Combination Of Irinotecan Research Articles

EGCG Enhances the Chemosensitivity of Colorectal Cancer to Irinotecan through GRP78-MediatedEndoplasmic Reticulum Stress.

This study aimed to explore the role of GRP78-mediated endoplasmic reticulum stress (ERS) in the synergistic inhibition of colorectal cancer by epigallocatechin-3-gallate (EGCG) and irinotecan (IRI). Findings showed that EGCG alone or in combination with irinotecan can significantly promote intracellular GRP78 protein expression, reduce mitochondrial membrane potential and intracellular ROS in RKO and HCT 116 cells, and induce cell apoptosis. In addition, glucose regulatory protein 78 kDa (GRP78) is significantly over-expressed in both colorectal cancer (CRC) tumor specimens and mouse xenografts. The inhibition of GRP78 by small interfering RNA led to the decrease of the sensitivity of CRC cells to the drug combination, while the overexpression of it by plasmid significantly increased the apoptosis of cells after the drug combination. The experimental results in the mouse xenografts model showed that the combination of EGCG and irinotecan could inhibit the growth of subcutaneous tumors of HCT116 cells better than the two drugs alone. EGCG can induce GRP78-mediated endoplasmic reticulum stress and enhance the chemo-sensitivity of colorectal cancer cells when coadministered with irinotecan.

Targeting BCL-XL in fibrolamellar hepatocellular carcinoma.

Fibrolamellar hepatocellular carcinoma (FLC) is a rare and often lethal liver cancer with no proven effective systemic therapy. Inhibition of the antiapoptotic protein BCL-XL was found to synergize with a variety of systemic therapies in vitro using cells dissociated from patient-derived xenografts (PDX) of FLC or cells dissociated directly from surgical patient resections. As BCL-XL is physiologically expressed in platelets, prior efforts to leverage this vulnerability in other cancers have been hampered by severe thrombocytopenia. To overcome this toxicity, we treated FLC models with DT2216, a proteolysis targeting chimera (PROTAC) that directs BCL-XL for degradation via the von Hippel-Lindau (VHL) E3 ligase, which is minimally expressed in platelets. The combination of irinotecan and DT2216 in vitro on cells directly acquired from patients or in vivo using several xenografts derived from patients with FLC demonstrated remarkable synergy and at clinically achievable doses not associated with significant thrombocytopenia.

412P Phase I study of intraperitoneal irinotecan in combination with standard systemic chemotherapy in patients with extensive peritoneal metastases of colorectal origin: The INTERACT trial

The prognosis of patients diagnosed with peritoneal metastasized (PM) colorectal cancer who are ineligible for cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) is poor. We hypothesize that adding intraperitoneal (IP) irinotecan to standard systemic palliative chemotherapy improves the prognosis of these patients. Therefore we conducted this phase I trial.

EP14.01-023 A Randomized Phase II Study of Irinotecan Plus Cisplatin With or Without Simvastatin in Ever-Smoking Small Cell Lung Cancer

Smoking pack-years are associated with a sharper increase in the risk of small cell lung cancer (SCLC). Statins are recognized as powerful anti-inflammatory agents, which reduce the risk of lung cancer in chronic obstructive pulmonary disease. Previously, we found a potential survival benefit of irinotecan and cisplatin (IP) in combination with simvastatin in heavy-smoking extensive disease (ED)-SCLC patients. This study evaluated whether a combination of simvastatin with IP improve clinical outcomes of ever-smoker ED-SCLC patients.

Treatment Effect and Safety of Nanoliposomal Irinotecan with Fluorouracil and Folinic Acid after Gemcitabine-Based Therapy in Patients with Advanced Pancreatic Cancer: A Multicenter, Prospective Observational Study.

Although the combination of nanoliposomal irinotecan plus fluorouracil/folinic acid (nal-IRI/FF) exhibited survival benefits in gemcitabine-refractory patients with advanced pancreatic cancer (APC) in the phase III NAPOLI-1 trial, there is limited data on the efficacy and safety of this regimen in real-world settings in Japan. This multicenter, prospective observational study enrolled patients with APC who received nal-IRI/FF after a gemcitabine-based regimen from July 2020 to June 2021. We collected and analyzed clinical data and conducted survival and multivariate analyses. Thirty-one (78%) of the 40 patients had metastases. Nal-IRI/FF was the second-line therapy in 36 patients (90%). The median duration was 3.2 months. The disease control rate was 57%. The median progression-free survival and overall survival (OS) were 4.5 months (95% confidence interval [CI]: 2.8–5.5) and 7.4 months (95% CI: 5.1–10.6), respectively. Common ≥grade 3 toxicities included neutropenia (28%) and fatigue (23%). Fatigue led to treatment discontinuation in 6 out of 10 patients. Multivariate analysis showed that a neutrophil-to-lymphocyte ratio > 4 was a significant risk factor for a short OS (hazard ratio (HR) = 3.08, 95% CI: 1.21–7.85, p = 0.02). In conclusion, nal-IRI/FF is an appropriate treatment option for APC following gemcitabine-containing regimens.

Prognostic and predictive value of CA 19-9 in locally advanced pancreatic cancer treated with multiagent induction chemotherapy: results from a prospective, multicenter phase II trial (NEOLAP-AIO-PAK-0113)

BackgroundThe prognostic and predictive value of carbohydrate antigen 19-9 (CA 19-9) in locally advanced pancreatic cancer (LAPC) has not yet been defined from prospective randomized controlled trials (RCTs).Patients and methodsA total of 165 LAPC patients were treated within the NEOLAP RCT for 16 weeks with multiagent induction chemotherapy [ICT; either nab-paclitaxel/gemcitabine alone or nab-paclitaxel/gemcitabine followed by FOLFIRINOX (combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin)] followed by surgical exploration of all patients without evidence of disease progression. CA 19-9 was determined at baseline and after ICT and correlated with overall survival (OS) and secondary R0 resection rate.ResultsFrom the NEOLAP study population (N = 165) 133 patients (81%) were evaluable for CA 19-9 at baseline and 81/88 patients (92%) for post-ICT CA 19-9 response. Median OS (mOS) in the CA 19-9 cohort (n = 133) was 16.2 months [95% confidence interval (CI) 13.0-19.4] and R0 resection (n = 31; 23%) was associated with a significant survival benefit [40.8 months (95% CI 21.7-59.8)], while R1 resected patients (n = 14; 11%) had no survival benefit [14.0 (95% CI 11.7-16.3) months, hazard ratio (HR) 0.27; P = 0.001]. After ICT most patients showed a CA 19-9 response (median change from baseline: –82%; relative decrease ≥55%: 83%; absolute decrease to ≤50 U/ml: 43%). Robust CA 19-9 response (decrease to ≤50U/ml) was significantly associated with mOS [27.8 (95% CI 18.4-37.2) versus 16.5 (95% CI 11.7-21.2) months, HR 0.49; P = 0.013], whereas CA 19-9 baseline levels were not prognostic for OS. Multivariate analysis demonstrated that a robust CA 19-9 response was an independent predictive factor for R0 resection. Using a CA 19-9 decrease to ≤61 U/ml as optimal cut-off (by receiver operating characteristic analysis) yielded 72% sensitivity and 62% specificity for successful R0 resection, whereas CA 19-9 nonresponders (<20% decrease or increase) had no chance for successful R0 resection.ConclusionsCA 19-9 response after multiagent ICT provides relevant prognostic and predictive information and is useful in selecting LAPC patients for explorative surgery.Clinical Trial numberClinicalTrials.govNCT02125136; https://clinicaltrials.gov/ct2/show/NCT02125136; EudraCT 2013-004796-12; https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-004796-12/results

Efficacy of the VIT (vincristine, irinotecan and temozolomide) regimen in adults with metastatic Ewing sarcoma

The goal of the research was to investigate if a combination of vincristine, irinotecan and temozolomide (VIT) could benefit adult patients with metastatic Ewing sarcoma who had already been heavily pretreated. Metastatic Ewing sarcoma patients had their data retrospectively analyzed. The patients' clinical, radiological and therapeutic data were recorded. Survival analyzes were performed with these data. The study enlisted the participation of sixteen patients. The average age was 25 years old (range: 20–42). The lung was the most prevalent metastatic location (81.3%). Patients had received at least two distinct chemotherapy combinations (87.5%) and palliative radiotherapy (37.5%) before receiving the (VIT) combination. The Median progression-free survival time was found as 3.4 (95% CI, 1.8–4.9) months. Five patients (31.3%) experienced a partial response, while the remaining patients (68.7%) had progressing disease. Thirteen individuals (81.3%) had grade 1–2 adverse events, whereas five (31.3%) had grade 3–4 adverse events. Hematological complications were the most common side effects (87.5%). Median overall survival was calculated as 5.6 (95% CI, 3.6–7.5) months in the patients after the beginning of VIT regimen. We demonstrated the efficacy of the VIT regimen in adult patients with metastatic Ewing sarcoma in this research. In these extensively pretreated patients, toxicities were a concern. Metastatic Ewing sarcoma patients have few treatment choices. In patients who have had a good performance status, VIT regimen may be considered for disease control.

Hepatic arterial infusion chemotherapy plus regorafenib in advanced colorectal cancer: a real-world retrospective study

BackgroundHepatic arterial infusion chemotherapy delivers the drug directly to the liver. We aim to explore the benefits and tolerability of Hepatic arterial infusion chemotherapy plus regorafenib in advanced colorectal liver metastasis refractory to standard systemic chemotherapy.MethodsThis study analyzed 47 patients treated with hepatic arterial infusion chemotherapy plus regorafenib after standard systemic oxaliplatin and/or irinotecan in combination with bevacizumab or cetuximab between Jan 2017 and Jun 2020. Regorafenib was given for only 3 weeks in a 4-week cycle.ResultsAmong 47 patients, 32 (68%) were males. The median age was 61 (29–75). With a median follow-up of 22.2 months (3.7–50.7 months). Before Hepatic arterial infusion chemotherapy administration in combination with regorafenib, 34 (72.3%) patients previously received ≥ 2 prior lines of systemic therapy and 37 (78.7%)patients previously received targeted biological treatment (anti-VEGF or anti-EGFR, or both). The initial doses of regorafenib were 40 mg/d (n = 1, 2.13%), 80 mg/d (n = 11, 23.43%), 120 mg/d (n = 2, 4.26%), and 160 mg/d (n = 23, 48.94%), while for 24.6% (n = 14) dose was unknown. Median Overall Survival was 22.2 months. Median Progression-Free Survival was 10.8 (95% CI: 9.0–13.7) months. Common Adverse Events were hand-foot skin reaction (12.77%), fatigue (6.38%), vomiting (6.38%), and decreased appetite (6.38%). Only 2 patients discontinued regorafenib due to Adverse Events.ConclusionsRegorafenib combined with Hepatic arterial infusion was effective and tolerable in patients with liver predominant metastasis of colorectal cancer. Hence, this therapy can be considered as an alternative for second- or subsequent lines of therapy in patients refractory to standard systemic chemotherapy.

PNA-Modified Liposomes Improve the Delivery Efficacy of CAPIRI for the Synergistic Treatment of Colorectal Cancer.

Tumor-associated antigen mucin 1 (MUC1) is highly expressed in colorectal cancer and is positively correlated with advanced stage at diagnosis and poor patient outcomes. The combination of irinotecan and capecitabine is standard chemotherapy for metastatic colorectal cancer and is known as XELIRI or CAPIRI, which significantly prolongs the progression-free survival and overall survival of colorectal cancer patients compared to a single drug alone. We previously reported that peanut agglutinin (PNA)-conjugated liposomes showed enhanced drug delivery efficiency to MUC1-positive liver cancer cells. In this study, we prepared irinotecan hydrochloride (IRI) and capecitabine (CAP)-coloaded liposomes modified by peanut agglutinin (IRI/CAP-PNA-Lips) to target MUC1-positive colorectal cancer. The results showed that IRI/CAP-PNA-Lips showed an enhanced ability to target MUC1-positive colorectal cancer cells compared to unmodified liposomes. Treatment with IRI/CAP-PNA-Lips also increased the proportion of apoptotic cells and inhibited the proliferation of colorectal cancer cells. The targeting specificity for tumor cells and the antitumor effects of PNA-modified liposomes were significantly increased in tumor-bearing mice with no severe cytotoxicity to normal tissues. These results suggest that PNA-modified liposomes could provide a new delivery strategy for the synergistic treatment of colorectal cancer with clinical chemotherapeutic agents.

Abstract 3888: Targeting Bcl-xL in fibrolamellar hepatocellular carcinoma

Abstract Fibrolamellar hepatocellular carcinoma (FLC) is a lethal pediatric cancer affecting adolescents and young adults. Besides surgical resection, there is no approved and effective therapy. FLC is driven by a fusion oncokinase, DNAJB1-PRKACA, that arises from a deletion fusing exon 1 of DNAJB1 and exons 2-10 of PRKACA, the catalytic subunit of protein kinase A. Expression of this chimeric oncokinase is capable of recapitulating the key histologic and transcriptomic features of FLC. Using PDXs, we tested therapeutics that have been used clinically for FLC or that target pathways identified via the transcriptomic signature of FLC, in addition to an agnostic library of clinical-stage drugs. Several compounds were identified with a varying degree of efficacy in different PDX lines as compared to our control line, primary human hepatocytes. One of the top hits was irinotecan, and its active metabolite SN38. Irinotecan is a topoisomerase I inhibitor and is clinically utilized in a wide variety of adult and pediatric cancers. A second top hit was Navitoclax, an inhibitor of the anti-apoptotic proteins Bcl-2 and Bcl-xL. Tool compounds that targeted Bcl-xL, but not bcl-2 were efficacious. This suggested a possible link between Bcl-xL, which is overexpressed in some PDX lines, and the resistance profile they showed in our screen. Unfortunately, Navitoclax has an on-target and dose-limiting toxicity of thrombocytopenia, which limits its clinical application. DT2216 is a VHL-based PROTAC that degrades Bcl-xL. DT2216 has two potential benefits over Navitoclax: 1) DT2216 is a more potent than Navitoclax against various Bcl-xL dependent tumor cells; and 2) it is less toxic to platelets than Navitoclax by targeting Bcl-xl to VHL that is poorly expressed in platelets to avoid induction of severe thrombocytopenia. A phase 1 clinical trial of DT2216 in relapsed/refractory malignancies is now ongoing (NCT04886622). We tested if the combination of DT2216 and irinotecan might have a therapeutic potential in FLC. Indeed, in vitro screening of the proposed combo, DT2216 and SN38, showed an additive or a synergistical effect in 4 validated FLC cell lines. We tested both the efficacy of DT2216 on Bcl-xL levels in FLC as well as platelet counts to identify any developing thrombocytopenia. DT2216 was less disruptive to platelets than Navitoclax at therapeutically relevant pre-clinical doses. Next, we tested 4 of our PDX models for FLC using various dosing regimens to identify the most efficacious regimen with the minimum side effects. Mice cohorts were evaluated for weight loss and tumor volume. Mice treated with DT2216 and SN38 showed consistent therapeutic benefit which was not evident in controls and less notable as monotherapy. In conclusion, TOPO1 and Bcl-xL prove to be promising targets of interest in FLC. Targeting both with DT2216 and irinotecan leads to tumor shrinkage in pre-clinical models and offer a potential therapeutic/pharmacological intervention for FLC. Citation Format: Bassem Shebl, Gadi Lalazar, Denise Ng, Tova Finkelstein, Guangrong Zheng, Peiyi Zhang, Carly Rosemore, Michael Ortiz, Daohong Zhou, Sanford Simon, Philip Coffino. Targeting Bcl-xL in fibrolamellar hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3888.

Abstract 853: The biological role and mechanisms of XPO1 R749Q mutation in colon cancer

Abstract Exportin-1 (XPO1) is known to be overexpressed or mutated in several cancer types. XPO1 is the target of selinexor, which has received approval in hematologic cancers but not in solid tumors. We recently performed a large-scale genomic analysis of 42,793 patients with cancer spanning 322 cancer types (Taylor et. al. Cancer Discovery 2019). We identified a highly statistically significant hotspot mutation in XPO1 R749Q occurring mainly in colorectal cancer patients. We have generated 2 different isogenic colorectal cancer cell lines bearing the XPO1 R749Q mutation (HCT116 and LS174T) using CRISPR-CAS9. We observed that in vitro and in vivo, these cell lines did not reveal a role for XPO1 R749Q on cell growth and proliferation. A chemical compound library screen of &amp;gt;200 FDA-approved cancer therapies revealed a strong therapeutic resistance of XPO1 R749Q cells relative to wildtype (XPO1 WT) cells, specifically to chemotherapies used in the treatment of colon cancer. However, XPO1 R749Q remained sensitive to inhibition with the selective XPO1 inhibitor selinexor. Mass spectrometry analysis of nuclear and cytoplasmic fractionated proteins revealed XPO1 R749Q mutant cells had increased export of proteins from the nucleus compared to XPO1 WT cells. Upon ionizing radiation or chemotherapy, XPO1 R749Q cells had less DNA damage as measured by comet assay and γ-H2Ax immunofluorescence. XPO1 R749Q cells are resistant to chemotherapy but respond to selinexor in vitro. Selinexor effectively blocked nuclear export of canonical cargoes of XPO1 in XPO1 R749Q and XPO1 WT cells. The combination of selinexor and irinotecan showed high levels of synergy in vitro. In vivo observations in mice xenografted with XPO1 R749Q mutant HCT116 cells showed moderate tumor response to selinexor or irinotecan monotherapies but prolonged tumor responses to combination therapy. Single-cell intracellular signaling protein analysis using the Isoplexis platform discovered increased mTOR signaling in the XPO1 R749Q vs. WT cells. Western blot validation confirmed increased mTOR signaling in XPO1 R749Q mutants. In conclusion, our current study sheds novel insights into therapeutic targeting of cancers where XPO1 mutations occur, such as colorectal cancer. Specifically, these mutations confer resistance to DNA-damaging therapies such as chemotherapy and radiation; however, they may predict for sensitivity to targeted agents such as XPO1 inhibition. We have generated unique genetic models for study of XPO1 that are currently lacking. Our study established the biological and mechanistic consequences of XPO1 R749Q mutations in cancer, thereby having a significant positive impact on the treatments of patients with cancer. Further work is ongoing for the identification of cargo proteins transported by mutated XPO1 that connect the effects of XPO1 R749Q mutation on nuclear export to response to DNA damage, mTOR signaling and XPO1 inhibition in tumors in vitro and in vivo. Citation Format: Tulasigeri M. Totiger, Monika Chojnacka, Jumana Afaghani, Sana Chaudhry, Skye Montoya, Maurizio Affer, Justin Taylor. The biological role and mechanisms of XPO1 R749Q mutation in colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 853.

Clinical Effect Study on the Second-line Treatment of Advanced Relapsed and Refractory Small Cell Lung Cancer with the Combination of Anlotinib and Irinotecan

Clinical Effect Study on the Second-line Treatment of Advanced Relapsed and Refractory Small Cell Lung Cancer with the Combination of Anlotinib and Irinotecan

HGG-50. Specific sensitivity of pediatric high-grade glioma with ATRX inactivation to PARP inhibitor combinations

Pediatric high-grade gliomas (pHGG) account for approximately 12% of pediatric brain tumors. Despite advances in molecular diagnosis and identification of discrete molecular subtypes, pHGG are the leading cause of cancer-related death in children. Thus, current research focuses on identifying novel therapeutic targets. Sequencing analyses across pediatric cancer types identified DNA repair perturbations as potentially targetable events in certain types of pediatric brain tumors. Herein, we investigated the potential of PARP inhibitors (PARPi), impeding the central role of PARP in DNA damage repair, in pHGG. We screened a patient-derived primary pHGG cell line panel (n=7) for their sensitivity towards 6 different PARPi (niraparib, olaparib, pamiparib, rucaparib, talazoparib, veliparib) using cell viability assays. Basal expression of DNA repair related proteins was assessed by immunoblot, and propidium iodide-based flow cytometry was used for cell cycle analysis. All pHGG were resistant towards single compound PARP inhibition. Interestingly, two H3F3A-G34R mutant pHGG models harboring inactivating ATRX mutations were characterized by elevated basal levels of pH2AX, suggesting increased stress resulting from DNA damage. Consequently, simultaneous targeting of PARP and other components of DNA repair in the respective models showed strong synergistic effects on cell viability, which was not observed to a comparable extent in other models such as BRAFV600E/TERT promotor mutant pHGG. Combination of talazoparib and irinotecan resulted in S-phase arrest. Within a precision oncology approach, we treated a 11-year-old child suffering from H3F3A-G34R mutant pHGG with ATRX mutation, that progressed during radiation, with niraparib and topotecan. The patient achieved partial remission and disease stabilization for 1 year. Taken together, PARPi combinations show potential for the treatment of pHGG with ATRX mutations. Currently, all cell models are characterized for DNA repair signatures by DNA sequencing. Further, in depth characterization of DNA damage responses upon concomitant PARP and topoisomerase inhibition in ATRX-mutated pHGG are ongoing.

Efficacy and Side Effects of Irinotecan Combined with Nedaplatin versus Paclitaxel Combined with Cisplatin in Neoadjuvant Chemotherapy for Locally Advanced Cervical Cancer and Tumor Marker Analysis: Based on a Retrospective Analysis.

Objective A case-control study was adopted to investigate the efficacy and side effects of irinotecan combined with nedaplatin (NP) versus paclitaxel combined with cisplatin for locally advanced cervical cancer (CC) neoadjuvant chemotherapy (NACT) and to analyze the changes in tumor marker levels. Methods A total of 96 patients with locally advanced CC who were treated from October 2019 to October 2021 were enrolled in our hospital as the research subjects, and their clinical data were collected for retrospective analysis and grouped according to their treatment regimens. Among them, 53 patients received paclitaxel combined with cisplatin as the control group, and the other 43 patients received irinotecan combined with NP as the observation group. The clinical effectiveness of neoadjuvant chemotherapy and alterations in tumor markers (CEA, AFP, CA125, and SCCA) were compared between the two groups. The incidence of common chemotherapy side effects was observed and compared between the two groups, including nausea and vomiting, abdominal pain and diarrhea, liver function impairment, bone marrow suppression, transient hyperglycemia, rash, ECG abnormalities, peripheral neurotoxicity, and muscle aches and pains. Results The clinical efficiency of neoadjuvant chemotherapy was 97.67% in the observation group and 81.13% in the control group, with no statistically significant difference between the groups (P > 0.05). There was no significant difference in CEA, AFP, and CA125 between the two groups before and after chemotherapy, but the decrease of SCCA before and after chemotherapy was statistically significant. There was no significant difference in the incidence of liver function damage, myelosuppression, abnormal ECG, and rash between the two groups (P > 0.05). There are statistically significant differences in the incidence of nausea and vomiting, transient hyperglycemia, peripheral neurotoxicity, and muscle aches between the observation and control groups (P < 0.05). The incidence of nausea and vomiting, transient hyperglycemia, peripheral neurotoxicity, and muscle aches was higher in the control group than in the observation group, with statistically significant differences (P < 0.05). The difference in the incidence of diarrhea and abdominal pain between the observation group and the control group was statistically significant (P < 0.05), and the incidence of diarrhea and abdominal pain in the observation group was higher than that in the control group. Conclusion Irinotecan in combination with nedaplatin can be an effective neoadjuvant chemotherapy regimen for advanced localized cervical cancer, particularly in patients with combined diabetes.

P-8 Long-term survival in patients with pancreatic cancer (PAC) treated with liposomal irinotecan in combination with 5-fluorouracil and leucovorin (nal-IRI+5-FU/LV)

PAC is an aggressive disease with 85% of patients being diagnosed at a locally advanced or metastatic (mPAC) stage; the prognosis is poor, as only 10% survive beyond 5 years after diagnosis. Current treatments include the use of gemcitabine (GEM)-based therapies in first line, followed by liposomal irinotecan (nal-IRI+5-FU/LV) after failure. Despite poor survival outcomes, some patients survive >1 year from the start of nal-IRI+5-FU/LV. No clear recommendations exist for the optimal treatment sequence with no precise characteristics or molecular markers to help select a chemotherapy regimen or personalized treatment.

Irinotecan combined with Panitumumab or cetuximab as third-line treatment for metastatic colorectal cancer.

e15551 Background: Literature suggests that the addition of cetuximab can overcome the resistance to irinotecan treatment for metastatic colorectal cancer (mCRC). It is unknown if the combination of panitumumab with irinotecan could also revert treatment resistance and offer a better response rate after progression on irinotecan monotherapy. In this study, we aim to compare the impact of panitumumab plus irinotecan (P+I) or cetuximab plus irinotecan (C+I) on overall survival as a third line mCRC treatment. Methods: This is a single institution, retrospective cohort analysis, evaluating the overall survival of mCRC patients exposed to an anti-EGFR antibody plus irinotecan, upon progression on irinotecan monotherapy. Overall survival function was estimated using the Kaplan-Meier method and compared using the log-rank test. Results: We identified 460 patients with mCRC that fulfilled inclusion criteria, treated between July 2008 and April 2018. One hundred eighty-three (183) patients received (I+C), and 277 received (I+P). Upon diagnosis, the median age was 55.9 years (range, 19 - 83 years), with a male to female ratio of 1.3:1. All patients received the combination of irinotecan and anti-EGFR targeting antibodies for at least one cycle (D1 and D15). Partial response occurred in 22.6% of patients [23.5% for (I+C) and 22.0% for (I+P)], and 25,2% had stable disease [27.8% for (I+C) and 23.6% for (I+P)]. Interestingly, response rate in patients with right-sided tumors was 3.3% in the (I+C) regimen and 14.3% in the (I+P) regimen. The disease control rate was 50.3% in the (I+C) combination and 45.7% in the (I+P) combination (p = 0.358). The median overall survival (mOS) for all patients was 9.63 months, 8.97 to the group C+I and 10.74 to P+I (p = 0.73). Regarding primary tumor location, the mOS was 6.34 mo for right-sided tumors and 10.74 mo for left-sided tumors (p = 0.022). The 3-year survival rate was 5.6% for the (C+I) treated patients and 3.2% for (P+I). Conclusions: (P+I) and (C+I) combinations showed similar response rate and mOS as a third-line treatment for mCRC, suggesting that both anti-EGFR agents can be used in this setting. A perceived tendency for a superior response with the (I+P) regimen in right-sided tumors might warrant further investigation in prospective studies.

Study protocol of an open-label, single-arm, phase II trial investigating the efficacy and safety of trifluridine/tipiracil combined with irinotecan as a second-line therapy in patients with cholangiocarcinoma (TRITICC).

TPS4176 Background: Biliary tract cancers (BTC) currently account for ̃15% of all primary liver cancers and ̃3% of gastrointestinal malignancies. Gemcitabine/Cisplatin has been the standard of care in the first-line therapy of BTC for a decade. Despite recently some survival benefit has been shown in adding a checkpoint inhibitor, further lines of treatment are only poorly defined. In the ABC-06 phase-3 study, second-line FOLFOX demonstrated a moderate but significant improvement of survival and might be regarded as a standard of care. The combination of liposomal Irinotecan and 5-FU infusion pump also improved survival after first line therapy. Both mentioned second-line regimens are based on limited evidence and questionable generalizability. Thus, there is a high need for novel treatment concepts in patients without targetable genetic alterations. Trifluridine/tipiracil (FTD/TPI) is a orally active, antimetabolite agent comprised of trifluridine, a thymidine-based nucleoside analogue, and tipiracil, a potent thymidine phosphorylase inhibitor. Recent reports provided evidence of an antitumor activity of FTD/TPI plus Irinotecan as well in patients with BTC. Therefore, the TRITICC trial was designed to evaluate the safety and efficacy of FTD/TPI plus irinotecan in patients with BTC refractory to previous Gemcitabine based treatment. Methods: TRITICC (NCT04059562) is an interventional, prospective, open-label, non-randomized, exploratory, multicenter, single-arm phase IIA clinical trial that evaluates the safety and efficacy of FTD/TPI (25 mg/m² body surface area (BSA), BID, orally on days 1-5 followed by a 9-days recovery period from day 6 trough day 14 of each 14-days treatment cycle) plus irinotecan (on day 1 of each cycle at a dose of 180 mg/m2) in adult patients with histologically verified locally advanced or metastatic BTC (including cholangiocarcinoma and gallbladder or ampullary carcinoma) with documented radiological disease progression to first-line gemcitabine based chemotherapy. A total of 28 patients is planned to be enrolled in 6 sites across Germany. Study treatment will be continued until disease progression according to RECIST 1.1 criteria or occurrence of unacceptable toxicity. The effect of FTD/TPI plus irinotecan on progression-free survival will be analyzed as primary endpoint. Safety (according to NCI-CTCAE), response rates and overall survival are secondary endpoints. In addition, a comprehensive translational research program is part of the study and might provide findings about predictive markers with regard to response, survival periods and resistance to treatment. Currently, 3 out of the planned 6 German study sites are opened for recruitment and 6 patients have been enrolled. The primary study endpoint is estimated to be evaluated in 2023. Clinical trial information: NCT04059562.

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.

TPS4196 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) is FDA approved in combination with 5-FU/LV 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. 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]

Camrelizumab plus famitinib in patients with metastatic colorectal cancer: Results from an open-label, multicenter phase II basket study.

3577 Background: Dual blockade of immune checkpoint and angiogenesis is an effective strategy for multiple cancers. We initiated an open-label, multicenter phase II basket study to evaluate the antitumor activity and safety of camrelizumab (an anti-PD-1 antibody) plus famitinib (a receptor tyrosine kinase inhibitor) in patients (pts) with advanced solid tumors. Herein, we report the results from the metastatic colorectal cancer (mCRC) cohort. Methods: Pts with histologically confirmed mCRC, who had received previous irinotecan, oxaliplatin, and fluoropyrimidine combination chemotherapy, and progressed after ≥ 2 lines of systemic treatment were enrolled to receive camrelizumab (200 mg i.v. every 3 weeks) and famitinib (20 mg orally once daily). Primary endpoint was objective response rate (ORR) per RECIST version 1.1. Results: Between Jul 10, 2020, and Jul 12, 2021, of all the 44 mCRC pts enrolled, 14 (31.8%) pts had colon cancer (CC) and 30 (68.2%) pts had rectal cancer (RC). As of Nov 30, 2021, the median time from enrollment to data cutoff was 10.6 months (range, 4.7-16.7). The ORR was 13.6% (95% CI, 5.2-27.4) and the DCR was 45.5% (95% CI, 30.4-61.2) in all mCRC pts. Of them, no pts with CC achieved response; six pts with RC achieved PR, with the ORR of 20.0% (95% CI, 7.7-38.6) and the DCR of 46.7% (95% CI, 28.3-65.7). Pts with RC showed a median duration of response (DoR) of 7.1 months (95% CI, 2.3-not reached [NR]). The median overall survival (OS) was 15.2 months (95% CI, 7.2-NR) in pts with RC. Of all 44 mCRC pts, 28 (63.6%) had grade 3 or higher treatment related adverse events (TRAEs), mainly hypertension (25.0%), proteinuria (18.2%), decreased platelet count (11.4%), decreased neutrophil count (11.4%) and palmar-plantar erythrodysaesthesia syndrome (11.4%). Three (6.8%) pts discontinued any study treatment due to TRAEs. No grade 5 TRAE was reported. Conclusions: Camrelizumab plus famitinib appeared to show encouraging antitumor activity in pts with mCRC, especially in those with RC, and the safety profile of this combination regimen seemed to be manageable and consistent with single agent alone. Clinical trial information: NCT04346381. [Table: see text]

Inflammatory-Dependent Bidirectional Effect of Bile Acids on NLRP3 Inflammasome and Its Role in Ameliorating CPT-11-Induced Colitis.

Irinotecan (CPT-11) in combination with 5-fluorouracil and leucovorin is a first-line chemotherapy regimen for the treatment of colorectal cancer; however, its clinical application is limited by the dose-limiting gastrointestinal toxicity of colitis. In our previous studies, several bile acids (BAs) were found significantly elevated in the colon of the CPT-11-induced rat colitis model. On the other hand, NLRP3 inflammasome has been reported to play important roles in mediating colitis. Interestingly, BA was stated to activate the NLRP3 inflammasome in some studies, while in some other reports, it showed an inhibitory effect. We assumed that the inflammatory status in different circumstances might have contributed to the controversial findings. In this study, we first discovered, under non-inflammatory conditions, that supplementing BA could activate the NLRP3 inflammasome in THP-1-differentiated macrophages and promote inflammation. In lipopolysaccharide (LPS)-induced inflammatory macrophages, however, BA inhibited the NLRP3 inflammasome and reduced inflammation. Further experiments demonstrated that Takeda G protein-coupled receptor 5 (TGR5) is essential in mediating the inhibitory effect of BA, while phospho-SP1 (p-SP1) is key to the activation. Furthermore, we applied the above findings to ameliorate CPT-11-caused colitis in rats by inhibiting SP1 with mithramycin A (MitA) or activating TGR5 using oleanolic acid (OA). Our findings may shed light on the discovery of effective interventions for reducing dose-limiting chemotherapy-induced colitis.