as 20 μM. In the probit analysis performed to calculate the cytotoxic effects of drugs on D. melanogaster, the LC50 value of umbelliferone was 2,5 μM, and the LC99 value was 13,4 μM. The LC50 value of irinotecan was found to be 0,1 μM, and the LC99 value was 0,28 μM. It was concluded that single and combined doses of chemicals in the invasion experiment significantly affected the spread of cells. As a result of expression analysis, a significant increase in HsamiR- 7 (Homo sapiens miRNA-7), Hsa-miR-14 (Homo sapiens miRNA-14), and Hsa-miR-11(Homo sapiens miRNA-11) expression was observed in cells treated with umbelliferone irinotecan compared to the control groups. In our study, it can be concluded that the cytotoxic effects of individual and combination doses of umbelliferone and irinotecan on MDA-MB-231 cells and D. melanogaster larvae are significant. In addition, the effects of umbelliferone and irinotecan on the expression level of miR-7, which is a common D. melanogaster and human miRNA, should be widely investigated. Expression analyses and docking studies of Hsa-miR-11 and Hsa-miR-14, which have been newly studied and are not in data repositories, are important for cancer research. In particular, the expression and binding energy of these miRNAs in new drug combinations and the expression level in different cancer cell lines are important for future studies. Another crucial point is that in vivo tests using different model species validate the usage of drugs at both single and mixed dosages. Other: As a result of this study, the in vivo, in vitro, and in silico effects of single and combined doses of umbelliferone and irinotecan were determined. In future studies, it would be useful to determine the binding energies of umbelliferone and irinotecan to other cancer-related proteins and to find their interactions with different miRNAs. Additionally, studies on different model organisms are also important.

Protocol amendment for ENSEMBLE study: A multicenter, randomized, phase III trial to test the superiority of consolidation irinotecan, capecitabine and oxaliplatin vs capecitabine and oxaliplatin following short course radiotherapy as total neoadjuvant therapy in patients with locally advanced rectal cancer—Changing the irinotecan dosage.

TPS99 Background: Total neoadjuvant therapy (TNT) presents a promising approach for treating patients (pts) with locally advanced rectal cancer (LARC). TNT not only enhances outcomes for LARC pts but also contributes to improving their quality of life by offering non-operative management (NOM) for patients with complete clinical response (cCR) or near-complete clinical response (nCR). We are currently conducting a phase III trial, the ENSEMBLE study, which was presented at ASCO Breakthrough 2023. At this stage, we have modified the protocol for this study. Additionally, we are conducting translational research (TR) to establish clear criteria for NOM following TNT. Methods: In the ENSEMBLE study, the experimental treatment group received short-course radiotherapy (SCRT) (5×5 Gy) followed by six cycles of CAPOXIRI (capecitabine 800 mg/m2 [orally, twice daily, days 1-14], oxaliplatin 130 mg/m2 [intravenously, day 1], and irinotecan 200 mg/m2 [intravenously, day 1, every 3 weeks]). The standard-of-care group received SCRT (5×5 Gy) followed by six cycles of CAPOX (capecitabine 1000 mg/m2 [orally, twice daily, days 1-14], oxaliplatin 130 mg/m2 [intravenously, day 1, every 3 weeks]). However, the experimental treatment group experienced a higher rate of adverse events due to the high starting dose of irinotecan. After consulting the data and safety monitoring committee (DSMC), it was recommended to reduce the starting dose of irinotecan. Results: Enrollment for the ENSEMBLE study commenced in November 2022. By August 2023, severe adverse events necessitating emergency reporting had occurred in the experimental treatment group. In response to these adverse events, the DSMC was consulted, leading to the reduction of the starting dose of irinotecan to 150 mg/m2. Following this adjustment, no severe adverse events requiring emergency reporting were observed during the experimental treatment with CAPOXIRI. We are currently continuing the ENSEMBLE study to advance treatment options for LARC pts. The TR component of the ENSEMBLE study involves genomic profiling through whole genome plus RNA sequencing of tissue and blood samples, as well as circulating nucleic acid sequencing (cNAS). Additionally, all imaging data (MRI, CT, and colonoscopy) and clinical information are being collected to develop criteria for NOM. Conclusions: A starting dose of irinotecan at 150 mg/m2 appears to be feasible after SCRT in the ENSEMBLE study. Furthermore, the ENSEMBLE study aims to establish clear NOM criteria through deep learning with TR. Clinical trial information: NCT05646511 / jRCTs031220342 .

Abstract A015: Exploiting endogenous replication stress with a novel targeted therapy in Ewing sarcoma

Abstract Ewing sarcoma (EwS) is a rare and aggressive disease that typically affects the bone of children and young adults. Although there are moderate 5-year survival rates for primary disease, there is a high rate of recurrence and a lack of targeted therapies in this setting. Furthermore, pediatric exposure to chemotherapies leads to an increased risk of long-term complications, including secondary cancers, cardiomyopathy, and infertility. Therefore, there is a desperate need for targeted therapies which improve therapeutic outcomes and reduce exposure to chemotherapy in these patients. Like many pediatric cancers, EwS has a low mutational burden. Instead, it is driven by chromosomal translocation between a FET family member, EWSR1, and an ETS family member, usually FLI1. The EWSR1-FLI1 fusion protein acts as an aberrant and oncogenic transcription factor, disrupting cell cycle control, cell migration, and proliferation. ETS family members in these fusions retain their ability to bind to the SWI/SNF chromatin remodeling complex, further dysregulating DNA methylation and gene expression. Although targeting of the EWSR1 fusion has not yet been successful, these elevated levels of replication stress (RS) present a unique element of vulnerability within the cell. To this end, our lab has previously identified replication stress response (RSR) inhibitors, DDKi and WEE1i, which can be utilized to exploit the characteristic ability of EwS to maintain high levels of replication stress (RS) and push EwS cells into mitotic catastrophe in vitro. Here, we evaluate the efficacy of the replication stress response inhibitors (RSRi) TAK931 (DDKi) and MK1775 (WEE1i) with chemotherapy regimens commonly utilized in the relapsed/refractory setting in vivo. Using cell line derived xenografts in NSG mice, we show that DDKi and WEE1i with irinotecan limits tumor growth significantly more than existing therapy (temozolomide + irinotecan). Dosing schedules are optimized through dosing de-escalation and alternative-day dosing strategies. We further demonstrate the ability of our RSRi combination to effectively limit tumor growth over time in vivo even when irinotecan dosage is decreased. We go on to investigate the RSRi combination in the presence of ultra-low dose irinotecan. Finally, we utilize reduced representation bisulfite sequencing to examine the epigenetic effects of these treatment regimens. Overall, the exploitation of high endogenous replication stress in EwS by targeted RSRi presents a promising potential therapeutic option for this pediatric patient population. Citation Format: Emily Isenhart, Ajay Gupta, Bryan Gillard, Kristopher Attwood, Joyce Ohm. Exploiting endogenous replication stress with a novel targeted therapy in Ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr A015.

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

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. 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). 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. 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.

Longitudinal patient-reported outcomes on genotype-guided irinotecan dosing: feasibility and clinical relevance.

Standard investigator-based adverse events (AE) assessment is via CTCAE for clinical trials. However, including the patient perspective through PRO (patient-reported outcomes) enhances clinicians' understanding of patient toxicity and fosters early detection of AEs. We assessed longitudinal integration of PRO-CTCAE within clinical workflow in a phase II trial. As a sub-study in a phase II trial of genotype-directed irinotecan dosing evaluating efficacy in patients with metastatic colorectal cancer receiving FOLFIRI and bevacizumab, patients reported on 13 AEs generating a PRO-CTCAE form. The primary objective was to estimate forms completed by patients and clinicians at least 80% of time. Secondary objectives were estimating concordance and time to first score of specific symptoms between patient and clinician pairs. Feasibility of longitudinal PRO-CTCAE integration was met as 96% of patients and clinician-patient pairs completed at least 80% of PRO-CTCAE forms available to them with 79% achieving 100% completion. Concordance between patient and clinician reporting a severe symptom was 73% with 24 disconcordant pairs, 21 involved patients who reported a severe symptom that the clinician did not. Although protocol-mandated dose reductions were guided by CTCAE not PRO-CTCAE responses, the median time to dose reduction of 2.53 months, and the time-to-event curve closely approximated time to patient-reported toxicity. Longitudinal integration of PRO-CTCAE paired CTCAE proved feasible. Compared to clinicians, patients reported severe symptoms more frequently and earlier. Patient-reported toxicity more closely aligned with dose decreases indicating incorporation into routine clinical practice may enhance early detection of toxicity improving patient safety and quality of life.

Association between homologous recombination deficiency (HRD) gene mutations and the efficacy of venadaparib in combination with irinotecan as third- or fourth-line treatment in patients with metastatic gastric cancer (mGC).

e16057 Background: Tumors with homologous recombination deficiency (HRD) have been suggested to be associated with a favorable response to poly (adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibitors. The aim of this exploratory analysis was to evaluate the association between the presence of HRD gene mutations and the efficacy of venadaparib, a novel PARP inhibitor, plus irinotecan in patients with mGC who had failed at least at least 2 lines of therapy. Methods: This was an exploratory analysis from a multi-national, phase 1b trial of venadaparib plus irinotecan in patients with mGC (NCT04725994). Tumor response was evaluated according to RECIST v. 1.1. Genomic analysis was conducted using ctDNA (GuardantOMNI Gene Panel version 1.0, Redwood City, CA) on Day 1 pre-dose. Results of the exploratory genomic analysis, which includes pathogenic or deleterious mutations of following genes: BRCA1/2, ATM, ATR, PALB2, RAD51, RAD51B/C/D, CHEK1/2, POLD1/2/3/4, BARD1, BRIP1, were analyzed with the efficacy outcomes. Results: In the dose-finding part of the clinical study, 26 patients were enrolled:13 had received two prior treatments and 13 had received three prior treatments, respectively. Of the 26 patients enrolled, 7 (26.9%) had mutations involved in HRD (4 with ATM, 1 with BRCA2, 1 with BARD1, and 1 with ATR mutations, respectively), and were treated with varying doses of venadaparib plus irinotecan. Among the 7 patients with a mutation in HRD genes, an objective response rate (ORR) was 57.1%, and median progression free survival (mPFS) was 5.6 months (95% confidence interval [CI] 1.2–not reached). For those without a mutation in HRD genes (n = 19), 1 patient achieved partial response and 13 achieved stable disease as best response with a mPFS of 4.0 (95% CI 2.9-5.5) months. Conclusions: Venadaparib in combination with irinotecan showed promising efficacy outcomes in patients with mGC, especially for those with mutations of HRD-related genes. Further development of this combination may consider a biomarker-based approach. Clinical trial information: NCT04725994 . [Table: see text]

Updated efficacy and safety results from the phase Ib/II study of surufatinib combined with camrelizumab and chemotherapy in patients with advanced colorectal cancer.

e15547 Background: Preclinical and clinical data have demonstrated the synergistic anti-tumor effects of surufatinib, a novel VEGFR1-3, FGFR and CSF-1R inhibitor, in combination with immune checkpoint inhibitors (ICIs)/chemotherapy. A phase Ib/II, open-label study (NCT04929652) was conducted to evaluate the efficacy and safety of surufatinib plus camrelizumab (anti-PD-1), irinotecan and GM-CSF as second-line treatment in advanced colorectal cancer (CRC). In the phase Ib part, this combination showed favorable safety and efficacy profile, which was presented at ASCO 2023 in poster format (#255). Here, we reported the updated results from the phase Ib and phase II dose escalation part together. Methods: In the phase Ib, pts with CRC received surufatinib at 250mg once daily (QD) as starting dose, in combination with fixed dose of camrelizumab (200 mg, d1), irinotecan (200 mg/m2, d1) and GM-CSF (5ug/kg, d2-d7), every 3 weeks (Q3W). It had been reported in phase Ib that surufatinib 300 mg QD was defined as the recommended phase 2 dose (RP2D). In phase II dose expansion part, a further 36 pts were treated with the same regimen. The primary endpoint of phase II was ORR as per RECIST 1.1. Secondary endpoints included PFS, DCR, OS and safety. Results: As of Jan 18, 2024, 30 CRC pts (median age 57) were enrolled in the study with 12 pts in the phase Ib part and 18 pts in the phase II part. 70% were male and 23% had ECOG PS 1. 24/30 (80%) pts were positive for KRAS, NRAS or BRAF mutations. Among the 30 efficacy evaluable pts, the ORR was 30.0% (95% CI 14.7–49.4; 9 PR) and DCR was 93.3% (95% CI 77.9–99.2; 28 PR+SD). Pts with RAS/BRAF mutations were more likely to achieve better responses (9 PR in 24 pts, ORR-37.5%). After a median follow-up time of 11.1 months, the median PFS was 6.34 months (95% CI 4.57-9.23) and median OS was not mature. The most common grade 1-2 treatment related adverse events (TRAEs) (≥35%) were diarrhea (70%), fatigue (40%), anemia (36.7%), proteinuria (36.7%) and nausea (36.7%). Eleven pts experienced at least one grade 3 or 4 TRAEs. Grade 3 or 4 TRAEs occurred in > 1 pt included diarrhea (n = 3, 10%) and neutrophil count decreased (n = 2, 6.7%). Conclusions: Surufatinib plus camrelizumab, irinotecan and GM-CSF demonstrated promising anti-tumor activity in pts with advanced CRC, with a manageable safety profile. Expansion enrollment is ongoing and updated information will be presented. Clinical trial information: NCT04929652 .

An open-label, multicenter, phase Ib/II study of the ATR inhibitor SC0245 in combination with irinotecan in patients with relapsed and refractory extensive stage small cell lung cancer (ES-SCLC).

8102 Background: Ataxia telangiectasia and Rad3 related (ATR) is activated in response to replication stress induced by topoisomerase 1 inhibitors (TOP1i) and other DNA damaging agents. SC0245 is a novel potent ATR inhibitor, showing synergistic inhibitory effects when combined with TOP1i in DMS-114 and H446 small cell lung cancer. This is the first report on an ongoing phase Ib/II study of SC0245 in combination with irinotecan (IRI) in patients (pts) with ES-SCLC (ClinicalTrials.gov: NCT05731518). Methods: Multiple escalating doses of SC0245 are being administered orally with a fixed dose of IRI. Pts are being enrolled into five escalating dose cohorts (80 mg once daily (QD), 120 mg QD, 80 mg twice daily (BID), 120 mg BID, 160 mg BID) using a BOIN design. SC0245 is administered daily for 3 days weekly x 3 (e.g, Days 1-3, 8-10 and 15-17) with IRI 80 mg/m2 on Days 1, 8 and 15. Cycles are repeated every 4 weeks. The primary endpoint is the rate of dose-limiting toxicity (DLT). Tumor assessments are being performed every 8 weeks using RECIST v1.1. Dose expansion in ES-SCLC patients will follow after definition of the recommended phase 2 dose (RP2D). Results: As of the data cut-off-date (December 21, 2023), 15 pts (median age, 65; male, 73.3%) with previously treated solid tumors have been enrolled, with 3, 4, 3 and 5 pts in 80mg QD, 120mg QD, 80mg BID and 120 mg BID dose cohorts, respectively. 12 of 15 pts were DLT evaluable, and one DLT event (Grade 3 febrile neutropenia) occurred in the 80 mg QD dose cohort. Cytopenia, diarrhea, and liver function test elevations, were the main adverse events (AEs) experienced in 73.3%, 46.7% and 40% pts, respectively. Most AEs were grade 1 or 2 in severity and manageable. The only ≥ Grade 3 TRAEs experienced by more than 2 subjects has been leukopenia (3/15, 20.0%). No drug-related deaths occurred. Among the 9 pts who were evaluable for tumor response, one confirmed partial response (PR) was reported in a pt with ES-SCLC (progressed on prior 1st line of etoposide + carboplatin + serplulimab treatment) treated in the 120mg QD dose cohort, and the response sustained for 32+ weeks; five pts (5/9, 55.6%) had stable disease (SD) as their best response. PK characteristics indicated that SC0245 was rapidly absorbed (median Tmax, 1.0 to 2.0 h), and drug exposure was proportional to dose for the QD and BID regimens. No drug-drug interactions (DDI) between SC0245 and either IRI or its active metabolite SN38 were observed. Conclusions: SC0245 exhibited favorable safety and PK characteristics when administered in combination with IRI at doses ranging from 80mg QD to 120mg BID and the regimen has demonstrated preliminary antitumor activity in ES-SCLC, supporting further evaluation of the regimen in ES-SCLC and other relevant malignancies. Clinical trial information: NCT05731518 .

SARC037: Phase II results of trabectedin given as a 1-hour (h) infusion in combination with low dose irinotecan in patients (pts) with relapsed/refractory Ewing sarcoma (ES).

SARC037: Phase II results of trabectedin given as a 1-hour (h) infusion in combination with low dose irinotecan in patients (pts) with relapsed/refractory Ewing sarcoma (ES).

Abstract 4607: Targeted nanoparticle delivery of irinotecan and Ewing sarcoma-specific siRNA is an effective combination therapy for Ewing sarcoma

Abstract Background: Ewing sarcoma (ES) is an aggressive bone and soft tissue tumor affecting children and adolescents with an overall survival rate of 50%. Irinotecan (IR) is an effective chemotherapeutic agent but is associated with significant toxicity. Using an anti-CD99 targeted hybrid polymerized lipid nanoparticle containing IR, NV103, in pre-clinical mouse xenograft model of the disease, tumor ablation was achieved at 2mg/kg of IR versus 50mg/kg for free IR. All ES harbor a chromosomal translocation resulting in expression of a fusion EWS-FLI1 protein or equivalent. This chimeric gene is a transcriptional regulator that upregulates the FEZF1 and FEZF1-AS1 genes. Both EWS-FLI1 and FEZF1-AS1 genes are unique to ES and are not expressed in normal adult tissues. EWS-FLI1 promotes cell growth while the FEZF1-AS1 complex promotes tumor metastasis, a hallmark of ES. In vitro RNAi targeting of EF and FEZF1-AS1 results in tumor cell death. We hypothesized that combining EWS-FLI1 and/or FEZF1-AS1 targeted RNAi therapy with NV103 cytotoxic therapy would be more effective than any single modality therapy. Methods: NV103 was provided by NanoValent Pharmaceuticals. siRNA containing lipid nanoparticles (LNP-siRNA) were generated using PreciGenome NanoGenerator. siRNA was quantified using the ribogreen assay. Nanoparticles were analyzed for size and particle numbers by NanoSight. siRNA was used to target the following genes- EWS-FLI1, FEZF1, FEZF1-AS1, or GFP. A673 cells expressing GFP were used for this in vitro study. Various doses of IR and siRNA were used in combination and cell growth/death was imaged live using Incucyte. ATP assay was used to confirm live cells and to determine minimum effective dose (MED) over 72 hours of treatment. Results: LNP-siRNA, mean diameter 70nm and PDI<0.2, encapsulated 90% of the siRNA in solution. LNP are stable at 4°C for at least 4 weeks with minimal-to-no loss of activity. NV103 had a MED of 1µM. MED of various siRNA was 30 to 50nM. Combination of NV103 and LNP-siRNA reduced MED of IR to 250nM. One treatment dose of LNP-siRNA followed by NV103 treatment three days later maintained significant cell death over 10 days post treatment initiation. Control cells were 97% more confluent than NV103/EWS-FLI1 siRNA treated ones, 85% more than NV103/FEZF1 siRNA cells and 92% more than NV103/FEZF1-AS1 treated cells. siRNA combinations of EWS-FLI1 and FEZF1 or FEZF1-AS1 along with NV103 added no further benefit. Conclusion: Combination nanoparticle therapy of IR and ES-specific siRNA reduces IR MED by four-fold. LNP delivery of siRNA enables tumor-specific gene targeting. Most have no available small molecule therapy. Targeting ES cells with both a low dose (250nM) of IR and 30-50nM of siRNA against unique tumor biomarkers results in increased cell death with no IR toxicity. Further animal studies are required to determine the effectiveness of such therapy in vivo. Citation Format: Sheetal A. Mitra, Jean-Hugues Parmentier, Hyung-Gyoo Kang, Timothy J. Triche. Targeted nanoparticle delivery of irinotecan and Ewing sarcoma-specific siRNA is an effective combination therapy for Ewing sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4607.

Predictive role of homologous recombination deficiency (HRD) for irinotecan in combination with venadaparib, a novel PARP1/2 inhibitor, as third- or fourth-line treatment in patients with advanced gastric cancer.

380 Background: Tumors with homologous recombination deficiency (HRD), including BRCA and ATM mutations, have shown to predict response to poly (adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibitors. The associations between treatment efficacy of PARP inhibitor-based regimen and mutations in BRCA (BRCAm) or ATM gene (ATMm) are not well known in previously treated advanced gastric cancer (GC). Combining PARP inhibitor and irinotecan is known to synergize cytotoxicity. The aim of this analysis was to evaluate the association of HRD and efficacy of irinotecan and venadaparib combined, in patients with metastatic GC who had failed at least 2 lines of therapy. Methods: MTT assays were performed in vitro to verify and characterize synergism between venadaparib and SN-38. Data were analyzed using the GraphPad Prism (version 9.5.1) and CompuSyn (version 1.0) software. Patients with at least two prior palliative treatments were enrolled in a multi-national phase Ib trial (NCT04725994). Tumor response was evaluated according to RECIST 1.1. Exploratory genomic analysis was included to assess the correlation between efficacy and HRD. Genomic analysis was conducted using ctDNA (GuardantOMNI Gene Panel version 1.0, Redwood City, CA) on Day 1 pre-dose. Results: In MTT assays, the combination of SN-38 and venadaparib exerted synergistic effect with combination indices (CI) ranging from 0.013 to 0.991 in SNU-638 (BRCA2m), SNU-668 (BRCA1m), AGS (low ATM) and SNU-484 (HR proficient) cells. We observe the synergistic effect between SN-38 and venadaparib remained consistent even at low concentrations of venadaparib (SN-38 IC50; without venadaparib → with 10 nM of venadaparib; SNU-638(1.72→0.28), SNU-668(10.7→1.5), AGS (0.62→0.049), SNU-484(2.25->0.38)). In the dose-finding part of the clinical study, 26 patients were enrolled, 13 had received two prior treatments and 13 had received three prior treatments. At data cut-off, median duration of follow-up (range) was 4.4 (1.3 – 23.7) months. Of the 26 patients enrolled, 5 (1 BRCA2m and 4 ATMm) had HRD (19.2%) and were treated with varying doses of irinotecan and venadaparib. In the five patients with HRD, an objective response rate (ORR) was 60% and median progression-free survival (mPFS) (95% CI) was not reached (1.2–21.5). Of the 26 patients enrolled, 11 received varying doses of venadaparib plus 100 mg/m2 of irinotecan, with an ORR of 36.4% and mPFS (95% CI) of 5.6 (3.5–not reached) months. Conclusions: Venadaparib in combination with irinotecan showed synergistic effect in vitro assays and promising clinical efficacy in the systemic treatment of refractory GC, particularly in patients with HRD. The dose expansion phase of the study is ongoing to investigate the optimal biological dose and patient selection strategies, in a randomized design. Clinical trial information: NCT04725994 .

Regorafenib plus FOLFIRI with irinotecan dose escalated according to UGT1A1 genotyping in patients with metastatic colorectal cancer.

125 Background: This multicenter, phase II, randomized, open-label, 2-arm parallel trial aims to compare the efficacy and safety profiles of regorafenib plus irinotecan dose-escalated FOLFIRI according to UGT1A1 genotyping with regorafenib alone in previously treated patients with metastatic colorectal cancer (mCRC). Methods: A total of 153 patients were planned to randomize at a ratio of 2:1 for receiving regorafenib plus FOLFIRI (arm A, 102 patients) or regorafenib alone (arm B, 52 patients), respectively. For both arms, regorafenib were given for 21 consecutive days (Day 1 to 21) of each 28-day cycle at a maintained dose of 120 mg. However, for arm A, patients received regorafenib plus FOLFIRI with dose-escalated irinotecan according to UGT1A1 genotypes. FOLFIRI were on the first day of each 28-day cycle only. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS) and disease control rate (DCR), and adverse events (AEs). Results: Finally, a total of 116 patients were enrolled to be analyzed, including 74 in arm A and 42 in arm B. The significantly better PFS was observed in arm A, 4.8 and 3.0 months, respectively ( p = 0.016). Moreover, in patients with RAS wild type, the significantly better PFS was observed in arm A, 6.3 and 2.1 months, respectively ( p = 0.003). The OS was not significantly different between group A and B, 9.8 and 12.6 months, respectively ( p = 0.970). However, in patients with RAS wild type, the trend of better OS was observed in arm A, 14.3 and 6.9 months, respectively ( p = 0.158). The marginally significant better DCR was observed in arm A, 55.4% and 38.1%, respectively ( p = 0.055). The marginally significant better DCR was observed in arm A, 55.4% and 38.1%, respectively ( p = 0.055). Combination treatment of regorafenib plus FOLFIRI was independent favorable prognostic factor for PFS ( P = 0.008; hazard ratio [HR], 1.892; 95% CI, 1.182 – 3.027). Regarding severe AEs, there were no significant differences between the two groups (all P>0.05). Conclusions: Combination treatment of regorafenib plus FOLFIRI with dose-escalated irinotecan according to UGT1A1genotyping results in a significant better PFS and comparable AEs. Moreover, patients with RAS wild type of CRC would be more beneficial for this combination treatment.

Real-world comparison of low- versus high-dose continuous 5FU infusion in patients receiving triplet chemotherapy plus bevacizumab for newly diagnosed metastatic colorectal cancer (mCRC).

62 Background: Several randomized trials demonstrated an overall survival (OS) benefit to triplet chemotherapy (5-FU, oxaliplatin, and irinotecan) plus bevacizumab compared to doublet chemotherapy plus bevacizumab in patients with newly diagnosed mCRC, though with higher rates of neutropenic fever and diarrhea. These trials used high-dose continuous infusion 5-FU (3,200 mg/m2/48 hours), but national guidelines suggest low-dose continuous infusion 5-FU (2,400mg/m2/48 hours) due to lower tolerance in U.S. patients. We performed a retrospective cohort study in a U.S. population to compare the effectiveness of low- vs high-dose continuous infusion 5FU in patients undergoing triplet chemotherapy plus bevacizumab for newly diagnosed mCRC. Methods: We used the nationwide Flatiron Health electronic health record-derived database, comprising de-identified patient-level structured and unstructured data curated via technology-enabled abstraction from ~280 cancer clinics. Patients with newly diagnosed mCRC who initiated triplet chemotherapy plus bevacizumab between 10/23/14 and 10/31/22 with non-missing height, weight, and dosing data were included. 5FU infusion doses of 2,000 – 2,799 mg/m2 were categorized as low-dose while those >/= 2,800 mg/m2 were categorized as high-dose. OS from first-line treatment initiation was assessed by dosing group using the Kaplan Meier method with log-rank testing. Multivariable analysis with adjustment for pre-specified variables with imbalance (defined by standardized difference < - 0.10 or > 0.10) was performed using multivariable Cox proportional hazards modeling. Missing data were imputed using multiple imputation with chained equations. Results: Among 320 patients included, 244 received low-dose and 76 patients received high-dose continuous infusion 5FU. Imbalance between low- and high-dose groups was observed in the use of 5FU bolus (23% vs 3%), year of metastatic diagnosis 2018 - 2022 (80% vs 55%), mean irinotecan dose (156.4 vs 160.5 mg/m2), left-sided primary (73% vs 64%), MMR deficiency (3% vs 6%) and mean CEA (478 vs 691 µg/L). In univariate analysis, median OS was 33 months (95% CI 26 – 39) in the low-dose group compared to 34 months (95% CI 24 – 48) in the high-dose group (HR 1.16; 95% CI 0.79 – 1.69; p = 0.44). After adjusting for imbalanced covariates, there was no difference in hazard of death between low- and high-dose groups (HR 0.99; 95% CI 0.64 – 1.53; p = 0.97). Conclusions: In this real-world, U.S. population with newly diagnosed mCRC receiving triplet chemotherapy plus bevacizumab, there was no association with survival between low- vs high-dose continuous infusion 5FU. This supports current guidelines recommending low-dose continuous infusion 5FU (2,400mg/m2/48 hours) for patients with mCRC receiving triplet chemotherapy in the U.S.

Anus preservation in low rectal adenocarcinoma based on MMR/MSI status (APRAM): a study protocol for a randomised, controlled, open-label, multicentre phase III trial

BackgroundAnus preservation has been a challenge in the treatment of patients with low rectal adenocarcinoma (within 5 cm from the anal verge) because it is difficult to spare the anus with its functioning sphincter complex under the safe margin of tumour resection. Patients with dMMR/MSI-H can achieve a favourable complete response (CR) rate by using a single immune checkpoint inhibitor. For patients with pMMR/MSS/MSI-L, intensified neoadjuvant three-drug chemotherapy may be the preferred option for anal preservation. In addition, the watch and wait (W&W) strategy has been proven safe and feasible for patients with rectal cancer who achieve a clinical complete response (cCR). Therefore, we initiated this clinical trial to explore the optimal neoadjuvant treatment pattern for patients with low locally advanced rectal cancer (LARC) with different MMR/MSI statuses, aiming to achieve a higher cCR rate with the W&W strategy and ultimately provide more patients with a chance of anus preservation.MethodsThis is a randomised, controlled, open-label, multicentre phase III trial. Patients with clinical stage T2-4 and/or N + tumours located within 5 cm from the anal verge are considered eligible. Based on the results of pathological biopsy, the patients are divided into two groups: dMMR/MSI-H and pMMR/MSS. Patients in the dMMR/MSI-H group will be randomly allocated in a 1:1 ratio to either arm A (monoimmunotherapy) or arm B (short-course radiotherapy followed by monoimmunotherapy). Patients in the pMMR/MSS group will be initially treated with long-term pelvic radiation with concurrent capecitabine combined with irinotecan. Two weeks after the completion of chemoradiotherapy (CRT), the patients will be randomly allocated in a 1:1 ratio to arm C (XELIRI six cycle regime) or arm D (FOLFIRINOX nine cycle regime). The irinotecan dose will be adjusted according to the UGT1A1-genotype. After treatment, a comprehensive assessment will be performed to determine whether a cCR has been achieved. If achieved, the W&W strategy will be adopted; otherwise, total mesorectal excision (TME) will be performed. The primary endpoint is cCR with the maintenance of 12 months at least, determined using digital rectal examination, endoscopy, and rectal MRI or PET/CT as a supplementary method.DiscussionAPRAM will explore the best anus preservation model for low LARC, combining the strategies of consolidation chemotherapy, immunotherapy, and short-course radiotherapy, and aims to preserve the anus of more patients using W&W. Our study provides an accurate individual treatment mode based on the MMR/MSI status for patients with low LARC, and more patients will receive the opportunity for anus preservation under our therapeutic strategy, which would transform into long-term benefits.Trial registrationClinicaltrials.gov NCT05669092 (Registered 28th Nov 2022).

Individual Irinotecan Therapy Under the Guidance of Pre-Treated UGT1A1*6 Genotyping in Gastric Cancer.

Background: Severe delayed diarrhea and hematological toxicity limit the use of irinotecan. Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) is a critical enzyme in irinotecan metabolism. The study aims to investigate the safety and efficacy of irinotecan under the guidance of the pre-treatment UGT1A1 genotype in the second-line treatment of gastric cancer. Methods: This study involved 110 patients. Irinotecan was injected intravenously every 3 weeks, and the dose of irinotecan was determined by polymorphism of the UGT1A1 gene, which was divided into three groups (125 mg/m2: GG type; 100 mg/m2: GA type; 75 mg/m2: AA type). The primary end point was overall survival (OS), the secondary end points were progression-free survival (PFS) and safety. Results: One hundred and seven patients received irinotecan treatment and three patients with AA type received paclitaxel treatment. Among 107 patients, there were no significant differences in PFS (4.8 m vs 4.9 m vs 4.4 m; p = 0.5249) and OS (9.3 m vs 9.3 m vs NA; p = 0.6821) among patients with GG/GA/AA subtypes after dose adjustment. For the patient with homozygosity mutation, treatment was switched to paclitaxel. There were no significant differences in PFS and OS among patients with different alleles or after dose adjustment (p > 0.05). There was a significant difference in the risk of delayed diarrhea (p = 0.000), leukopenia (p = 0.003) and neutropenia (p = 0.000) in patients with different UGT1A1*6 genotypes, while no difference in patients with different UGT1A1*28 genotypes. Additionally, grade 3/4 diarrhea, neutropenia, and leukopenia were significantly more common in AA genotype patients compared to GG (2%, 19%, 24%) or GA (23%, 31%, 31%) genotype patients. Conclusion: Individual irinotecan treatment shows encouraging survival and tolerability outcomes in patients with GG/GA subtype. Irinotecan may be not suitable for patients with AA subtype.

Intraperitoneal irinotecan with concomitant FOLFOX and bevacizumab for patients with unresectable colorectal peritoneal metastases: protocol of the multicentre, open-label, phase II, INTERACT-II trial

IntroductionThe peritoneum is the second most affected organ for the dissemination of colorectal cancer (CRC). Patients with colorectal peritoneal metastases (CPM) face a poor prognosis, despite the majority of patients...

Current insight on irinotecan dose adjustment in advanced colorectal cancers based on pharmacogenetic studies: an updated review

Current insight on irinotecan dose adjustment in advanced colorectal cancers based on pharmacogenetic studies: an updated review

Current insight on irinotecan dose adjustment in advanced colorectal cancers based on pharmacogenetic studies: an updated review

Despite advancements in colorectal cancer screening and treatment, the occurrence, severity, and mortality rates have consistently risen among younger patients. Precision medicine aims to personalize cytotoxic drug dosages, such as irinotecan, by considering the pharmacogenetic specificity of glucuronidation backgrounds. Our search, focused on recent developments (2020-2024) in categorizing Uridine 5'-diphosphate-glucuronosyltransferase (UGT)1A1 variants related to irinotecan's safety, effectiveness, and cost-benefit in metastatic colorectal cancer patients identified 32 relevant clinical studies and recent reviews from 296 abstracts in PubMed and PubMed Central databases. This updated review emphasizes racial disparities in the incidence and essential variants influencing irinotecan's activated metabolite (SN-38). While UGT1A1*28 homozygosity is the primary cause of toxicity in North America, Europe, and a Middle Asian country, UGT1A1*6 is the prominent variant responsible in East Asian countries. Despite various methods employed for dose adjustment based on pharmacogenomic findings, individualization of the dose has been associated with reduced toxicity, improved response, and enhanced patient survival. The recommended irinotecan dose in the FOLFIRI regimen can be variable between 120mg/m2 to 350 mg/m2 based on the UGT1A1 genotype variant. Moreover, this approach appears to be cost-effective, as suggested by European and Chinese studies.

Recombinant Methioninase Decreased the Effective Dose of Irinotecan by 15-fold Against Colon Cancer Cells: A Strategy for Effective Low-toxicity Treatment of Colon Cancer.

Irinotecan (IRN), a topoisomerase I inhibitor and pro-drug of SN-38, is first-line treatment of colon cancer as part of FOLFIRI and FOLFOXIRI combination chemotherapy. However, IRN causes dose-limiting adverse events such as neutropenia and diarrhea. Dose reductions are sometimes required, which reduce efficacy. Recombinant methioninase (rMETase) targets the fundamental basis of cancer, methionine addiction, known as the Hoffman effect, and enhances the efficacy of numerous chemotherapy drugs. The present study determined the efficacy of rMETase when administered in combination with IRN. Cell viability was assessed by cultivating the HCT-116 human colorectal cancer cell line in 96-well plates at 1×103 cells per well in Dulbecco's modified Eagle's medium (DMEM). Subsequently, HCT-116 cells were treated with increasing concentrations of SN-38, the active form of IRN, ranging from 0.5 nM to 32 nM, and/or rMETase ranging from 0.125 to 8 U/ml. After treatment for 72 h, the half-maximal inhibitory concentration (IC50) of SN-38 alone and rMETase alone for HCT-116 cells were determined. Using the IC50 concentration of rMETase, we determined the IC50 of SN-38 in combination with rMETase. Cell viability was determined with the cell-counting Kit-8 with the WST-8 reagent.. The IC50 of rMETase alone for the HCT-116 cells was 0.55 U/ml, and the IC50 of IRN (SN-38) alone was 3.50 nM. rMETase at 0.55 U/ml lowered the IC50 of SN-38 to 0.232 nM (p<0.0001), a 15-fold reduction. rMETase and IRN are strongly synergistic, giving rise to the possibility of lowering the effective dose of IRN for the treatment of patients with colon cancer, thereby reducing its severe toxicity. This new strategy will allow more patients with cancer to be effectively treated with IRN.

UGT1A1 genotype-guided irinotecan dosing during neoadjuvant chemoradiotherapy for locally advanced rectal cancer: A prospective analysis of SN-38 concentration.

Irinotecan plays a crucial role in the neoadjuvant chemoradiotherapy (nCRT) of rectal cancer, but its optimal dosing is still unclear. In this study, we included 101 eligible patients with the UGT1A1*28 genotype of UGT1A1*1*1 (74.3%) and UGT1A1*1*28 (25.7%) and UGT1A1*6 genotypes of GG (63.4%), GA (32.7%), and AA (3.9%). All patients received preoperative radiotherapy (50 Gy/25 fractions) with concurrent irinotecan (UGT1A1*1*1: 80 mg/m2 ; UGT1A1*1*28: 65 mg/m2 ) and capecitabine (CapIri). SN-38 concentrations were measured at 1.5, 24, and 49 h post-administration. Patients were divided into four groups (Q1-Q4) based on the SN-38 concentration. The complete-response (CR) rate was the primary endpoint. The analysis demonstrated that the 49 h SN-38 concentration was relatively optimal for predicting efficacy and toxicity. The Q4 group had a significantly higher CR rate than the Q1 group (p = .019), but also higher rates of adverse events (p = .009). We screened the recommended 49 h SN-38, with a 0.5-1.0 ng/mL concentration range. We also validated the correlation between UGT1A1*6 polymorphism and SN-38 concentration, along with the clinical efficacy of irinotecan. In conclusion, our study identified the relatively optimal timepoint and concentration range for monitoring SN38 concentrations and revealed the clinical significance of UGT1A1*6 and UGT1A1*28 polymorphisms in guiding irinotecan administration, offering meaningful insights for personalised irinotecan dosing.