Irinotecan Therapy Research Articles

Characterizing Sensitivity to Vincristine, Irinotecan, and Telomerase-targeted Therapy in Diffuse Anaplastic Wilms Tumor Patient-derived Xenografts☆.

Characterizing Sensitivity to Vincristine, Irinotecan, and Telomerase-targeted Therapy in Diffuse Anaplastic Wilms Tumor Patient-derived Xenografts☆.

Trifluridine tipiracil with bevacizumab in refractory metastatic colorectal cancer with a convenient two weekly schedule: An Indian single center experience.

e15612 Background: Refractory metastatic colorectal cancer (CRC) is a challenging situation with most patients showing modest response to treatment with trifluridine tipiracil (FTD-TPI) or regorafenib. In the recent phase 3 Sunlight trial, FTD-TPI with bevacizumab showed better efficacy than FTD-TPI alone with median overall survival (OS) of 10.8 months versus 7.5 months, and median progression free survival (PFS) of 5.6 months versus 2.4 months respectively, making this a preferred 3 rd line option. The most common adverse events were neutropenia, nausea, and anemia and discontinuation of the trial regimen was reported in 12.6%. We evaluated this regimen in Indian patients, as there is limited data of treatment with this regimen from India. Methods: This was a retrospective observational study of refractory metastatic CRC patients treated between April 2023 to Dec 2024 at Manipal Hospital, Bangalore, India. FTD-TPI was given at 35mg/m 2 , twice daily, on days 1-5 and days 15-19 with bevacizumab at 5 mg/kg on days 1 and 15, and the cycle was repeat 4 weekly. Two weekly schedule was evaluated to reduce toxicity of low counts and to make the regimen convenient, thus, improving compliance. The endpoints were PFS, OS and safety. Results: 27 patients received treatment with FTD-TPI with bevacizumab. There were 8 females and 19 males. 18 had left sided and 9 had right sided cancer. Biomarker analysis revealed 16 KRAS mutations with 2 having K RAS G12C, 2 NRAS mutations, 2 B-RAF mutation, 1 MMR deficient and 1 Her2 3+ overexpression. 17 patients (63%) received this combination in 3 rd line and 10 (37%) received in 4 th line and beyond. All patients had progressed on fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab and anti-EGFR therapy (in RAS and B RAF wild type patients) in the prior lines. The median PFS was 6 months and median OS was 14 months. Most common side effects were fatigue, neutropenia and anemia. 15 patients (55.5%) required dose reduction of FTD-TPI due to toxicities and 3 patients (11%) discontinued treatment due to intolerance. Conclusions: The combination of FTD-TPI with bevacizumab was an effective option in our refractory metastatic CRC patients. Two weekly regimen was better tolerated and also convenient in this heavily pre-treated population. Considering the significant dose reductions due to low counts, we would suggest studying this two weekly combination regimen at a lower starting dose of FTD-TPI in a larger study in India.

Precemtabart tocentecan (M9140), an anti-CEACAM5 ADC with exatecan payload, in patients with metastatic colorectal cancer (mCRC): Results from the dose optimization of the phase 1 PROCEADE CRC-01 study.

3038 Background: CEACAM5 is overexpressed in ~90% of CRCs, with limited expression on healthy cells. Precemtabart tocentecan (M9140), the first anti-CEACAM5 ADC with an exatecan payload (topoisomerase 1 inhibitor), showed a predictable, manageable safety profile and promising early clinical activity in the dose escalation of the Phase 1 PROCEADE-CRC-01 study (NCT05464030) in heavily pretreated patients with mCRC. Methods: This global Phase 1 study in 3L adult patients with locally advanced/mCRC (ECOG PS ≤1; previous irinotecan therapy) evaluates clinical activity, safety, and tolerability of precemtabart tocentecan. Here, we report on dose optimization of precemtabart tocentecan tested at 2.8 mg/kg Q3W (Arm A1) or 2.4 mg/kg Q3W (A2; 1:1 randomization) to select the recommended phase 2 dose (RP2D). Results: As of Jan 2025, 60 patients (recruited Apr–Oct 2024) had been treated (A1, n = 29; A2, n = 31). Median age was 60.0 years, and 51.7% were male. In A1, 18 (62.1%) patients remained on treatment and 16 (51.6%) in A2. Treatment-emergent AEs (TEAEs) were reported in all patients; grade ≥3 in 38 (63.3%) patients (A1: n = 19 [65.5%]; A2: n = 19 [61.3%]); anemia and neutropenia (any grade; grade ≥3) were most common. Serious TEAEs were reported in 18 (30.0%) patients (A1: n = 8 [27.6%]; A2: n = 10 [32.3%]). Grade ≥3 hematologic AEs were reported in 32 (53.3%) patients: anemia (A1, n = 9; A2, n = 10), neutropenia (A1, n = 14; A2, n = 12), thrombocytopenia (n = 6 both), leukopenia (A1, n = 7; A2, n = 6), lymphopenia (A1, n = 1; A2, n = 2), febrile neutropenia (n = 3 both), and pancytopenia (A1, n = 0; A2, n = 1). Treatment was discontinued in 26 (43.3%) patients (A1: progressive disease (PD), n = 9, patient withdrawal, n = 1, other, n = 1; A2: PD, n = 14, death, n = 1). No treatment-related deaths were reported. Overall, PK profiles were consistent with previous data, with overlap attributed to high between-subject variability. Partial responses were reported in 7 (24.1%; n = 4 [13.8%] confirmed) patients in A1 and 3 (9.7%; n = 1 [3.2%] confirmed) in A2 (all responders remain on treatment), stable disease in 15 (51.7%) and 21 (67.7%), and PD in 5 (17.2%) and 6 (19.4%) patients, respectively. DCR at 12 weeks was 72.4% in A1 and 67.7% in A2. Conclusions: These preliminary results corroborate the encouraging efficacy and safety data from the dose escalation part of the PROCEADE CRC-01 study, with no new relevant safety findings. ORR was higher at 2.8 mg/kg, with similar tolerability at both doses. The ORR of 24.1% (13.8% confirmed) at 2.8 mg/kg compares favorably with current monotherapy SoCs (ORRs 1-2%) and recent phase 3 data with trifluridine–tipiracil + bevacizumab (ORR 6.1%) in 3L+ mCRC. These results suggest 2.8 mg/kg as the RP2D for further development in CRC, and other solid tumors (NCT06710132). More mature data, including PFS, will be presented at the congress. Clinical trial information: NCT05464030 .

Long-term survival with complete remission after irinotecan plus cisplatin therapy for metachronous liver metastasis from a gastric mixed neuroendocrine-non-neuroendocrine neoplasm: a case report.

Gastric mixed neuroendocrine-non-neuroendocrine neoplasm, which consists of both exocrine and endocrine components, is rare and exhibits aggressive biological behavior and poor prognosis. A 64-year-old man underwent investigation for abdominal pain. An endoscopic examination revealed a 30-mm protruded lesion in the gastric antrum for which distal gastrectomy with lymph node dissection was performed. Histopathological examination showed two distinct components, an adenocarcinoma component and neuroendocrine carcinoma component, with immunohistochemical staining positive for CD56, chromogranin A, and synaptophysin. The final diagnosis was mixed neuroendocrine-non-neuroendocrine neoplasm, pT2, pN3, M0, stage IIIA. Multiple liver metastases were detected 3months after surgery. The patient received irinotecan plus cisplatin therapy, which was effective, and the liver metastases disappeared. The patient remains alive, without any recurrence, more than 10years after surgery. We present a rare case of gastric mixed neuroendocrine-non-neuroendocrine neoplasm and review the literature to contribute to improving our understanding of this kind of tumor.

Abstract LB266: A multicenter phase 1-2a clinical study of Orotecan® (oral irinotecan HCl, VAL-413) in patients with recurrent pediatric solid tumors

Abstract Background: Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. An off-label regimen of IRN-IV administered as a 60-min i.v. infusion daily for 5-10 days, bi-weekly in combination with other agents such as temozolomide has been recommended for use in treating children with solid tumors (Blaney. ClinCanRes, 2001; Slotkin. PedBloodCan, 2023). While this regimen has shown promise in published clinical trials across a range of pediatric cancers including Ewing sarcoma, neuroblastoma, rhabdomyosarcoma, hepatoblastoma and medulloblastoma, the protracted administration schedule of IRN-IV is costly and inconvenient thereby negatively impacting patients’ quality of life. Oral regimens utilizing IRN-IV have been developed and implemented with favorable tumor responses (Wagner. ClinSarcRes, 2015). Unfortunately, the palatability of the IRN-IV is poor, leading to reduced compliance. Development of an advanced oral formulation to improve tolerability and patient compliance is an important unmet need. VAL-413 is a novel formulation developed to improve the palatability of oral irinotecan. This ongoing Phase 1-2a multi-center clinical trial seeks to examine the safety and tolerability of this novel formulation and assess pharmacokinetics compared to the already established oral regimen. Methods: Eligibility: Up to 20 patients ≥ 1 year of age or ≤ 30 years of age with recurrent pediatric solid tumors and adequate bone marrow, renal and liver function, for whom irinotecan therapy is a treatment option will be enrolled. Trial Design: Two different dose levels of VAL-413, 90mg/m2/day or 110mg/m2/day are being studied in combination with fixed-dose temozolomide (100mg/m2/day) using a standard 3 + 3 phase I design. In the event a dose of 90 mg/m2/day is not tolerable due to toxicity, a lower dose of 75 mg/m2/day may be implemented. Treatment: During the first cycle of treatment, each patient will receive 4 daily doses of VAL-413 and one daily dose of the intravenous preparation of irinotecan taken orally (IRN-IVPO). During all subsequent cycles, only VAL-413 will be given with temozolomide in 5-day courses administered every 21 days, as tolerated. Outcome Measures: Toxicity is assessed by NCI CCTCAEv5; tumor response is assessed by RECIST 1.1. A taste survey instrument will assess palatability of VAL-413 vs. IRN-IVPO; comparative intrapatient pharmacokinetics of irinotecan and its metabolites is assessed. This trial is ongoing (CT.gov: NCT04337177) and has completed two planned dose cohorts, with no dose limiting toxicity observed to date. A Phase 2 expansion is underway. Ongoing pharmacokinetic observations demonstrate similarity for the Orotecan (VAL-413) formulation and i.v. irinotecan given orally for both the parent compound and its active metabolites. Citation Format: Jeffrey Bacha, Dennis Brown, James Geller, Javier Oesterheld, Patrick Thompson, Aerang Kim, Meghann McManus, Sarath Kanekal, Markos Leggas, Lorena Lopez, Neil Sankar, Noymi Yam, Lars Wagner. A multicenter phase 1-2a clinical study of Orotecan® (oral irinotecan HCl, VAL-413) in patients with recurrent pediatric solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB266.

Development of new therapeutic strategies to enhance the effectiveness of irinotecan in colorectal cancer treatment.

217 Background: Chemotherapy plays an important role in the treatment of colorectal cancer. Irinotecan, a topoisomerase I inhibitor, is used in therapies such as FOLFIRI and FOLFOXIRI. However, many patients become resistant to irinotecan, and the detailed mechanisms of resistance are not fully understood. The aim is to develop new therapeutic strategies by elucidating the mechanisms of irinotecan resistance. Methods: We used in vitro approach to demonstrate the mechanism of topoI degradation. Immunohistochemistry staining was used to explore the biomarker for irinotecan, Finally, in vivo approach was used to develop a new strategy for irinotecan treatment. Results: Mechanism of topoisomerase I (topoI) degradation: We investigated the molecular mechanism of topoI degradation in detail. After irinotecan administration, double-strand breaks occur in the DNA, activating DNA-PK. This activated DNA-PK phosphorylates the S10 residue of topoI, and BRCA1-BARD1 ubiquitinates the phosphorylated topoI. Eventually, topoI is degraded by the proteasome. Colorectal cancer cell lines where topoI degradation occurred after irinotecan administration showed irinotecan resistance. Development of a biomarker for irinotecan sensitivity: We created a monoclonal antibody that labels the phosphorylated S10 residue of topoI (topoI-pS10). We examined topoI-pS10 expression in colorectal cancer cases with a history of irinotecan treatment. The results showed a sensitivity of 87.5%, accuracy of 70%, positive predictive value of 70.7%, and negative predictive value of 87%, indicating that topoI-pS10 expression could serve as a biomarker for irinotecan sensitivity.Development of new therapeutic strategies: The degradation of topoI, which causes irinotecan resistance, is carried out via the ubiquitin-proteasome pathway. It is expected that combining irinotecan with a proteasome inhibitor, which blocks this pathway, will enhance irinotecan’s effectiveness. When irinotecan was combined with a proteasome inhibitor in irinotecan-resistant colorectal cancer cell lines, cell death occurred at a higher rate compared to when they were not combined. Similar results were observed in experiments using mice. Conclusions: Based on the mechanism of topoI degradation, we developed a biomarker for irinotecan sensitivity and a new therapeutic strategy. This study suggests the potential for further improvements in irinotecan therapy.

A phase 2 study of intravenous pembrolizumab and intratumorally injected autologous dendritic cells (DCs) in refractory colorectal cancer (CRC).

TPS319 Background: Immune checkpoint inhibitors (ICIs) have shown limited benefit in CRC outside the microsatellite instability high (MSI-H) population. Deficient cytotoxic T lymphocyte (CTL) trafficking to the tumor microenvironment (TME) and excess pro-tumorigenic cytokines and immunosuppressive cells may contribute to primary ICI resistance in microsatellite stable (MSS) CRC. Selective enrichment of T cells with specific chemokine receptors may enhance antitumor immunity. Studies highlight the role of IL-12 in improving progression-free survival (PFS) and overall survival (OS) in patients on DC therapies. Our group developed ST-aDC1s, optimized for high production of high levels of IL-12 and CTL-attracting chemokines when injected intratumorally. In preclinical models, ST-aDC1s combined with anti-PD-1/PD-L1 therapy showed therapeutic synergy, suggesting ST-aDC1s as a promising alternative to traditional DC vaccines for inducing CTL entry into tumors. Methods: We designed an open-label, non-randomized, phase 2 study of intratumoral autologous ST-αDC1 combined with pembrolizumab in recurrent/metastatic unresectable MSS CRC. Eligible patients must have prior treatment with, or contraindication to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF, and anti-EGFR therapy (if RAS wild type), be anti-PD-1/PD-L1 therapy naïve, have ECOG PS ≤1, and have at least two target lesions, one amendable to biopsy and injection. Leukapheresis will collect monocytes for ST-αDC1 generation. Patients will receive intratumoral ST-αDC1s (6 million) on days 1 and 8 with biopsies, and an optional dose on day 50 before a third pembrolizumab dose. Pembrolizumab 200 mg IV will start on day 8, given every 3 weeks for 4 doses during the study period. Pembrolizumab will continue as conventional care afterwards. CT scans will occur after 2 and 4 doses of pembrolizumab. A safety lead-in cohort will include six patients, with up to 17 patients enrolled. The primary endpoint is objective response rate (ORR) at 12 weeks per RECIST 1.1. Secondary endpoints are safety, PFS, OS, and ORR per iRECIST. Correlative analysis will assess baseline levels and post-treatment changes in infiltrating T cells, CD4/CD8 ratios, FoxP3+ Tregs, and Teff-attracting and Treg-favoring chemokines from biopsy specimens, and immune cell subsets and cytokine levels from peripheral blood. With an expected ORR under 5% for standard treatment, 17 patients are required to show at least a 25% ORR with 81.2% power and a one-sided type I error rate of 0.05. A Simon two-stage Optimal design will enroll 9 patients in stage 1, and if ≥1 response occurs, 8 more patients will be added in stage 2. If ≥3 responses are observed, the treatment will be deemed promising for further study. Clinical trial information: NCT05518032 .

Multimodal Treatment Approach for Mixed Neuroendocrine-Non-Neuroendocrine Neoplasms of the Gallbladder: A Case Report of a Patient with a Favorable Survival Outcome.

Mixed neuroendocrine-non-neuroendocrine neoplasm of the gallbladder (GB-MiNEN) is an exceptionally rare and aggressive tumor with no established treatment guidelines. We herein present the case of a 53-year-old woman with GB-MiNEN who was treated with irinotecan and cisplatin therapy, which led to a significant tumor reduction and subsequent conversion surgery. Despite a later recurrence, multimodal therapy extended survival for over two and a half years. This case underscores the potential benefit of conversion surgery combined with systemic chemotherapy, thus suggesting that multimodal treatment may improve the outcomes of GB-MiNEN. Our findings highlight the need for further studies to optimize the treatment strategies for this rare malignancy.

Pharmacogenetic Considerations for Irinotecan Therapy

Pharmacogenetic testing provides a valuable tool for personalizing irinotecan therapy, which is often used to treat pancreatic cancer, as well as many others such as colorectal cancer. Genetic variability in Uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1), which contributes to the metabolism of irinotecan, has been shown to significantly influence the risk of experiencing severe toxicity. Emerging evidence has demonstrated assessing patients for genetic variation in UGT1A1 can help to minimize adverse effects and clinical guidelines for genotype-guided irinotecan dosing are available.

Laparoscopic Radical Antegrade Modular Pancreatosplenectomy with Portal Vein Reconstruction and Celiac Axis Resection for Pancreatic Neck-Body Cancer.

Laparoscopic radical antegrade modular pancreatosplenectomy combined with celiac axis resection and portal vein reconstruction is a new procedure for the treatment of pancreatic cancer. This surgical technique may offer patients with pancreatic cancer involving the portal vein and celiac axis an opportunity for radical surgical resection. We aim to evaluate the short- and long-term efficacy and describe the surgical details of this technique. A 74-year-old man was diagnosed with pancreatic neck-body cancer, with a tumor size of 2.5 × 2.0 × 1.5 cm and local vascular invasion of the celiac axis, common hepatic artery, and portal vein. After four cycles of modified neoadjuvant folinic acid, fluorouracil, oxaliplatin, and irinotecan (FOLFIRINOX) therapy, reevaluation showed that the tumor size had considerably reduced, and the surrounding enlarged lymph nodes disappeared. Laparoscopic radical antegrade modular pancreatosplenectomy, combined with celiac axis resection and portal vein reconstruction, was performed. The operative time was 300 min, with blood loss of 200 mL. The drainage tube was removed 5 days postoperatively, and the patient was discharged 9 days later. The patient received eight cycles of modified FOLFIRINOX chemotherapy over the following month. After 15 months of follow-up, no tumor recurrence or metastasis was observed. Laparoscopic radical antegrade modular pancreatosplenectomy, combined with celiac axis resection and portal vein reconstruction, is a safe and effective treatment option for patients with pancreatic neck-body cancer involving the celiac axis and portal vein.

Hinokiflavone from Platycladi cacumen as a potent broad-spectrum inhibitor of gut microbial Loop-1 β-glucuronidases: Inhibition kinetics and molecular simulation

Hinokiflavone from Platycladi cacumen as a potent broad-spectrum inhibitor of gut microbial Loop-1 β-glucuronidases: Inhibition kinetics and molecular simulation

SALIRI-based (raltitrexed plus irinotecan) therapy as a second-line treatment for patients with metastatic colorectal cancer (SALLY): A prospective, multicenter, non-interventional, registry study.

SALIRI-based (raltitrexed plus irinotecan) therapy as a second-line treatment for patients with metastatic colorectal cancer (SALLY): A prospective, multicenter, non-interventional, registry study.

1020 Drug-Eluting Bead, Irinotecan (DEBIRI) Therapy for Refractory Colorectal Liver Metastasis: A Systematic Review

Abstract Introduction Colorectal cancer and related mortality present a profound challenge in its management, even in this modern age. DEBIRI is a new technique that involves embolisation of the feeding vessels to the tumour and delivering irinotecan for its chemotherapeutic effects. A significant amount of literature compares DEBIRI as an adjunct to various lines of chemotherapy. However, so far, not much data is available on DEBIRI as a singular treatment for those patients who have had multiple chemotherapies and still progressed and are not fit for liver resection. In this systematic review, we aim to highlight and bring together the results of those studies which focused on this specific patient group. Method A systematic review of the literature, was conducted to identify articles documenting patients who had disease progression despite chemotherapy and were not fit for surgical resection. The level of evidence and quality was assessed by two independent reviewers. Results Out of seven studies that met the final criteria, we found a pooled cohort of 302 patients.The majority of the studies reported only G1/G2 toxicities among the patients, with maximal toxicity of G4 in a few selected patients. The median overall survivll in our pooled cohort was 19.52 months. The median progression-free survival in our data was 5.76 months. Conclusions Our systematic review concludes that DEBIRI is undoubtedly a useful treatment modality with an acceptable toxicity profile. This treatment offers a good overall survival benefit for refractory colorectal liver metastasis.

Rapid detection of the irinotecan-related UGT1A1 & 5-fluorouracil related DPYD polymorphism by asymmetric polymerase chain reaction melting curve analysis

Rapid detection of the irinotecan-related UGT1A1 & 5-fluorouracil related DPYD polymorphism by asymmetric polymerase chain reaction melting curve analysis

New approach in Understanding Colorectal Cancer Immunosuppression and Immunotherapy-Based Strategies in the Treatment of Microsatellite Stable Colorectal Cancer

Abstract Except the widely accepted use of immune Checkpoint inhibitors in the treatment of microsatellite instability-high (MSI-H) mismatch repair-deficient (MMRd) CRCs representing about 5% of all metastatic (m)CRC patients, new strategies are applied to cure MMR-proficient (MMRp) mCRC patients. Tumor microenvironment (TME) is decisive for cancer development. The determination of some immunoeffective and immunosuppressive immune cells and some cytokines, chemokines and growth factors in the TME gives Information about the use of immune Checkpoint inhibitors in MMRp CRCs. The increased level of IL-6 in the serum and increased number of IL-6+ immune cells in TME, the increased number of IL-17+ Th17 cells, and of FoxP3+ cells are used to determine the use of anti-IL-6 antibody and of anti-FoxP3 antibody for treatment. The determination of high CD8+, high PD-1 expression and little or no Th17 cells appoint better response to anti-PD-1 therapy. The used combination therapies are: combination of immunotherapy with chemotherapy, with radiation therapy, with targeted therapy, with vaccines, oncolytic viruses and bispeeifie antibodies. Classical treatment of CRC patients has included chemotherapy, radiotherapy and surgery. Recently, immunotherapy has been added as a mainstay for therapy of CRC. The main checkpoint inhibitors used in CRC immunotherapy are pembrolizumab and nivolumab (anti-PD-1), durvalumab (anti-PD-L1), ipilimumab (anti-CTLA-4), favezelimab (anti-LAG3), etc. They are applied after fluorapyrimidine, oxaliplain, and irinotecan therapy. In conclusion, we may state that the future treatment of MSS CRC is in combination therapies, i.e. conventional and immunotherapies. We consider that immune infiltrate in TME must be assessed in order to determine combination therapies.

The future is now: Implementation of standard of care, preemptive pharmacogenomic testing in patients with gastrointestinal cancers.

1546 Background: Preemptive germline pharmacogenomic (PGx) testing provides insight into the safety of high-risk chemotherapy and effective use of supportive care medications in gastrointestinal (GI) cancers. Advances in clinical practice guidelines and clinician support have accelerated the appetite for PGx testing, particularly for drugs with severe adverse reactions. The objective of this study was to assess operational outcomes associated with end-to-end electronic health record (EHR) integration of standard of care, preemptive multigene PGx testing in patients with GI cancers. Methods: Patients in two UCHealth GI oncology clinics were tested for five PGx genes related to 5-fluorouracil (5-FU, DPYD), irinotecan ( UGT1A1), and supportive care therapies ( CYP2C19, CYP2D6, CYP2C9). The PGx test order was embedded in all GI oncology treatment plans. Patient samples were genotyped, and PGx results were returned as discrete data to the EHR. Automated clinical decision support (CDS) tools provided PGx-guided recommendations at the point of prescribing. We leveraged the EPIS process framework and evaluated operational outcomes such as number of patients tested, lab turnaround time, patients with actionable phenotypes, and number of CDS alerts and clinical actions. Results: The analysis included 89 patients who received results for DPYD/UGT1A1 and 83 patients who received results for supportive care genes. Among samples tested, DPYD/UGT1A1 and supportive care gene results were returned to the EHR in an average of 4.7 ± 2 days (range 1-8) and 17.3 ± 3 days (range 9-24), respectively. The number of patients with abnormal phenotypes, defined as poor metabolizers for UGT1A1 and any non-normal phenotypes for the other genes, were UGT1A1, n=10 (11.2%); DPYD, n=4 (4.5%); CYP2C19, n=43 (51.8%); CYP2D6, n=31 (41.3%; 8 uninterpretable results); and CYP2C9, n=19 (22.9%). This equated to 14/89 (15.7%) and 68/83 (81.9%) patients having an abnormal result for DPYD/UGT1A1 and at least one supportive care gene, respectively. CDS alerts fired for 32 drug-gene interactions for 25 distinct patients. Of the alerts, 7 (21.9%) were for 5-FU or irinotecan, which showed for 7/89 patients (7.9%); 25 (78.1%) were for supportive care medications, which showed for 23/83 patients (27.7%). There were 9 clinical actions taken in response to the PGx alerts, 7 (77.8%) for 5-FU or irinotecan and 2 (22.2%) for supportive care drugs. Appropriate clinical actions were taken for 100% of patients with 5-FU or irinotecan drug-gene interactions. Conclusions: End-to-end EHR integration of PGx testing and prescribing guidance facilitated clinician adoption of preemptive, standard of care multigene PGx testing, with test results driving important medication changes. Future studies will evaluate the impact of PGx testing on clinical outcomes and cost effectiveness metrics in this population.

Abstract CT058: A multicenter phase 1-2a clinical study of Orotecan (oral irinotecan HCl, VAL-413) in patients with recurrent pediatric solid tumors

Abstract Background: Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. An off-label regimen of IRN-IV administered as a 60-min i.v. infusion daily for 5-10 days, bi-weekly in combination with other agents such as temozolomide has been recommended for use in treating children with solid tumors (Blaney. ClinCanRes, 2001; Slotkin. PedBloodCan, 2023). While this regimen has shown promise in published clinical trials across a range of pediatric cancers including Ewing sarcoma, neuroblastoma, rhabdomyosarcoma, hepatoblastoma and medulloblastoma, the protracted administration schedule of IRN-IV is costly and inconvenient thereby negatively impacting patients’ quality of life. Oral regimens utilizing IRN-IV have been developed and implemented with favorable tumor responses (Wagner. ClinSarcRes, 2015). Unfortunately, the palatability of the IRN-IV is poor, leading to reduced compliance. Development of an advanced oral formulation to improve tolerability and patient compliance is an important unmet need. VAL-413 is a novel formulation developed to improve the palatability of oral irinotecan. This Phase 1-2a multi-center clinical trial seeks to examine the safety and tolerability of this novel formulation and assess pharmacokinetics compared to the already established oral regimen. This trial is ongoing (CT.gov: NCT04337177) and currently enrolling the 110mg/m2/day cohort, with no dose limiting toxicity observed to date. Initial pharmacokinetic observations demonstrate similarity for the VAL-413 formulation and i.v. irinotecan given orally for both the parent compound and SN38 active metabolite. TABLE 1. NAND Methods Eligibility: Up to 20 patients ≥ 1 year of age or ≤ 30 years of age with recurrent pediatric solid tumors and adequate bone marrow, renal and liver function, for whom irinotecan therapy is a treatment option will be enrolled. Trial Design: Two different dose levels of VAL-413, 90mg/m2/day or 110mg/m2/day are being studied in combination with fixed-dose temozolomide (100mg/m2/day) using a standard 3 + 3 phase I design. In the event a dose of 90 mg/m2/day is not tolerable due to toxicity, a lower dose of 75 mg/m2/day may be implemented. Treatment: During the first cycle of treatment, each patient will receive 4 daily doses of VAL-413 and one daily dose of the intravenous preparation of irinotecan taken orally (IRN-IVPO). During all subsequent cycles, only VAL-413 will be given with temozolomide in 5-day courses administered every 21 days, as tolerated. Outcome Measures: Toxicity is assessed by NCI CCTCAEv5; tumor response is assessed by RECIST 1.1. A taste survey instrument will assess palatability of VAL-413 vs. IRN-IVPO; comparative intrapatient pharmacokinetics of irinotecan and its metabolites is assessed. Citation Format: James Geller, Patrick Thompson, Javier Oesterheld, Aerang Kim, Meghann McManus, Jeffrey Bacha, Dennis M. Brown, Markos Leggas, Sarath Kanekal, Neil Sankar, Lorena Lopez, Noymi Yam, Lars M. Wagner. A multicenter phase 1-2a clinical study of Orotecan (oral irinotecan HCl, VAL-413) in patients with recurrent pediatric solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT058.

Efficacy of adding levofloxacin to gemcitabine and nanoparticle-albumin-binding paclitaxel combination therapy in patients with advanced pancreatic cancer: study protocol for a multicenter, randomized phase 2 trial (T-CORE2201)

BackgroundAdvanced pancreatic cancer is one of the leading causes of cancer-related deaths. For patients with advanced pancreatic cancer, gemcitabine and nanoparticle albumin-binding paclitaxel (nabPTX) combination (GEM/nabPTX) therapy is one of the recommended first-line treatments. Several retrospective studies have suggested that the addition of levofloxacin improves the efficacy of GEM/nabPTX therapy in patients with advanced pancreatic cancer. This prospective study aims to evaluate whether the addition of antibiotics improves the treatment efficacy of GEM/nabPTX as a first-line chemotherapy in patients with advanced pancreatic cancer.MethodsThis multicenter, prospective, randomized, phase 2 trial will included 140 patients. Patients with advanced pancreatic cancer will be randomized in a 1:1 ratio to either the GEM/nabPTX therapy group or the GEM/nabPTX plus levofloxacin group. The primary endpoint for the two groups is median progression-free survival time (mPFS) for the full analysis set (FAS). The secondary endpoints for the two groups are median overall survival (mOS), response rate (RR), disease control rate (DCR), and adverse event (AE) for the FAS and mPFS, mOS, RR, DCR, and AE for the per-protocol set. This study will enroll patients treated with GEM/nabPTX as the first-line chemotherapy for stage IV pancreatic adenocarcinoma.DiscussionGEM/nabPTX is a standard first-line chemotherapy regimen for patients with advanced pancreatic cancer. Recently, the superiority of 5-fluorouracil, liposomal irinotecan, and oxaliplatin combination therapy (NALIRIFOX) to GEM/nabPTX as first-line therapy for pancreatic cancer has been reported. However, the efficacy of NALIRIFOX is inadequate. Based on previous retrospective studies, it is hypothesized that treatment efficacy will improve when levofloxacin is added to GEM/nabPTX therapy. If the AEs (such as leukopenia, neutropenia, and peripheral neuropathy) that occur at an increased rate with levofloxacin and GEM/nabPTX combination therapy can be carefully monitored and properly managed, this simple intervention can be expected to improve the prognosis of patients with advanced pancreatic cancer.Trial registrationThis study was registered with the Japan Registry of Clinical Trials (jRCT; registry number: jRCTs021230005).

Genotyping of <i>UGT1A1</i> and <i>DPYD</i> polymorphisms in patients with colorectal cancer. A review

The main treatment regimen for patients with metastatic colorectal cancer is still cycle-based chemotherapy with fluoropyridines combined with oxaliplatin and/or irinotecan. The activity of these chemotherapeutic agents depends on a predominant specific metabolism pathway. Therefore, the genetic features of the patient become important as a prognostic factor for the occurrence and severity of adverse events during therapy. The review addresses current views about the mechanisms of toxic activity of irinotecan and fluoropyrimidines, analyzes the results of pharmacogenotyping of UGT1A1 and DPYD polymorphisms, and published studies assessing the relationship between genetic variants of these genes and the safety of chemotherapy. A significant role of the population component is noted both in the distribution of gene allele frequencies and in their phenotypic expression. For some polymorphisms of the DPYD gene, dose-dependent associations with the toxicity of 5-fluorouracil have been established. Nevertheless, they determine only 1–8% of cases out of 40–60% of patients with adverse events and DPD protein deficiency associated with other enzyme activity reduction mechanisms. The pharmacological significance of UGT1A1 genetic variations is associated with toxicity prediction and helps allocate patients for more effective high-dose irinotecan therapy. Data is presented on the pharmacogenotyping of these markers to establish the dose of drugs in various national guidelines. Currently, the heterogeneity of the available pharmacogenetic data leaves open the question of determining the most appropriate dosing strategies for irinotecan and fluoropyrimidines. The widespread introduction of UGT1A1 and DPYD genotyping into clinical practice balances the economic feasibility and predictive value of biomarkers. As pharmacogenomics evolves rapidly, more robust research would overcome existing hurdles and facilitate personalized drug dosage decisions.

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.