Irinotecan Research Articles

RECIST and iRECIST criteria for the evaluation of nivolumab + ipilimumab combination in patients (pts) with microsatellite instability-high/mismatch repair-deficient (MSI/dMMR) metastatic colorectal cancer (mCRC): Results of the GERCOR NIPICOL phase II study.

101 Background: Immune checkpoint inhibitors (ICKi) are highly effective for MSI/dMMR mCRC pts. RECIST1.1 criteria are reported to underestimate response to ICKi. The GERCOR NIPICOL phase II study aimed to evaluate disease control rate (DCR) using RECIST1.1 and iRECIST for MSI/dMMR mCRC pts treated with nivolumab (NIVO) and ipilimumab (IPI). Methods: MSI/dMMR mCRC pts previously treated with fluoropyrimidines (FP), oxaliplatin (OX) and irinotecan (IRI) ± targeted therapies received NIVO 3 mg/kg + IPI 1 mg/kg Q3W for 4 cycles then NIVO 3 mg/kg Q2W until progression or a maximum of 20 cycles. CT-scan tumor assessments were done every 6 weeks during 24 weeks and then every 12 weeks. Primary objective was DCR at 12 weeks (12wDCR) according to RECIST1.1 and iRECIST by central review. Response rates and progression-free survival (PFS) by central review were secondary objectives. A one-stage Fleming design was used with a targeted improvement of 12wDCR from 70% to 85%. Results: Of 57 pts included between Dec 2017 and Nov 2018, 43.9% had received ≥ 3 prior lines including FP (100%), OX (100%), IRI (95.5%), antiangiogenics (57.9%) and anti-EGFRs (45.6%). 17.5% of pts had BRAF mutation and 27.5% Lynch syndrome. Grade 3-4 treatment-related adverse events were reported in 49.1% of pts, mainly hepatitis (12.3%). 12wDCR was 86.0% and 87.7% using RECIST1.1 and iRECIST respectively, with only 1 pseudo-progression (1.8%) observed during the first 12 weeks, and one later. Kappa coefficient between RECIST and iRECIST 12wDCR was 0.92 (95%CI 0.77-1.0). Best observed responses with RECIST1.1/iRECIST were: 2/2 complete responses (3.5/3.5%), 19/19 partial responses (33.3/33.3%), 30/31 stable diseases (52.6/54.4%) and 3/2 disease progressions (5.3/3.5%), with 3 pts not evaluable (cancer-related deaths before first evaluation). Conclusions: Combination of NIVO and IPI in MSI/dMMR mCRC is associated with a low frequency of pseudo-progression and high DCR rate. PFS will be evaluated in Dec 2019, with all pts having completed the predefined 1-year of ICKi therapy. Clinical trial information: NCT033501260.

Breaking the selectivity-uptake trade-off of photoimmunoconjugates with nanoliposomal irinotecan for synergistic multi-tier cancer targeting

BackgroundPhotoimmunotherapy involves targeted delivery of photosensitizers via an antibody conjugate (i.e., photoimmunoconjugate, PIC) followed by light activation for selective tumor killing. The trade-off between PIC selectivity and PIC uptake is a major drawback limiting the efficacy of photoimmunotherapy. Despite ample evidence showing that photoimmunotherapy is most effective when combined with chemotherapy, the design of nanocarriers to co-deliver PICs and chemotherapy drugs remains an unmet need. To overcome these challenges, we developed a novel photoimmunoconjugate-nanoliposome (PIC-Nal) comprising of three clinically used agents: anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody cetuximab (Cet), benzoporphyrin derivative (BPD) photosensitizer, and irinotecan (IRI) chemotherapy.ResultsThe BPD photosensitizers were first tethered to Cet at a molar ratio of 6:1 using carbodiimide chemistry to form PICs. Conjugation of PICs onto nanoliposome irinotecan (Nal–IRI) was facilitated by copper-free click chemistry, which resulted in monodispersed PIC–Nal–IRI with an average size of 158.8 ± 15.6 nm. PIC–Nal–IRI is highly selective against EGFR-overexpressing epithelial ovarian cancer cells with 2- to 6-fold less accumulation in low EGFR expressing cells. Successful coupling of PIC onto Nal–IRI enhanced PIC uptake and photoimmunotherapy efficacy by up to 30% in OVCAR-5 cells. Furthermore, PIC–Nal–IRI synergistically reduced cancer viability via a unique three-way mechanism (i.e., EGFR downregulation, mitochondrial depolarization, and DNA damage).ConclusionIt is increasingly evident that the most effective therapies for cancer will involve combination treatments that target multiple non-overlapping pathways while minimizing side effects. Nanotechnology combined with photochemistry provides a unique opportunity to simultaneously deliver and activate multiple drugs that target all major regions of a cancer cell—plasma membrane, cytoplasm, and nucleus. PIC–Nal–IRI offers a promising strategy to overcome the selectivity-uptake trade-off, improve photoimmunotherapy efficacy, and enable multi-tier cancer targeting. Controllable drug compartmentalization, easy surface modification, and high clinical relevance collectively make PIC–Nal–IRI extremely valuable and merits further investigations in living animals.

Combinatorial miRNA-34a replenishment and irinotecan delivery via auto-fluorescent polymeric hybrid micelles for synchronous colorectal cancer theranostics.

The synergistic combination of microRNA (miRNA) modulation and chemotherapy has emerged as an effective strategy to combat cancer. Irinotecan (IRI) is a potent antitumor chemotherapeutic in clinical practice and has been used for treating various malignant tumors, including colorectal cancer (CRC). However, IRI is not effective for advanced CRC or metastatic behavior. Herein, novel polymeric hybrid micelles were engineered based on two different amphiphilic copolymers, polyethyleneimine-poly(d,l-lactide) (PEI-PLA) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethyleneglycol) (DSPE-PEG), in which IRI and a tumor suppressive microRNA-34a (miR-34a) gene were efficiently co-loaded (MINPs) to achieve a chemo-miRNA combination therapy against CRC. MINPs were successfully constructed by two-step film dispersion and electrostatic interaction methods. IRI and miR-34a could be efficaciously encapsulated as MINPs and transferred to CRC cells. After encapsulation, MINPs would then upregulate miR-34a expression and regulate miR-34a-related downstream genes, which in turn led to enhanced cell cytotoxicity and apoptosis ratios. MINPs presented an excitation-dependent multi-wavelength emission feature due to the intrinstic fluorescence properties of PEI-PLA and could be utilized for in vitro/vivo imaging. According to the in vivo experimental results, MINPs possess the great characteristic of accumulating in situ in a tumor site and lightening it after intravenous administration. Furthermore, MINPs presented extraordinary antitumor efficacy owing to the combined therapy effects of IRI and miR-34a with good biocompability. Overall, our findings validated MINPs-mediated miR-34a replenishment and IRI co-delivery to serve as an effective theranostic platform and provided an innovative horizon for combining chemo-gene therapy against CRC.

Phase 1/2 study of concurrent chemoradiotherapy with weekly irinotecan hydrochloride for advanced/recurrence uterine cancer: A multi-institutional study of Kansai Clinical Oncology Group.

ObjectiveConcurrent chemoradiotherapy using cisplatin was thought to be standard treatment for squamous cell carcinoma of cervix, but it had not been effective for adenocarcinoma. Concurrent chemoradiotherapy using irinotecan hydrochloride (CPT-11) had been effective for colorectal cancer, thus, we chose CPT-11 as a candidate for gynecologic adenocarcinoma. To evaluate the maximum tolerated dose (MTD) of weekly CPT-11 with external pelvic radiotherapy, a phase 1/2 study was conducted according to modified Fibonacci method.MethodsEligible patients were advanced uterine cancer with measurable diseases [performance score (PS): 0−2]. Study period was from August 1st, 2002 to December 31st, 2008. The starting dose level (DL) of CPT-11 was 30 mg/m2 (DL1) given weekly for 4 weeks. Subsequently, dose escalation was scheduled in 10 mg/m2 increments to 60 mg/m2 (DL4). The fixed radiotherapy consisted of whole pelvic 1.8 Gy/d, once a day in weekday for five weeks and it amounted to 45 Gy (25 fractions) in total. ResultsSeventeen patients were enrolled. As for toxicities, one (1/17: 5.9%) grade (G) 4 neutropenia lasting 7 days had been seen in DL4. G2 diarrhea was identified in 35.3% (6/17) of the patients, and 11.8% (2/17) G3 diarrhea was observed in DL3 and DL4. Thus, the MTD of CPT-11 was defined as dose of 60 mg/m2. The recommended dose was decided as 50 mg/m2. The response rate was 88.2% [9 complete response (CR), 3 partial response (PR), 3 stable disease (SD), 2 not evaluable (NE)]. Disease control rate at 1 month after treatment completion was 100% but distant metastases were found in 24% (4/17) in longer outcome. ConclusionsMTD was 60 mg/m2 and recommended dose was set as 50 mg/m2. This concurrent chemoradiation using weekly CPT-11 was feasible at 50 mg/m2, and it might be effective even in adenocarcinoma of the uterus.

The Concept “Quality by Design” in development of Liposomal cytostatics

The purpose of this paper is an analysis of technology for obtaining liposomal cytostatics from the point of view of the Quality by Design approach. Liposomes were manufactured by a lipid film with further high-pressure extrusion method. Number of critical stages of technology that are necessary for the study have been circled during the pharmaceutical development. Optimization of the intraliposomal pH was demonstrated by the example of obtaining the liposomal doxorubicin hydrochloride. The study of the high pressure extrusion parameters was carried out in the development of the liposomal oxaliplatin technology. An optimization of lipid bilayer composition is shown for liposomal irinotecan. It was shown that the optimal pH value for the liposomal form of doxorubicin hydrochloride was at 3 ± 0.5. The optimal composition of the lipid bilayer for the liposomal form of irinotecan is the Egg phosphatidylcholine/Cholesterol ratio, 80/20% (wt.). Which provides a liposome size of 108 ± 3.1, and the degree of encapsulation of irinotecan hydrochloride into liposomes was 87 ± 0.8%. The oxidation index was studied on model samples of liposomal forms of irinotecan hydrochloride (Io = 0.372) and oxaliplatin (Io = 0.323).

Optimisation of a gas chromatography-mass spectrometry method for the simultaneous determination of tetrahydrocannabinol and its metabolites in rat urine.

In order to evaluate the effect of irinotecan (IRI) on urinary elimination of delta-9-tetrahydrocannabinol (THC) in a rat experimental model, we developed an analytical method for the determination of the mass concentration of THC and its metabolites [11-hydroxy-delta-9-tetrahydrocannabinol (THC-OH) and 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (THC-COOH)] in the urine of rats treated only with THC and treated simultaneously with THC and irinotecan. For this purpose, hydrolysis and solid phase extraction conditions of the investigated analytes were optimised and a gas chromatography-mass spectrometry (GC-MS) method was developed to determine all three analytes in rat urine. The most effective hydrolysis method for THC, THC-OH, and THC-COOH conjugates was so-called tandem hydrolysis by the β-glucuronidase enzyme from Escherichia coli at 50 °C for 2 hours and followed by alkaline hydrolysis. The proposed method was then applied for determining concentrations of analytes in 24-hour rat urine. THC was not detected in either sample, THC-OH was detected in 50 % of samples, and THC-COOH in all of the samples. Enhanced urinary THC-COOH excretion was noted in rats administered combined treatment compared to single THC treatment. The method described herein was suitable for determining the mass concentration of THC metabolites in the rat urine due to its sensitivity (detection limits: 0.8-1.0 μg/L), accuracy (>96 %), and precision (RSD <6 %).

Human medicines European public assessment report (EPAR): Onivyde pegylated liposomal (previously known as Onivyde), irinotecan hydrochloride trihydrate, Pancreatic Neoplasms, Date of authorisation: 14/10/2016, Revision: 4, Status: Authorised

Human medicines European public assessment report (EPAR): Onivyde pegylated liposomal (previously known as Onivyde), irinotecan hydrochloride trihydrate, Pancreatic Neoplasms, Date of authorisation: 14/10/2016, Revision: 4, Status: Authorised

Human medicines European public assessment report (EPAR): Onivyde pegylated liposomal (previously known as Onivyde), irinotecan hydrochloride trihydrate, Pancreatic Neoplasms, Date of authorisation: 14/10/2016, Revision: 4, Status: Authorised

Human medicines European public assessment report (EPAR): Onivyde pegylated liposomal (previously known as Onivyde), irinotecan hydrochloride trihydrate, Pancreatic Neoplasms, Date of authorisation: 14/10/2016, Revision: 4, Status: Authorised

Insulin enhancement of the antitumor activity of chemotherapeutic agents in colorectal cancer is linked with downregulating PIK3CA and GRB2

The present state of cancer chemotherapy is unsatisfactory. New anticancer drugs that marginally improve the survival of patients continue to be developed at an unsustainably high cost. The study aimed to elucidate the effects of insulin (INS), an inexpensive drug with a convincing safety profile, on the susceptibility of colon cancer to chemotherapeutic agents: 5-fluorouracil (FU), oxaliplatin (OXA), irinotecan (IRI), cyclophosphamide (CPA) and docetaxel (DOC). To examine the effects of insulin on cell viability and apoptosis, we performed an in vitro analysis on colon cancer cell lines Caco-2 and SW480. To verify the results, we performed in vivo analysis on mice bearing MC38 colon tumors. To assess the underlying mechanism of the therapy, we examined the mRNA expression of pathways related to the signaling downstream of insulin receptors (INSR). Moreover, we performed Western blotting to confirm expression patterns derived from the genetic analysis. For the quantification of circulating tumor cells in the peripheral blood, we used the maintrac method. The results of our study show that insulin-pretreated colon cancer cells are significantly more susceptible to commonly used chemotherapeutics. The apoptosis ratio was also enhanced when INS was administered complementary to the examined drugs. The in vivo study showed that the combination of INS and FU resulted in significant inhibition of tumor growth and reduction of the number of circulating tumor cells. This combination caused a significant downregulation of the key signaling substrates downstream of INSR. The results indicate that the downregulation of PIK3CA (phosphatidylinositol 3-kinase catalytic subunit alpha), which plays a critical role in cell signaling and GRB2 (growth factor receptor-bound protein 2), a regulator of cell proliferation and differentiation may be responsible for the sensitizing effect of INS. These findings were confirmed at protein levels by Western blotting. In conclusion, these results suggest that INS might be potentially applied to clinical use to enhance the therapeutic effectiveness of chemotherapeutic drugs. The findings may become a platform for the future development of new and inexpensive strategies for the clinical chemotherapy of tumors.

Clinical impact of first-line bevacizumab plus chemotherapy in metastatic colorectal cancer of mucinous histology: a multicenter, retrospective analysis on 685 patients.

In metastatic colorectal cancer (MCRC), mucinous histology has been associated with poor response rate and prognosis. We investigated whether bevacizumab combined with different chemotherapy regimens may have an impact on clinical outcomes of MCRC patients with mucinous histology. 685 MCRC patients were classified in mucinous adenocarcinoma (MC) and non-mucinous adenocarcinoma (NMC) and were treated with first-line bevacizumab plus fluoropyrimidine (FP)-based, oxaliplatin (OXA)-based, irinotecan (IRI)-based, or FOLFOXIRI. Ninety-four (13.7%) patients had MC. With a median follow-up of 50months, MC patients had a median overall survival (OS) of 28.2months compared with 27.7months for the NMC group [hazard ratio (HR) = 0.92; 95% confidence interval (CI) 0.70-1.19, P = 0.530]. The overall response rates for MC and NMC were 41.5% (95% CI 31.5-51.4) and 62.4% (95% CI 58.4-66.3), respectively (Chi-square test, P <0.003). After correcting for significant prognostic factors by multivariate Cox regression analysis, age, resection of the primary tumour, and number of metastatic sites were found to be associated with poorer OS, but not mucinous histology. Compared with NMC, MCRC patients with mucinous histology treated with bevacizumab plus chemotherapy had comparable OS despite lower overall response rate.

Genomic DNA detection frequently-used chemotherapeutic drugs and their adverse drug reactions in children with rhabdomyosarcoma

Objective To analyze and summarize the results of genomic DNA test findings of chemotherapeutic drugs commonly used in pediatric rhabdomyosarcoma (RMS) in children, and to analyze the relationship between adverse reactions to chemotherapy toxicity and genomic DNA polymorphisms, so as to provide evidence for guiding treatment. Methods Retrospective analysis was conducted in RMS children admitted at Hematology Oncology Center, Beijing Children′s Hospital, Capital Medical University from January 2017 to June 2018.The criteria for enrollment were definite diagnosis of RMS, regular treatment and follow-up at Hematology Oncology Center, Beijing Children′s Hospital, Capital Medical University, and detection of peripheral blood DNA fluorescence hybridization sequence for several commonly chemotherapy drugs.The toxicity of chemotherapeutic drugs was detected based on the National Cancer Institute routine toxicity criteria (NCI-CTCAE version 4.0). Summary and analysis indicators included primary and metastatic site, size, international RMS clinical stage (TNM-UICC), Intergroup Rhabdomyosarcoma Study(IRS) Clinical Grouping Classification, risk grouping, pathological type, changes in major organ functions, as well as processes of surgery, chemotherapy and radiotherapy, and the association between toxicity and DNA polymorphism of drug genes was analyzed.SPSS 22.0 software was used for χ2 test. Results A total of 32 children were enrolled, and 20 cases were male and 12 cases were female, their median age was 50 months (15-120 months). The primary tumor of 9 cases were sited in the chest, abdomen and basin, 8 cases in the head and neck (non-meningeal), 7 cases in bladder prostate, 3 cases in limbs, 2 cases in the meningeal area, 1 case in urogenital tract (non-bladder prostate), 2 cases in other parts.Seventeen cases were embryonic type and 15 cases were alveolar type.Five cases were TNM-Ⅰ stage, 5 cases were TNM-Ⅱ stage, 10 cases TNM -Ⅲ stage, 12 cases were TNM-Ⅳ stage, 21 cases were IRS-Ⅲ, 11 cases were IRS-Ⅳ.Twenty-two cases were moderate-risk (MR), 10 cases were high-risk (HR). Twenty-two cases were detected UGT1A1*6 gene, 18 cases in GG type, 13 cases in GA type, and 1 case in AA type.ABCB1 gene monitoring was performed in 27 children, 14 cases of CT type and 13 cases of TT type; 29 cases were detected GSTP1 gene, 7 cases of GA type and 2 cases of GG type, 19 cases of AA type, 1 case of AG type; 30 cases were detected CYP3A5 gene, 2 cases of GA type, 13 cases of GG type, AG 15 cases.All patients were treated according to the BCH-RMS-2007 protocol using VAC (Vincristine, Doxorubicin, and Cyclophosphamide) as the basis for chemotherapy.From 2017, VAC and VI regimen (Vincristine, Irinotecan) were defined as the standard of backbone chemotherapeutic regimen for MR.Nine cases underwent surgery before chemotherapy and 10 cases had surgery after chemotherapy, among them, 5 cases underwent twice operation.Local radiotherapy was performed on the 12th week of chemotherapy, and the central nervous system involvement cases started in the first week.Hematological toxicity was mainly caused by neutropenia, with 2 cases of grade 3 and 30 cases of grade 4.Liver function damage of grade 2 was 6 cases, grade 3 was 3 cases.Four patients with grade 1 diarrhea, 3 patients with grade 2, 5 patients with grade 3, 3 patients with grade 4.There was significant diffe-rence between the severity of diarrhea and UGT1A1*6 genotype polymorphism(P<0.05). Conclusions Chemothe-rapy for RMS patients is highly safety.If the genomic DNA test of chemotherapy drugs show a slow metabolism type, the dose of chemotherapy should be reduced, and the toxicity of chemotherapy drugs should be monitored dynamically. Key words: Rhabdomyosarcoma; Side effect; Pharmacogenomics; Irinotecan

Safety and efficacy of irinotecan administered after nivolumab for advanced gastric cancer

Abstract Background Nivolumab (NIVO) showed a survival benefit compared to placebo in patients (pts) with advanced gastric cancer (AGC) after two or more previous lines of chemotherapy. It has been reported that prior treatment with immune check point inhibitors might improve responses to salvage chemotherapy without unexpected safety signals in non-small cell lung cancer. However, safety and efficacy of irinotecan (IRI) administered after NIVO in pts with AGC remains unclear. Methods Pts with AGC treated with IRI after NIVO (cohort A) or IRI before NIVO (cohort B) from September 2017 to December 2018 were analyzed in this study. Clinical outcomes after IRI were compared between two groups. Results A total of 44 pts (14 in cohort A and 31 in cohort B) were included in this study. Common grade 3 or worse adverse events in cohort A were leukocytopenia (21%), neutropenia (14%), thrombocytopenia (7%) and diarrhea (7%), which were not significantly different in cohort B. No immune related adverse events occurred in cohort A. The ORR-IRI was 21% in cohort A and 16% in cohort B (p = 0.48), and the median PFS-IRI was 2.67 and 2.37 months (HR = 0.87, p = 0.68), respectively. In cohort A, the PFS of IRI was longer than that of NIVO in 9 of 14 pts (64%). Conclusions IRI administered after NIVO was manageable without unexpected adverse events. Although prior NIVO did not seem to improve responses to IRI, it was notable that IRI showed a longer PFS than that of prior NIVO in a substantial number of pts.

471P - Lurbinectedin (LUR) in combination with irinotecan (IRI) in patients (pts) with advanced solid tumours

BackgroundLUR is a new agent that exerts antitumor activity through inhibition of trans-activated transcription and modulation of tumor microenvironment. Preclinical synergism/additivity in combination with IRI has been reported, thus prompting the conduct of this trial. MethodsPhase I trial to evaluate escalating doses of LUR on Day (D) 1 plus a fixed dose of IRI 75mg/m2 on D1 and D8 every 3 weeks (q3w) in pts with advanced solid tumors, enrolled following a standard 3+3 dose escalation design. Results39 pts were treated at 5 dose levels (DL); 13 at the recommended dose (RD). 56% were females, 69% had ECOG PS=1; median age was 58 years; median of 2 prior chemotherapy lines for advanced disease (range, 0−4) per pt. RD was defined as LUR 2.0mg/m2 on D1 + IRI 75mg/m2 on D1 and D8 q3w + GCSF. Dose-limiting toxicities in Cycle 1 were observed in 2/3 evaluable pts at the maximum tolerated dose (MTD) and in 3/13 evaluable pts at the RD. At the MTD and the RD, DLTs were skipping IRI D8 doses due to grade (G) 3-4 neutropenia (n=3 patients) or G2-4 thrombocytopenia (n=2). At the RD common G1/2 toxicities were nausea, vomiting, fatigue, diarrhea, anorexia and neuropathy; G3/4 hematological abnormalities comprised neutropenia (33%), but no thrombocytopenia. Objective RECIST responses were documented in 6/34 evaluable pts (18%): 3/11 pts with small cell lung cancer (SCLC), 2/2 pts with endometrial carcinoma (EC) and 1/3 pts with glioblastoma (GB). Most responses (5/12 evaluable patients [42%]) were at the RD. One pt with EC has an ongoing PR after 20 cycles. Prolonged SD>4 months were observed in pancreatic carcinoma (3/6 pts), soft tissue sarcoma (STS) (5/9 pts) and SCLC (6/11, including 4 with SD for 6, 9, 11 and 26+ months). ConclusionsThe combination of LUR and IRI is well tolerated, with no unexpected toxicities. Myelosuppression was dose-limiting, but predictable and manageable. The RD is LUR 2.0mg/m2 on D1 + IRI 75mg/m2 on D1 and D8 q3w with GCSF. Notable antitumor activity was observed, especially in SCLC, EC, GB and STS. Expansion in these indications is warranted. Clinical trial identificationNCT02611024. Legal entity responsible for the studyPharmaMar SA. FundingPharmaMar. DisclosureS. Ponce Aix: Advisory / Consultancy: Roche; Speaker Bureau / Expert testimony: Roche, BMS, MSD. G. Coté: Advisory / Consultancy: Agios; Research grant / Funding (institution), Research funding to my institution for the conduct of clinical trials; no salary support: Epizyme, Eisai, Macrogenics, Boston Biomedical, Plexxicon, Merck KGaA/EMD Serono Research and Development Institute, CBA Inc, Bayer. R. Nuñez: Shareholder / Stockholder / Stock options, Full / Part-time employment: PharmaMar. M. Siguero: Shareholder / Stockholder / Stock options, Full / Part-time employment: PharmaMar. M. Insa: Full / Part-time employment: PharmaMar. M. Cullell-Young: Shareholder / Stockholder / Stock options, Full / Part-time employment: PharmaMar. C. Kahatt: Shareholder / Stockholder / Stock options, Full / Part-time employment: PharmaMar. A. Zeaiter: Shareholder / Stockholder / Stock options, Full / Part-time employment: PharmaMar. L. Paz-Ares: Advisory / Consultancy: Amgen; AstraZeneca; Boehringer Ingelheim; Bristol-Myers Squibb; Clovis Oncology; MSD; Novartis; Pfizer; Roche; Takeda. All other authors have declared no conflicts of interest.

P2.12-13 Lurbinectedin (L) Combined with Paclitaxel (P) or Irinotecan (I) in Relapsed SCLC. Results from Two Phase Lb Trials

P2.12-13 Lurbinectedin (L) Combined with Paclitaxel (P) or Irinotecan (I) in Relapsed SCLC. Results from Two Phase Lb Trials

Clinical outcome of salvage chemotherapy after oxaliplatin based chemotherapy for metastatic small bowel adenocarcinoma

Abstract Background Although palliative chemotherapy (CTx) for metastatic small bowel adenocarcinoma (mSBA) has not been established, fluoropyrimidine plus oxaliplatin (FOx) is globally accepted as a standard CTx based on several studies. While CTx for colorectal cancer has been recommended in NCCN guidelines, limited efficacy of irinotecan (IRI) and panitumumab for mSBA had also been shown in western countries. Thus, there has been no salvage line chemotherapy (SLC) which can be recommended for mSBA after failure to FOx. The aim of this study was to provide the information of clinical outcomes of SLC for mSBA after failure of FOx. Methods mSBA patients (pts) who received SLC after failure of FOx from 2010 to 2019 in our institute were retrospectively analyzed. Pts who received 1st line CTx other than FOx, ongoing FOx, or with insufficient follow-up were excluded. Results Of 59 mSBA pts, eligible 33 were extracted from our database. Age (median): 58 year-old, PS (0/1/>=2): 3/21/9, primary site (duodenum/jejunum and ileum): 13/20, stage (IV/recurrence): 23/10. Metastatic sites were peritoneum in 25 (75.8%) pts, and liver in 12 (36.4%). Twenty-two (66.7%) pts received SLC, pts with good PS (0-1) tended to receive SLC. As 2nd line CTx, 16 of 22 pts (72.7%) received IRI-based CTx and gemcitabine (GEM) in 3. Eight of 22 pts received 3rd line CTx; nab-paclitaxel (off-label use for APC-wild type) in 4, and GEM in 2. MST in all pts was 4.5 months, which was longer in pts treated with SLC than those with best supportive care (5.7 vs 1.7 months, p Conclusion Limited efficacy of SLC for mSBA was shown also in Japanese population. This is very important baseline data to lead to the future drug development.

829TiP - Multicenter randomized phase II trial of 5-fluorouracil/leucovorin (5-FU/LV) with or without liposomal irinotecan (nal-IRI) in metastatic biliary tract cancer (BTC) as second-line therapy after progression on gemcitabine plus cisplatin (GemCis): NIFTY trial

BackgroundPatients with BTC have dismal prognosis with 5-year survival of less than 10%. GemCis is the globally established first-line therapy based on the phase III ABC-02 trial. However, there is no standard second-line therapy after failure of 1st line GemCis, although 5-FU-based therapy has been widely used. Nal-IRI (Onivyde®) comprises irinotecan sucrosofate salt encapsulated in pegylated liposomes that protect the drug from premature conversion in the liver. This randomized phase 2 trial is designed to compare the clinical outcomes between nal-IRI plus 5-FU/LV with 5-FU/LV alone as 2nd line therapy in patients with BTC who progressed on 1st line Gem/Cis. Trial designNIFTY trial is a multicenter, open-label, randomized, phase II trial and 5 referral cancer centers in Korea participated in this study. Histologically documented biliary tract cancer (intrahepatic and extrahepatic cholangiocarcinoma, and gallbladder cancer), documented progression on 1st line Gem/Cis, and at least one measurable lesion are key inclusion criteria. Eligible patients are randomized with 1:1 ratio to experimental arm (80mg/m2 irinotecan hydrochloride trihydrate salt equivalent to 70mg/m2 irinotecan free base over 90minutes, followed by 400mg/m2 LV over 30min, and then 2400mg/m2 5-FU over 46h, every 2 weeks) and control arm (400mg/m2 LV over 30min, and then 2400mg/m2 5-FU over 46h, every 2 week). Response evaluation is graded by RECIST v1.1 and conducted every 6 weeks. Primary endpoint is progression-free survival and secondary endpoints are overall survival, response rates, quality of life assessed by EORTC QLQ-C30 and safety profile. We hypothesized that the addition of nal-IRI to 5-FU/LV would enhance the PFS to median 3.3 months (P1) from median 2.0 (P0) with 5-FU/LV alone. With alpha of 0.05, power of 80%, and drop-out rates of 10%, a total of 174 patients (87 patients per each arm) are needed based on this hypothesis. As of March 2019, a total of 89 patients (51% of the target number) are enrolled. Clinical trial identificationNCT03524508. Legal entity responsible for the studyThe authors. FundingShire and Servier. DisclosureC. Yoo: Research grant / Funding (self): Shire; Advisory / Consultancy, Research grant / Funding (self): Servier; Honoraria (self): Ipsen. All other authors have declared no conflicts of interest.

Double-Crosslinked Nanocomposite Hydrogels for Temporal Control of Drug Dosing in Combination Therapy

Temporal control of drug dosing is indispensable for a successful combination therapy that utilizes cisplatin (CDDP) and irinotecan (IRN), with clinical evidence supporting a higher response rate when CDDP was administered prior to IRN. Herein, a peptide-based nanocomposite hydrogel (CDDP-Pept-AlgNP) was designed for sequential release of CDDP and IRN to maximize synergism of two drugs. First, a double-crosslinking strategy was exploited for structural reinforcement of hydrogel, with integration of coordination interactions between CDDP and hydrogelator (Pept) as well as electrostatic interactions between Pept and alginate nanoparticles (AlgNP), that afforded nanocomposite hydrogel with 42-fold increase in storage modulus comparing to peptide gel alone. Next, the nanocomposite hydrogel with excellent injectability served as a depot for controlled release of dual drugs, and guaranteed a fast release of CDDP prior to a tunable release of IRN that is dependent on fraction ratios of AlgNP in the composite materials. Comparing to simple mixture of CDDP and IRN solution, CDDP-Pept-AlgNP hydrogel formulation demonstrated excelling synergism of CDDP and IRN in cell inhibition studies, with efficacious antitumor potency further proved in tumor regression studies in vivo. We believe that the strategy of utilizing co-assembly of multiple pairs of entities (i.e. drug-gelator, nanoparticle-gelator) in composite materials provides a generalized method for designing mechanically stable supramolecular hydrogels, and further promises an exact temporal control of drug dosing by packing individual drugs in co-assembled structures/domains to satisfy clinical demands from combination therapy.

Irinotecan hydrochloride trihydrate loaded folic acid-tailored solid lipid nanoparticles for targeting colorectal cancer: development, characterization, and in vitro cytotoxicity study using HT-29 cells

Aim: The aim of this investigation was to evaluate the potential of folic acid-tailored solid lipid nanoparticles (SLNs) for encapsulation as well as for in vitro cytotoxicity study of irinotecan hydrochloride trihydrate (IHT) against colorectal cancer (CRC) by using HT-29 cells.Methods: Solvent diffusion technique was employed for the preparation of SLNs. Further, the formulations were optimised via three-level, three-factor Box–Behnken design (BBD).Results: The uncoupled SLNs (IRSLNs) and folic acid-coupled SLNs (IRSLNFs) formulations revealed not only high %entrapment efficiency but also small particle size. Moreover, in vitro drug release results from IRSLNs and IRSLNFs confirmed that they followed sustained-release effect for up to 144 h. Whereas, in vitro cell viability study against HT-29 cell line suggested significantly (p < 0.05) higher cytotoxicity (IC50 = 15 µg/ml) of IRSLNFs over IRSLNs and IHT solution.Conclusions: Outcomes suggested that the engineered IRSLNFs hold great potential for targeting CRC for an extended period of time.

P14.125 Retrospective analysis of long-term response to bevacizumab in combination with irinotecan for recurrent glioblastoma: identification of prognostic factors

Abstract BACKGROUND In absence of standard treatment for recurrent glioblastoma (rGBM), numerous prospective and retrospective studies have evaluated the off-label combination of bevacizumab (BEV) with irinotecan (IRI) in patients with rGBM. We report here our single center experience with this combination and we investigated prognostic factors for long-term response. MATERIAL AND METHODS We performed a retrospective analysis of consecutive patients treated initially by Stupp protocol and with BEV-IRI for a rGBM between 2007 and 2017. Times to progression and overall survival, as well as toxicities, were investigated and analysed. Patients without progression at least 12 month after the first administration of BEV-IRI were considered as long-term responders. The primary end-point was overall survival post-BEV-IRI (OS-BEV-IRI). RESULTS One-hundred eleven patients were eligible for the analysis. Median age at the diagnosis was 57 years and the value of WHO Performance Status (PS) at the recurrence was 0 to 1 for 67,5% of patients. Kaplan-Meier median progression-free survival (PFS-BEV-IRI) and overall survival (OS-BEV-IRI) at recurrence estimates (calculated from start of BEV-IRI) were 6.51 and 10.41 months, respectively. The median OS (calculated from diagnosis) was 22,4 months. Twenty-Three patients (20,7%) were long-term responders to BEV-IRI regimen. This subgroup was not significantly different than the short-term responders according to age or PS distribution, but the relative proportion of biopsy in comparison to other surgery modalities was significantly increased in long-term responders (p&lt;0,0001). Univariate analysis showed that PS 0–1 (p=0,007), biopsy (p=0,0022) are significantly associated with a better prognosis, but not age. Eighty three patients (75%) had toxicities, mainly grade 1 and 2 (92%), such as hypertension, proteinuria, haemorrhage, thrombosis, nausea, diarrhoea, fatigue or neutropenia. Most of the grade 3 and grade 4 toxicities were related to BEV treatment. Adverse events were significantly more frequent in long-term responders (p=0,0096). CONCLUSION BEV-IRI Combination is well tolerated and may offer some clinical benefits in recurrent GBM patients, more particularly if only biopsy was performed instead of surgery. Our results strengthened the role of these agents for the treatment of recurrent GBM.

Development and validation of high-performance liquid chromatographic method for quantification of Irinotecan and its active metabolite SN-38 in colon tumor bearing NOD/SCID mice plasma samples: application to pharmacokinetic study

Irinotecan (IRT) is an antineoplastic agent widely used in the treatment of various cancers primarily in colorectal cancer. A new, simple and sensitive high-performance liquid chromatography (HPLC) method coupled with fluorescence detector was developed and validated to quantify IRT and its active metabolite SN38 in the plasma of non-obese diabetic/severe combined immune-deficient mice (NOD/SCID) mice bearing colon tumor. The plasma samples were extracted by precipitation method using acetonitrile with 0.1% formic acid. The chromatographic separation was achieved using mobile phase consisted of water and acetonitrile (57:43 v/v) pH 3 at the flow rate of 0.8 mL/min in C18 column (internal diameter, 250 × 4.6 mm; pore size, 5 μm). The method was validated according to the bioanalytical guidelines defined by Food and Drug Administration (FDA) and European Medicine Agency (EMA). A regression (R2) value of 0.999 and 0.997 for IRT and SN38 suggested the good linearity in the range of 0.1–10 μg/mL and 5–500 ng/mL, respectively. The calculated lower limit of quantification (LLOQ) and limit of detection (LOD) for IRT were 0.1 and 0.065 μg/mL, respectively. However, for SN38, LLOQ and LOD were 5 and 2 ng/mL, respectively. The intra-day and inter-day variations (coefficient of variance; % CV) observed during the validation were found to be within the set limit of 15%. Both accuracy and percentage recovery analyzed and calculated from the quality control samples were in the between the defined range of 85–115%. Plasma samples were found to be stable when stored at room temperature for 2 h, after 2 freeze–thaw cycles and at −80 °C for 2 months. The developed method was successfully applied to study the plasma elimination profile of IRT in NOD/SCID mice with tumor. The results from plasma concentration time profile and pharmacokinetic parameter analyzed suggested the rapid elimination of IRT and SN38 from the plasma of NOD/SCID mice.