Combination Of Irinotecan Research Articles

A randomized phase II study (B2151005) of the intravenous phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor PF-05212384 plus irinotecan versus cetuximab plus irinotecan in patients with wild-type KRAS metastatic colorectal cancer (mCRC).

TPS3649 Background: The combination of cetuximab plus irinotecan is considered a standard of care regimen for third-line treatment of patients with wild-type KRAS metastatic colorectal cancer (mCRC...

A randomized phase III study of cisplatin (CDDP), etoposide (ETOP) and irinotecan versus topotecan as second-line chemotherapy in patients with sensitive relapsed small-cell lung cancer (SCLC): Japan Clinical Oncology Group study JCOG0605

7504 Background: ETOP and irinotecan are drugs known to exert promising activity in SCLC. A phase II study of weekly chemotherapy using a combination of CDDP, ETOP and irinotecan (PEI), which are k...

A 3-weekly schedule of irinotecan and panitumumab for wild-type KRAS metastatic colorectal cancer

SUMMARY Aim: We investigated the combination of irinotecan and panitumumab as a 3-weekly schedule in patients with wild-type KRAS metastatic colorectal cancer, who had progressed after standard chemotherapy. Material & methods: Patients received concomitant irinotecan (350 mg/m2) and panitumumab (9 mg/kg) once every 3 weeks. The primary end point was response rate. Secondary end points included progression-free survival (PFS), overall survival (OS) and translational research. Results: Inclusion was stopped early owing to lack of efficacy (n = 31). The response rate was 16%, median PFS and OS was 2.0 months (95% CI: 1.9–4.0) and 7.8 months (95% CI: 4.6–8.8), respectively. The most commonly encountered adverse event was skin rash (84% any grade). Pretreatment cell-free DNA levels were significantly related to disease control (p = 0.04), PFS (p = 0.04) and OS (p = 0.002), respectively. Conclusion: The present treatment regimen was less effective than expected and is not recommended. The clinical importance of cell-free DNA deserves further research.

Oncolytic reovirus preferentially induces apoptosis in KRAS mutant colorectal cancer cells, and synergizes with irinotecan.

Reovirus is a double stranded RNA virus, with an intrinsic preference for replication in KRAS mutant cells. As 45% of human colorectal cancers (CRC) harbor KRAS mutations, we sought to investigate its efficacy in KRAS mutant CRC cells, and examine its impact in combination with the topoisimerase-1 inhibitor, irinotecan. Reovirus efficacy was examined in the KRAS mutant HCT116, and the isogenic KRAS WT Hke3 cell line, and in the non-malignant rat intestinal epithelial cell line. Apoptosis was determined by flow cytometry and TUNEL staining. Combination treatment with reovirus and irintoecan was investigated in 15 CRC cell lines, including the HCT116 p21 isogenic cell lines. Reovirus preferentially induced apoptosis in KRAS mutant HCT116 cells compared to its isogenic KRAS WT derivative, and in KRAS mutant IEC cells. Reovirus showed a greater degree of caspase 3 activation with PARP 1 cleavage, and preferential inhibition of p21 protein expression in KRAS mutant cells. Reovirus synergistically induced growth inhibition when combined with irinotecan. This synergy was lost upon p21 gene knock out. Reovirus preferentially induces apoptosis in KRAS mutant colon cancer cells. Reovirus and irinotecan combination therapy is synergistic, p21 mediated, and represents a novel potential treatment for patients with CRC.

Regorafenib (BAY 73‐4506): Antitumor and antimetastatic activities in preclinical models of colorectal cancer

Regorafenib, a novel multikinase inhibitor, has recently demonstrated overall survival benefits in metastatic colorectal cancer (CRC) patients. Our study aimed to gain further insight into the molecular mechanisms of regorafenib and to assess its potential in combination therapy. Regorafenib was tested alone and in combination with irinotecan in patient-derived (PD) CRC models and a murine CRC liver metastasis model. Mechanism of action was investigated using in vitro functional assays, immunohistochemistry and correlation with CRC-related oncogenes. Regorafenib demonstrated significant inhibition of growth-factor-mediated vascular endothelial growth factor receptor (VEGFR) 2 and VEGFR3 autophosphorylation, and intracellular VEGFR3 signaling in human umbilical vascular endothelial cells (HuVECs) and lymphatic endothelial cells (LECs), and also blocked migration of LECs. Furthermore, regorafenib inhibited proliferation in 19 of 25 human CRC cell lines and markedly slowed tumor growth in five of seven PD xenograft models. Combination of regorafenib with irinotecan significantly delayed tumor growth after extended treatment in four xenograft models. Reduced CD31 staining indicates that the antiangiogenic effects of regorafenib contribute to its antitumor activity. Finally, regorafenib significantly delayed disease progression in a murine CRC liver metastasis model by inhibiting the growth of established liver metastases and preventing the formation of new metastases in other organs. In addition, our results suggest that regorafenib displays antimetastatic activity, which may contribute to its efficacy in patients with metastatic CRC. Combination of regorafenib and irinotecan demonstrated an increased antitumor effect and could provide a future treatment option for CRC patients.What's new?Regorafenib is a multikinase inhibitor with antiangiogenic activity recently approved in the US and in Europe for the treatment of metastatic colorectal cancer in patients who failed previous therapies. Here, a research team led by Bayer Pharma AG, the discoverer of the drug, confirms inhibition of key mediators of angiogenesis and lymphangiogenesis (VEGFR2 and VEGFR3) as the potential antiangiogenic mechanism of action of the drug. Regorafenib further inhibited growth of established and prevented formation of new liver metastases, and in combination with the chemotherapeutic drug irinotecan led to significant tumor growth delay in four patient-derived colorectal cancer xenograft models. The authors speculate that combination treatments including regorafenib may provide novel therapeutic opportunities for patients with therapy-resistant colorectal cancer.

A pilot study of adjuvant chemotherapy with irinotecan and cisplatin for completely resected high-grade pulmonary neuroendocrine carcinoma (large cell neuroendocrine carcinoma and small cell lung cancer)

BackgroundLarge cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC) are recognized as high-grade neuroendocrine carcinomas (HGNEC) of the lung. In patients with completely resected HGNEC, platinum-based adjuvant chemotherapy may be considered. However, the optimum chemotherapy regimen has not been determined. We conducted a multicenter single-arm phase II trial to evaluate irinotecan and cisplatin in postoperative adjuvant chemotherapy for HGNEC patients. Patients and methodsPatients with completely resected stage I–IIIA HGNEC received four cycles of irinotecan (60mg/m2, day 1, 8, 15) plus cisplatin (60mg/m2, day 1). This regimen was repeated every 4 weeks. The primary endpoint was the rate of completion of chemotherapy (defined as having undergone three or four cycles), and secondary endpoints were the rate of 3-year relapse-free survival (RFS), rate of 3-year survival and toxicities. ResultsForty patients were enrolled between September 2007 and April 2010. Patients’ characteristics were: median age (range) 65 [45–73] years; male 85%; ECOG-PS 1 60%; LCNEC 57% and SCLC 43%; stage IA/IB/IIB/IIIA 32/35/8/5%; 95% received lobectomy. The rate of completion of chemotherapy was 83% (90%C.I.; 71–90%). The rate of overall survival at 3 years was estimated at 81%, and that of RFS at 3 years was 74%. The rates of overall survival and RFS at 3 years were 86 and 74% among 23 LCNEC patients, and 74 and 76% among 17 SCLC patients, respectively. Nineteen patients (48%) experienced grade 3 or 4 neutropenia, but only five patients (13%) developed febrile neutropenia. Two patients (5%) developed grade 3 diarrhea, and four patients (10%) had grade 3 nausea. No treatment-related deaths were observed in this study. All 40 specimens were also diagnosed as HGNEC by central pathological review. ConclusionsThe combination of irinotecan and cisplatin as postoperative adjuvant chemotherapy was feasible and possibly efficacious for resected HGNEC.

Immediate Induction and Consolidation Therapy May Improve Outcomes for Patients with Anaplastic Astrocytoma: a Case Series

Despite advances in chemotherapy and radiation, prognosis for all patients with high grade gliomas remains poor. In anaplastic astrocytomas (WHO III) GTR is associated with a 5 year progression free survival (PFS) of 44% compared to 22% when surgical resection is sub-total. While initial studies demonstrated post-radiation chemotherapy improved outcomes, successive chemotherapeutic trials were unable to significantly improve outcomes. Recent trials in adults with recurrent glioblastoma multiforme have shown that the combination of Bevacixumab and Irinotecan have improved 6 month PFS was 46% and overall survival (OS) at 6 months of 77%. Although these adult studies were encouraging, results were not replicated in children with similar pathology. This case series presents two pediatric patients with anaplastic astrocytoma treated with an induction therapy of Temozolamide (90mg/m2 x 42 days) plus standard radiation therapy (5400 cGy) very shortly after surgical resection, followed by a consolidation treatment regimen of 8-cycles of chemotherapy with Bevacizumab (10mg/m2) and Irinotecan (125mg/m2), given on days 1 and 15 of 21 day cycles. These patients did extraordinarily well on this therapeutic regimen, surpassing expectations, with one patient having 18 months of PFS and one patient achieving CR1 at the time of this publication for 20 months. The treatment regimen was well tolerated without unanticipated toxicities or episodes of severe neutropenia induced by this therapy. We are encouraged by the improvements in PFS and OS in these two patients as well as the acceptability of toxicity in this case series and thus recommend prompt induction and consolidation chemotherapy following resection of these neoplasms.

Synergistic Antitumor Activity of Cetuximab and Namitecan in Human Squamous Cell Carcinoma Models Relies on Cooperative Inhibition of EGFR Expression and Depends on High EGFR Gene Copy Number

Despite the frequent overexpression of epidermal growth factor receptor (EGFR) in squamous cell carcinoma (SCC), the efficacy of cetuximab alone is limited. Given the marked activity of namitecan, a hydrophilic camptothecin, against SCC models, the present study was performed to explore the efficacy of the cetuximab-namitecan combination in a panel of SCC models. We examined the antiproliferative and antitumor activities of the cetuximab-namitecan combination in four SCC models characterized by a different EGFR gene copy number/EGFR protein level. We also assessed the effects of the combination on EGFR expression at both mRNA and protein levels and investigated the molecular basis of the interaction between the two agents. Cetuximab and namitecan exhibited synergistic effects, resulting in potentiation of cell growth inhibition and, most importantly, enhanced therapeutic efficacy, with high cure rates in three SCC models characterized by high EGFR gene copy number, without increasing toxicity. The synergistic antitumor effect was also observed with the cetuximab-irinotecan combination. At the molecular level, the two agents produced a cooperative effect resulting in complete downregulation of EGFR. Interestingly, when singly administered, the camptothecin was able to strongly decrease EGFR expression mainly by transcriptional inhibition. Our results (i) demonstrate a marked efficacy of the cetuximab-namitecan combination, which reflects a complete abrogation of EGFR expression as a critical determinant of the therapeutic improvement, in SCC preclinical models, and (ii) suggest EGFR gene copy number as a possible marker to be used for patient selection in the clinical setting.

Role of aflibercept in the treatment of advanced colorectal cancer

SUMMARY Colorectal cancer is the third most common cancer in men, representing 10% of cases, and the second most common cancer in women, representing 9.4% of cases, worldwide. It is estimated that 50–60% of patients will develop metastases during the course of their disease, while 15–25% will present with synchronous metastatic lesions, reducing the probability of 5-year survival to 12%. Colon cancer represents the fourth most common cause of death from cancer worldwide and the second most common cause in developed countries. First-line therapy of advanced or metastatic colorectal carcinoma (mCRC) usually consists of the administration of oxaliplatin or irinotecan in combination with leucovorin and 5-fluorouracil. In the first- or second-line settings, monoclonal antibodies can be added to chemotherapy. Bevacizumab (anti-VEGF monoclonal antibody) is utilized with fluoropyrimidine-containing regimens in combination with oxaliplatin or irinotecan. Cetuximab can be administered in combination with irinotecan or as a single agent in patients who have wild-type KRAS. Panitumumab has also been approved for third-line single-agent therapy in KRAS wild-type patients and recently in first- and second-line therapy in combination with chemotherapy. There are no standard second-line treatments of mCRC specifically used in combination with FOLFIRI, and no drugs have been approved for patients with prior bevacizumab treatment. Aflibercept is a new angiogenesis inhibitor with a unique mechanism of action. Aflibercept is a recombinant fusion protein consisting of VEGF-binding portions from extracellular domains of the human VEGFR1 and 2 fused to the Fc portion of human IgG1. Aflibercept acts as a soluble decoy receptor that binds to VEGF-A with higher affinity than its native receptors, as well as the related ligands PIGF and VEGF-B. Aflibercept interferes with the biological actions of VEGF by ‘trapping’ VEGF and preventing it from interacting with its receptors on endothelial cells, blocking the activation of VEGFRs and the subsequent proliferation of endothelial cells; this results in inhibition of the growth of new vessels. The role of aflibercept in the management of mCRC was studied in the VELOUR trial, which showed that its addition to the FOLFIRI regimen resulted in a survival benefit, giving a statistically significant log-rank test with p = 0.0032 (hazard ratio: 0.817; 95.34% CI: 0.713–0.937). This benefit was supported by subgroup and sensitivity analyses, the increased median progression-free survival, and improved response rates observed in the aflibercept arm. Aflibercept toxicity is acceptable, manageable and within the established range of other VEGF inhibitors.

Efficacy and safety of raltitrexed combinations with uracil-tegafur or Mitomycin C as salvage treatment in advanced colorectal cancer patients.

662 Background: Oxaliplatin and irinotecan in combination with 5-fluorouracil and leucovorin for metastatic colorectal cancer (mCRC) accepted as the standard treatment. There is no standard treatment approach for patients after progression with these agents. In this study aimed to evaluate the efficacy and side effects of patients with previously treated metastatic colorectal cancer a salvage combination with oral 5-fluorouracil (tegafur-uracil UFT) or Mitomycin C and Raltitrexed. Methods: In the 7 centers, data of 62 patients who received Raltitrexed 2.6 mg/m2 (max. 5 mg) (day 1) and UFT 500 mg/day (1-14. days), or Mitomycin C 6mg/m2 (day 1) every 3 weeks, with a diagnosis of metastatic colorectal cancer, between December 2008 and June 2013 has been analyzed retrospectively. Overall survival (OS), progression-free survival (PFS), and toxicity profiles were evaluated. Results: The median age of patients was 51 (min-max: 18-76 years), and 35 (56%) were male and 27 (44%) were female. Thirty nine patients (63%) had ECOG performance status 0 and 1. Four patients (10%) received a combination of UFT and Raltitrexed at the second line and 38 patients (90%) had third, fourth, and fifth lines. Otherwise Mitomycin C plus Raltitrexed protocol used at the second and third lines. Twelve patients (19%) developed grade 3/4 toxicities as diarrhea and fatigue and 13 patients (21%) needed to dose reduction. In all patients the median PFS was 3 months (%95 CI, 2,65–3,34) and the median OS was 6 months (%95 CI, 2,09–9,90). Two groups were evaluated separately; the median PFS was 3 months (%95 CI, 2,60–3,39) and median OS was 6 months (%95 CI, 2,47–9,53) in UFT arm and, the median PFS was 3 months (%95 CI, 1,64–4,35) and median OS was 12 months (%95 CI, 2,83–21,1) in Mitomycin C arm. Statistical significance could not be determined (p>0.05). Conclusions: Thecombination of Raltitrexed with UFT and Mitomycin C showed an acceptable survival time and toxicity in the treatment of patients with previously treated mCRC. It could be considered as a salvage treatment option in mCRC.

A dose-escalation study of oxaliplatin/capecitabine/irinotecan (XELOXIRI) and bevacizumab (bev) as a first-line therapy for patients with metastatic colorectal cancer.

612 Background: In a recent study by Loupakis, F. et al. (ASCO-GI 2013), a FOLFOXIRI and bevacizumab regimen showed promising activity and conversion rate in patients (pts) with metastatic colorectal cancer (mCRC). In order to evaluate a treatment regimen that was easier to administer, we conducted a dose-escalation study to determine the recommended dose (RD) of irinotecan (IRI) in combination with oxaliplatin and capecitabine and bevacizumab (XELOXIRI/bev) in pts with mCRC. Methods: Pts were eligible if they had mCRC (liver and/or other metastases), ECOG PS 0-1, were either negative or heterozygous for UGT1A1*6 or UGT1A1*28 and were not pretreated for metastatic disease. Treatment consisted of oxaliplatin (100 mg/m2 day 1), capecitabine (1700 mg/m2/day from day 2 to 15), IRI (100,120,150 mg/m2 for dose levels 1, 2, or 3, day 1) and bev (7.5 mg/kg, day 1), repeated every 3 weeks. The dose of IRI was escalated if dose limiting toxicities (DLT) were absent in the first three pts per cohort, or if <2 DLTs were observed in six pts. If the MTD was not reached at the planned dose levels, the RD of IRI was defined as 150mg/m2, which is the maximum dosage approved for use in Japan. Results: 12 pts (F/M: 4/8, median age: 58 years, PS 0/1: 11/1) received a median of 6 cycles of therapy (range 2-12). The DLT was grade 4 neutropenia, which was observed in 1 of 6 pts at dose level 2. MTD was not reached at dose level 3. Therefore, the RD of IRI was defined as 150 mg/m2. Most common grade ≥ 3 toxicities were neutropenia (58.3%), anemia (16.6 %), diarrhea (8.3%), and febrile neutropenia (8.3 %). The response rate was 83.3%(95% CI 60-89), including 1 CR, 9 PRs. The disease control rate was 100%(95% CI 80-100). At a median follow-up of 8 months, median PFS was 15 months and median OS was not yet reached. Conclusions: XELOXIRI/bev is a feasible regimen; neutropenia was the DLT; recommended dose of IRI is 150 mg/m². The observed response rate of 83.3% is very promising and warrants further investigation. Clinical trial information: UMIN000005440.

A randomized phase I/II study of everolimus, irinotecan, and cetuximab versus capecitabine and oxaliplatin in gemcitabine-resistant patients with pancreatic cancer.

337 Background: Little evidence exists on 2nd line therapy for gemcitabine resistant patients. The combination of oxaliplatin (Ox) and 5-FU has shown efficacy in small trials. We wanted to establish a tolerable dose of the combination of irinotecan, cetuximab and everolimus(ICE), and test it vs. the combination of capecitabine (Cap) and Ox in a randomized phase I/II setting. Methods: Patients were initially recruited in a 3+3 dose finding design with an expanded MDT cohort. After establishing MDT; patients were randomized between ICE (at MDT-1) and CapOx (Cap: 1250 mg/m2 BID and Ox: 70 mg/m2q14d). Patients that progressed could cross-over to the other arm. (NCT01042028). Results: Between January 2010 and November 2012, 40 patients were recruited. Due to DLT toxicity (mainly mucositis) at dose level 1 of the phase I trial, the protocol was amended and patients were treated at dose level -1. Ten patients were safely treated at this dose. The final dose for everolimus was 2.5 mg q1d, for irinotecan 180 mg/m2 q14d and 500 mg/m2q14d for cetuximab. At this dose level patients were randomized to either ICE or CapOx. Planned accrual was 90 patients, but due to the emergence of FOLFIRINOX and slow accrual, the study was terminated after randomization of 26 patients. One patient died before randomization. Median PFS for the ICE regime was 3.8 months (2.5-7.8), CapOx 3.5 (1.7-5.3) p=0.72. Median OS for ICE was 7.7 (4.5-11.8) and for CapOx 4.5 (2.2-7.4) p=0.04. Six patients crossed from CapOx to ICE, and 3 patients from ICE to CapOx upon progression. RR for ICE was 25% (5-57), CapOx 29% (8-58). Toxicity grade 3+ in the ICE regime was acne-like-rash (20%), fatigue (16%), infection (16%) and emboli (12%). CapOx was associated with grade 3+ neuropathy (21%), emboli (14%), pain (21%) and PPE (14%). Conclusions: The triple combination of ICE displayed similar PFS but significantly increased OS compared to CapOx. Both regimes displayed cancer activity with acceptable response rates. Toxicity was manageable. Due to early termination no solid conclusions can be drawn. Selected patients may benefit from dual-targeted therapy. Clinical trial information: NCT01042028.

Complete pathological response (ypT0N0M0) after preoperative chemotherapy alone for stage IV rectal cancer

BackgroundComplete pathological response occurs in 10–20% of patients with rectal cancer who are treated with neoadjuvant chemoradiation therapy prior to pelvic surgery. The possibility that complete pathological response of rectal cancer can also occur with neoadjuvant chemotherapy alone (without radiation) is an intriguing hypothesis.Case presentationA 66-year old man presented an adenocarcinoma of the rectum with nine liver metastases (T3N1M1). He was included in a reverse treatment, aiming at first downsizing the liver metastases by chemotherapy, and subsequently performing the liver surgery prior to the rectum resection. The neoadjuvant chemotherapy consisted in a combination of oxaliplatin, 5-FU, irinotecan, leucovorin and bevacizumab (OCFL-B). After a right portal embolization, an extended right liver lobectomy was performed. On the final histopathological analysis, all lesions were fibrotic, devoid of any viable cancer cells. One month after liver surgery, the rectoscopic examination showed a near-total response of the primary rectal adenocarcinoma, which convinced the colorectal surgeon to perform the low anterior resection without preoperative radiation therapy. Macroscopically, a fibrous scar was observed at the level of the previously documented tumour, and the histological examination of the surgical specimen did not reveal any malignant cells in the rectal wall as well as in the mesorectum. All 15 resected lymph nodes were free of tumour, and the final tumour stage was ypT0N0M0. Clinical outcome was excellent, and the patient is currently alive 5 years after the first surgery without evidence of recurrence.ConclusionThe presented patient with stage IV rectal cancer and liver metastases was in a unique situation linked to its inclusion in a reversed treatment and the use of neoadjuvant chemotherapy alone. The observed achievement of a complete pathological response after chemotherapy should promote the design of prospective randomized studies to evaluate the benefits of chemotherapy alone in patients with stages II-III rectal adenocarcinoma (without metastasis).

FOLFIRI as Second-line Chemotherapy after Failure of FOLFOX4 in Advanced Colorectal Cancer: A Korean Single-center Experience

The incidence of colorectal cancer has been increasing every year in Korea. Irinotecan- or oxaliplatin-based regimens including biologic agents are known to be effective in patients with advanced colorectal cancer. But in practice, FOLFOX (combination of oxaliplatin, 5-fluorouracil, and leucovorin) or FOLFIRI (combination of irinotecan, 5-fluorouracil, and leucovorin) regimens without biologic agents are more commonly used in Korea due to of the high costs of biologic agents. The aim of this study was to evaluate the efficacy and toxicity of FOLFIRI following FOLFOX4 in patients with advanced colorectal cancer. A total of 54 patients with advanced colorectal cancer who were treated between May 2005 and May 2013 with FOLFOX4 as first-line chemotherapy and with FOLFIRI as second-line chemotherapy at Kosin University Gospel Hospital (Busan, Korea) were reviewed retrospectively. A total of 54 patients received second-line FOLFIRI chemotherapy. Five patients (9.3%) had a partial response, 29 patients (53.7%) had a stable disease. The median overall survival was 8.90 months and the median time to progression was 4.33 months. Toxicities were tolerable. In a Korean population, FOLFIRI as second-line chemotherapy is effective and well tolerated in patients with advanced colorectal cancer after failure of FOLFOX4. Although the efficacy of FOLFIRI in this study was lower than that of second-line FOLFIRI with biologic agents, these results can help in the formulation of a treatment strategy for financially troubled patients.

TDP1/TOP1 Ratio as a Promising Indicator for the Response of Small Cell Lung Cancer to Topotecan.

Background and objectiveSmall cell lung cancer (SCLC) is one of the most challenging tumors to treat due to high proliferation rate, early metastatic dissemination and rapid development of chemotherapy resistance. The current treatment protocols involve the use of topoisomerase 1 (TOP1) poisons such as irinotecan and topotecan in combination with platinum-based compounds. TOP1 poisons kill cancer cells by trapping TOP1 on DNA, generating lethal DNA double-strand breaks. A potential mechanism employed by cancer cells to resist killing by TOP1 poisons is to overexpress enzymes involved in the repair of TOP1-DNA breaks. Tyrosyl DNA phosphodiesterase 1 (TDP1) is a key player in this process and despite its importance, no data is currently available to correlate TDP1 protein and mRNA levels with catalytic activity in SCLC. In addition, it is not known if TDP1 and TOP1 protein levels correlate with the cellular response of SCLC to TOP1 based therapies.Methods and resultsWe report a remarkable variation in TDP1 and TOP1 protein levels in a panel of SCLC cell lines. TDP1 protein level correlates well with TDP1 mRNA and TDP1 catalytic activity, as measured by two newly developed independent activity assays, suggesting the potential utility of immunohistochemistry in assessing TDP1 levels in SCLC tissues. We further demonstrate that whilst TDP1 protein level alone does not correlate with topotecan sensitivity, TDP1/TOP1 ratio correlates well with sensitivity in 8 out of 10 cell lines examined.ConclusionThis study provides the first cellular analyses of TDP1 and TOP1 in SCLC and suggests the potential utility of TDP1/TOP1 ratio to assess the response of SCLC to topotecan. The establishment and validation of an easy-to-use TDP1 enzymatic assay in cell extracts could be exploited as a diagnostic tool in the clinic. These findings may help in stratifying patients that are likely to benefit from TOP1 poisons and TDP1 inhibitors currently under development.

FOLFOX/FOLFIRI pharmacogenetics: the call for a personalized approach in colorectal cancer therapy.

While 5-fluorouracil used as single agent in patients with metastatic colorectal cancer has an objective response rate around 20%, the administration of combinations of irinotecan with 5-fluorouracil/folinic acid or oxaliplatin with 5-fluorouracil/folinic acid results in significantly increased response rates and improved survival. However, the side effects of systemic therapy such as myelotoxicity, neurotoxicity or gastrointestinal toxicity may lead to life-threatening complications and have a major impact on the quality of life of the patients. Therefore, biomarkers that would be instrumental in the choice of optimal type, combination and dose of drugs for an individual patient are urgently needed. The efficacy and toxicity of anticancer drugs in tumor cells is determined by the effective concentration in tumor cells, healthy tissues and by the presence and quantity of the drug targets. Enzymes active in drug metabolism and transport represent important determinants of the therapeutic outcome. The aim of this review was to summarize published data on associations of gene and protein expression, and genetic variability of putative biomarkers with response to therapy of colorectal cancer to 5-fluorouracil/leucovorin/oxaliplatin and 5-fluorouracil/leukovorin/irinotecan regimens. Gaps in the knowledge identified by this review may aid the design of future research and clinical trials.

A Phase I/II Trial of Irinotecan Plus Amrubicin Supported with G-CSF for Extended Small-cell Lung Cancer

This study reports the findings of a Phase I/II, cohort, dose-escalation trial of amrubicin and irinotecan with the support of granulocyte colony-stimulation factor. This study aimed to determine the dose-limiting toxicity of the combination and to define the maximum-tolerated dose, as a recommended dose for Phase II trials. We also sought to obtain preliminary data on the efficacy of this combination as a frontline therapy for extensive-disease small-cell lung cancer. We included 23 chemo-naïve patients with extensive-disease small-cell lung cancer in the trial. The amrubicin dose was escalated from 35 to 40 mg/m(2) (Levels 1 and 2, respectively) to determine the dose-limiting toxicity, with an unchanged dose of irinotecan at 50 mg/m(2). Of nine patients, three experienced dose-limiting toxicities at Level 1 of prolonged Grade 4 neutropenia, Grade 3 febrile neutropenia and Grade 3 febrile neutropenia with Grade 3 diarrhea. At Level 2, two patients experienced dose-limiting toxicities of Grade 4 neutropenia and Grade 3 neutropenia with Grade 4 diarrhea. The maximum-tolerated doses and recommended doses for amrubicin and irinotecan were therefore determined to be 35 and 50 mg/m(2), respectively. The Level 1 trial was then expanded to 21 patients, 14 (70%) of whom showed partial responses to the recommended dose. The median progression-free and overall survival times were 6.37 and 15.21 months, respectively. The combination of amrubicin and irinotecan with the support of granulocyte colony-stimulation factor produced a potent effect in chemo-naïve extensive-disease small-cell lung cancer patients. The use of biomarkers for this regimen may identify patients who are likely to suffer from treatment-ending severe adverse effects.

Abstract OT3-1-08: The PROCEED trial KCSG BR11-01: Phase III multicenter randomized open label study of irinotecan plus capecitabine versus capecitabine in patients previously treated with anthracycline and taxane for HER2 negative metastatic breast cancer

Abstract Background: Most patients with metastatic breast cancer (MBC) experience disease progression after being treated with an anthracycline or taxane. Irinotecan, a semisynthetic agent derived from the natural alkaloid camptothecin is metabolized to the active metabolite SN-38 which targets topoisomerase I leading to single and double strand DNA breaks. Irinotecan as a single agent demonstrated tumor activity with an objective response rate ranging from 5 to 23% in patients with MBC refractory to taxane and anthracycline. Irinotecan increased the activity of 5-FU, the active metabolite of capecitabine, and overcomes the negative effect of thymidylate synthase overexpression, which is the main target of an active metabolite of 5-FU. A phase II study that evaluated the efficacy and safety of irinotecan and capecitabin combination (IX) showed that the median progression free survival (PFS) was 7.6 months (95% CI, 5.0-10.2months), and the median OS was 22.6 months (95% CI, 15.4 – 29.8 months) with good tolerability in anthracycline and taxane pretreated MBC patients. Based on these results, we planned to conduct a multicenter, randomized phase III study which assesses the efficacy of irinotecan and capecitabine combination therapy compared with capecitabine alone in patients with anthracycline and taxane resistant MBC. Methods: In this trial, patients with HER2 normal tumor who previously received anthracycline and taxane based chemotherapies are enrolled. Eligible patients are randomly assigned in a 1:1 ratio to receive irinotecan plus capecitabine or capecitabine alone. The primary end point of this trial is PFS and a total number of accrual patients will be 222. Randomization is done using a random block size permutation method and stratified by hormone receptor status (negative vs. positive), first line vs. ≥second lines, visceral metastasis (negative vs. positive). Patients receive irinotecan at 80 mg/m2 on day 1 and 8 every 3 weeks and capecitabine 1000mg/m2 bid from day 1 to day 14 every 3 weeks. In control arm, patients receive capecitabine 1250mg/m2 bid from day 1 to day 14 every 3 weeks. Response will be assessed using RECIST1.1 criteria and toxicity will be graded according to NCI-CTCAE 4.0 criteria. Study Status: A total of 107 patients consented for the study since June 2011, and accrual is ongoing. Clinical trial information: NCT01501669. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-1-08.

Panitumumab Monotherapy Compared with Cetuximab and Irinotecan Combination Therapy in Patients with Previously Treated KRAS Wild-Type Metastatic Colorectal Cancer

The survival benefit for single-agent anti-epidermal growth factor receptor (egfr) therapy compared with combination therapy with irinotecan in KRAS wildtype (wt) metastatic colorectal cancer (mcrc) patients in the third-line treatment setting is not known. The objective of the present study was to describe the characteristics of, and to compare survival outcomes in, two cohorts of patients treated with either singleagent panitumumab or combination therapy with cetuximab and irinotecan. The study enrolled patients with KRAS wt mcrc previously treated with both irinotecan and oxaliplatin who had received either panitumumab or combination cetuximab-irinotecan before April 1, 2011, at the BC Cancer Agency (bcca). Patients were excluded if they had received anti-egfr agents in earlier lines of therapy. Data were prospectively collected, except for performance status (ps), which was determined by chart review. Information about systemic therapy was extracted from the bcca Pharmacy Database. Of 178 eligible patients, 141 received panitumumab, and 37 received cetuximab-irinotecan. Compared with patients treated with cetuximab-irinotecan, panitumumab-treated patients were significantly older and more likely to have an Eastern Cooperative Oncology Group (ecog) ps of 2 or 3 (27.7% vs. 2.7%, p = 0.001). Other baseline prognostic variables and prior and subsequent therapies were similar. Median overall survival was 7.7 months for the panitumumab group and 8.3 months for the cetuximab-irinotecan group. Multivariate analysis demonstrated that survival outcomes were similar regardless of the therapy selected (hazard ratio: 1.28; p = 0.34). An ecog ps of 2 or 3 compared with 0 or 1 was the only significant prognostic factor in this treatment setting (hazard ratio: 3.37; p < 0.01). Single-agent panitumumab and cetuximab-irinotecan are both reasonable third-line treatment options, with similar outcomes, for patients with chemoresistant mcrc.

O1–137 - PHASEII Study of S-1 with Irinotecan Combination Therapy for EGFR-Mutated NSCLC Resistant to EGFR-TKI: NJLCG0804

Backgroud: Basic experiments showed high sensitivity offluoropyrimidine agent to EGFR-TKI resistant cell-line and the synergistic effect of S-1 (a novel oral fluorouracil derivative) and irinotecan combination. We therefore conducted a phase II trial to evaluate the efficacy and safety of S-1 and irinotecan combination for EGFR-mutated NSCLC resistant to both platinum-based chemotherapy and EGFR-TKI. Methods: Eligible patients (pts) had NSCLC with EGFR mutation, ECOG performance status (PS) 0 to 1, failure of EGFR-TKI following one or two