Combination Of Irinotecan Research Articles

A Rational Combination Therapy Approach with Radiation Therapy in Ewing Sarcoma

Ewing sarcoma (EWS) is the second most common malignant bone tumor primarily occurring in adolescents and young adults. Radiation therapy (RT) is usually used in tumors not amenable to surgery or in those resected with compromised margins. It is also used in metastatic disease. Despite advances in the treatment of EWS that have improved the survival substantially to 70% in localized disease, outcome for metastatic, relapsed and recurrent disease remains dismal. Therefore, newer therapeutic approaches, in combination with conventional chemotherapy and RT are needed to improve outcome. Given known deficits in DNA damage repair in EWS, we hypothesize that adding poly-ADP ribose polymerase inhibitors (PARPis), which selectively target the DNA damage response, to the current treatment combinations may potentially improve the therapeutic outcome. We investigated primary and recurrent standard of care (SOC) chemotherapeutics and PARPis as single agents and in combination with RT in the treatment of several human EWS cell lines using colony forming assay. We also compared the result to a radioresistant osteosarcoma cell line, U2OS. DNA damage was assessed using immunofluorescence microscopy by quantifying γ-H2A.X foci. The effect of drugs on DNA repair was measured using a combined intra-chromosomal homologous recombination (HR) / mutagenic non-homologous end joining (mNHEJ) assay. To determine whether sensitivity of PARPis depends on the expression of PARP1, we established a stable cell line which PARP1 was knocked down when induced with doxycycline. The drug combinations were tested in vivo using orthotopic xenograft models of EWS with image-guided fractionated irradiation and tumor burden was monitored via bioluminescence. At physiologically-relevant concentrations of the PARPi talazoparib (TAL), the combination of RT+TAL showed the highest synergist effect and combined efficacy compared to the other PARPis and SOC chemotherapeutics in human EWS cell lines. Differences in radiosensitivity across systemic agents were partially correlated to their ability to induce DNA damage. Moreover, PARPis did not significantly affect HR or mNHEJ DNA repair pathways and inducible PARP knockdown affected EWS (ES8) cells’ sensitivity to TAL. The combinations of irinotecan (IRN)-TAL-RT was found to have equivalent tumor growth inhibition to IRN-TAL-temozolomide (TMZ), a combination currently under clinical investigation in pediatric patients with recurrent/refractory sarcoma (NCT02392793) in EWS mouse xenografts. Taking together, our work suggested the combination of TAL and IRN may be a useful therapeutic strategy when RT is used in the progressive disease setting.

Bone sarcoma patient-derived xenografts are faithful and stable preclinical models for molecular and therapeutic investigations

Standard therapy of osteosarcoma (OS) and Ewing sarcoma (EW) rests on cytotoxic regimes, which are largely unsuccessful in advanced patients. Preclinical models are needed to break this impasse. A panel of patient-derived xenografts (PDX) was established by implantation of fresh, surgically resected osteosarcoma (OS) and Ewing sarcoma (EW) in NSG mice. Engraftment was obtained in 22 of 61 OS (36%) and 7 of 29 EW (24%). The success rate in establishing primary cell cultures from OS was lower than the percentage of PDX engraftment in mice, whereas the reverse was observed for EW; the implementation of both in vivo and in vitro seeding increased the proportion of patients yielding at least one workable model. The establishment of in vitro cultures from PDX was highly efficient in both tumor types, reaching 100% for EW. Morphological and immunohistochemical (SATB2, P-glycoprotein 1, CD99, caveolin 1) studies and gene expression profiling showed a remarkable similarity between patient’s tumor and PDX, which was maintained over several passages in mice, whereas cell cultures displayed a lower correlation with human samples. Genes differentially expressed between OS original tumor and PDX mostly belonged to leuykocyte-specific pathways, as human infiltrate is gradually replaced by murine leukocytes during growth in mice. In EW, which contained scant infiltrates, no gene was differentially expressed between the original tumor and the PDX. A novel therapeutic combination of anti-CD99 diabody C7 and irinotecan was tested against two EW PDX; both drugs inhibited PDX growth, the addition of anti-CD99 was beneficial when chemotherapy alone was less effective. The panel of OS and EW PDX faithfully mirrored morphologic and genetic features of bone sarcomas, representing reliable models to test therapeutic approaches.

Abstract 4720: Ataxia telangiectasia mutated (ATM) kinase inhibitor AZD0156 in combination with 5-fluorouracil and irinotecan in preclinical models of colorectal cancer

Abstract Background: AZD0156 is an oral inhibitor of ATM, a serine threonine kinase that plays a key role in DNA damage response associated with DNA double strand breaks. Topoisomerase-I inhibitors like irinotecan induce single-strand DNA breaks, which are converted to double-strand breaks during DNA replication. Thus the combination of AZD0156 and irinotecan is a rational combination for clinical use. Irinotecan is used clinically to treat a variety of malignancies, including colorectal cancer (CRC), usually in combination with 5-fluorouracil (5FU) as FOLFIRI. An ongoing phase 1 clinical trial is evaluating AZD0156 in combination with single-agent irinotecan and FOLFIRI in patients with refractory cancers (NCT02588105). The purpose of this study is to evaluate AZD0156 in combination with irinotecan and 5FU in preclinical models of CRC to help inform clinical use. Methods: Anti-proliferative effects of single-agent AZD0156 and combination therapy with SN38 (active metabolite of irinotecan) and 5FU were evaluated in CRC cell lines using the Cell-Titer Glo assay. Immunoblotting and cell cycle analysis were performed to determine the mechanism of enhanced combination effects. Four CRC patient derived xenograft (PDX) models were treated with AZD0156, irinotecan, and 5FU alone and in combination for assessment of tumor growth inhibition (TGI). Results: An enhanced antiproliferative effect was observed with the combination treatment over either single agent. A more significant synergistic effect was demonstrated with the combination of AZD0156 and SN38 as compared with the combination of AZD0156 and 5FU. Cell cycle data demonstrated enhanced cell cycle arrest with combination therapy as compared to single agents. Immunoblotting results suggest a decrease in phosphorylated gamma-H2AX in cell lines treated with combination therapies. Increased TGI was observed in CRC PDX models treated with the combination of AZD0156 and irinotecan as compared to single-agent therapy in 3 of 4 models. There was not a significant change in TGI with the addition of 5FU for triplet therapy in the majority of models. Conclusions: The combination of AZD0156 with irinotecan is synergistic in in vitro models and is associated with increased TGI in CRC PDX in vivo models. The addition of 5FU to AZD0156 and irinotecan did not result in increased TGI as compared to doublet therapy in CRC PDX models, though did not decrease the AZD0156/irinotecan combination effect. An ongoing clinical trial is evaluating this combination in patients with cancers refractory to standard treatments (NCT02588105). Citation Format: S. Lindsey Davis, Marina I. Schlaepfer, Stacey M. Bagby, Sarah J. Hartman, Betelehem W. Yacob, Tonia Tse, Dennis M. Simmons, Jennifer R. Diamond, Christopher H. Lieu, Alexis D. Leal, Elaine B. Cadogan, Gareth D. Hughes, Stephen T. Durant, Wells A. Messersmith, Todd M. Pitts. Ataxia telangiectasia mutated (ATM) kinase inhibitor AZD0156 in combination with 5-fluorouracil and irinotecan in preclinical models of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4720.

Clinical experience: ramucirumab with FOLFIRI/XELIRI as a second line for patients with metastatic gastric cancer

Introduction: Previous studies demonstrated that the combination of chemotherapy with ramucirumab improved the treatment results in advanced gastric cancer (GC). One of the available options for the second line chemotherapy is the combination of irinotecan with fluoropyrimidines. As angiogenesis inhibitors can enhance the efficacy of chemotherapy, we investigated the combination of irinotecan and fluoropyrimidines with ramucirumab in metastatic GC. Methods: Eligible patients had advanced-morphologically-verified GC and disease progression during or within 4 months following first-line therapy. They received FOLFIRI plus ramucirumab(8 mg/kg on day 1) or XELIRI in combination with ramucirumab(8 mg/kg on days 1 and 8). The primary end point was progression-free survival (PFS). Secondary end-points were overall survival (OS), disease control rate (DCR) and safety. Results: Between September 2015 and October 2018, 23 patients were enrolled. Median number of cycles was 9 (2-20). Six patients achieved a partial response (PR) for an objective response rate of 26.1%. A total of 15 (65.2%) patients had stable disease (SD) for a DCR of 91.3%. With a median follow up 8,2 months, median PFS was 7.6 months (95% CI 5.9-9.2) and the median OS was 9.5 months (95% Cl 6.74 – 12.3). Median duration of PR response was 4,5 months (2,7-5,2 +) and median duration of SD was 4,2 months (2,1-10,1+ ).The main treatment-related grade 3 or 4 adverse events were decreased neutrophil count (1/23; 4.3%), anemia (1/23; 4.3%) and diarrhea (1/23; 4.3). The most frequent adverse events of special interest (AESIs) any grade were hypertension (10/23; 43.4%), bleeding/hemorrhage (5/23; 21.7%), proteinuria (5/23; 21.7%) and venous thromboembolic events (6/23; 26%). Gastrointestinal perforation developed in two patients (2/23; 8.7%). No treatment-related deaths occurred. Conclusion: In our research, ramucirumab with irinotecan and fluoropyrimidines demonstrated high activity and a manageable safety profile in patients with pre-treated metastatic GC.

Adjuvant treatment of pancreatic cancer.

Pancreatic cancer will soon become one of the most common causes of cancer death. Early detection of pancreatic cancer remains impossible and only 20% of patients are suitable for surgery once diagnosed. Even in this specific subgroup of patients, and despite improvements in surgery, overall survival remains poor, with an 80% recurrence rate. Consequently, many attempts have been made to prevent recurrence by adding chemotherapy, radiotherapy, or both. Here, we will focus on results of randomized trials evaluating the role of different postoperative treatments. Over 15 years ago, a trial demonstrated that chemoradiotherapy has a deleterious effect on survival. The same trial recommended adjuvant chemotherapy with fluorouracil as standard of care. Subsequent trials sought to identify better chemotherapy regimens. Two recently published trials evaluated the role of combination therapies for resected pancreatic cancer and demonstrated better outcomes with a gemcitabine and capecitabine combination and a fluorouracil, oxaliplatin, and irinotecan combination (FOLFIRINOX) versus gemcitabine alone. Results from recent trials suggest that FOLFIRINOX should be considered standard of care for fit patients.

Efficacy and tolerability of the combination of Liposomal irinotecan and 5-fluorouracil/leucovorin in advanced pancreatic cancers: post-approval clinic experience

Efficacy and tolerability of the combination of Liposomal irinotecan and 5-fluorouracil/leucovorin in advanced pancreatic cancers: post-approval clinic experience

Abstract 3592: Evaluation of OT-82, a nicotinamide phosphoribosyltransferase inhibitor (NAMPTi), as a potential therapeutic option for Ewing sarcoma

Abstract Targeting NAMPT, the rate-limited enzyme in the NAD salvage pathway, is a potentially attractive anticancer strategy, since cancer cells preferentially rely on this pathway to produce NAD. We explored the use of NAMPTi in Ewing sarcoma (ES), an aggressive pediatric malignancy for which novel therapeutic options are critically needed. We previously showed that ES cells are exceptionally sensitive to NAMPTi compared to other cancer types and have single agent activity in vitro and in vivo. We also demonstrated that combining NAMPTi with PARP inhibitors results in enhanced efficacy in vitro and in vivo. In this study, we further characterized the mechanisms of action of OT-82, a NAMPTi expected to enter early phase clinical trials, in ES cells and evaluated various dosing schedules for OT-82 combinations with cytotoxic therapy. On-target activity of OT-82 was assessed using NAD quantification assays and rescue experiments with multiple NAD intermediates. Characterization of NAD salvage pathway enzyme expression was performed by western blot. Mechanistic studies of cell cycle analysis, DNA damage, and cell death were performed using flow cytometry, western blotting, and comet assays. Glycolytic profiles of ES cell lines were analyzed using the Agilent Extracellular Flux Analyzer. Orthotopic ES cell line and PDX models in immunodeficient mice were used to evaluate in vivo combinations. Tumor measurements were performed with calipers twice weekly and toxicity was assessed with weekly body weights and general observations. Tumors were harvested at intermediate time points and at endpoints for biology and pharmacodynamic studies. Treatment with OT-82 revealed dose-dependent reduction of NAD both in vitro and in vivo. Addition of NMN, the product of NAMPT, rescued ES cell viability, indicating on-target activity of OT-82. While delayed NMN administration up to 48 hours after treatment with OT-82 rescued viability, a 72-hour delay rendered the effects irreversible in all cell lines. Treatment with OT-82 resulted in DNA damage, G2/M arrest and induction of apoptosis at 72 hours. Extracellular flux analysis indicated that OT-82 treatments resulted in a decrease in both oxidative and glycolytic activity. While NAMPT expression did not correlate with sensitivity to OT-82, low expression of NAPRT, an enzyme in a parallel NAD salvage pathway, appeared to be predictive of greater sensitivity to OT-82. Further, ES cells that expressed NAPRT could be fully rescued with addition of NA, the substrate of NAPRT, whereas low expressers could not. In vivo studies of the combination of OT-82 and irinotecan revealed enhanced antitumor activity. Studies of dosing schedule and tumor biology are ongoing and will be reported. OT-82 is an on-target NAMPTi that may be a novel targeted approach for the treatment of ES, especially in rational combinations. Citation Format: Anna Gibson, Choh Yeung, Arnulfo Mendoza, Sameer Isaaq, Christine Heske. Evaluation of OT-82, a nicotinamide phosphoribosyltransferase inhibitor (NAMPTi), as a potential therapeutic option for Ewing sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3592.

Results of the use of ramucirumab in combination with irinotecan and fluoropyrimidines in the second-line chemotherapy for disseminated gastric cancer

Background: Several studies show that the combination chemotherapy with ramucirumab allows to improve the treatment results of advanced gastric cancer (GC). Irinotecan with fluoropyrimidines is own of the second line chemotherapy options for these patients. As angiogenesis inhibitors can enhance the efficacy of chemotherapy, we investigated the combination of irinotecan and fluoropyrimidines with ramucirumab in metastatic GC.Methods: Eligible patients had advanced morphologically verified GC and disease progression during or within 4 months following first-line therapy. They received FOLFIRI plus ramucirumab (8 mg/kg on day 1) or XELIRI in combination with ramucirumab (8 mg/kg on days 1 and 8). The primary end point was progression-free survival (PFS). Secondary end-points were disease control rate (DCR) and safety.Results: Between September 2015 and April 2019, 39 patients (pts) were enrolled and 38 were evaluated for efficacy and toxicity. Median number of cycles was 9 (2-20). Seven patients achieved a partial response (PR) for an overall response rate of 17.9%. A total of 29 (74.4%) patients had stable disease (SD) for a DCR of 92.3%. With a median follow up 7,5 months, median PFS was 7.58 months (95% CI 6.6-8.5) and the median OS has not yet been reached. Median duration of PR response was 8,7 months (4,11-10,94+) and median duration of SD was 4,14 months (1,84-11,99+). The main treatment-related grade 3 or 4 adverse events were neutropenia (7/38; 18.4%), anemia (1/38; 2.6%) and diarrhea (2/38; 4.3%).The most frequent adverse events of special interest (AESIs) any grade were hypertension (16/38; 42.1%), bleeding/hemorrhage (10/38; 26.3%), proteinuria (6/38; 15.7%) and venous thromboembolic events (10/38; 26,3%). Gastrointestinal perforation developed in two patients (2/38; 5.3%). No treatment-related deaths occurred.Conclusion: In our research ramucirumab with irinotecan and fluoropyrimidines demonstrate the high activity and a manageable safety profile in patients with pre-treated metastatic GC

Prognostic value of Bax expression in the primary colon tumor of patients with metastatic colorectal cancer receiving first-line treatment with a triple combination of irinotecan + oxaliplatin + long-term infusion of 5-fluorouracil

Objective: to evaluate the prognostic value of Bax expression in the primary colon tumor of patients with metastatic colorectal cancer (mCRC) receiving first-line treatment with a triple combination of irinotecan + oxaliplatin + long-term infusion of 5-fluorouracil. Materials and methods . The study included patients with mCRC (morphologically (histologically) verified diagnosis of colonic adenocarcinoma) that have never received treatment for disseminated disease. Study participants received a new first-line treatment regimen with a triple combination of irinotecan + oxaliplatin + long-term infusion of 5-fluorouracil. We evaluated both short-term and long-term treatment outcomes. We also assessed the level of Bax expression in primary tumor samples (biopsy/surgery specimens) collected prior to initiation of first-line treatment using immunohistochemical methods. We analyzed the correlation between the levels of Bax expression and short-term/long-term treatment outcomes. Results. Seventeen out of 20 mCRC patients included in the study were tested for Bax expression in the primary tumor using immunohistochemical staining. The analysis of correlation between Bax expression in tumor tissue and time-to-progression in patients with mCRC receiving first-line treatment with a triple combination of drugs demonstrated that high Bax expression was a favorable prognostic factor associated with longer time-to-progression. Median time-to-progression was significantly longer in patients with Bax overexpression than in those with low levels of Bax expression or no expression: 15.7 15,7 ± 3.38 months vs 8.6 15,7 ± 0.6 months, р = 0.012. When analyzing the impact of Bax expression on the overall survival (OS) in patients with mCRC, we found that patients with Bax overexpression demonstrated better OS (median follow-up time 17.3 15,7 ± 2.54; OS was not reached; mean value 31.26 15,7 ± 2.85 months) than patients with low Bax expression or no expression (median OS 13.60 15,7 ± 3.03 months), p = 0.021. Conclusion. Our results suggest that Bax overexpression in the primary colon tumor is a favorable prognostic factor associated with longer progression-free survival and OS in mCRC patients receiving first-line treatment with a triple combination of drugs.

A phase I study of the oral administration of irinotecan in combination with the potent P-glycoprotein (P-gp) inhibitor HM30181A.

3032 Background: Irinotecan is a prodrug of the potent topoisomerase inhibitor SN-38. In animals, oral administration of irinotecan with the selective minimally absorbed P-gp inhibitor HM30181A increased the bioavailability of irinotecan. Oral administration of irinotecan may also increase the conversion to SN-38. Objectives: To determine the MTD and DLT of orally administered irinotecan in combination with HM30181A 15 mg on day 1 of a 21-day cycle. Additional objectives include determining the recommended phase 2 dose and the PK of irinotecan and SN-38. Methods: This was a phase 1 dose escalation study enrolling cohorts of 3-6 patients with advanced malignancies. Patients had Hb ≥9 gm/dL, ANC ≥ 1.5x109/L, platelets ≥ 100x109/L, adequate hepatic and renal function, ECOG 0-1 and were not homozygous for UGT1A1*28. Patients were administered HM30181A 15 mg and oral irinotecan 20, 40, 80, 120, 160, 200, 240, 280 and 320mg/m2. Results: Thirty male and female patients, mean age 60.9 (range 33-78) were enrolled into this ongoing study. The most common cancers were ovarian (6), colorectal (4), breast (4), endometrial (3), and pancreatic (3). The median number of cycles administered was 3 (range 1-9). Treatment-related Grade 3-4 AEs were experienced by 12 (40%) subjects. The most common were nausea 7 (23%), vomiting 6 (20%) and abdominal pain 3 (10%). Treatment-related SAEs were experienced by 6 (20%) patients (nausea or vomiting in 4 subjects). DLTs occurred in 2 patients at the 320 mg/m2 dose level (neutropenia and C. Difficile diarrhea) and additional patients are being enrolled at the 280mg/m2 dose level to define the MTD. Acute cholinergic diarrhea has not been observed. The best response was stable disease in 9/21 evaluable patients. PK at the three highest dose levels is summarized below. Conclusions: Oral administration of HM30181A in combination with irinotecan tablets results in pharmacologically active concentrations of SN-38. Confirmation of the MTD when dosed on a 21-day cycle is ongoing. Phase 2 studies are being planned. Clinical trial information: NTC02250157. [Table: see text]

Anlotinib and irinotecan for advanced Ewing sarcoma after failure of standard therapy: A multicenter, two-cohort, single-arm, open label, phase Ib/II trial (NCT03416517).

11012 Background: Both protracted irinotecan and anti-angiogenesis therapy have shown promising results in Ewing sarcoma. We did this phase Ib/II trial to first define the proper dose of irinotecan in combination with anlotinib in Ewing sarcoma and then evaluate efficacy. Methods: Patients diagnosed with recurrent or refractory Ewing sarcoma were enrolled and sub-classified into cohort A (≥16y) or cohort B ( < 16y). In the dose-defining phase Ib portion, anlotinib was given at a fixed dose of 12mg D1-14every 21 days, while the de-escalated 3+3 design was used to detect the recommended dose of irinotecan in each cohort from an initial level of 20mg/m2/d dx5x2. Recommended phase 2 dose (RP2D) was defined as the highest dose at which no more than 30% patients experience a DLT in the first two courses. In the next dose-expanding phase II portion, the primary endpoint was objective response rate at 12 weeks (ORR12w). A conventional two-stage study design model was used. Results: 41 patients were enrolled with 29 in cohort A and 12 in cohort B. For cohort A, first 5 patients were treated at initial level in phase Ib portion, two of whom subsequently experienced delayed diarrhea as dose-limiting toxicity (DLT). Additional six patients were then treated at a lower dose of 15mg/m2. Since no more DLT was recorded, it was used as RP2D. 23/24 patients in cohort A phase II were available for response evaluation at 12 weeks, with one complete response (CR), 14 partial response (PR) (including one CMR who has a negative PET/CT scan but still abnormal lesions in MR scan), 2 stable disease (SD) and 6 progressive disease (PD). ORR12wwas 62.5%. For cohort B, no DLT was noticed in the first six patients treated at the initial level which was used as RP2D later. Finally, 12 patients were included in cohort B. ORR12wwas 83.3% with two CR, 8 PR (including one CMR) and two PD. Although effective, cohort B were closed because of slow enrollment. Most common grade 3/4 adverse events were diarrhea, abdominal pain and neutropenia. The genotype of UGT1A1*1 and UGT1A1*28 were not associated with the risk of diarrhea. Conclusions: The combination of irinotecan and anlotinib demonstrated an acceptable toxicity profile with promising evidence of clinical efficacy in advanced Ewing sarcoma. Clinical trial information: NCT03416517.

Randomized phase 2 trial of the combination of vincristine and irinotecan with or without temozolomide, in children and adults with refractory or relapsed rhabdomyosarcoma (RMS).

10000 Background: Vincristine with Irinotecan (VI) is effective in patients with relapsed RMS but outcomes remain poor. The addition of temozolomide to VI (VIT) is attractive owing to different resistance mechanisms and distinct toxicity profiles. Methods: The VIT-0910 trial, an EpSSG-ITCC randomized phase 2 trial, evaluated efficacy and safety of VI and VIT in patients (pts) aged 0.5-50 years with relapsed/refractory RMS. Pts received Vincristine 1.5 mg/m2 d1, d8, Irinotecan 50mg/m2 d1-d5 +/- Temozolomide 125 mg/m² d1-d5 (150 mg/m² from cycle 2 if no toxicity > grade 2); 21-day cycles were given until progression/unacceptable toxicity. The primary endpoint was centrally reviewed objective response rate (ORR) after 2 cycles (primary lesion, WHO response criteria: metastatic sites, RECIST 1.1 ). Secondary endpoints included progression-free survival (PFS), overall survival (OS) and adverse events (NCI-CTCAE v4). Initially a Simon 2-stage design was used to analyse separately 40 pts/arm. After amendment, the trial sample size was increased to 120, and a comparison between arms, adjusted for confounding factors, was added to the statistical plan. Results: 120 pts (60 VIT, 60 VI) were recruited in 37 European centers from 03/2012-04/2018. Median age was 11 years (0.75-46), 89% pts relapsed RMS. ORR was 24/55 (44%) for VIT vs 18/58 (31%) for VI; adjusted odds ratio =0.50, 95%CI, 0.22-1.12, p=0.09. The VIT arm achieved significantly better PFS (adjusted Hazard Ratio (HR)=0.65, 95%Cl, 0.43-0.97, p=0.036) and OS (HR=0.53, 95%CI, 0.33-0.83, p=0.005) compared to VI. PFS and OS results were similar when only relapsed patients were included. Adverse events ≥ grade 3 were more frequent in VIT compared to VI, but only hematological toxicity was significantly increased (81% for VIT, 59% for VI, odds ratio=1.36, 95%CI, 1.06-1.76, P=0.02). Conclusions: The addition of temozolomide to VI improves PFS and OS of pts with relapsed/refractory RMS. VIT is now standard treatment for relapsed RMS in Europe. Clinical trial information: NCT01355445.

Gender and survival benefit from initial irinotecan in metastatic colorectal cancer: Analysis of the XELAVIRI (AIOKRK0110) study.

3559 Background: XELAVIRI compared initial vs sequential irinotecan (iri) in combination with fluoropyrimidine (FP) plus bevacizumab (bev) in patients (pts) with mCRC, trial identification: NCT01249638. In the full analysis set of the study, non-inferiority of time to failure of strategy (TFS) was not shown (primary endpoint). Pts with RAS/BRAF wildtype (wt) tumors benefitted from initial iri. Methods: The study endpoints objective response rate (ORR), progression-free survival (PFS), time to failure of strategy (TFS) as well as overall survival (OS) were evaluated in female vs. male pts as well as molecular subgroups (i.e. RAS mutational status). Interaction of treatment and gender was tested by likelihood ratio tests. Results: Of 421 patients, 281/140 were male/female. In male patients, ORR was 33.6% without and 58.3% with initial iri (P < 0.001). PFS (HR: 0.54 (95%CI 0.42-0.69) P < 0.001) and OS (HR: 0.63 (95%CI 0.47-0.85), P = 0.002), were also significantly better with initial iri. In the subgroup analysis, this effect was especially pronounced in pts with RAS/BRAF wt tumors. In female pts, ORR was 43% in both arms, PFS was similar (HR: 1.09 (95%CI 0.76-1.55), P = 0.65) without and with initial iri. In OS, a strong trend for inferior outcome with initial iri was seen (HR: 1.46 (95%CI 0.95-2.24), P = 0.08) that reached significance in the multivariate analysis (HR: 1.73 (95%CI 1.04-2.86, P = 0.034). Female patients with RAS/BRAF wt tumors did not benefit from initial iri (HR 1.05 (95% CI 0.46-2.41), P = 0.903 for OS). Formal interaction of treatment and gender was seen for ORR (P = 0.018), PFS (P = 0.002) and OS (P = 0.001). There were some trends for more pronounced toxicities in female pts treated with Irinotecan. Conclusions: This unplanned exploratory analysis suggests that gender might interact with efficacy of initial iri when used in the context of FP and bev. While especially male RAS wild-type patients derived a significant and clinically meaningful benefit from initial use of iri, this was not observed in female patients with RAS wt tumors. Clinical trial information: NCT01249638.

Combination of apatinib mesylate and second-line chemotherapy for treating gastroesophageal junction adenocarcinoma

ObjectiveTo investigate the safety and efficacy of acitinib mesylate combined with chemotherapy in the treatment of patients with gastroesophageal junction adenocarcinoma.MethodsA total of 119 patients with gastroesophageal junction adenocarcinoma were enrolled and randomized into an experimental group (n = 60) and a control group (n = 59). Both groups were treated with a combination of taxane, irinotecan and fluorouracil, while the experimental group also received acitinib mesylate. The clinical efficacy, survival time and adverse reactions of patients in two groups were recorded and analyzed.ResultsThe total remission rate in the experimental group and the control group was 15.79% and 3.23%, respectively; the disease control rate was 73.68% and 54.84%, respectively; and progression-free survival was 3.72 months (1–13.5 months) and 3.04 months (1–6 months), respectively. Overall survival was 13.66 months (5–24 months) and 10.08 months (6.5–19.5 months), in the experimental group and the control group, respectively. In addition, the incidence of adverse events in the experimental group was significantly lower than that in the control group.ConclusionApatinib mesylate combined with chemotherapy for the treatment of patients with gastroesophageal junction adenocarcinoma was safe and effective, with improved survival benefit compared with control.

Trabectedin and irinotecan combination regresses a cisplatinum-resistant osteosarcoma in a patient-derived orthotopic xenograft nude-mouse model

Recurrent osteosarcoma is a chemotherapy-resistant disease. Individualized precision therapy is needed for this disease. Toward this goal, we have developed the patient-derived othotopic xenograft (PDOX) mouse model of all major cancer types including osteosarcoma. Synergistic efficacy of trabectedin (TRAB) and irinotecan (IRT) has been reported in Ewing's sarcoma, soft-tissue sarcoma, and ovarian cancer. However, the efficacy of this combination on osteosarcoma is not known. The goal of present study was to determine the efficacy of the TRAB and IRT combination on cisplatinum (CDDP)-resistant osteosarcoma PDOX. The osteosarcoma PDOX models were randomized into five treatment groups of six mice: Untreated control; CDDP alone; TRAB alone; IRT alone; and TRAB and the IRT combination. Tumor size and body weight were measured during the 14 days of treatment. Tumor growth was regressed only by the TRAB-IRT combination. Tumors treated with the TRAB-IRT combination had the most tumor necrosis with degenerative change. The present study demonstrates the power of the PDOX model to identify a novel effective treatment strategy of the TRAB and IRT combination for chemotherapy-resistant osteosarcoma.

Comparative Effectiveness of Gemcitabine plus Nab-Paclitaxel and FOLFIRINOX in the First-Line Setting of Metastatic Pancreatic Cancer: A Systematic Review and Meta-Analysis.

Gemcitabine and nab-paclitaxel (GEM-NAB) and the combination of 5-fluorouracil, oxaliplatin, and irinotecan (FOLFIRINOX) are valid first-line options for advanced or metastatic pancreatic cancer (mPC). However, no randomized trials comparing the two schemes have been performed. This meta-analysis aims to compare GEM-NAB and FOLFIRINOX in terms of safety and effectiveness, taking into account data from real-life studies on mPC. We systematically searched PubMed, EMBASE and Cochrane library up to November 2018 to identify retrospective or cohort studies on mPC comparing GEM-NAB and FOLFIRINOX. We included 16 retrospective studies, including 3813 patients (2123 treated with GEM-NAB and 1690 treated with FOLFIRINOX). Despite a median weighted overall survival (OS) difference in favor of FOLFIRINOX (mean difference: 1.15, 95% confidence interval CI 0.08–2.22, p = 0.03), in whole population OS was similar (hazard ratio (HR = 0.99, 95% CI 0.84–1.16; p = 0.9). PFS was also not different between the two arms (HR = 0.88, 95% CI 0.71–1.1; p = 0.26). The overall response rate was similar (25 vs. 24% with GEM-NAB and FOLFIRINOX). Among grade 3–4 toxicities, neutropenia, febrile neutropenia, and nausea were lower with GEM-NAB, while neurotoxicity and anemia were lower with FOLFIRINOX. In conclusion, despite a numerically longer median OS with FOLFIRINOX as compared to GEM-NAB, the overall risk of death and progression were similar. Their toxicity was different with less nausea, neutropenia, and febrile neutropenia with GEM-NAB, as compared to less neurotoxicity and anemia with FOLFIRINOX. Therefore, analysis of non-randomized “real world” studies to date has not provided evidence of a major benefit of one regimen over the other.

An open label phase 1 study evaluation safety, tolerability, and maximum tolerated dose of oral administration of irinotecan in combination with capecitabine.

Oral administration of chemotherapy offers several advantages in comparison with intravenous administration. Previously, data on a new oral formulation of irinotecan have been published. The aim of the present study was to evaluate the safety, tolerability, and Maximum Tolerated Dose (MTD) of the new oral irinotecan formulation in combination with oral capecitabine. The study was an open label, phase 1, single center, extension part in which oral irinotecan was investigated in combination with capecitabine. The MTD of irinotecan in combination with capecitabine was 17.5mg/m2 once daily for 14 consecutive days in combination with capecitabine 800mg/m2 twice daily. Eligible patients were adults with metastatic or unresectable solid tumors for which no standard curative or palliative therapies existed. 14 patients were included in the extension part. No grade 3 or 4 hematologic toxicities were observed. Non-hematological toxicities included grade 1 and 2 diarrhea, fatigue, cholinergic syndrome, vomiting, and weight loss. Totally, 3 grade 3 toxicities and no grade 4 event were reported. No objective responses were observed. Five patients had stable disease lasting median 14 weeks. Capecitabine in combination with oral irinotecan could be a new treatment option offering a more convenient and patient friendly treatment strategy compared to intravenous irinotecan. The combination is fairly tolerated; however, further investigations are needed to assess the efficacy of this regimen.

Irinotecan plus S-1 versus S-1 in patients with previously treated recurrent or metastatic esophageal cancer (ESWN 01): a prospective randomized, multicenter, open-labeled phase 3 trial

BackgroundThe benefit of systemic treatments in esophageal squamous cell carcinoma (ESCC) which has progressed after chemotherapy is still uncertain and optimal regimens based on randomized trials have not yet been established. We aimed to compare the efficacy of irinotecan plus S-1 with S-1 monotherapy in recurrent or metastatic ESCC patients who had resistance to platinum- or taxane-based chemotherapy.MethodsWe conducted a prospective randomized, multicenter, open-label, phase 3 trial in 15 centers across China. Eligible patients were adults with histologically confirmed recurrent or metastatic ESCC, and were randomly assigned (ratio, 1:1) to receive either irinotecan plus S-1 (intravenous infusion of irinotecan [160 mg/m2] on day 1 and oral S-1 [80–120 mg] on days 1–10, repeated every 14 days) or oral S-1 monotherapy (80–120 mg/day on days 1–14, repeated every 21 days) using a central computerized minimization procedure. The primary endpoint was progression-free survival (PFS).ResultsBetween December 23, 2014 and July 25, 2016, we screened 148 patients and randomly assigned 123 patients to receive either irinotecan plus S-1 regimen (n = 61) or S-1 monotherapy (n = 62). After a median follow-up of 29.2 months (95% confidence interval [CI] 17.5–40.9 months), the median PFS was significantly longer in the irinotecan plus S-1 group than in the S-1 monotherapy group (3.8 months [95% CI 2.9–4.3 months] vs. 1.7 months [95% CI 1.4–2.7 months], hazard ratio = 0.58, 95% CI 0.38–0.86, P = 0.006). The objective response rates were 24.6% in the irinotecan plus S-1 group and 9.7% in the S-1 monotherapy group (P = 0.002). The patients in the irinotecan plus S-1 group presented with increased rates of grade 3–4 leukopenia (16.4% vs. 0%), neutropenia (14.8% vs. 1.6%), and nausea (4.9% vs. 0%). No significant difference in grade 3–4 diarrhea and no treatment-related deaths were observed in both groups.ConclusionsThe combination of irinotecan with S-1 was similarly tolerable but significantly prolonged PFS compared to S-1 monotherapy as a second- or third-line treatment in patients with recurrent or metastatic ESCC.Clinical Trial Registration NCT02319187. Registered on December 9, 2014

Dasatinib can enhance paclitaxel and gemcitabine inhibitory activity in human pancreatic cancer cells

ABSTRACT SRC and its activated form, phospho-SRC (pSRC), are aberrantly activated in pancreatic cancer and SRC represents a potential target for pancreatic cancer therapy. In this paper, we examined the inhibitory effect of dasatinib, a potent SRC inhibitor in combination with paclitaxel or gemcitabine on human and murine pancreatic cancer cell lines. The results showed that p-SRC can be highly expressed in most human and mouse pancreatic cancer cell lines compared with normal human cell lines and can be induced by paclitaxel or gemcitabine in HPAC cells. Dasatinib can enhance the efficacy of paclitaxel or gemcitabine by reducing the cell viability and inhibiting the cell proliferation. Dasatinib with paclitaxel combination exhibits statistically greater inhibition of the cell migration ability than single agent alone, paclitaxel with gemcitabine or FOLFIRINOX (combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin) in HAPC, PANC-1, and BXPC-3 human pancreatic cancer cell lines as well as 8–285 APR and 8–365 APR mouse pancreatic cancer cell lines. In addition, dasatinib with gemcitabine combination also showed statistically greater inhibition of cell migration than single agent alone, paclitaxel with gemcitabine, or FOLFIRINOX in HAPC, PANC-1 and 8–285 APR cells. The combination of dasatinib with paclitaxel or gemcitabine also showed greater inhibition of the colony formation ability of pancreatic cancer cells compared with single-agent monotherapy or FOLFIRINOX. Dasatinib with paclitaxel or gemcitabine combination also inhibits p-SRC, p-STAT3, p-AKT, and/or p-ERK in these pancreatic cancer cells. Therefore, our results support that combined dasatinib and paclitaxel or gemcitabine therapy may be a viable therapeutic approach for human pancreatic cancer.

Influence of initial dose intensity on efficacy of FOLFIRINOX in patients with advanced pancreatic cancer.

The combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) is the standard of care for advanced pancreatic cancer, but causes hematological and gastrointestinal toxicities, leading to treatment delay and dose reduction; optimal modification based on toxicities is needed. Therefore, we evaluated the effect of initial relative dose intensity (RDI) on FOLFIRINOX efficacy by conducting a Japanese nationwide survey. We evaluated overall survival (OS) and progression-free survival (PFS) of patients administered two or more cycles of FOLFIRINOX, and determined RDIs for each drug within the first two cycles. RDI’s effect on efficacy was evaluated using a multivariate analysis with a Cox regression hazard model. Of 399 patients enrolled, 359 and 346 were evaluated for OS and PFS, respectively. Median RDI was 71.8%, 64.7%, 23.4%, and 76.9% for oxaliplatin, irinotecan, and bolus and continuous infusions of 5-FU, respectively. A high RDI for 5-FU bolus resulted in poor prognosis in terms of PFS (hazard ratio: 1.34; p = 0.022) and negatively correlated with objective response (coefficient: −0.70; p = 0.021), and a high RDI for CPT-11 positively correlated with objective response (coefficient: 1.02; p = 0.031). In conclusion, low and high RDIs for irinotecan and 5-FU bolus, respectively, resulted in poor FOLFIRINOX efficacy.