Nanoliposomal Irinotecan Research Articles

Real-world analysis of the correlation between overall survival and progression-free survival in advanced pancreatic cancer: Results of NAPOLEON-1 and 2 studies.

Fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) improve overall survival (OS) and progression-free survival (PFS) in patients with pancreatic cancer, compared with gemcitabine (GEM). However, whether PFS is a surrogate marker of OS in pancreatic cancer chemotherapy focusing on FOLFIRINOX or GEM plus nab-paclitaxel remains unknown. We aimed to verify whether PFS can be a surrogate marker of OS in prognosis prediction. This was an integrated analysis of the NAPOLEON study and retrospective cohort of the NAPOLEON-2 study-a multicenter observational study conducted in Japan, using real-world data. The primary and secondary endpoints were OS and PFS, respectively. The correlation between OS and PFS in first- and second-line treatments was assessed using Method of Moments estimation. An analysis was performed in patients with confirmed OS at the end of follow-up. The NAPOLEON-2 cohort included only patients who received 5-fluorouracil, leucovorin, and nanoliposomal irinotecan (NFF) as second-line treatment. Among 479 patients, the correlation between PFS and OS from first- and second-line chemotherapies was calculated in 310 and 225 patients, respectively. The R-squared values for the correlation between PFS and OS from first- and second-line chemotherapies were 0.74 and 0.76, respectively. There was no statistically significant difference in first-line treatment between the FOLFIRINOX and gemcitabine plus nab-paclitaxel groups (P=0.92). Therefore, the FOLFIRINOX group may not have shown a stronger correlation than the NFF group. PFS can be a surrogate marker of OS in first- and second-line therapies. Appropriate prognostic estimation might contribute to proper treatment selection.

Quantitative determination of liposomal irinotecan and SN-38 concentrations in plasma samples from children with solid tumors: Use of a cryoprotectant solution to enhance liposome stability

Preclinical studies have demonstrated that liposomal irinotecan (CPT-11), a topoisomerase I inhibitor, has broad activity against adult cancers, including pancreatic, gastric, colon, lung, glioma, ovarian, and breast cancer. Encapsulation of irinotecan into liposomes can modify its pharmacokinetic properties dramatically. Also, the pharmacokinetic profiles of liposomal drug formulations are not fully understood; thus, bioanalytical methods are needed to separate and quantify nonencapsulated vs. encapsulated concentrations. In this study, two robust, specific, and sensitive LC-MS/MS methods were developed and validated to separate and quantify the nonencapsulated CPT-11 (NE-CPT-11) from the sum-total CPT-11 (T-CPT-11) and its major metabolite, SN-38, in human plasma after intravenous administration of liposomal irinotecan. NE-CPT-11 and SN-38 were separated from plasma samples by using solid-phase extraction, and T-CPT-11 was measured by protein precipitation. The liposomal CPT-11 formulation was unstable during sample storage and handling, resulting in elevated NE-CPT-11 concentration. To improve the stability of liposomal CPT-11, a cryoprotectant solution was added to human plasma samples prior to storage and processing. CPT-11, SN-38, and their respective internal standards, CPT-11-d10 and SN-38-d3, were chromatographically separated on a reversed-phase C18 analytical column. The drugs were detected on a triple quadrupole mass spectrometer in the positive MRM ion mode by monitoring the transitions 587.3 > 124.1 (CPT-11) and 393.0 > 349.1 (SN-38). The calibration curves demonstrated a good fit across the concentration ranges of 10–5000 ng/mL for T-CPT-11, 2.5–250 ng/mL for NE-CPT-11, and 1–500 ng/mL for SN-38. The accuracy and precision were within the acceptable limits, matrix effects were nonsignificant, recoveries were consistent and reproducible, and the analytes were stable under all tested storage conditions. Finally, the LC-MS/MS methods were successfully applied in a phase I clinical pharmacokinetic study of nanoliposomal irinotecan (Onivyde®) in pediatric patients with recurrent solid malignancies or Ewing sarcoma.

A phase I/II study of nanoliposomal irinotecan and carboplatin in patients with advanced or metastatic, poorly differentiated gastroenteropancreatic neuroendocrine carcinoma characterized by tissue and liquid next-generation sequencing.

52 Background: For locally advanced or metastatic gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs), standard chemotherapy typically incorporates etoposide or irinotecan plus platinum agents. Herein, we initiate a phase I/II trial to apply Nal-IRI in combination with carboplatin as the 1st line treatment in patients with GEP-NECs to define the dose-limiting toxicity (DLT) and recommended phase II dose (RP2D). Methods: In the phase I part, traditional 3+3 design was applied. Enrolled patients would receive escalating dose of 60 (level -1), 80 (starting dose, level 0) or 100 (level 1) mg/m2 salt-form nal-IRI plus carboplatin AUC=4 with maximum total dose of 600 mg on D1, every 21 days as a cycle. DLTs were evaluated during the first one cycle of treatment with tumor assessment every 6 weeks. Prophylaxis G-CSF was not allowed in the first cycle Paired testing of tissue (TBx) and liquid biopsy (LBx) was done by Illumina TSO500 platform before treatment. The second LBx would be repeated for confirmed partial responders when progression. Results: Totally 6 GEP-NEC patients with primary sites of colon in three, and each one in esophagus, ampulla of Vater and pancreas were enrolled to level 0. One patient had DLT of grade 4 neutropenia lasting for 3 days even under salvage G-CSF. Treatment-related adverse events showed grade 3/4 neutropenia (33.4%), grade 2 anemia (16.7%), grade 3 fatigue (16.7%), and grade 2 skin rash (16.7%). Four patients achieved confirmed partial response and 2 patients got stable disease, with the objective response rate of 66.7% (95% confidence interval: 22%-96%). After the data and safety monitoring board meeting, level 0 was decided as RP2D but not escalation to level 1 because of acceptable toxicity profiles and promising efficacies. Comprehensive genomic profiling showed that driver mutations were identified in three cases including two harboring BRAFV600E mutation and one with KRASG12D mutation. The other three cases lacking driver mutation showed frequent copy number alteration including 1 with MDM2 amplification (copy number 27) and a wild-type TP53. Homologous recombination deficiency (HRD), as determined by GIS score, was identified in a colon GEP-NEC who remained to be HRD-positive at progression but a higher TMB (from 4.7 to 10.2 Muts/Mb) and a higher BRAFV600E mutation allele frequency (from 24.1% to 43.6%) in tumor tissue, compared to the baseline profiling. Conclusions: Based on current data, the RP2D is 80 mg/m2 of nal-IRI (salt-form) and carboplatin of AUC=4, every 3 weeks. The extension phase II study in GEP-NEC is ongoing. Clinical trial information: NCT05385861 .

Nanoliposomal irinotecan with fluorouracil and folinic acid, FOLFIRINOX, and S-1 as second-line treatment for unresectable pancreatic cancer after gemcitabine/nab-paclitaxel

This study aimed to compare second-line treatment outcomes for patients with unresectable pancreatic cancer previously treated with gemcitabine plus nab–paclitaxel (GnP) therapy. We conducted an integrated analysis of two retrospective studies included 318 patients receiving nanoliposomal irinotecan + 5-fluorouracil/folinic acid (NFF) (n = 102), S-1 (n = 57), or FOLFIRINOX (n = 14) as second-line treatment. Median overall survival (OS) in the NFF group was 9.08 months, significantly better than S-1 (4.90 months, P = 0.002). FOLFIRINOX had a median OS of 4.77 months, not statistically different from NFF. Subgroup analyses of OS indicated NFF was generally superior, however, a statistical interaction was observed between the treatment regimen in serum Alb < 3.5 g/dL (P = 0.042) and serum CRP ≥ 0.3 mg/dL (P = 0.006). Median progression-free survival (PFS) was 2.93 months for NFF, significantly better than S-1 (2.53 months, P = 0.024), while FOLFIRINOX had a comparable PFS (3.04 months, P = 0.948). Multivariate analysis identified the serum CRP, serum CA19-9, duration of first-line GnP therapy, and use (yes/no) of S-1 for second-line treatment as independent predictors for OS. This study concludes that second-line NFF therapy demonstrated a more favorable OS compared to S-1 therapy, however, it is still important to consider the patient background characteristics while selecting the most appropriate treatment.

Head-to-head comparison of treatment sequences in advanced pancreatic cancer-Real-world data from the prospective German TPK clinical cohort study.

There are no clear guidelines regarding the optimal treatment sequence for advanced pancreatic cancer, as head-to-head phase III randomised trials are missing. We assess real-world effectiveness of three common sequential treatment strategies by emulating a hypothetical randomised trial. This analysis included 1551 patients with advanced pancreatic cancer from the prospective, clinical cohort study Tumour Registry Pancreatic Cancer receiving FOLFIRINOX (n = 613) or gemcitabine/nab-paclitaxel (GEMNAB; n = 938) as palliative first-line treatment. We used marginal structural modelling to compare overall survival (OS) and time to deterioration (TTD) of health-related quality of life (HRQoL) between three common first- to second-line treatment sequences, adjusting for time-varying potential confounding. The sequences were: FOLFIRINOX→GEMNAB, GEMNAB→FOLFOX/OFF and GEMNAB→nanoliposomal irinotecan (NALIRI) + 5-fluorouracil. Outcome was also calculated stratified by patients' prognostic risk according to the Pancreatic Cancer Score. Median OS and TTD of HRQoL independent of risk were 10.7 [8.9, 11.9] and 6.4 [4.8, 7.7] months for FOLFIRINOX→GEMNAB, 8.4 [7.4, 9.7] and 5.8 [4.6, 7.1] months for GEMNAB→FOLFOX/OFF and 8.9 [7.8, 10.4] and 4.6 [4.1, 6.1] months for GEMNAB→NALIRI+5-fluorouracil. Compared to FOLFIRINOX→GEMNAB, OS and TTD were worse for poor-risk patients with GEMNAB→FOLFOX/OFF (OS: HR 2.09 [1.47, 2.98]; TTD: HR 1.97 [1.19, 3.27]) and those with GEMNAB→NALIRI+5-fluorouracil (OS: HR 1.35, [0.76, 2.39]; TTD: HR 2.62 [1.56, 4.42]). Brackets denote 95%-confidence intervals. The estimated real-world effectiveness of the three treatment sequences evaluated were largely comparable.Poor-risk patients might benefit from intensified treatment with FOLFIRINOX→GEMNAB in terms of clinical and patient-reported outcomes. Future randomised trials on sequential treatments in advanced pancreatic cancer are warranted.

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

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

Nanoliposomal irinotecan in advanced biliary tract cancers

Nanoliposomal irinotecan in advanced biliary tract cancers

CLARITY-PanTumor01: A phase 2 trial of the claudin 18.2-specific antibody-drug conjugate AZD0901 (CMG901) in patients with CLDN18.2-expressing advanced solid tumors.

TPS3163 Background: Gastric/gastroesophageal junction (G/GEJ) and pancreatic cancer are associated with poor outcomes and high unmet need. Claudin 18.2 (CLDN18.2) is highly expressed in gastric, esophageal, and pancreatic ductal adenocarcinoma (PDAC), and is a clinically validated target. AZD0901 is a potential first-in-class antibody-drug conjugate (ADC) comprising a humanized anti-CLDN18.2 IgG1 antibody conjugated via a protease-cleavable linker to monomethyl auristatin E (MMAE), a cytotoxic microtubule-disrupting agent. Interim results from the ongoing, first-in-human, Phase 1 trial of AZD0901 monotherapy in patients with G/GEJ cancer (NCT04805307) who were refractory to and/or intolerant of standard therapies demonstrated promising efficacy and a manageable safety profile. Here we describe an ongoing, Phase 2 study of AZD0901 in patients with CLDN18.2-expressing advanced solid tumors, including G/GEJ cancer and PDAC. Methods: This open-label, multicenter study (NCT06219941) comprises multiple substudies. Substudy 1 is recruiting patients with human epidermal growth factor receptor 2 (HER2)-negative, CLDN18.2-expressing G/GEJ cancer with ≤2 prior lines of therapy for unresectable or metastatic disease, who are randomized 1:1 to receive AZD0901 1.8 or 2.2 mg/kg intravenous (IV) every 3 weeks (Q3W). Substudy 2 is recruiting patients with previously untreated CLDN18.2-expressing metastatic PDAC to receive AZD0901 (up to 2.2 mg/kg IV Q3W) and either a combination of 5-fluorouracil 2400 mg/m2 IV on Days 1 and 2 Q2W, leucovorin 400 mg/m2 or l-leucovorin 200 mg/m2 IV on Days 1 and 2 Q2W, and irinotecan 150 or 180 mg/m2 or nanoliposomal irinotecan 50 mg/m2 IV on Day 1 Q2W (Arm 1), or gemcitabine 1000 mg/m2 IV on Days 1 and 8 Q3W (Arm 2), per investigator’s choice. Treatment continues until disease progression, unacceptable toxicity, or withdrawal of consent. Eligible patients are aged ≥18 years with histologically confirmed, unresectable or metastatic disease, ≥1 measurable lesion per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, and Eastern Cooperative Oncology Group performance status 0–1. Key exclusion criteria include unstable and/or active peptic ulcer disease or digestive tract bleeding, ascites requiring drainage, central nervous system metastases, and prior exposure to an MMAE-based ADC or CLDN-18.2-targeted agents other than an anti-CLDN18.2 targeted monoclonal antibody. Primary endpoints include safety, tolerability, and objective response rate per RECIST v1.1. Secondary endpoints include overall survival, progression-free survival, duration of response, disease control rate, best change in target lesion size, pharmacokinetics, immunogenicity, and pharmacodynamics. Recruitment began in December 2023, and sites across Australia, Asia, Europe, and North America will enroll patients. Clinical trial information: NCT06219941 .

Risk Factors for Adverse Events of Nanoliposomal Irinotecan Plus 5-Fluorouracil and L-leucovorin.

The regimen with nanoliposomal irinotecan plus 5-fluorouracil and L-leucovorin (nal-IRI/FL) is used for metastatic pancreatic cancer. A clinical study has indicated that the uridine diphosphate-glucuronosyltransferase (UGT) 1A1 polymorphism is associated with neutropenia during nal-IRI/FL treatment; however, no studies have reported risk factors for the occurrence of adverse events in the clinical setting. This study aimed to explore the risk factors for adverse events of nal-IRI/FL. This study included patients with metastatic pancreatic cancer who started nal-IRI/FL treatment. Patient information, including laboratory data before nal-IRI/FL initiation and adverse events during nal-IRI/FL treatment, was retrospectively obtained from medical records. This study consisted of 36 patients, including 16, 16, and 4 with UGT1A1*6 or *28 wild-type (-/-), heterozygous (+/-), and homozygous (+/+), respectively. Patients with UGT1A1*6 or *28 (+/+) exhibited significantly lower nadir counts of white blood cells (p=0.033) and neutrophils (p=0.043). Multiple regression analyses revealed that the decreased white blood cell count was significantly associated with the genotype of UGT1A1*6 or *28 (+/+) (p=0.009), high aspartate aminotransferase (AST) value before the therapy (p=0.019), and pancreatic head cancer (p=0.030). Also, the decreased neutrophil count was significantly related to the genotype of UGT1A1*6 or *28 (+/+) (p=0.017). Patients with UGT1A1*6 or *28 (+/+) should be especially concerned about neutropenia and leukopenia during nal-IRI/FL treatment. Additionally, high AST value and pancreatic head cancer may be risk factors for leukopenia during nal-IRI/FL treatment.

Is There Room for Liposomal Irinotecan in Biliary Tract Cancer? A Meta-analysis of Randomised Trials

AimsThe combination of 5-fluorouracil/leucovorin (5-FU/LV) plus oxaliplatin (FOLFOX) is widely acknowledged as the standard regimen for second-line treatment in patients with advanced biliary tract cancer. Nanoliposomal irinotecan (nal-IRI) has demonstrated its activity in patients with advanced pancreatic cancer. Recent studies have investigated the activity of nal-IRI in combination with 5-FU/LV for biliary tract cancer. However, the results have been contradictory. We conducted a meta-analysis to assess survival outcomes and response rates in randomised trials investigating the activity of nal-IRI in previously treated biliary tract cancer patients. Materials and methodsWe systematically collected potentially relevant findings from PubMed/Medline, the Cochrane library and EMBASE. Abstracts presented at major international oncological meetings were also reviewed. We extracted hazard ratios and 95% confidence intervals for progression-free survival and overall survival, as well as odds ratios and 95% confidence intervals for objective response rate. The outcomes of the accessible randomised studies evaluating the activity of nal-IRI plus 5-FU/LV were analysed. ResultsThe combination therapy exhibited a statistically significant decrease in the risk of progression (hazard ratio 0.70; 95% confidence interval 0.50–0.97) when compared with 5-FU/LV alone. Additionally, the dual regimen yielded longer overall survival and a higher objective response rate. ConclusionOur meta-analysis showed that nal-IRI plus 5-FU/LV had a superior activity in comparison with 5-FU/LV. Further investigations are required to elucidate the role of nal-IRI in this setting and to identify subgroups of patients who could derive the greatest benefit from its administration.

Results from a Phase II study of nanoliposomal irinotecan (nal-IRI) with 5-fluorouracil (5-FU)/leucovorin in refractory advanced high-grade neuroendocrine cancer (HG-NEC)

Results from a Phase II study of nanoliposomal irinotecan (nal-IRI) with 5-fluorouracil (5-FU)/leucovorin in refractory advanced high-grade neuroendocrine cancer (HG-NEC)

Immunofluorescence profiling of collagen subtypes is a predictor of treatment outcomes in pancreatic cancer

Desmoplasia in pancreatic ductal adenocarcinoma (PDAC) is characterized by elevated levels of tumor collagen. Desmoplasia restricts drug delivery in PDAC, contributes to treatment resistance, and is associated with poor survival outcomes. We have previously shown that photodynamic therapy (PDT)-based treatment remediates desmoplasia in orthotopic PDAC tumors by reducing second harmonic generation signals from collagen by >90% and by reducing collagen alignment by >103-fold [19]. Remediating desmoplasia correlated with improved survival outcomes in mice. To understand this phenomenon at a fundamental level, it is important to dissect the impact of therapy on collagen subtypes. In this study, we demonstrate that immunofluorescence profiling of collagen subtypes I, II, III and IV in PDAC tumors 72 h following multiple treatment regimens is predictive of long-term outcomes. Treatment regimens include nanoliposomal irinotecan chemotherapy (nal-IRI; akin to ONIVYDE™), a combination of nal-IRI chemotherapy with PDT encapsulated in a single photoactivable multi-inhibitor liposome (PMIL) and an EGFR-targeted PMIL construct (TPMIL). Results show that the relative tumor content of collagen I, II and III was inversely correlated with overall survival (P ≤ 0.0013, P ≤ 0.0001, P ≤ 0.0011, respectively), while, surprisingly, the relative tumor content of collagen IV was directly correlated with overall survival (P ≤ 0.0001). Similar relationships were observed between the relative tumor content of collagen subtypes and the residual tumor volume at day 88 following treatment. Considering that the relationship between collagen subtypes and treatment outcomes is observed across multiple treatment regimens, immunofluorescence profiling at 72 h following treatment appears to be predictive of tumor growth inhibition and survival in PDAC. Early immunofluorescence collagen subtype profiling may therefore aid in treatment personalization and may inform the dosimetry and scheduling of combination regimens for PDAC, such as chemotherapy and emerging PDT-based combinations, to maximize patient survival benefit.

MO7-4 Impact of biliary drainage for pancreatic cancer treated with nanoliposomal irinotecan, fluorouracil and folinic acid

MO7-4 Impact of biliary drainage for pancreatic cancer treated with nanoliposomal irinotecan, fluorouracil and folinic acid

160P Interim analysis of the NAPOLEON-2 study: Safety evaluation of nano-liposomal irinotecan with fluorouracil and folinic acid for advanced pancreatic cancer

160P Interim analysis of the NAPOLEON-2 study: Safety evaluation of nano-liposomal irinotecan with fluorouracil and folinic acid for advanced pancreatic cancer

152P Interim analysis of the NAPOLEON-2 study: Safety evaluation of nanoliposomal irinotecan with fluorouracil and folinic acid for unresectable pancreatic cancer patients with prior biliary drainage

152P Interim analysis of the NAPOLEON-2 study: Safety evaluation of nanoliposomal irinotecan with fluorouracil and folinic acid for unresectable pancreatic cancer patients with prior biliary drainage

A Pilot Study of Paricalcitol plus Nanoliposomal Irinotecan and 5-FU/LV in Advanced Pancreatic Cancer Patients after Progression on Gemcitabine-Based Therapy.

Vitamin D analogues remodel the desmoplastic stroma, and improve vascularity and efficacy of chemotherapy in preclinical pancreas cancer models. We conducted a pilot study to evaluate the safety and preliminary efficacy of the vitamin D analogue paricalcitol in combination with nanoliposomal irinotecan (Nal-iri) plus 5-fluorouracil/leucovorin (5-FU/LV) in patients with advanced pancreatic cancer who had progressed on gemcitabine-based therapy. Two dose levels (DL) of paricalcitol were tested: fixed dose weekly (75 mcg, DL1) and weight-based weekly (7 mcg/kg, /DL2). The primary endpoint was safety, and secondary endpoints included overall response rate, progression-free survival (PFS), and overall survival (OS). Correlative objectives aimed to identify molecular predictors of response and alterations in the tumor stroma. Twenty patients (10 each in DL1 and DL2) enrolled between March 2019 and May 2021. No grade 3/4 adverse events related to paricalcitol were observed. The most common toxicities were nausea, diarrhea and fatigue, which were similar in both cohorts. Three patients discontinued study after one cycle and were not radiographically evaluable. Of the remaining 17 evaluable patients, 2 had partial response and 12 had stable disease. The median PFS for response-evaluable patients in DL1 was 4.14 months, for DL2 was 4.83 months. Intent-to-treat median OS was 6.15 and 6.66 months for DL1 and DL2, respectively. Correlative studies showed increased tumor vascularity in posttreatment samples in patients receiving the higher dose of paricalcitol (DL2). Paricalcitol at 7 mcg/kg/week in combination with Nal-iri/ 5-FU/LV is safely tolerated, may increase tumor vascularity and warrants further investigation.

Systemic treatment of patients with locally advanced or metastatic cholangiocarcinoma - an Austrian expert consensus statement.

Locally advanced or metastatic cholangiocarcinoma is an aggressive carcinoma with a dismal prognosis. For the first-line treatment of locally advanced or metastatic cholangiocarcinoma, cisplatin/gemcitabine has been the standard of care for more than 10 years. Its combination with the immune checkpoint inhibitor durvalumab resulted in an efficiency improvement in the phase III setting. Regarding the use of chemotherapy in the second line, positive phase III data could only be generated for FOLFOX. The evidence base for nanoliposomal irinotecan (Nal-IRI) plus 5-fluorouracil (5-FU) and leucovorin (LV) is contradictory. After the failure of first-line treatment, targeted therapies can be offered if the molecular targets microsatellite instability-high (MSI-H), IDH1, FGFR2, BRAF V600E, and NTRK are detected. These targeted agents are generally preferable to second-line chemotherapy. Broad molecular testing should be performed, preferably from tumor tissue, at the initiation of first-line therapy to timely identify potential molecular targets.

The role of nanoliposomal irinotecan plus fluorouracil/leucovorin in the continuum of care of patients with metastatic pancreatic ductal adenocarcinoma.

The NAPOLI-I trial showed better outcome of nanoliposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (5-FU/LV) compared to 5-FU/LV in patients with advanced pancreatic ductal adenocarcinoma cancer (advPDAC) progressed to gemcitabine-based therapy. This study aims to explore the real-world efficacy and safety of 5-FU/LV-nal-IRI. This is a retrospective multicenter analysis including advPDAC patients receiving 5-FU/LV-nal-IRI after failure of gemcitabine-based therapy. Survival analyses were performed using Kaplan-Meier method, univariate and multivariate analyses by Cox regression. A total of 296 patients (median age 64.4 years, ECOG PS ≥1 in 56% of cases) were treated at 11 Italian institutions between 2016 and 2018. 34% of them underwent primary tumor resection, and 79% received gemcitabine-nabpaclitaxel as first line. 5-FU/LV-nal-IRI was administered as second-line in 73% of cases. Objective response and disease control rate were 12% and 41%, respectively. Treatment was well tolerated with dose reductions in 50% of patients but no one permanent discontinuation; the commonest grade ≥3 toxicities were neutropenia (14%) and diarrhea (12%). Median PFS and OS from 5-FU/LV-nal-IRI initiation was 3.2 and 7.1 months, respectively. These real-world data confirm the 5-FU/LV-nal-IRI efficacy and safety in advPDAC patients progressed to gemcitabine-based therapy, with outcomes comparable to NAPOLI-1, even in a less-selected population and with more modern therapeutic algorithm.

P-231 Interim results of a phase II study of fluorouracil (FU), leucovorin (LV), and nanoliposomal irinotecan (nal-IRI) in previously treated advanced biliary tract cancer (NAPOLI-2)

P-231 Interim results of a phase II study of fluorouracil (FU), leucovorin (LV), and nanoliposomal irinotecan (nal-IRI) in previously treated advanced biliary tract cancer (NAPOLI-2)

CheMo4METPANC: A phase 2 study with combination chemotherapy (gemcitabine and nab-paclitaxel), chemokine (C-X-C) Motif receptor 4 inhibitor (motixafortide), and immune checkpoint blockade (cemiplimab) in metastatic treatment-naïve pancreas adenocarcinoma.

TPS4200 Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) is a uniformly fatal disease for which treatments result in limited benefit. Failure of immune checkpoint blockade is attributed to multiple immunosuppressive pathways within the tumor microenvironment. The C-X-C motif chemokine receptor 4 (CXCR4)/C-X-C motif chemokine ligand 12 (CXCL12) axis results in exclusion of anti-tumor immune cells. Preclinical studies demonstrated that simultaneous CXCR4 inhibition (CXCR4i) and anti-programmed cell death 1 (aPD1) resulted in tumor stabilization. We extended these findings by testing multiple combinations of CXCR4i, aPD1, and gemcitabine in the KPC mouse model of PDAC. Mice treated with gemcitabine, CXCR4i, and aPD1 (triple therapy) experienced a survival benefit compared to mice treated with either gemcitabine alone, or with CXCR4i/aPD1. Tumors from mice treated with triple therapy demonstrated increased apoptosis and a favorable tumor immune microenvironment (TIME). Motixafortide with pembrolizumab, fluorouracil, and nanoliposomal irinotecan has shown encouraging results in the second-line setting in mPDAC with a confirmed ORR of 13.2% and progression free survival (PFS) of 3.8 months (m). The goal of this first-in-man trial is to test preliminary safety and efficacy of Motixafortide (CXCR4i), Cemiplimab (aPD1), Gemcitabine, and Nab-paclitaxel (MCGN) in treatment naïve mPDAC. Methods: This is an open label, multicenter, investigator-initiated simon-2-stage phase 2 clinical trial in mPDAC testing MCGN. The study includes a six-patient safety run-in cohort and an additional 4 patients comprising a pilot efficacy signal seeking study (N=10). If ≥3 of the 10 patients within the pilot stage were to experience a partial response (PR) by RECIST criteria within 16 weeks, the combination would be considered promising and an expansion cohort of an additional 30 patients was planned. On 09/21/22, we amended the study to forego the planned open-label expansion cohort (N=30) and transition directly to a randomized phase 2 trial testing MCGN compared toGemcitabine and Nab-paclitaxel (GN) alone (N=102), after completion of the pilot phase of the study. The primary endpoint is PFS. The study has 80% power to detect an improvement in PFS from 6 to 9.2 m (HR 0.65) with a one-sided alpha of 0.20. One interim analysis for futility is planned when 50% of the PFS events are observed. Secondary objectives include ORR, disease control rate, duration of clinical benefit and OS. Required (pilot portion) and optional (randomized portion) paired tumor biopsies will undergo exploratory analysis including interrogation of the TIME. This trial was started in September 2020 and has enrolled 10 patients to the pilot stage as of 02/2023. Clinical trial information: NCT04543071 .