Irinotecan Research Articles

Analysis of RAS/BRAF mutations in a randomized phase II WJOG6510G study of panitumumab plus irinotecan versus cetuximab plus irinotecan in chemorefractory metastatic colorectal cancer.

624 Background: A randomized phase II WJOG6510G study demonstrated non-inferiority of panitumumab (Pmab) plus irinotecan (IRI) to cetuximab (Cmab) plus IRI in terms of progression-free survival (PFS) in wild-type (WT) KRAS exon 2 metastatic colorectal cancer (mCRC). Here, we performed exploratory analyses of updated survival data using KRAS exon 2 and RAS/BRAF statuses. Methods: In this trial, patients with WT KRAS exon 2 mCRC who progressed after failure of fluoropyrimidine, IRI, and oxaliplatin were randomized to receive Pmab or Cmab in combination with IRI. An independent central laboratory performed RAS/BRAF testing using a PCR-reverse sequence specific oligonucleotide method which can detect 48 types of KRAS/NRAS and 34 types of BRAF mutations. Results: In the ITT population, patient characteristics included the following (Pmab/Cmab): number 61/59; male 69%/63%; median age 64 y/64 y; ECOG PS 0 62%/54%; left-sided primary tumor 85%/88%; multiple sites of metastases 51%/66%. At the time of updated analysis, 113 (94%) and 117 (98%) out of 120 patients had OS and PFS events, respectively. Median PFS was 5.42 months in the Pmab arm and 4.27 months in the Cmab arm (HR 0.674, unstratified log-rank p = 0.035). Median overall survival (OS) was 14.85 months in the Pmab arm and 11.53 months in the Cmab arm (HR 0.675, p = 0.037). In 83 patients, RAS/BRAF tests revealed 19 patients (23%) with RAS and 4 patients (5%) with BRAF mutations (two with V600E, two with non-V600E). Patients with RAS and BRAF mutations did not respond to the treatments. In the RAS WT population, a better PFS trend was observed for Pmab treatment (median 6.06 months vs. 5.26 months, HR 0.629, p = 0.08); however, OS was similar in both arms (median 14.85 months vs. 11.26 months, HR 0.818, p = 0.449). Conclusions: In this analysis, a modest survival benefit was found to be associated with Pmab plus IRI compared to Cmab plus IRI in WT KRAS exon2 mCRC, which warrants further evaluation in the WT RAS population. The number of analytic cases of RAS/BRAF status will be updated in the presentation. Clinical trial information: UMIN000006643.

Oxaliplatin (OX), chronomodulated capecitabine, and UGT1A1 genotype-directed dosing of irinotecan (IR) triplet chemotherapy (OXIRI) in patients (pts) with advanced pancreatic cancer (APC).

411 Background: The FOLFIRINOX regimen is highly active in APC, but its use is limited by toxicity. Irinotecan (IR) toxicity is correlated with UGT1A1 genotype status and chronomodulated delivery of fluoropyrimidines may reduce toxicity and increase efficacy. We have presented the dose escalation (DES) of OXIRI. In dose expansion (DXP), several pts required dose reduction after cycle 1 and we evaluated a lower starting dose. We now present data of the recommended Phase II dose (RP2D) and DES combined. Methods: Pts with APC and ECOG performance status ≤2, adequate organ function were enrolled. Previous OX or IR exposure was disallowed. During DES, APC pts homozygous for UGT1A1*6/*6 or UGT1A1*28/*28 were excluded. During DXP, only pts progressing on ≥ 1 line prior chemo was allowed and IR was dosed according to UGT1A1 genotype. At RP2D, pts received iv OX 37.5mg/m2 and IR 50mg/m2 on D1, 8 and po capecitabine 2650mg once at midnight on D1-14 every 21D until progression. Results: A total of 25 pts were enrolled, 17 in DES and 8 in DXP, 21 had metastatic and 4 had locally advanced APC. Male:Female 11:14, median (range) age and ECOG PS was 65yrs (50-77) and 0 (0-1) respectively. Pts with 0, 1 or 2 lines of prior chemo were 4 (16%) , 14 (56%) and 7(28%) respectively. Grade 3/4 AEs (≥5%) related to OXIRI were neutropenia (32%), anaemia (12%), diarrhoea (16%). No events of febrile neutropenia were reported. At data cut-off on 31 Aug 2017, 4 pts are on study. Median progression-free and overall survival was 22 and 35 wks respectively. Response rate (RR) was 5/25 (20%, overall); 5/20 (25%, evaluable pts) including 1 complete response and 1 unconfirmed partial response. Disease control rate for ≥ 12wks was 16/25 (64%) with 3 pts > 52wks. CA19-9 decrease of ≥ 20% was seen in 9/25 pts. Conclusions: OXIRI is an active regimen with RR of 20% despite 84% of pts having prior chemo, with disease control for ≥ 12wks in 64% of pts. Predominant toxicity was neutropenia. This study was supported by the National Medical Research Council Singapore. Clinical trial information: NCT02368860.

Development of pH‐sensitive nanogels for cancer treatment using crosslinked poly(aspartic acid‐graft‐imidazole)‐block‐poly(ethylene glycol)

ABSTRACTpH‐sensitive nanogels (NGs) based on poly(aspartic acid‐graft‐imidazole)‐poly(ethylene glycol) were developed using linear PEG with different molecular weights (2000 and 4000 Da) as crosslinkers. The pH‐sensitive NGs showed reversible size changes during continuously alternating pH changes. The anticancer treatment potential of pH‐sensitive NGs was studied using a model drug, irinotecan (IRI). IRI‐loaded NGs (ILNs) showed different drug release kinetics in acidic versus neutral pH, in addition to pH‐dependent cytotoxicity. Due to its longer crosslinker, ILN 4 (crosslinked with PEG 4000) showed faster IRI release and a greater magnitude of IRI release than ILN 2 (crosslinked with PEG 2000), resulting in greater cytotoxicity against HCT 116 colorectal cancer cells. These pH‐sensitive NGs could potentially be used in cancer treatment by mediating the accumulation and release of IRI from ILNs in the acidic tumor environment and by reducing systemic toxicity due to reversible swelling–shrinkage. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018, 135, 46268.

The consensus molecular subtypes of colorectal cancer as a predictive factor for chemotherapies against metastatic colorectal cancer.

736 Background: Since treatment options of chemotherapy for metastatic colorectal cancer (mCRC) have been diversified, biomarkers which could predict efficacy of chemotherapies are needed for optimal treatment. In this study, we analyzed the association of the treatment outcomes by several chemotherapies and the consensus molecular subtypes (CMS), which was developed from large-scale comprehensive gene expression analysis of colorectal cancer (Guinney J et al. Nat Med 21:1350-6, 2015). Methods: A total of 193 patients with previously treated mCRC were classified in 4 subtypes, CMS1 to CMS4 by using the microarrays data of primary tumors and the “CMS classifier” package for the R software. Then the association between the subtypes and the treatment outcomes was analyzed retrospectively. Results: The193 cases were classified into 21 CMS1, 53 CMS2, 69 CMS3 and 50 CMS4. The molecular characteristics of each subtype such as mutation status of KRAS and BRAF genes, and DNA methylation status were consistent with those of the previous study. First-line chemotherapies of the 193 patients were oxaliplatin (OX)-based treatment (121 patients), irinotecan (IRI)-based treatment (59 patients) and others (13 patients). In CMS4, the median progression-free survival (PFS) of the IRI-based group was significantly longer than that of the OX-based group (21.8 months vs. 10.5 months, p < 0.01). The median overall survival (OS) and objective response rate of the IRI-based group were also better than that of the OX-based group in CMS4. Among 193 patients, 103 were RAS wild-type and treated with anti-EGFR antibody. The effect of the anti-EGFR treatment was low in CMS1 (median PFS: 2.4 months, p < 0.01, median OS: 5.7 months, p < 0.01) and whereas was high in CMS2 (median PFS: 8.0 months, p = 0.05, median OS: 26.6 months, p = 0.02). CMS significantly correlated with PFS and OS after anti-EGFR treatment by univariate analysis. However the most useful predictive biomarker was a DNA methylation status by multivariable analysis. Conclusions: The biological characteristics of CMS may affect the therapeutic effect of anti-cancer agents in mCRC and, therefore, might be a new predictive factor of anti-cancer treatment.

FOLFIRINOX as a first line therapy in locally advanced pancreatic cancer and borderline resectable pancreatic cancer: a Meta-analysis

Objective To evaluate the efficacyof the first line chemotherapy FOLFIRINOX (5-Fu, Leucovorin calcium, Irinotecan, Oxaliplatin) as the treatment of pancreatic cancer. Methods Pertinent studies were identified from the PubMed, Cochrane Library and EMBASE. The outcomes were resection rate and radical (R0) resection rate were analyzed. Data were expressed as weighted pooled proportions with 95% confidence intervals (95%CI). Results There were thirteen studies with 408 patients with LAPC and BRPC included. After the treatment, 42.0% (95% CI: 28.0%~56.0%) tumorswere resected and 41.0% (95% CI: 37.0%~45.0%) were underwentR0 resection, and median overall survival ranged from 15.5 to 34.5 months, median progression-free survival ranged from 10.0 to 17.8 months. Conclusion The meta-analysis shows that down-staging after first line FOLFIRINOX-based therapy is noticeable in patients with borderline resectable/unresectable PC, and the adverse events were in control. Key words: Pancreatic cancer; FOLFIRINOX; Resection; Chemotherapy

LAL test and RPT for endotoxin detection of CPT-11/DSPE-mPEG2000 nanoformulation: What if traditional methods are not applicable?

Endotoxin detection is an important step in drug characterization. Herein we found that a chemotherapeutic drug nanoformulation composed of irinotecan hydrochloride (CPT-11) and an amphiphilic molecule DSPE-mPEG2000 can interfere with the limulus amebocyte lysate assay (LAL). Furthermore, the rabbit pyrogen test (RPT) results indicated that at a relatively high dosage, the drug irinotecan hydrochloride can induce a hypothermia effect which may render the RPT results ambiguous in determination of the safety of the drug formulation.Our findings demonstrate limitations of endotoxin detection in micellar drugs, and call for the necessity of developing reliable endotoxin detection methods that can overcome the interference of nanomaterials in order to better ensure the drug safety of patients in future pharmaceutical drug development.

Abstract LB-B13: Pediatric Preclinical Testing Consortium evaluation of the CHK1 inhibitor prexasertib

Abstract Introduction: Prexasertib is a CHK1 inhibitor that has entered clinical evaluation in adults and children with cancer. CHK1 plays a central role in pausing cell cycle progression in response to DNA damage, and an RNAi screen identified CHK1 as a therapeutic target for neuroblastoma (Cole KA, PNAS 2011; 108: 3336-41). Methods: Prexasertib was tested in vitro against a 23 cell line panel at concentrations from 0.1 nM to 1 µM. In vivo treatment groups included: prexasertib at 7.5 and 10 mg/kg given BID on days 1-3 x 3 weeks (Regimen [Reg] F & B, respectively); prexasertib at 4 mg/kg given BID days 1, 3, 5 (Reg C); irinotecan (IR) at 2.5 mg/kg days 1-5 (Reg D); and the combination of the agents (Reg E) with prexasertib as per Reg C and IR as per Reg D. For solid tumor testing, events are defined as 4X increase in tumor volume from day 0 and for CNS tumor testing as animals becoming moribund or developing severe neurologic deficit. The Kaplan-Meier method was used to compare EFS between treated and control groups. The objective response categories are progressive disease (PD, which is subdivided into progressive disease without and with growth delay, PD1 and PD2 respectively), stable disease (SD), partial response (PR), complete response (CR) and maintained complete response (MCR) (Houghton PJ, et al. Pediatr Blood Cancer 2007;49:928-40). Prexasertib was provided for testing by Lilly. Results: The prexasertib median IC50 for the pediatric cell lines was 3.2 nM, with a range from 0.9 nM to 22 nM and with no evidence for histotype specificity. Prexasertib as a single agent at 7.5 mg/kg consistently slowed tumor growth but failed to induce regressions in the 9 xenograft lines tested. Prexasertib at 10 mg/kg induced PR or CR in 6 of 6 neuroblastoma, 1 of 2 rhabdomyosarcoma, 0 of 1 Ewing sarcoma, and 0 of 2 osteosarcoma xenografts tested, and it induced a MCR in a rhabdoid tumor xenograft. Prexasertib single agent activity was comparable to that observed for single agent IR. The combination of IR and prexasertib (4 mg/kg) was significantly better than prexasertib (10 mg/kg) at prolonging EFS for only 1 of 6 NB, and the combination was significantly better than single agent IR for only 1 of 6 NB. For the remaining 7 xenograft lines, the combination was significantly superior to single agent IR for 3 lines (2 OS and 1 rhabdoid tumor), but the combination was significantly inferior to prexasertib (10 mg/kg) for the rhabdoid tumor line. Prexasertib had no effect as a single agent or in combination with XRT for two orthotopic medulloblastoma xenografts. Conclusions: Prexasertib at 10 mg/kg shows consistent tumor regressing activity as a single agent for neuroblastoma xenografts, confirming recently published data (Lowery, et al. CCR 23: 4354-63, 2017), and it shows tumor regressing activity for other histotypes. The limited activity of prexasertib at 7.5 mg/kg suggests a dose-response effect and that clinical trial design should seek the highest tolerated dose in children. For most xenografts, the combination of IR with prexasertib (at a reduced dose as required for tolerability) was no better than either single agent prexasertib at an optimized dose/schedule or single agent IR. An important area for future research is identifying agents that can be effectively combined with prexasertib for neuroblastoma and other childhood cancers. (Supported by NCI Grants/Contracts: CA199222, CA199221; CA199297; CA199288; CA199287; NO1-CM-42216) Citation Format: Kristina A. Cole, Peter J. Houghton, Raushan T. Kurmasheva, Richard Gorlick, E. Anders Kolb, Min Kang, C. Patrick Reynolds, Xiao-Nan Li, Holly Lindsay, Stephen W. Erickson, Yuelong Guo, Beverly A. Teicher, Malcolm A. Smith, John M. Maris. Pediatric Preclinical Testing Consortium evaluation of the CHK1 inhibitor prexasertib [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B13.

Non-methylated MGMT as Predictive Factor in Newly Diagnosed Glioblastoma Multiforme Treated with Bevacizumab Concurrent with Radiotherapy Followed by Adjuvant Bevacizumab plus Irinotecan versus Temozolomide Concurrent with Radiotherapy Followed by Adjuvant Temozolomide

Background and Purpose: Temozolomide is the standard treatment for patients with newly diagnosed glioblastoma multiform that had methylated O6- methylguanine–DNA methyltransferase promotor, but it had a limited efficacy in non-methylated MGMT. Thus the aim of this study is to compare bevacizumab plus irinotecan versus standard temozolomide in newly diagnosed non methylated MGMT glioblastome multiforme. Patients and Methods: This study was carried out in oncology department, Tanta university hospital. Patients were randomized into two groups with ratio 2:1, group A received bevacizumab (BEV) (10 mg/kg every 2 weeks) during radiotherapy, followed by maintenance BEV (10 mg/kg every 2 weeks) plus irinotecan (IRI) (125 mg/m2 every 2 weeks) until progressive disease. Patients in the group B received 75 mg/m2 daily temozolomide (TMZ) during RT followed by adjuvant chemotherapy six cycles of TMZ (200 mg/m2 once daily for 5 days every 4 weeks). In recurrence in group B; patients could receive second-line BEV+IRI. The primary end point was the progression-free survival rate. Results: There was improvement in progression free survival, overall response and overall survival in favour of BEV+IRI versus TMZ. In univariate analyses for progression free survival, age, sex, performance status, extent of resection and line of treatment was statically significance while in multivariate they remained statistically significant. As regard overall survival all prognostic factors were significant in univariate analysis but only line of treatment was statically significant in multivariate analysis. Conclusion: BEV+IRI could be a good alternative to TMZ in nm MGMT newly diagnosed GBM but required larger studies.

Determination of irinotecan and its metabolite SN-38 in dried blood spots using high-performance liquid-chromatography with fluorescence detection

Irinotecan (IRI) is an antineoplastic drug widely used for the treatment of colorectal and advanced pancreatic cancer. Despite its clinical utility, the clinical use of IRI is associated with potentially severe hematopoietic and gastrointestinal toxicities. The quantification of IRI and its active metabolite SN-38 in dried blood spots (DBS) may be an alternative to individualize the drug dose through a minimally invasive and easy collection method. The aim of this study was to develop and validate a simple and fast HPLC-FL assay for simultaneous IRI and SN-38 measurement in DBS, with adequate analytical performance for clinical use. The method employs liquid extraction of one 8mm disk of whole blood, followed by separation in a reversed phase Eclipse Plus C8 column (150×4.6mm, 5μm). Detection was performed with a fluorescence detector, with excitation wavelength of 370 and emission of 420 for IRI and 540nm for SN-38 and internal standard (camptothecin). Total analytical run time was 17min. Mobile phase was a mixture of 0.1M phosphate buffer pH 4.0 and acetonitrile (80:20, v/v), at 1mLmin−1. The assay was linear in the range 10–3,000ngmL−1 and from 0.5 to 300ngmL−1 for IRI and SN-38, respectively. Precision assays presented CV% of 2.71-5.65 and 2.15-10.07 for IRI and SN-38, respectively, and accuracy in the range of 94.26-100.93 and 94.24-99.33%. IRI and SN-38 were stable at 25 and 42°C for 14days in DBS samples. The method was applied to DBS samples obtained from fingerpicks from 19 volunteers receiving IRI in single or combined chemotherapy regimens, collected 1 and 24h after beginning of the infusion. The estimated plasma concentration of IRI and SN-38 in sample collected 1h after star of infusion had 16 of 19 values within the ±20% range of the measured plasma concentrations. On the other hand, predictions of IRI and SN-38 plasma concentrations from DBS measurements obtained 24h after the beginning of the infusion were poor. AUC of IRI that was calculated using plasma and DBS-estimated concentrations, with a high correlation (r=0.918). The method presented suitable characteristics for the clinical use. However, translation of IRI and SN-38 DBS to plasma concentrations is challenging due to the compound’s variable plasma/blood partition.

Temozolomide combined with irinotecan regresses a cisplatinum-resistant relapsed osteosarcoma in a patient-derived orthotopic xenograft (PDOX) precision-oncology mouse model.

Relapsed osteosarcoma is a recalcitrant tumor. A patient's cisplatinum (CDDP)-resistant relapsed osteosarcoma lung metastasis was previously established orthotopically in the distal femur of mice to establish a patient-derived orthotopic xenograft (PDOX) model. In the present study, the PDOX models were randomized into the following groups when tumor volume reached 100 mm3: G1, control without treatment; G2, CDDP (6 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks); gemcitabine (GEM) (100 mg/kg, i.p., weekly, for 2 weeks) combined with docetaxel (DOC) (20 mg/kg, i.p., once); temozolomide (TEM) (25 mg/kg, p.o., daily, for 2 weeks) combined with irinotecan (IRN) (4 mg/kg i.p., daily for 2 weeks). Tumor size and body weight were measured with calipers and a digital balance twice a week. After 2 weeks, all treatments significantly inhibited tumor growth except CDDP compared to the untreated control: CDDP: p = 0.093; GEM+DOC: p = 0.0002, TEM+IRN: p < 0.0001. TEM combined with IRN was significantly more effective than either CDDP (p = 0.0001) or GEM combined with DOC (p = 0.0003) and significantly regressed the tumor volume compared to day 0 (p = 0.003). Thus the PDOX model precisely identified the combination of TEM-IRN that could regress the CDDP-resistant relapsed metastatic osteosarcoma PDOX.

Effect of different chemotherapy regimens on nutritional status in patients with advanced colon cancer

Objective To observe the effect of two different chemotherapy regimens, including irinotecan, folinic acid and FU chemotherapy regimen (FOLFIRI) versus folinic acid, FU and oxaliplatin chemotherapy regimen (mFOLFOX6) on nutritional status in patients with advanced colon cancer. Methods A total of 110 patients with advanced colon cancer in Shanxi Cancer Hospital were divided into FOLFIRI(group A) and mFOLFOX6 (group B). To investigate the effect of two different regimens on the patients with advanced colon cancer by toxicity, the traditional methods of nutritional assessment, scored patient-generated subjective global assessment (PG-SGA), nutrition risk screening-2002 (NRS-2002). Shapiro-Wilk was used to detect the normality of small samples, t test was used to analyze measurement data conformed to the normal distribution, Wilcoxon non-parametric test was used to analyze the abnormal distribution data, and enumeration data was detected by using chi-square test. Results The incidence of vomiting, diarrhea and alopecia in group A and group B was respectively 53.8% (28/52) vs. 29.3% (17/58), 65.4% (34/52) vs. 43.1% (25/58), 46.2% (24/52) vs. 20.7% (12/58) respectively, and there was a significant difference (all P 0.05). Conclusions FOLFIRI and mFOLFOX6 scheme can reduce the patient's nutritional status. The probability of gastrointestinal adverse reaction of FOLFIRI regimen is high, which may have an obvious impact on nutritional status of patients compared with mFOLFOX6 scheme. Key words: Advanced colon cancer; Antineoplastic combined chemotherapy protocols; Nutritional status

Pegylated Liposomal Irinotecan Hydrochloride Trihydrate for Treating Pancreatic Cancer After Gemcitabine: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Shire Pharmaceuticals) of pegylated liposomal irinotecan hydrochloride trihydrate (liposomal irinotecan) to submit clinical and cost-effectiveness evidence for its use in combination with 5-fluorouracil (5-FU) and folic acid/leucovorin (LV) for treating patients with pancreatic cancer following prior treatment with gemcitabine as part of the institute's Single Technology Appraisal process. The Liverpool Reviews and Implementation Group at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG). This article presents a summary of the company's evidence, the ERG review and the resulting NICE guidance (TA440), issued on 26 April 2017. Clinical evidence for liposomal irinotecan+5-FU/LV versus 5-FU/LV was derived from 236 patients with metastatic pancreatic cancer in the multinational, open-label, randomised controlled NAPOLI-1 trial. Results from analyses of progression-free survival and overall survival showed statistically significant improvements for patients treated with liposomal irinotecan+5-FU/LV compared with those treated with 5-FU/LV. However, 5-FU/LV alone is rarely used in National Health Service clinical practice for patients with metastatic pancreatic cancer previously treated with gemcitabine. The company, ERG and Appraisal Committee (AC) all agreed that oxaliplatin+5-FU/LV is the most commonly used treatment. Oxaliplatin+5-FU/LV was compared with 5-FU/LV in two trials identified by the company. However, the company and the ERG both considered attempts to compare the efficacy of liposomal irinotecan+5-FU/LV with oxaliplatin+5-FU/LV to be methodologically flawed; not only was there heterogeneity between trials and their populations but also the proportional hazards assumption required to conduct a robust indirect treatment comparison (ITC) was violated. Nonetheless, data derived from an ITC were used to inform the company's economic model. Using the discounted patient access scheme price for liposomal irinotecan+5-FU/LV, the company reported an incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained of £54,412 for the comparison with oxaliplatin+5-FU/LV. The ERG considered that the company's base-case cost-effectiveness results for the comparison of liposomal irinotecan+5-FU/LV versus oxaliplatin+5-FU/LV were underestimates and should be interpreted with extreme caution. Following implementation of a number of model amendments, the ERG's modified exploratory ICER for the comparison of liposomal irinotecan+5-FU/LV versus oxaliplatin+5-FU/LV was £106,898 per QALY gained. The AC accepted the majority of the ERG's amendments to the model, and also highlighted that the total QALYs for oxaliplatin+5-FU/LV were lower than for 5-FU/LV in the company's model, which the AC considered to be clinically implausible. The AC therefore considered results from exploratory analyses, undertaken by the ERG, which included altering the QALY difference between liposomal irinotecan+5-FU/LV and oxaliplatin+5-FU/LV by±10%. These analyses resulted in ICERs for the comparison of liposomal irinotecan+5-FU/LV versus oxaliplatin+5-FU/LV of between £201,019 per QALY gained to liposomal irinotecan+5-FU/LV being dominated by oxaliplatin+5-FU/LV. Therefore, despite uncertainty around the clinical-effectiveness evidence and cost-effectiveness results, the AC was confident that the ICER was in excess of £50,000 per QALY gained. The final guidance issued by NICE is that liposomal irinotecan+5-FU/LV is not recommended within its marketing authorisation for treating metastatic adenocarcinoma of the pancreas in adults whose disease has progressed after gemcitabine-based therapy.

Combined SN-38 and gefitinib treatment promotes CD44 degradation in head and neck squamous cell carcinoma cells.

The aim of the present study was to search for an effective regimen among existing chemotherapies for head and neck squamous cell carcinoma (HNSCC). Among the tested drugs, we focused on combined SN-38, which is the active metabolite produced from irinotecan hydrochloride - a typeI DNA topoisomerase inhibitor - after it is metabolized by carboxylesterase in the liver and gefitinib, an EGFR tyrosine kinase inhibitor treatment, based on the ability of this combination to inhibit HNSCC cell growth. Contrary to our expectation, invivo, there was no significant difference in tumor growth suppression between gefitinib-only treatment and gefitinib plus SN-38. However, when tumor measurements were continued after treatment ceased, we found that several tumors showed renewed growth in the gefitinib-only group. The tumors that resumed growing after treatment showed increased CD44 expression compared with tumors from the combined treatment group. Next, we investigated the mechanism whereby SN-38 and gefitinib inhibited CD44 expression invitro. These studies revealed that the combined treatment promoted lysosomal degradation of CD44. The present study revealed that combined gefitinib and SN-38 treatment inhibits CD44 expression by promoting its lysosomal degradation in HNSCC cells. However, it is still unclear whether inhibition of CD44 expression in HNSCC cells can directly suppress tumor regrowth after therapy. Thus, it may be necessary to elucidate the relationship between the effects of these chemotherapeutic agents on CD44 expression and tumor recurrence/metastasis in future studies.

Efficacy of combination chemotherapy using irinotecan and nedaplatin for patients with recurrent and refractory endometrial carcinomas: preliminary analysis and literature review

We aimed to retrospectively evaluate the efficacy and toxicity of an irinotecan hydrochloride (CPT) and nedaplatin (N) combination therapy for recurrent and refractory endometrial carcinoma, administered based on UGT1A1 genotype. Between 2009 and 2017, 21 patients who received CPT-N therapy for recurrent endometrial carcinoma as second- or third-line chemotherapy at our hospital were identified. The CPT-N regimen included 40-70mg/m2 of CPT-11 on days 1, 8, and 15, and 50mg/m2 of nedaplatin on day 1, q4 weeks. The median patient age was 63years. The number of prior chemotherapeutic regimens ranged from 1 to 2. Two patients had prior pelvic irradiation. The response rate [ratio of complete remission (CR) to partial remission (PR)] of CPT-N therapy was 3 of 21 (14.3%), and clinical benefit rate (CBR) [the combined percentages of CR, PR, and stable disease (SD)] was 9 of 21 (42.8%). Toxicities included grade 3 neutropenia [4 (19.0%) cases], grade 3 febrile neutropenia [2 (9.5%) cases], and grade 3 diarrhea [3 (14.3%) cases]; all resolved with conservative treatment. Patients with a wild-type UGT1A1 status received higher doses of CPT-11 (p = 0.048) and had similar RR and CBR compared to those with a UGT1A1*6 and *28 status. There were no significant differences in frequencies of hematological or non-hematological toxicities, regardless of UGT1A1 status. The CPT-N regimen for recurrent and refractory endometrial carcinoma had tolerable side effects and significant efficacy. This regimen is a viable treatment option for endometrial carcinoma.

Clinical application of FOLFIRINOX regimen for pancreatic cancer

Clinical studies have confirmed the FOLFIRINOX regimen (oxaliplatin+ irinotecan+ fluo-rouracil+ leucovorin) is an effective regimen for advanced pancreatic cancer patients with good performance status. Current clinical studies on FOLFIRINOX regimen mainly include neoadjuvant therapy for unresectable and borderline resectable pancreatic cancer and first-line therapy for locally advanced pancreatic cancer and metastatic pancreatic cancer, which improved patient′s surgical resection opportunities and survival. In addition, the toxicity, safety of FOLFIRINOX regimen and effective population selection for FOLFIRINOX regimen are also the problems concerned by researchers. Key words: Pancreatic neoplasms; Drug therapy; FOLFIRINOX regimen

Inhibition of ERK signaling potentiates the anti-tumor activity of FL118 on hepatocellular carcinoma cells

Background: A novel camptothecin analogue, FL118, has been shown to exhibit superior anticancer activity over irinotecan on colon and lung cancer cells. It was reported that FL118 mainly performs its broadspectrum anticancer activity through inducing cancer cell apoptosis. Accumulated evidence indicated that ERK pathway was constitutively activated in liver cancer, thereby promoting tumorigenesis, development, metastasis and recurrence. In this study, we aimed to investigate the anticancer potency of FL118 on liver cancer cell lines and the effect of FL118 on extracellular regulated protein kinase (ERK) pathway. Methods: Viability of PLC and Huh7 cells was detected by MTT assay. Western blot assay was performed to assess phosphorylated and total ERK protein. And cell apoptosis was measured by Hochest-PI staining. Results: Our results revealed that FL118 can inhibit PLC and Huh7 cell viability and markedly induce their apoptosis. Western blot results indicated that ERK pathway was activated in huh7 and PLC cells after administration of FL118. In addition, the pro-apoptotic and antiviability ability of FL118 can be potentiated by ERK-specific inhibitor U0126. Conclusions: Our study confirmed good anticancer activity of FL118 on liver cancer, and targeting ERK pathway can significantly improve its anticancer potency.

Clinical efficacy of modified FOLFIRINOX as neoadjuvant chemotherapy for borderline resectable pancreatic cancer

Objective To investigate the clinical efficacy of modified FOLFIRINOX as neoadjuvant chemotherapy for borderline resectable pancreatic cancer. Methods The retrospective cross-sectional study was conducted. The clinicopathological data of 28 patients diagnosed as borderline resectable pancreatic cancer who were admitted to the Tianjin Medical University Cancer Institute and Hospital between April 2013 and October 2015 were collected. Twenty-eight patients were treated with modified FOLFIRINOX( irinotecan 135 mg/m2, oxaliplatin 64 mg/m2, leucovorin 400 mg/m2, 5-FU 2 400 mg/m2, repeat the regimen every 2 weeks) as neoadjuvant chemotherapy. After the completion of neoadjuvant chemotherapy, patients were evaluated operation feasibility and developed surgical planning in 3 weeks. Observation indicators: (1) Efficacy of neoadjuvant chemotherapy; (2) adverse events of neoadjuvant chemotherapy; (3) surgical and postoperative situations; (4) follow-up situations. Follow-up using outpatient examination, telephone interview and we-chat was performed to etect survival of patients up to January 2017. Measurement data with skewed distribution were described as median (range). The survival curve was drawn by Kaplan-Meier method and the survival analysis was done by Log-rank test. Results (1) Efficacy of neoadjuvant chemotherapy: 28 patients received chemotherapy with a median cycle of 6 cycles (range, 3-12 cycles). Chemotherapy reaction of 28 patients: 14 had partial remission, 10 had stable disease and 4 had progressive disease. (2) Adverse events of neoadjuvant chemotherapy: there were 22 adverse events of 28 patients during chemotherapy, including 15 with grade1-2 and 7 with grade 3-4. (3) Surgical and postoperative situations: of 28 patients, 18 received radical resection for pancreatic cancer including 11 receiving pancreaticoduodenectomy, 7 receiving distal pancreatectomy with splenectomy. Surgeries included 6 with portal vein and superior mesenteric vein resection and reconstruction, 1 with coeliac trunk resection. Ten patients received R0 resection and 8 received R1 resection. Of 18 patients, 8 with postoperative complications were improved by conservative treatment, including 2 with pancreatic fistula, 1 with biliary fistula, 3 with delayed gastric empty, 1 with anastomotic hemorrhage, 1 with lympha fistula. No patient received re-operation or died within 30 days postoperatively. Pathological TNM staging: 2 patients were detected in stage Ⅰ-Ⅱ, 14 in stage Ⅲ and 2 in stage Ⅳ. All the 18 patients received chemotherapy after operation. Ten patients without operation continued chemotherapy. (4) Following up: 28 patients were followed up for 5-21 months with a median time of 13 months. Of the 15 died patients, 5 received operation and 10 received no operation. The median progression-free survival time and median overall survival time were 14 months and 19 months in the 18 operative patients, 7 months and 11 months in the 10 non-operative patients, respectively, with statistically significant differences (χ2=7.335, 9.950, P<0.05). Conclusions Modified FOLFIRINOX as neoadjuvant chemotherapy for borderline resectable pancreatic cancer is safe and effective, and patients can tolerate mild adverse reactions. Operable patients undergo surgeries after chemotherapy have relatively good outcome. Key words: Pancreatic neoplasm; Neoadjuvant chemotherapy; Modified FOLFIRINOX

Irinotecan and 5-fluorouracil-co-loaded, hyaluronic acid-modified layer-by-layer nanoparticles for targeted gastric carcinoma therapy.

For targeted gastric carcinoma therapy, hyaluronic acid (HA)-modified layer-by-layer nanoparticles (NPs) are applied for improving anticancer treatment efficacy and reducing toxicity and side effects. The aim of this study was to develop HA-modified NPs for the co-loading of irinotecan (IRN) and 5-fluorouracil (5-FU). A novel polymer–chitosan (CH)–HA hybrid formulation (HA–CH–IRN/5-FU NPs) consisting of poly(d,l-lactide-co-glycolide) (PLGA) and IRN as the core, CH and 5-FU as a shell on the core and HA as the outmost layer was prepared. Its morphology, average size, zeta potential and drug encapsulation ability were evaluated. Human gastric carcinoma cells (MGC803 cells) and cancer-bearing mice were used for the testing of in vitro cytotoxicity and in vivo antitumor efficiency of NPs. HA–CH–IRN/5-FU NPs displayed enhanced antitumor activity in vitro and in vivo than non-modified NPs, single drug-loaded NPs and drugs solutions. The results demonstrate that HA–CH–IRN/5-FU NPs can achieve impressive antitumor activity and the novel targeted drug delivery system offers a promising strategy for the treatment of gastric cancer.

530P - Safety analysis of phase Ib study of FOLFOXIRI plus ramucirumab as first-line therapy for patients with metastatic colorectal cancer

Background: Ramucirumab (Rmab), an anti-VEGFR-2 antibody, inhibits VEGF-A, -C, -D binding and endothelial cell proliferation, although bevacizumab (Bmab) binds to and blocks circulating VEGF-A. We conducted a phase Ib study to determine the recommended phase II dose (RP2D) of FOLFOXIRI plus Rmab for metastatic colorectal cancer (mCRC) patients. Methods: The eligibility criteria included patients with histologically confirmed unresectable colorectal adenocarcinoma, aged 20-75 years, ECOG PS 0-1 (patients > 70 years were eligible if their ECOG PS was 0), wild-type or heterozygous UGT1A1 *28 or *6, no history of prior chemotherapy, and adequate organ function. Three dose levels were planned as follows; oxaliplatin and Rmab dose was fixed at 85 mg/m2 and 8 mg/kg, respectively. Level 1: 5-fluorouracil (5-FU) 3200 mg/m2, irinotecan (IRI) 165 mg/m2, Level 0 as starting dose: 5-FU 2400 mg/m2, IRI 150 mg/m2, and Level -1: 5-FU 2400 mg/m2, IRI 120 mg/m2. Patients were enrolled with a 3 + 3 design manner to evaluate the dose-limiting toxicity (DLT) in the first cycle. Results: From September 2016 to February 2017, we enrolled a total of 10 patients (4 patients in the Level 0 and 6 patients in the Level 1). The patients’ characteristics were as follows: median age (range), 64 (44-68); male/female, 6/4; ECOG PS 0/1, 8/2; RAS wild/mutant, 1/9; UGT1A1 *1*1/*1*28, 4/6. One patient was excluded for the DLT evaluation due to lack of safety evaluation on cycle 1 day 8. No DLT was observed in the 9 DLT-evaluable patients. In the first cycle, major adverse events were G 4 neutropenia (n = 2), G 3 neutropenia (n = 1), G 3 hypertension (n = 1), G 1/2 diarrhea (n = 6), G 1/2 anorexia (n = 3), G 2 allergic reaction (n = 1), G 1 fatigue (n = 4), G 1 peripheral neuropathy (n = 4), G 1 nausea (n = 2) and G 1 stomatitis (n = 2). G-CSF was administered in 2 patients during the first cycle. Conclusions: The RP2D for FOLFOXIRI plus Rmab was determined at the Level 1. A randomized phase II study of FOLFIRI plus Rmab versus FOLFOXIRI plus Rmab for chemotherapy-naïve mCRC patients (WJOG9216G trial; UMIN000026527) is on-going. The update results will be presented in the congress. Clinical trial identification: UMIN000023277 Legal entity responsible for the study: Shizuoka Cancer Center Funding: Shizuoka Cancer Center Disclosure: All authors have declared no conflicts of interest.

486O - Sequential first-line therapy of metastatic colorectal cancer (mCRC) starting with fluoropyrimidine (FP) plus bevacizumab (BEV) vs. initial FP plus irinotecan (IRI) and BEV: German AIO KRK0110 (ML22011) study

486O - Sequential first-line therapy of metastatic colorectal cancer (mCRC) starting with fluoropyrimidine (FP) plus bevacizumab (BEV) vs. initial FP plus irinotecan (IRI) and BEV: German AIO KRK0110 (ML22011) study