Combination Of Irinotecan Research Articles

Phase II Study of Ramucirumab Plus Irinotecan Combination Therapy as Second-Line Treatment in Patients with Advanced Gastric Cancer: HGCSG1603

BackgroundRamucirumab is a human IgG1 monoclonal vascular endothelial growth factor receptor-2 antibody that inhibits tumor cell growth and affects the tumor cell microenvironment. We assessed the efficacy and safety of ramucirumab plus irinotecan combination therapy as second-line treatment in patients with previously treated advanced gastric cancer.Materials and MethodsPatients with advanced gastric cancer refractory or intolerant to primary chemotherapy were included. Ramucirumab 8 mg/kg plus irinotecan 150 mg/m2 combination therapy was administered every 2 weeks. The primary endpoint was progression-free survival rate at 6 months and secondary endpoints were overall survival, progression-free survival, response rate, safety, and dose intensity for each drug.ResultsThirty-five patients were enrolled between January 2018 and September 2019. The progression-free survival rate at 6 months was 26.5% [95%CI, 13.2%–41.8%, P = .1353)]. Median progression-free and overall survivals were 4.2 months (95%CI, 2.5-5.4 months) and 9.6 months (95%CI, 6.4-16.6 months), respectively. The overall response rate was 25.9% (95%CI, 11.1-36.3%) and disease control rate was 85.2% (95%CI, 66.3-95.8%). Grade ≥3 adverse events that occurred in >10% of patients included neutropenia, leucopenia, anemia, anorexia, and febrile neutropenia. No death or new safety signals with a causal relation to the study treatment were observed.ConclusionAlthough the primary endpoint was not achieved statistically, combination therapy of ramucirumab plus irinotecan showed anticancer activity and a manageable safety profile for second-line treatment of patients with advanced gastric cancer.

Arvanil, a synthetic capsaicin mimetic, synergizes with Irinotecan to trigger enhanced apoptosis in Cisplatin‐resistant Human Lung Cancer

Cisplatin‐based combination therapy is the first line treatment for human lung cancer patients. Initially, cisplatin shows excellent therapeutic response inducing remission in about 80% of lung cancer patients; however, the tumor inevitably relapses (within a year) and this relapsed tumor is resistant to cisplatin. Patients with platinum‐resistant or refractory disease have very limited options, as the only standard chemotherapy with an FDA‐approved drug, irinotecan has an objective response rate of approximately 3% and little or no survival benefit. Therefore, agents which improve the therapeutic response (of human lung cancers) towards irinotecan may be useful for the treatment of cisplatin‐resistant human lung cancer. Our published data show that the nutritional compound capsaicin sensitized human lung cancer cells towards the pro‐apoptotic activity of camptothecin (an analog of irinotecan) in cell culture and athymic mouse models. The administration of capsaicin causes stomach cramps, gastrointestinal irritation, gut pain and vomiting in patients. Arvanil is a non‐pungent synthetic capsaicin‐analog which displays potent growth‐suppressive activity in human lung cancer. The present study aims to investigate the combinatorial apoptotic activity of arvanil and irinotecan in cisplatin‐resistant lung cancer. Caspase‐3 activity assays reveal that the combination of irinotecan and arvanil displayed greater apoptotic activity in H69‐CPR human cisplatin‐resistant SCLC cells than the drugs used alone. These experiments were repeated in a second cisplatin‐resistant lung cancer cell line PC9‐CDDP and similar results were obtained. Chou‐Talalay isobologram analysis showed the interaction between irinotecan and arvanil is synergistic in H69‐CPR and PC9‐CDDP cells. The combination of arvanil/irinotecan showed a greater anti‐tumor activity in H69‐CPR tumors xenografted on chicken chorioallantoic membrane (CAM) and in SCID mice. In summary, the results of our studies pave the way for novel combination therapies for the management and treatment of drug resistant lung cancers in patients.

Trabectedin-irinotecan, a potentially promising combination in relapsed desmoplastic small round cell tumor: report of two cases

Effective new drugs are urgently needed for desmoplastic small round cell tumor (DSRCT), an extremely rare and aggressive disease with a generally poor prognosis. We describe two heavily-pretreated young patients with advanced-stage DSRCT given third-line treatment with a combination of trabectedin and irinotecan, based on our preclinical data demonstrating its effect on patient-derived xenografts. This trabectedin-irinotecan treatment showed a limited toxicity. One patient had a mixed response (overall stable disease), the other a complete tumor remission. This is the first report of preliminary findings to suggest that combining trabectedin and irinotecan is worth further investigating as a potentially valuable chemotherapy for DSRCT.

Class III β-Tubulin Expression Is of Value in Selecting nab -Paclitaxel and Gemcitabine as First-Line Therapy in Unresectable Pancreatic Cancer.

Nab -paclitaxel and gemcitabine (GnP) or FOLFIRINOX (a combination of leucovorin, fluorouracil, irinotecan, and oxaliplatin [FFX]) is currently recognized as the standard first-line regimen for unresectable pancreatic ductal adenocarcinoma (PDAC). Class III β-tubulin (TUBB3) has the potential to predict resistance to taxane in various tumors; therefore, this study aimed to clarify whether TUBB3 is a predictive marker for GnP response. We retrospectively reviewed 113 patients with PDAC who received GnP or FFX as first-line chemotherapy and examined immunohistochemically the TUBB3 expression in specimens obtained by endoscopic ultrasound-guided fine-needle aspiration. High TUBB3 expression was associated with a significantly lower disease control rate ( P = 0.017) and shorter progression-free survival (PFS) ( P = 0.019), and multivariate analysis revealed that TUBB3 expression was an independent variable for PFS in the GnP first-line group ( P = 0.045). In addition, in the FFX first-line group, TUBB3 expression was not correlated with PFS or overall survival (OS). In all 113 patients, TUBB3 expression was not also associated with OS. Class III β-tubulin might be a predictive factor for the response of GnP, but not a prognostic factor for OS, helping the selection of an optimized first-line chemotherapy regimen for unresectable PDAC.

Irinotecan plus temozolomide in relapsed Ewing sarcoma: an integrated analysis of retrospective studies

BackgroundThe prognosis of patients with relapsed Ewing sarcoma is poor. In this study, we aimed to pooled-analyze the efficacy and safety of the combination of irinotecan and temozolomide in treating patients with relapsed Ewing sarcoma.MethodsPubMed, Cochrane CENTRAL, Web of Science, and EMBASE were systematically searched on September 27, 2021. The primary outcomes were rates of objective response and disease control, and the secondary outcomes were toxicities.ResultsSix retrospective studies with 184 patients were enrolled in the analysis. The median age ranged from 14 to 21. The integrated rates were 44% (95% confidence interval [CI] 31–58) for objective response and 66% (55–77) for disease control. Grade 3–4 neutropenia, thrombocytopenia, and diarrhea occurred in 8% (3–16), 7% (3–11), and 8% (5–10) of chemotherapeutic cycles, respectively. 18% (7–32) and 6% (2–11) of patients suffered grade 3–4 neutropenia and thrombocytopenia after irinotecan plus temozolomide treatment.ConclusionIrinotecan plus temozolomide combination chemotherapy showed antitumor activity and an acceptable safety profile in patients with relapsed Ewing sarcoma. More future prospective studies are needed to confirm the retrospective results.

Vincristine, Irinotecan, and Temozolomide in Patients With Relapsed/Refractory Neuroblastoma.

PurposeThe combination of irinotecan, temozolomide and vincristine has been proposed as an effective salvage regimen for some pediatric malignancies. Thus, we sought to evaluate this combination for patients with relapsed and refractory neuroblastoma (NB).Patients and MethodsIn this retrospective study, forty-six patients with relapsed or refractory NB were treated with the combination of vincristine (1.5 mg/m2 i.v. day 1), irinotecan (50 mg/m2/day i.v. days 1–5) and temozolomide (100 mg/m2/day p.o. days 1–5) (VIT) during the period 2011–2019. All toxicities were documented.ResultsA total of 251 cycles (median 6 cycles/patient) were administered. A complete response (CR) was achieved in 5 patients, partial response (PR) in 27 patients, stable disease (SD) in 8 patients, and progression disease (PD) in 6 patients, with an overall objective response rate (CR+PR) of 69.6%. Eighteen patients developed diarrhea with Grade 3 or less. Grade 1-2 hematologic toxicity occurred in 10 patients. Grade 3-4 hematologic toxicity developed in 32 patients. VIT was an effective regimen for different metastatic sites. UGT1A*28 genotyping performed in 7 patients revealed wild type. Diarrhea occurred in 4 of them.ConclusionThe shorter, 5-day VIT regimen is an active and well-tolerated salvage regimen in relapse/refractory NB.

Phase 1 study of nanoliposomal irinotecan in combination with trifluridine/tipiracil in refractory solid tumors.

660 Background: Nal-IRI is irinotecan (as known as CPT-11) encapsulated in a nanoliposome drug delivery system (nanoliposomal irinotecan; nal-IRI). Nal-IRI + 5-FU/LV has been approved in patients with metastatic pancreatic cancer after gemcitabine-based therapy through the NAPOLI-1 study. TAS-102 is a combination drug of trifluridine (FTD), an antineoplastic thymidine analog, and tipiracil hydrochloride (TPI), a thymidine phosphorylase inhibitor. TAS-102 has been approved in metastatic colorectal cancer and gastric or gastroesophageal junction adenocarcinoma. Given both drugs show antitumor activity in various cancers, this study is to identify the MTD (maximum tolerated dose) and recommended phase II dose (RP2D), and to explore the preliminary efficacy of nal-IRI and TAS-102 combination in solid tumors. Methods: This multi-center phase I study consists of a classical 3 + 3 dose finding portion and an expansion portion. Eligible patients have pathologically confirmed solid malignancies with no standard treatment available. Patients will be treated with nal-IRI at dose of 60, 70, 80 mg/m2 over 90 minutes on day 1, and oral TAS-102 25, 30, 35 mg/m2 twice daily on day 1-5, every 14 days. Patients who have homozygous for the UGT1A1*28 allele ( TA7/TA7) or UGT1A1*6 allele ( A/A), or double heterozygous for both UGT1A1*28 allele ( TA6/TA7) and UGT1A1*6 allele ( G/A) will be excluded from the dose finding portion. This trial is registered with ClinicalTrials.gov, NCT 03810742. Results: From February 2019 to May 2021, a total of 43 (male/female: 27/16; median age 56, range 25-69) patients (pts) were treated, including 28 in the dose finding portion in which 3, 3, 3, 3, 7, 3 and 6 pts were at levels 1, 2A, 2B, 3, 4A, 4B and 5, respectively, and 15 pts in the expansion portion. The results here are reported from the dose finding portion. The most common cancer types were cholangiocarcinoma (N = 6), neuroendocrine tumor (N = 3), and ampulla of Vater (N = 3). DLTs were noted at one patient who had G4 sepsis and G3 diarrhea at level 4A (80/30), and two subjects who had G3 diarrhea and G3 dehydration at level 5 (80/35). The dosage of the level 4A is determined to be the MTD and it is also the RP2D for the expansion phase. Most common treatment related toxicities during the DLT observation period (the first 2 cycles) are neutropenia, thrombocytopenia, diarrhea, fatigue, and vomiting. In this dose finding portion, 4 pts had partial response and 17 pts had stable disease as the best response. Conclusions: The MTD of Nal-IRI in combination with TAS-102 every 2 weeks is 80/30 mg/m2, which is also the RP2D for expansion study. The clinical benefit was observed in pts at different dose levels. The expansion portion of the study is still ongoing and pts will be followed until disease progression or consent withdrawal. Clinical trial information: NCT03810742.

A phase II, open-label pilot study evaluating the safety and activity of liposomal irinotecan (Nal-IRI) in combination with 5-FU and oxaliplatin (NALIRIFOX) in preoperative treatment of pancreatic adenocarcinoma: NEO-Nal-IRI study.

TPS619 Background: Neoadjuvant treatment for potentially curable pancreatic cancer (PDAC) is increasing in acceptability, but a standard regimen has yet to be established. Multiple studies have demonstrated feasibility and effectiveness of the FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) regimen in the perioperative setting. However, FOLFIRINOX often requires dose modifications, delays and growth factor support due to excessive toxicity which can complicate care delivery when given pre-op. Liposomal irinotecan injection (Nal-IRI) in combination with 5FU/LV is FDA approved with a well-tolerated safety profile in relapsed, refractory metastatic PDAC. The current study aims to substitute Nal-IRI for traditional irinotecan in the standard FOLFIRINOX regimen (NALIRIFOX) and to demonstrate safe and effective neoadjuvant delivery. Methods: This phase 2, open-label, multicenter single-arm study focuses on patients (pts) with operable PDAC without metastatic disease. Other key eligibility criteria include age ≥18 years, resectability confirmed by multiD GI tumor board (resectable vs. borderline), adequate cardiac, renal, hepatic function and ECOG performance status of 0 to 1. Pts receive NALIRIFOX regimen as per the table every 2 weeks for four months followed by disease reassessment. Pts who remain surgical candidates will undergo surgical resection within 4 to 8 weeks following last dose of therapy. The primary endpoint is to assess safety and feasibility of regimen in pre-op setting. Secondary endpoints include R0 resection rate, clinical, biochemical and radiological response rate and patient-reported quality of life during treatment as measured by the NCI validated FACT-G scale. Exploratory ctDNA and stool microbiome analyses are also planned. Enrollment continues to a maximum of 28 evaluable pts to demonstrate a reduction in historical 30-day post-op complication rate. Clinical trial information: NCT03483038. [Table: see text]

Randomized phase II study of nalicap (nal-IRI/capecitabine) compared to NAPOLI (nal-IRI/5-FU/LV) in gemcitabine-pretreated advanced pancreatic cancer: Trial-in-progress.

TPS621 Background: Liposomal irinotecan (nal-IRI) in combination with fluorouracil (5-FU) and folinic acid (LV), called the NAPOLI regimen, improves survival in advanced pancreatic cancer patients who failed gemcitabine-based chemotherapy (Wang-Gillam A et al. 2016). Capecitabine is an oral anti-cancer agent as the prodrug of 5-FU. Capecitabine has proven its efficacy in gastrointestinal cancers like stomach cancer, colon cancer, or pancreatic cancer. Replacing continuous 5-FU infusions with oral capecitabine with equivalent efficacy has been tested and is now widely used. However, in pancreatic cancer, replacing continuous infusion of 5-FU with an oral drug has not yet been tested. Therefore, this trial is being conducted with the aim of improving patient convenience while maintaining efficacy, when the continuous infusion of 5-FU/LV in NAPOLI (nal-IRI/5-FU/LV) regimen are replaced with oral capecitabine. This study is a two-arm, open-label, multicenter, randomized phase 2 trial to assess whether capecitabine plus nal-IRI combination treatment (NaliCap) is non-inferior to NAPOLI regimen in gemcitabine-pretreated patients with advanced pancreatic cancer. Methods: Eligible patients have histologically confirmed pancreatic adenocarcinoma who have failed to gemcitabine-based chemotherapy. This trial is composed of two parts: safety lead-in-part and randomization part. NaliCap regimen consists of administration of capecitabine twice daily for day 1-14 and intravenous administration of nal-IRI for day 1 every 3weeks. To figure out recommended phase 2 dose of the NaliCap combination regimen, the safety lead-in-part is being conducted as a 3+3 design. In the randomization part, patients will be assigned to NAPOLI or NaliCap in a 1:1 ratio. The planned enrollment is 184 patients in the randomization part. Patients allocated to the NaliCap group will receive recommended phase 2 dose of NaliCap determined through the safety lead-in-part. Patients allocated with the NAPOLI group will receive nal-IRI 70mg/m2 intravenously day 1, LV 400mg/m2 IV day 1, and continuous 5-FU 2400mg/m2 infusion over 48hours every 2weeks. Response assessments are performed every 6 weeks using the RECIST criteria version 1.1 (every 2 cycles in the NaliCap group and every 3 cycles in the NAPOLI group). The primary endpoint is progression-free survival, with a non-inferior margin of the hazard ratio of 1.4. Key secondary endpoints are overall response rate, disease control rate, overall survival, safety, and quality of life. This study is prospectively registered at ClinicalTrials.gov, NCT04371224. Clinical trial information: NCT04371224.

Cisplatin and Irinotecan as First-Line Chemotherapy for Previously Untreated Metastatic Thymic Carcinoma: Updated Analysis.

Platinum-based chemotherapy is the de facto standard treatment for metastatic or unresectable thymic carcinoma. The optimal chemotherapy regimen has not yet been determined, including whether this should be combined with a second- or third-generation anti-cancer agent. We retrospectively evaluated the data of patients with metastatic or unresectable thymic carcinoma who were treated with a combination of cisplatin and irinotecan as first-line chemotherapy between 2002 and 2021 (trial registration UMIN000012175). The primary endpoint was response rate according to the RECIST criteria version 1.1. Secondary endpoints were disease control rate, progression-free survival (PFS), overall survival (OS), and toxicity (adverse events). Some patients analyzed in this study were also included in the previous trial, which was terminated early. For this analysis, we included 18 patients with a median age of 56 years and an Eastern Cooperative Oncology Group performance status of 0 or 1. All patients had clinical stage IVa or IVb thymic carcinoma according to the Masaoka-Koga staging system. The response rate was 44% and the disease control rate was 89%. The median PFS was 8.4 months (95% confidence interval (CI): 2.7–11.6 months) and the median OS was 45.6 months (95% CI: 15.7–69.1 months). Grade 3 or worse hematological toxicity was observed in 5 patients and grade 3 or worse non-hematological toxicity was observed in 3 patients. None of the patients developed febrile neutropenia, and no treatment-related deaths occurred. Thus, the combination of cisplatin and irinotecan as first-line chemotherapy for metastatic thymic carcinoma showed efficacy and acceptable toxicity.

A retrospective analysis of irinotecan and bevacizumab combination therapy in recurrent high-grade glioma and glioblastoma multiforme

Introduction: High-grade gliomas comprise central nervous system (CNS) World Health Organization (WHO) Grade 3 and CNS WHO Grade 4 gliomas. Recurrence is seen in almost all patients who underwent treatment. Recurrent high-grade gliomas have poor prognosis. There are phase two trials that assessed the role of irinotecan and bevacizumab as combination regimen in recurrent High-grade gliomas and showed overall survival (OS) and progression-free survival (PFS) benefit. We did a retrospective analysis of our institutional experience on treating recurrent high-grade gliomas with combination of irinotecan and bevacizumab. Materials and Methods: This was a retrospective analysis including 58 patients treated at our center from January 1, 2010 to December 31, 2020. All patients were diagnosed case of CNS WHO Grade 3 and Grade 4 glioma, who received at least one modality of treatment. All patients received inj. Irinotecan 125 mg/m2 intravenous (IV) and inj. Bevacizumab 10 mg/kg IV, every 2 weekly. A base line radiological evaluation has been done with magnetic resonance imaging brain with contrast and repeated every 3 months. Patients have been assessed both for PFS and OS. Results: Median PFS was 6 months (95% confidence interval [CI] 4.395–7.605). Median OS was 8 months (95%CI 5.894–10.106). Six months PFS rate is 49% and 6 months OS is 58%. CNS WHO Grade 3 gliomas responded better to combination therapy as compared with CNS WHO Grade 4 gliomas. Conclusion: Combination of Bevacizumab and Irinotecan is well tolerated and improves OS and PFS in patients with recurrent high-grade gliomas. The effect of combination systemic therapy is more evident in CNS WHO Grade 3 gliomas as compared with glioblastoma multiforme.

Drug treatment for chemotherapy-induced peripheral neuropathy in patients with pancreatic cancer.

Pancreatic cancer (PC) is a lethal disease where most tumors are too advanced at diagnosis for resection, leaving chemotherapy as the mainstay of treatment. Although the prognosis of unresectable PC is poor, it has been dramatically improved by new chemotherapy treatments, such as the combination of 5-fluorouracil, oxaliplatin, irinotecan, and leucovorin (FOLFIRINOX) or gemcitabine plus nab-paclitaxel. However, as oxaliplatin and paclitaxel are common neurotoxic drugs, chemotherapy-induced peripheral neuropathy (CIPN) is a common and severe adverse effect of both treatments. As there are no agents recommended in the ASCO guidelines, we review the methods used to treat CIPN caused by PC treatment. The efficacy of duloxetine was observed in a large randomized controlled trial (RCT). In addition, pregabalin was more effective than duloxetine for CIPN in two RCTs. Although duloxetine and pregabalin can be effective for CIPN, they have several side effects. Therefore, the choice between the two drugs should be determined according to effect and tolerability. Mirogabalin is also used in patients with PC and there is hope it will yield positive outcomes when treating CIPN in the future.

Long-term Survival, Tolerability, and Safety of First-Line Bevacizumab and FOLFIRI in Combination With Ginsenoside-Modified Nanostructured Lipid Carrier Containing Curcumin in Patients With Unresectable Metastatic Colorectal Cancer.

Background:Colorectal cancer is the third most common malignant disease and the second leading cause of death worldwide. Previous studies showed improved bioavailability and cytotoxicity of ginsenoside-modified nanostructured lipid carrier containing curcumin (G-NLC) in human colon cancer cell lines. This study aimed to evaluate the safety and tolerability with long-term survival rates in patients with colorectal cancer with unresectable metastases after treatment with first-line bevacizumab/FOLFIRI (folinic acid, bolus/continuous fluorouracil, and irinotecan) in combination with a dietary supplement of G-NLC.Methods:This study was a prospective, observational, single-group analysis. The enrolled patients had colorectal cancer with unresectable metastases and were administered bevacizumab and FOLFIRI in combination with daily oral G-NLC as first-line treatment. Overall survival, progression-free survival, tumor response, and adverse events were evaluated.Results:A total of 44 patients were enrolled between 2015 and 2019. The median age was 65 (range 45-81) years and the sex ratio was 31:13 (male:female). The primary tumor locations were the colon (31 patients) and rectum (13 patients). The metastatic sites included, liver only (n = 20), lung only (n = 6), both liver and lung (n = 12), and others (n = 6). The median duration of curcumin supply was 7.9 (range 0.9-16.6) months. The most common grade 3 or higher adverse events were neutropenia (n = 15, 34.1%), followed by nausea (n = 4, 9.1%) and vomiting (n = 4, 9.1%). Within the median follow-up period of 22.8 months, the median overall survival was 30.7 months, and the median progression-free survival was 12.8 months. None of the patients achieved complete response (CR); however, 9 patients showed partial response (PR), and 3 patients underwent conversion surgery.Conclusions:Bevacizumab/FOLFIRI with G-NLC as first-line chemotherapy in patients with colorectal cancer with unresectable metastases presented comparable long-term survival outcomes with acceptable toxicity outcomes. Additional randomized controlled studies are needed to establish definitive conclusions regarding this new regimen for metastatic colorectal cancer.

The Chemosensitizing Effect of Portulaca oleracea Methanol Extract on Human Colorectal and Lung Cancer Cells Against Irinotecan

Cancer is a major health problem and it has been causing great damage in recent years worldwide. Serious side effects of chemotherapeutics used in cancer treatment make natural products valuable. Combined use of chemotherapy drugs and herbal products is an important approach in reducing side effects and revealing a more effective treatment. In this study, the effects of methanolic extract from Portulaca oleracea (POM) alone and in combination with Irinotecan were investigated against human colorectal carcinoma cell line HCT-116 and human lung adenocarcinoma cell line A549. The antiproliferative/anti-colony formation effects were determined using WST-1 assay and clonogenic assay. Cell death detection Elisa assay was employed to exhibite the triggered apoptosis, and quantitative real time polimerase chain reaction (qRT-PCR) was performed to evaluate the mRNA expression of mTOR, Akt and PTEN genes, which are significant modulators of apoptotic and survival pathways. It was determined that 72 h treatment with increasing concentrations of POM (0-1000 mg mL-1) decreased the viability of HCT116 and A549 cells in a dose-dependent manner. Also, POM and Irinotecan exhibited synergistic effects in both cell lines. The combination of POM and Irinotecan suppressed the colony forming capacity of HCT116 and A549 cells by 84% and 79%, respectively. POM also altered mTOR, Akt and PTEN gene expressions in HCT-116 and A549 carcinoma cells, both alone and in combination with Irinotecan. This study shows that the phytotherapeutic effect of P. oleracea needs to be studied more intensively.

Assessment of Drug–drug Interaction and Optimization in Capecitabine and Irinotecan Combination Regimen using a Physiologically Based Pharmacokinetic Model

Capecitabine and irinotecan (CPT-11) combination regimen (XELIRI) is used for colorectal cancer treatment. Capecitabine is metabolized to 5-fluorouracil (5-FU) by three enzymes, including carboxylesterase (CES). CES can also convert CPT-11 to 7-ethyl-10-hydroxycamptotecin (SN-38). CES is involved in the metabolic activation of both capecitabine and CPT-11, and it is possible that drug–drug interactions occur in XELIRI. Here, a physiologically based pharmacokinetic (PBPK) model was developed to evaluate drug–drug interactions. Capecitabine (180 mg/kg) and CPT-11 (180 mg/m2) were administered to rats, and blood (250 μL) was collected from the jugular vein nine times after administration. Metabolic enzyme activities and Ki values were calculated through in vitro experiments. The plasma concentration of 5-FU in XELIRI was significantly decreased compared to capecitabine monotherapy, and metabolism of capecitabine by CES was inhibited by CPT-11. A PBPK model was developed based on the in vivo and in vitro results. Furthermore, a PBPK model-based simulation was performed with the capecitabin dose ranging from 0 to 1000mol/kg in XELIRI, and it was found that an approximately 1.7-fold dosage of capecitabine was required in XELIRI for comparable 5-FU exposure with capecitabine monotherapy. PBPK model-based simulation will contribute to the optimization of colorectal cancer chemotherapy using XELIRI.

Nanoliposomal irinotecan in combination with leucovorin and 5-fluorouracil in advanced biliary tract cancers.

Biliary tract cancers (BTC) are rare but aggressive. Due to limited anti-tumor effects of current second- and later-line treatment regimens, novel treatment options are required. Nanoliposomal irinotecan in combination with leucovorin and 5-fluorouracil (FOLFnal-IRI) achieved promising results as a second-line treatment in patients with pancreatic cancer, warranting further investigation in BTC. In the present study, a retrospective analysis of patients receiving FOLFnal-IRI after initial platinum-based chemotherapy for advanced BTC between January 2016 and August 2020 at the University Hospital Cologne (Cologne, Germany) was performed. A total of 11 patients were identified who met the inclusion criteria. A total of 4 patients (36.4%) were female and the median age was 54 years. The proportion of patients suffering from gallbladder carcinoma, intrahepatic and extrahepatic cholangiocarcinoma was 18.2, 63.6 and 9.1%, respectively. Furthermore, 7 patients (63.6%) received FOLFnal-IRI as their second-, 3 (27.3%) as third- and one (9.1%) as their fourth-line therapy. The disease control rate was 54.5% and 3 grade III toxicities were recorded. Progression-free survival and overall survival (OS) after initiation of FOLFnal-IRI was 5.1 and 12.4 months, respectively. OS after initial diagnosis was 24.7 months. FOLFnal-IRI demonstrated promising antitumor potential with an acceptable safety profile as a subsequent therapy regimen in advanced biliary tract malignancies. Further randomized controlled trials of its value as a treatment option for BTC appear justified.

Effect of capecitabine combined with irinotecan on the safety of colon cancer treatment, patients’ adverse reactions and quality of life

Purpose: To study the impact of the combination of capecitabine and irinotecan on the safety of colon cancer treatment, adverse reactions and wellbeing of patients.Methods: Colon cancer subjects (n =120) admitted to Guangzhou First People’s Hospital, Guangzhou, China were assigned equally to two groups (A and B) according to their order of admission, and they received intravenous infusion of irinotecan. In addition, group A patients were administered capecitabine, but those in B group were given tegafur, gimeracil and oteracil porassium. The patients in groups A and B were compared with respect to the incidence of unwanted effects, quality of life (QoL), and overall clinical efficacy of the treatments.Results: Cases of nausea and vomiting, delayed diarrhea and sensory neuropathy of the patients were significantly reduced in group A, relative to group B. Moreover, QoL score after treatment was markedly higher in group A than in group B, while the objective response rate (ORR) of colon cancer patients in group A was also significantly higher than that in group B (p < 0.05). However, no obvious difference in disease control rate (DCR) was observed between groups A and B (p > 0.05).Conclusion: Combined capecitabine and irinotecan therapy effectively improves clinical prognosis, reduces the incidence of adverse reactions, and is safe in colon cancer patients. Therefore, the combined treatment may be beneficial in the management of colon cancer.

Mirogabalin vs pregabalin for chemotherapy-induced peripheral neuropathy in pancreatic cancer patients

BackgroundThe prognosis of pancreatic cancer (PC) has been improved by new chemotherapy regimens (combination of 5-fluorouracil, oxaliplatin, irinotecan, and leucovorin (FOLFIRINOX) or gemcitabine plus nab-paclitaxel (GnP)). Unfortunately, chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse event of these two regimens. The efficacy of pregabalin for CIPN has been reported in previous studies. However, the efficacy of mirogabalin for CIPN remains unknown. Thus, in this study, we aimed to clarify which drug (mirogabalin or pregabalin) was more valuable for improving CIPN.MethodsA total of 163 PC patients who underwent FOLFIRINOX or GnP between May 2014 and January 2021 were enrolled. Among them, 34 patients were diagnosed with CIPN. Thirteen patients were treated with mirogabalin (mirogabalin group), and twenty-one patients were treated with pregabalin (pregabalin group). Treatment efficacy was compared between the two groups.ResultsIn both the mirogabalin group and the pregabalin group, the grade of patients with CIPN at 2, 4, and 6 weeks after the initiation of treatment showed significant improvement compared to the pretreatment grade. Notably, the rate of CIPN improvement was higher in the mirogabalin group than in the pregabalin group (2 weeks: 84.6% (11/13) vs 33.3% (7/21), P value = 0.005; 4 weeks, 6 weeks: 92.3% (12/13) vs 33.3% (7/21), P value = 0.001).ConclusionsAlthough both mirogabalin and pregabalin were effective at improving CIPN, mirogabalin might be a suitable first choice for CIPN in PC patients.Trial registrationNot applicable

The MK2/Hsp27 axis is a major survival mechanism for pancreatic ductal adenocarcinoma under genotoxic stress.

Combination chemotherapies remain the cornerstone treatment for pancreatic ductal adenocarcinoma (PDAC), but de novo and acquired resistance is common. In this study, we aimed to identify and characterize resistance mechanisms to a FIRINOX chemotherapy regimen (a combination of 5-fluorouracil, irinotecan, and oxaliplatin) because it is the most aggressive regimen currently used clinically for patients with PDAC. Using an unbiased reverse-phase protein array, we detected phospho-activation of heat shock protein 27 (Hsp27) as the most up-regulated event after FIRINOX treatment in PDAC cells. Silencing HSP27 by RNA interference or by a small-molecule inhibitor enhanced apoptosis caused by FIRINOX in vitro. Mechanistically, FIRINOX up-regulated tumor necrosis factor–α (TNFα), causing autocrine phosphorylation and activation of transforming growth factor–β–activated kinase 1 (TAK1), MAPK activated protein kinase 2 (MAPKAPK2 or MK2), and, ultimately, Hsp27. Targeting MK2, the kinase that directly phosphorylates Hsp27, abrogated Hsp27 activation, sensitized PDAC cells to apoptosis, and suppressed SN-38–induced protective autophagy in vitro, in part by blocking phospho-activation of Beclin1. In an autochthonous PDAC mouse model, the MK2 inhibitor ATI-450 decreased PDAC development and progression. When combined with FIRINOX, ATI-450 eliminated most PDAC foci and marked prolonged mouse survival without causing additional toxicity. Last, we found that high phospho-MK2 expression in tumors was associated with poorer survival of patients with PDAC. Our study identified MK2 as a mediator of genotoxic stress–induced activation of prosurvival pathways and provides preclinical support for combining an MK2 inhibitor with FIRINOX-based chemotherapies to treat PDAC.

Abstract P077: SCO-101 mediates re-sensitization of irinotecan (SN38) resistant colorectal cancer cells

Abstract Introduction: Annually, more than 500.000 die from Colorectal Cancer (CRC). Three types of chemotherapy are currently being used worldwide to treat CRC patients: 5FU, oxaliplatin and irinotecan. Unfortunately, chemotherapy resistance is present or develops in the majority of metastatic CRC patients. Resistance to anti-cancer drugs represents the main cause of cancer-related deaths. Thus, re-sensitization of chemotherapy resistant cancer cells constitutes a highly unmet medical need. The small molecule drug, SCO-101, is an oral drug and has passed 4 Phase I clinical trials where it demonstrated excellent PK and favourable safety profile. Materials and Methods: We used pairs of parental (sensitive) and SN38-resistant (SN38 is the active metabolite of irinotecan) human colon cancer cell lines (HT29 and LoVo). Inhibition of ABCG2 was known re-sensitize the SN38 resistant cells and SCO-101 was investigated for effects on ABCG2 by dye-flux assays, bi-directinal fluz assays and vesicular uptake assays. The impact on the levels of ABCG2 was investigated in the presence or absence of SCO-101. Furthermore, a kinase screen revealed that the kinase SRPK1 was inhibited by SCO-101 and the importance of SRPK1 activity in re-sensitization of SN38 resistant colon cancer cells was investigated by two different synthetic SRPK1 inhbitors. The effect of SCO-101 was investigated by cell viability assays (MTT/PresoBlue) in vitro during 72h exposure to SCO-101 and/or SN38. Results: Updated results from the various flux assays clearly demonstrated that SCO-101 inhibited the activity of ABCG2 (BCRP). Protein analysis further demonstrated that SCO-101 causes degradation of ABCG2/BCRP and in silco docking predicted SCO-101 to bind in the part of ABCG2 whwere also SN38 binds. Cell viability assays with two different SRPK1 inhibitors demonstrated that this kinase is involved in re-sensitization to SN38. Exposing SN38-resistant cells to the combination of SCO-101 and SN38, had a significant inhibitory effect on cell viability compared to either drug alone, suggesting an additive or synergistic effect between these two drugs with SCO-101 re-sensitizing the resistant cells to SN38. Conclusion and future perspectives: These preclinical studies demonstrate that SCO-101 sensitizes SN38-resistant colon cancer cells to SN38 through inhibition of the SRPK1 kinase and inhibition/degradation of the ABCG2/BCRP drug efflux pump. In conclusion, SCO-101 represents a unique drug with an innovative dual mechanism of action. Scandion Oncology has reported the outcome of the first part of the ongoing Phase II clinical CORIST trial with metastatic CRC patients, who have developed acquired resistance to irinotecan containing treatment. These patients were be re-exposed to the combination of irinotecan containing treatment and SCO-101 (www.clinicaltrials.gov/ct2/show/NCT04247256?term=scandion&draw=2&rank=2). Citation Format: Jan Stenvang, Nicklas Lindland Roest, Peter Michael Vestlev, Bo Rode Hansen. SCO-101 mediates re-sensitization of irinotecan (SN38) resistant colorectal cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P077.