bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized, phase II study of two doses of pemetrexed as first-line chemotherapy for locally advanced or metastatic breast cancer (MBC): Clinical results and exploratory pharmacogenomic analysis
Authors: Llombart-Cussac A. , Martin M. , Harbeck N. , Anghel R. , Eniu A. , Melemed A. , Clark R. , Simms L. , Kaiser C. , Ma D.
Published: March 2020

3077

Background: Pemetrexed, a folate antimetabolite, has shown varied response in MBC, depending on the dose, vitamin supplementation, and patient pre-treatment status. We conducted a randomized, double-blind, phase II study, in patients with locally advanced or MBC to evaluate 2 doses of pemetrexed. Primary objective was to assess the response rates on the 2 arms. Methods: Women with histologic/cytologic diagnosis of breast cancer, evidence of locally recurrent disease or distant metastasis, not amenable to local therapy were eligible. Patients received pemetrexed (600 mg/m2 Arm A; or 900 mg/m2 Arm B), on D1 of a 21-day cycle. All patients received folic acid and vitamin B12 supplementation. Forty-three patients were planned on each arm. Results: Ninety-two patients (median age 57 years, range 33–81) enrolled: 47 on arm A and 45 on arm B. Arms A and B had response rates of 17.0% (95% CI, 7.7%-30.8%), and 15.6% (95% CI, 6.5%-29.5%), median progression free survival times of 4.2 and 4.1 months, and median times to tumor progression (TtTP) of 4.2 and 4.6 months, respectively. On both arms, a median of 6 cycles was delivered. Toxicity was mild (grade 3/4 toxicity on both arms; neutropenia <20%, leucopenia <9%). Primary tumor samples from 49 patients were assessed for 10 folate or pyrimidine metabolism related gene expressions by reverse transcriptase-polymerase chain reaction methodology. Two markers, folypolyglutamate synthase (FPGS) and thymidine phosphorylase (TP), showed significant results. Best response rates and median TtTP for high vs low FPGS expression subgroups were 37.5% vs 10.0% and 8.6 vs 3.0 months. The corresponding results for TP were 27.6% vs 6.3% and 5.4 vs 1.9 months. Conclusions: Efficacy and safety of the two pemetrexed doses were similar; thus, the lower dose (600 mg/m2) is suitable in patients with MBC. Exploratory biomarker analysis suggests efficacy correlation for FPGS and TP. Further evaluation of these markers appears warranted.

[Table: see text]
Lack of association with epidermal growth factor receptor gene polymorphisms with clinical outcome in patients with advanced colorectal cancer treated with platinum-based chemotherapy
Authors: Park D. J. , Zhang W. , Gordon M. , Yang D. Y. , Ladner R. , Iqbal S. , Groshen S. , Vallbohmer D. , Lenz H. , Fazzone W.
Published: March 2020

3079

Background: We had previously shown an association between functional polymorphisms of the epidermal growth factor receptor gene and clinical outcome to platinum-based chemotherapy in advanced colorectal cancer in a retrospective study. Specifically, patients with <20 CA repeats in intron-1 of the EGFR gene were shown to have increased risk of disease progression. Here in, we report our findings of a confirmatory prospective study. Methods: Between September 2001 and August 2004, 173 patients with advanced refractory colorectal cancer were enrolled. Patients received 5-FU 200 mg/m2/day as continuous infusion and oxaliplatin 130 mg/m2, in three week cycles. Blood samples for genomic analysis were available for 152 patients. EGFR intron 1 CA-repeat and HER1- R497K polymorphisms and their relationship with clinical response, time-to-progression, overall survival, and toxicity, either alone or in combination were assessed prospectively. In addition, we were able to perform quantitative gene expression analysis of EGFR through RT-PCR in a subset of 58 patients. Results: Our cohort of 152 patients comprised 78 males and 74 females, with a median age of 60. There were 105 Caucasians, 24 Asians, 5 Blacks, and 18 Hispanics. The median number of cycles received was 5. The median survival was 10.3 months with a median follow-up of 18.6 months. There were 28 responders (19%). Asians were more likely to possess longer CA repeats and the HER1- 497K variant (Fisher’s exact test p<0.05). Neither EGFR intron-1 CA repeat nor the HER1- R497K polymorphisms were associated with clinical response, time-to-progression, overall survival, toxicity (p>0.10). EGFR gene expression was not associated with clinical outcome (p>0.10). Shorter EGFR intron-1 CA repeats (<20) was associated with higher EGFR gene expression (Kruskal-Wallis t test p=0.013)Conclusion: We were not able to confirm prospectively a previously reported association between functional EGFR gene polymorphisms and clinical outcome to platinum-based therapy in patients with advanced colorectal cancer. In-vitro studies assessing differential oxaliplatin sensitivity with respect to EGFR expression are on-going.

[Table: see text]
Phase I clinical trial of CX-3543, a pro-apoptotic antitumor agent
Authors: Marschke R. F. , Ricart A. D. , Von Hoff D. D. , Lim J. K. , Papadopoulos K.
Published: March 2020

3082

Background: CX-3543 is a novel small molecule specifically designed to target three dimensional nucleic acid motifs, and thus induce apoptosis in cancer cells. Preclinically, CX-3543 demonstrated potency in suppressing xenograft tumor growth with a broad therapeutic window. The objectives of this phase I study are: to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs), to establish the pharmacokinetics (PKs), and to determine the recommended dose for further clinical development of CX-3543. Methods: Eligible patients with advanced solid tumors or lymphomas whose tumors progressed on standard therapy or for whom there are no standard therapies receive CX-3543 in successive dose cohorts at: 10, 20, 40, 80 and 160 mg/m2. Dosing is by one hour intravenous infusion daily for five consecutive days repeated on a three week cycle. Therapy is continued until the patient shows signs of intolerance to CX-3543 or evidence of advancing disease. Response by RECIST criteria is determined after every 2 cycles. Results: Ten patients with solid tumors (3–4 per cohort) have received intravenous CX-3543. Doses have been well tolerated. Seven grade 3 adverse events have been reported during the study, but none of these are related to CX-3543. To date no objective responses have been observed. One patient with advanced refractory prostate cancer has stable disease of longer than 4 months duration. CX-3543 has demonstrated good linearity in PK parameters between the dose cohorts with a terminal half life of approximately 12 hours following the first dose. Conclusions: To date, CX-3543 has shown no drug related toxicity and has predictable PKs. No DLTs have yet been observed, and the MTD remains to be defined in this Phase I study. Further enrollment to the planned dose escalation cohorts is ongoing.

[Table: see text]
Optimal dose of cetuximab (C) given every 2 weeks (q2w): A phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of weekly (q1w) and q2w schedules in patients (pts) with metastatic colorectal cancer (mCRC)
Authors: Tabernero J. , Cervantes A. , Martinelli E. , Vega-Villegas E. , Rojo F. , Pérez-Fidalgo A. , Casado E. , Ciardiello F. , Zubel A. , Baselga J.
Published: March 2020

3085

Background: The anti-EGFR Mab C is active in mCRC. Since C has a long terminal half-life and it is frequently given in combination with q2w chemotherapy, we decided to compare the safety and PK/PD of a more convenient q2w schedule with the currently approved q1w schedule in pts with EGFR-expressing mCRC. Methods: In this study C was given q2w at the standard q1w regimen (400 mg/m2 initial dose and 250 mg/m2 weekly) to 10 pts as a comparator. In the experimental arm, C was given q2w with a dose escalation in sequential steps for cohorts of 10 pts each (400, 500, 600 & 700 mg/m2). Dose levels were escalated if no dose-limiting toxicities (DLTs) were observed. DLTs were defined as grade 3–4 toxicities (except for hypersensitivity reactions and grade 3 skin toxicity), and/or administration of less than 66% of the assigned dose due to toxicity. In order to conduct the PK/PD studies, all treatment groups were given C alone for 6 weeks and subsequently, the FOLFIRI regimen was added. Complete PK profile was obtained during the initial 6 weeks of treatment. Skin and tumor biopsies for PD profiling were obtained prior to therapy and on day 28 (steady state) and have been analyzed by IHC for total (t) and phospho (p)-EGFR, p-MAPK, p-Akt, proliferation (Ki67) & p27 expression. Results: 29 pts have been included so far: 9 in the q1w group and 20 in the q2w group (10 pts each at 400 and 500 mg/m2). To date there have been no DLTs. PK data are predictable (Cmin, AUC) and comparable (t1/2, CLss) between both regimens (see table below). Preliminary skin PD studies show no major difference in the EGFR-signaling inhibition by C in the q1w and q2w regimens. Conclusions: C can be safely administered in a q2w regimen at 400 and 500 mg/m2. The MTD of q2w C has not yet been reached and dose escalation is ongoing. Our findings show no major difference in PK and PD profiles with the q1w and q2w schedules. C given q2w may be an alternative and convenient schedule of administration.

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[Table: see text]
Clinical pharmacokinetics (PK) of AMN107, a novel inhibitor of Bcr-Abl, in healthy subjects and patients with imatinib resistant or intolerant chronic myelogenous leukemia (CML) or relapsed/refractory Ph+ acute lymphocytic leukemia (Ph+ALL)
Authors: Tanaka C. , Smith T. , Kantarjian H. , Giles F. , Ottmann O. , Bhalla K. , Grouss K. , Sethuraman V. , Thomas K. , Schran H.
Published: March 2020

3095

Background: AMN107, a selective and potent inhibitor of Bcr-Abl tyrosine kinase, has demonstrated activity against imatinib resistant forms of Bcr-Abl in patients with CML or Ph+ALL in a phase I study. This study characterizes clinical PK of AMN107 for the safe and effective use of the drug. Methods: Serum samples were collected in 119 patients with CML or Ph+ALL treated with once (QD) or twice daily (BID) oral AMN107 (doses of 50 to 1200 mg/day). PK parameters were derived from serum concentration-time data by non-compartmental methods. In separate multi-period crossover studies 92 healthy subjects were treated with single doses of AMN107 to assess the food effect on PK, and to assess the potential for drug-drug interactions with medications which inhibit (ketoconazole) or are metabolized by CYP3A4 (midazolam). Results: Steady-state AMN107 PK in patients were stable over time, and showed a dose-dependency with less than dose-proportional increases in systemic exposure at dose levels higher than 400 mg QD. Daily exposure at 400 mg BID, which maintains serum AMN107 levels at least 30 times higher than the IC50 of cellular phosphorylation of Bcr-Abl, was greater than at 800 mg QD. The effective half-life was 15 hours. Bioavailability of AMN107 administered with a high-fat meal was increased by 82% compared to fasting. CYP3A4 inhibition by concomitantly administered ketoconazole produced 3-fold increases in systemic exposure to AMN107, whereas AMN107 appeared a weak inhibitor of CYP3A4 with 30% increase in systemic exposure of midazolam given concomitantly. Conclusions: Systemic AMN107 levels at an oral AMN107 dose of 400 mg BID in patients with CML or Ph+ALL were well above the IC50 of Bcr-Abl. The food/drug interaction results provide further guidance for the safe use of AMN107 in the clinical setting.

[Table: see text]
Response rate using conventional criteria is a poor surrogate for clinical benefit on progression-free (PFS) and overall survival (OS) in metastatic colorectal cancer (mCRC): A comparative analysis of N9741 and AVF2107
Authors: Grothey A. , Hedrick E. E. , Mass R. D. , Sarkar S. , Ramanathan R. K. , Hurwitz H. , Goldberg R. M. , Sargent D. J.
Published: March 2020

3516

Background: A previous report noted that patients (pts) in the phase III study of IFL ± BV who received BV had significantly longer PFS and OS regardless of whether or not they responded according to RECIST criteria (Mass et al, ASCO 2005). It is unclear if this phenomenon is specific to the addition of a biologic to chemotherapy (CT) or a more general benefit from improved therapy since it has been suggested that stable as well as responding disease is beneficial for pts. We repeated the analysis of Mass et al on pts enrolled in N9741, a study which established the superiority of FOLFOX over IFL and contained no biologic compound. Methods: For this retrospective analysis, pts were defined as ‘responders‘ or ‘nonresponders‘ according to whether criteria for complete or partial response (by RECIST -AVF2107g or WHO criteria -N9741) were either achieved (responders) or not achieved (nonresponders). PFS and OS were estimated from Kaplan-Meier curves; hazard ratios (HR) for progression and death in each subgroup were estimated by Cox regression. Results: In both trials, response was associated with superior outcome. However, statistically significant improvements in PFS and OS were observed in both responders and non-responders treated with either IFL + BV or FOLFOX versus IFL, and the magnitude of improvement was similar regardless of response ( Table ). Conclusions: Analysis of two large recent mCRC phase III trials clearly demonstrate that pts who do not achieve a response according to traditional criteria still have significant benefit from the superior regimen, with a similar magnitude of benefit for responders and non-responders, regardless if the regimen called for CT alone or included the antiangiogenic biologic BV. These data support the conclusion that PFS and the percentage of pts experiencing tumor control may more accurately reflect pt benefit than does response rate in phase III trials in mCRC.

[Table: see text]

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Efficacy and safety of bevacizumab in combination with irinotecan and infusional 5-FU as first-line treatment for patients with metastatic colorectal cancer
Authors: Sobrero A. , Ackland S. , Carrion R. P. , Chiara S. , Clarke S. , Giron C. G. , Langer B. , Zurlo A. , Young S.
Published: March 2020

3544

Background: Bevacizumab is a monoclonal antibody that, by inhibiting VEGF, inhibits tumour angiogenesis. It has been proven to improve overall (OS) and progression-free survival (PFS) when administered first-line in combination with the bolus 5-FU-based IFL regimen to patients with metastatic colorectal cancer [Hurwitz et al. NEJM 2004;350:2335–42]. We have conducted a multicentre, open-label trial to further evaluate the efficacy and safety of first-line bevacizumab in combination with regimens combining irinotecan with infusional 5-FU (FOLFIRI). Methods: Eligible patients had: metastatic colorectal cancer; no surgery within 28 days; no prior chemotherapy for metastatic disease; ECOG PS 0/1; adequate organ function; no CNS metastases. Chemotherapy consisted of 6 cycles of irinotecan plus infusional 5-FU and leucovorin, according to the classical FOLFIRI regimen; however, such variations as the simplified FOLFIRI or the weekly regimen were allowed. Bevacizumab 5mg/kg was given on day 1 of chemotherapy, every 2 weeks until disease progression. Safety assessments were made at the time of chemotherapy administration during the first 12 weeks and every 4 weeks thereafter. Tumour assessments were performed every 3 months for the first year and 4-monthly thereafter. The primary objective was PFS; secondary objectives were to evaluate the safety profile of this combination as well as to determine the overall response rate, time to response, duration of response and OS. Results: A total of 209 patients were enrolled at 31 centres in Australia, Canada, Italy, Spain and China between April 2005 and November 2005. 60% of patients were male and median age was 61.9 (range 31–82) years. All patients will be eligible for interim analysis, that will be performed after the last patient enrolled has been followed for a minimum of 12 weeks (6 cycles of chemotherapy), in February 2006. Data on safety and efficacy from this analysis will be presented. Conclusions: This is the largest clinical trial that will report efficacy and safety data for bevacizumab in combination with an irinotecan and infusional 5-FU regimen.

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MABEL—A large multinational study of cetuximab plus irinotecan in irinotecan resistant metastatic colorectal cancer
Authors: Wilke H. , Glynne-Jones R. , Thaler J. , Adenis A. , Preusser P. , Aranda Aguilar E. , Aapro M. , Van Den Berg N. , Eggleton S. , Siena S.
Published: March 2020

3549

Background: Cetuximab is an IgG1 anti-EGFR monoclonal antibody, active alone and in combination with irinotecan in metastatic colorectal cancer (mCRC) patients (pts) who failed irinotecan (Cunningham et al, NEJM 2004). MABEL investigated cetuximab plus irinotecan in an uncontrolled, multicenter study in pts with EGFR-detectable mCRC whose last treatment regimen contained irinotecan. MABEL is to date the largest cetuximab study published in this setting. Methods: Primary endpoint was the progression-free survival (PFS) rate at 12 weeks (wks), (expected rate 50% ± 3%). Study treatment was cetuximab, initial dose 400 mg/m2, weekly 250 mg/m2, plus irinotecan with dose and schedule as pre-study: Regimen A: 125 mg/m2 weekly for 4/6 wks, B: 180 mg/m2 q 2 wks, or C: 350 mg/m2 q 3 wks. Results: 197 centers from 7 countries screened tumors of 1681 pts for EGFR expression: 1461 (87%) pts had EGFR-detectable tumors. 1123 pts are currently evaluable: median age is 62 years (25–84), Karnofsky status ≥70% in all pts, and 64% pts were male. 64% pts had ≥ 2 prior therapy lines. 76% pts were also pretreated with oxaliplatin. On-study distribution of pts to irinotecan regimens was A: 92, B: 674, C: 357. 12-week PFS rates were: A: 60% (50–71%); B: 60% (56–64%); C: 63% (58–68%); overall: 61% (58–64%), and at 24 wks: A: 29% (19–39%); B: 32% (28–36%); C: 39% (34–45%); overall 34% (31–37%). The current estimate of median survival, based on 717 deaths, is 9.2 (8.7–9.9) months. Treatment was generally well tolerated with grade 3/4 adverse events >5%: diarrhea 20%, skin and subcutaneous tissue disorders incl. acne-like rash 19%, neutropenia 9%, asthenia 8%. Grade 3/4 immune system disorders incl. hypersensitivity reactions occurred in 1.5%, hypomagnesemia in 0.4% pts. Conclusions: The PFS rates observed in this heavily pretreated population fully met the primary endpoint of this study. Similar PFS rates were seen at 12 weeks (overall 61%) and 24 weeks (overall 34%) for all irinotecan regimens. Estimated survival time is in line with previously published results. MABEL clearly confirmed in a wider setting the efficacy and safety of cetuximab plus irinotecan seen in previous studies.

[Table: see text]
Phase I study of preoperative cetuximab, capecitabine, and external beam radiotherapy in patients with rectal cancer
Authors: Machiels J. P. , Sempoux C. , Scalliet P. , Coche J. C. , Coster B. , Canon J. L. , Kerger J. , Van Cutsem E. , Peeters M. , Haustermans K.
Published: March 2020

3552

Background: Capecitabine has the potential to replace 5-FU as standard agent in combination with radiotherapy in rectal cancer. Cetuximab is a monoclonal antibody directed against the epidermal growth factor receptor. Both agents are active in the treatment of colorectal cancer and have demonstrated radiosensitising properties. The aim of this study was to assess the feasibility of combining cetuximab and capecitabine with concurrent radiation in the preoperative treatment of patients with rectal cancer. Methods: Twenty patients with rectal cancer (T3-T4 and/or N+, endorectal ultrasound) received radiotherapy (1.8 Gy, 5 days a week over 5 weeks, total dose 45 Gy, 3D conformal technique) in combination with cetuximab (initial dose 400 mg/m2 given one week before the beginning of radiation followed by 250 mg/m2/week for 5 weeks) and 2 different doses of capecitabine for the duration of radiotherapy (650 mg/m2 twice-daily, first dose level; 825 mg/m2 twice-daily, second dose level, including weekends). During treatment all patients were scored weekly using the NCI-CTC v.2.0. Dose-limiting toxicity (DLT) was defined acccording to Dunst (JCO 2002). Six to 8 weeks after the end of chemoradiation surgery was performed. Results: Four and six patients were treated at the first and second dose level of capecitabine, respectively. No DLT occurred at either capecitabine dose. Ten additional patients were treated at the higher dose level. Out of these 20 patients, Grade 3 toxicity included diarrhea (n=2), rectal pain (n=5), ileitis (n=2), radiation dermatitis (n=1) and neutropenia (n=1). The most frequent grade 1/2 side effects were acneiform rash (n=16, 80%), fatigue (n=12, 60%), and diarrhea (n=12, 60%). Until now, 2 pathological complete responses were observed in 19 evaluable patients. Conclusions: Preoperative radiotherapy in combination with capecitabine and cetuximab is feasible and well-tolerated with promising efficacy results. The recommended doses for phase II evaluation are capecitabine 825 mg/m2 twice-daily without interruption during the duration of radiotherapy and cetuximab at an initial dose of 400 mg/m2 followed by 250 mg/m2/week.

No significant financial relationships to disclose.
Cetuximab with irinotecan in first-line treatment of epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer (mCRC): Preliminary safety results (CRYSTAL)
Authors: Lang I. , Zaluski J. , Changchien C. R. , Makhson A. , Pinter T. , D’Haens G. , Lim R. , Nippgen J. , Van Cutsem E.
Published: March 2020

3555

Background: Cetuximab is an IgG1 monoclonal antibody targeting the EGFR with proven activity in previously treated mCRC patients (pts). The modified two-weekly de Gramont regimen of irinotecan with infusional 5-fluorouracil (5-FU)/folinic acid (FA) (FOLFIRI) is a standard for metastatic disease. This randomized trial investigates the effectiveness of cetuximab with this chemotherapy combination versus chemotherapy alone in (pts) with EGFR-expressing mCRC previously untreated for metastatic disease. Methods: This phase III trial compares cetuximab (400 mg/m2 week 1 then 250 mg/m2 weekly) added to FOLFIRI (irinotecan 180 mg/m2, FA 400 mg/m2, 5-FU bolus 400 mg/m2, 2400 mg/m2 infusional 5-FU) (group A) vs. FOLFIRI alone (group B) in pts with EGFR-detectable tumors. 1080 pts are planned to detect a difference of ≥ 2 months in PFS with 80% power. The Data Safety Monitoring Board (DSMB) has performed an independent preplanned safety evaluation of 401 treated pts. Results: Pts (M/F 252/149, median age 62 years [range, 19–84], ECOG performance status [PS]: PS0, 57.1%: PS1, 38.4%: PS2, 4.5%) received at least 3 treatment cycles to date. Of the 401 pts, 83 (20.7%) pts completed/discontinued the trial. There were 11 deaths (2.7%) within 30 days of the last study treatment: 5 related to disease, 3 to chemotherapy, and 3 other (2 unknown, 1 intercurrent illness). Most common adverse events of the pooled safety data were skin reactions, diarrhea and nausea. Conclusions: After review of all relevant safety information by the DSMB, the trial continues. Recruitment was completed with 1220 patients in December 2005.

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[Table: see text]
FOLFOX-4 + cetuximab in untreated patients with advanced colorectal cancer. A phase II study of the Gruppo Oncologico dell’Italia Meridionale (prot. GOIM 2402)
Authors: Colucci G. , Giuliani F. , Mattioli R. , Garufi C. , Mallamaci R. , Pezzella G. , Lopez M. , Maiello E.
Published: March 2020

3559

Background: Cetuximab is an IgG monoclonal antibody targeting the EGFR showing to be effective both as single agent or in combination with Irinotecan (CPT-11) or Irinotecan/FU/FA in patients (pts) with EGFR-expressing metastatic colorectal cancer (CRC) in the first and second/subsequent-line setting. The current trial was designed to evaluate the efficacy and the safety of Cetuximab plus Folfox-4 as first -line treatment. The main objective was the percentage of confirmed objective response rate. Methods: Chemonaivepts with non-resectable metastatic CRC and expressing EGFR were treated with Cetuximab (400 mg/m2 week 1 and 250 mg/m2 weekly thereafter) plus Folfox-4 (every 2 weeks: Oxaliplatin 85 mg/m2, day 1; FA 100 mg/m2 2h, simultaneously with OH-P, and FU 400 mg/m2 iv bolus followed by 600 mg/m2 iv for 22h on days 1 and 2). The first evaluation of disease status (Recist criteria) was performed after the first 4 cycles and confirmed after one month. The treatment was continued until a maximum of 12 cycles of chemotherapy; the maintenaice with Cetuximab was permitted. Preliminary results: On the 65 screened pts, 47 (72%) had EGFR-expressing metastatic disease and were enrolled. Their main characteristics were: median Ecog PS 0; median age 66 yrs (range 43–74); main sites of disease: liver 31, lung 12, lymph-nodes 3, others 8. To date twenty-two pts are evaluable for activity and 27 for toxicity; 2 pts are not evaluable and 25 are too early. We observed 16 PR (72.7%), 5 NC (22.7%) and 1 PD (4.6%) for an ORR of 72.7% and a TGCR of 95.4%; the confirmed PR were 15 (68%). To date 2 pts undergone surgery of their metastases both for lung. The main adverse events grade 3/4 (NCI criteria) were: acne-like rush 18.5%, diarrea 7%, nausea/vomiting 4% and anemia 4%. Conclusions: Our preliminary results confirm that the combination of Cetuximab plus Folfox-4 has an high activity and a good safety profile in advanced CRC pts. The study is ongoing.

No significant financial relationships to disclose.
Epidermal growth factor gene amplification is not frequent and cannot account for antitumor activity of cetuximab plus chemotherapy in advanced colorectal cancer patients
Authors: Garufi C. , Mottolese M. , Cianciulli A. , Zeuli M. , Buglioni S. , Torsello A. , Vanni B. , Campanella C. , Merola R. , Terzoli E.
Published: March 2020

3561

Cetuximab has been shown to be active in the metastatic colorectal cancer, but EGFR detection by immunohistochemistry is not predictive for tumor response. Moroni et al (Lancet Oncology 2005) showed that, in patients responsive to Cetuximab, EGFR gene copy number, assessed by FISH, was increased. On this basis, copy number and protein status of EGFR were investigated in 70 primary and/or metastatic colorectal carcinomas. Protein expression was assessed by immunohistochemistry (IHC) using DAKO EGFRPharmDX kit. Gene and chromosome 7 copy numbers were identified by fluorescent in situ hybridization (FISH). Dual-target, dual-color FISH assays were performed using the LSI EGFR SpectrumOrange/CEP 7 Spectrum Green probe. EGFR gene copy number, chromosome 7 copy number and the average EGFR gene to chromosome 7 signal ratio were reported as FISH genetic variables. Chromosome 7 was polysomic when cancer cells showed multiple centromere signals: low polysomy (2 to 5 signals), high polysomy (>5 signals). Samples with a ratio value ≥ 2.0 were considered to be amplified. EGFR protein was overexpressed in 57 out of 70 patients (81%). In the group of 58 patients evaluated as polysomic, 48 (82,7%) had a low polysomy level, whereas 20 (12.7%) had a high polysomy level. Gene amplification was seen only in 3/70 patients. High polysomy was evidenced only in the group of patients displaying an EGFR IHC score 2+/3+. Forty-six pretreated patients received a cetuximab-based treatment. Response to treatment has been already evaluated in 26 FISH-negative patients while for the other 20 it is still too early. We observed 7 PR (27%), 9 SD (35%) and 10 PD (38%). This study shows that in this series of advanced colorectal cancer patients, EGFR amplification, measured by FISH, is a rare event (4%) and could be considered together with chromosome 7 polysomy for the antitumor activity.

No significant financial relationships to disclose.
Angiogenesis modifications are predictive of response and outcome in heavily pretreated advanced colorectal cancer patients during therapy with cetuximab plus irinotecan
Authors: Vincenzi B. , Santini D. , Russo A. , Dicuonzo G. , Michele G. , Battistoni F. , Avvisati G. , Rocci L. , Gebbia N. , Tonini G.
Published: March 2020

3562

Background: Angiogenesis has been correlated with increased invasion and metastases in a variety of human neoplasms. Inadequate inhibition of the growth of tumor microvessels by anticancer agents may result in treatment failure, rated clinically as progressive or stable disease. We designed this trial to investigate if Vascular Endothelial Growth Factor (VEGF) circulating levels modifications may be related with clinical response and outcome in advanced colorectal cancer patients during treatment with a weekly combination of cetuximab plus irinotecan. Methods: 45 heavily pretreated metastatic colorectal cancer patients were prospectively evaluated for circulating levels of VEGF during the treatment with cetuximab (initial dose of 400 mg per square meter, followed by weekly infusions of 250 mg per square meter) plus weekly irinotecan (90 mg per square meter). VEGF circulating levels were assessed at the following time-points: just before and at 1, 21, 50 and 92 days after the start of cetuximab plus irinotecan treatment. Results: Basal serum VEGF median levels were significantly decreased just at the first day (after the first treatment infusion (P=0.016). The VEGF persisted at the following time points reaching the highest statistical significance 92 days after the first infusion (P<0.0001). Twenty-two patients showed a reduction in median VEGF circulating levels of at least 50% 92 days after the first infusion respect to the basal time point. In the group of patients with at least 50% reduction of VEGF levels the response rate was 59.1% vs 21.7% in the non reduced VEGF group (P=0.024). Moreover, the median time to progression was 6.12 months (95% C.I.: 3.9 - 7.1) in the reduced VEGF group vs 2.3 months (95% C.I.: 1.6 - 3.5) in the other patients (P=0.001). Finally, also overall survival was longer in patients who developed VEGF reduction (12.3 months; 95% C.I.: 8.65 - 15.9) than this recorded in patients without the reduction (6.4 months; 95% C.I.: 5.6 - 8.4) (P=0.05). Conclusions: The present data represent the first evidence that suggest a role of VEGF reduction in the prediction of efficacy of treatment with cetuximab plus weekly irinotecan in heavily pretreated advanced colorectal cancer patients.

No significant financial relationships to disclose.
Folinic acid modulated bolus 5-FU or infusional 5-FU for adjuvant treatment of patients of UICC stage III colon cancer: Preliminary analysis of the PETACC-2-study
Authors: Carrato A. , Köhne C. , Bedenne L. , Popov I. , Bouche O. , Gaspar E. , Rougier P. , Schubert U. , Biertz F. , Becker H.
Published: March 2020

3563

Background: Patients with stage III colon cancer have a high risk for recurrence. Infusional 5-FU may be more active than bolus application. Methods: From 01/1997 to 03/2004 a total of 1601 patients with UICC stage III colon cancer were randomized to receive the Mayo-Clinic regimen or infusional 5-FU either the weekly high dose AIO regimen, the bi-weekly LV5FU2 regimen or the Spanish weekly high dose TTD-regime. The major aim of this study was to demonstrate a difference of 7 % in the 5 year survival rate in favour of the infusional arm for which a total of 424 events were required. Results: After a median follow-up of 31 months 478 events have occurred. 804 patients received the standard arm and 797 the experimental arm (AIO N=331, EORTC N=92, FFCD N=211, TTD N=163). The median age was 64 years; patients were well distributed according to TNM-category (T3 73 vs. 75%, T4 17 vs. 16%, N2 31 vs. 34%), vascular and lymphatic invasion and grading. The bolus regimen induced a higher rate of grade 3 or 4 leukopenia (7.1% versus 2.0%), stomatitis grade 3 or 4 (9.8% versus 3.3%) or diarrhea grade 3 or 4 (16% vs. 15%). Hand-Foot-Syndrome was more frequent in the experimental arm (4.4% versus 0.4%). There was no difference in the recurrence free survival at 5 years (57% versus 56%; hazard ratio 1.00, 95% CI, 0.84 to 1.21; P=0.9) or overall survival at 5 years 71% versus 72%; hazard ratio 0.91, 95% CI, 0.71 to 1.16; P=0.44). Conclusions: Infusional 5-FU does not improve RFS or overall survival of stage III colon cancer compared to the Mayo regimen but is less toxic. Supported by Deutsche Krebshilfe

No significant financial relationships to disclose.
Prognostic significance of mesenteric tumor nodules in patients with stage III colorectal cancer
Authors: Lo D. S. , Pollett A. , Gallinger S. , Siu L. L. , Burkes R. L.
Published: March 2020

3566

Background: Tumor nodules are occasionally found in adjacent mesentery of colorectal cancer specimens, but their prognostic significance is unclear. According to the TNM staging system, mesenteric nodules are classified as part of T or N categories, but clinically they are regarded to reflect a worse prognosis, more like M1. We investigated the clinical significance of mesenteric tumor nodules. Methods: We reviewed 786 patients with stage III colorectal cancer referred between 1995 and 1999. We standardized TNM staging by assigning N status based on number of definite lymph nodes. Mesenteric nodules were considered separately and not assigned to T or N categories. Survival analyses were performed. Results: Mesenteric tumor nodules were found in 116 patients (14.8%); 48 with colon cancer (41.4%) and 68 rectal cancer (58.6%). Mean age at surgery was 62.8±1.0 yrs (SE), and the male: female ratio was 1.2. All tumors were adenocarcinomas with an average size of 4.3±0.1 cm, and the majority were moderately differentiated. Resection margins were clear except in 7 cases. With respect to high risk features, 6 cases (5.2%) had bowel perforation, 12 (10.3%) obstructive symptoms, 41 (35.3%) lymphovascular invasion, and 11 (9.5%) were T4 lesions. Adjuvant chemotherapy was given to 84.8% of colon cancer patients. Two (2.9%) rectal cancer patients received neoadjuvant chemo-radiation, and 63 (92.6%) received adjuvant therapy; chemotherapy, radiation or both. In the cohort with mesenteric nodules, the median time to progression was 23.1 months; the median 5-yr disease free survival was 35%; and the median overall survival (OS) was 47.9 months, with 44% OS at 5 yrs. After TNM standardization, 19 (16.4%) patients were down-staged to either stage I or II, and their 5-yr OS was 60% (SEER Stage II 5 yr survival 82.5%). In the remaining cohort-patients with stage III disease after standardization, the 5-yr OS was 40% (SEER 5yr survival Stage IIIc 44.3%; Stage IV 8.1%). Conclusions: In comparison to SEER survival data, the presence of mesenteric nodules appears to worsen prognosis of any T/N0 disease to that of overall stage III disease. Patients with mesenteric nodules in the setting of any T/N1+ disease had prognosis similar to that of stage IIIC disease, but their prognosis was better than M1 disease.

No significant financial relationships to disclose.
Preoperative uracil/tegafur and concomitant radiotherapy in locally advanced rectal (LAR) cancer: Updated results with a median follow-up of 5 years and analysis of prognostic factors (PF)
Authors: Fernandez-Martos C. , Romero I. , Aparicio J. , Bosch C. , Girones R. , Campos J. M. , Garcera S. , Safont M. J. , Maeztu I. , Climent M. A.
Published: March 2020

3573

Background: Preop chemoradiotherapy (CRT) with CI 5-FU is a standard of care for LAR cancer. Oral fluoropyrimidines, an attractive alternative to intravenous 5-FU, are perceived by patients as more convenient. Methods: We performed a phase II study in patients with potentially resectable tumors, localized in middle or distal rectum, ultrasonographically staged as T3 or T4 or N+ who were treated with UFT (400 mg/m2/d, 5 days a week for 5 weeks) and concomitant RT to the pelvis (45 Gy; 1.8 Gy/d over 5 weeks). Pts underwent surgery 5 to 6 weeks later followed by four cycles of 5-FU/LV (Mayo Clinic Scheme). Early end points of efficacy (pCR, downstaging, sphincter preserving surgery) and toxicity have already been reported (JCO 2004;22:3016). We now present data on secondary objectives (RFS, DFS and OS) and univariate and multivariate analysis of clinical and pathological PF. Results: 94 patients were included and complete information on 88 (94%) is availablewith a median follow-up of 5 years (60.4 months). Actuarial Kaplan-Meier DFS, RFS and OS are 61%, 66%, and 70 %. Patterns of failure are 7% pelvic and 25% distant. Univariate analysis results are shown in the table . Survival rate was also higher among patients with no or few residual disease after CRT but did not reach statistical significance. In Cox multivariate analysis both ypT and ypN are independent PF for DFS and RFS but only ypT is an independent PF for OS. Conclusions: This approach with preop UFT/RT reproduces the results that have been accomplished with 5-FU. ypT and ypN could be helpful to identify different risk groups and to select adjuvant treatments.

[Table: see text]

No significant financial relationships to disclose.
Capecitabine plus irinotecan versus 5-FU/FA/irinotecan ± celecoxib in first line treatment of metastatic colorectal cancer (CRC). Long-term results of the prospective multicenter EORTC phase III study 40015
Authors: De Grève J. , Koehne C. , Hartmann J. , Lang I. , Vergauwe P. , Becker K. , Braumann D. , Debois M. , Bethe U. , Van Cutsem E.
Published: March 2020

3577

Background: Oral fluoropyrimidines in combination with irinotecan may be an alternative to infusional 5-FU/FA+irinotecan. Cox-2 inhibitors may enhance the antineoplastic activity of chemotherapy (CT). Methods: Patients with ECOG PS<2, age>18 and measurable disease were randomised in a 2×2 factorial design to FOLFIRI (Douillard’s regimen) or capecitabine 2×1g/m2 d1–14 plus irinotecan 250mg/m2 d1, qd22 (CAPIRI), and to daily celecoxib 2x400mg (C) or placebo (P). 692 patients were planned to compare PFS as primary endpoint. The trial was suspended after 85 pts (44 CAPIRI and 41 FOLFIRI) due to the occurrence of 8 fatal events unrelated to disease progression (Köhne, ASCO 2005, A3525). Results: Baseline characteristics were well balanced. Three pts did not start treatment. Of the pts who started CT, 53% (23/43) in the CAPIRI and 33% (13/39) in the FOLFIRI arms required a dose reduction. Grade ≥3 diarrhoea occurred in 37% (16/43) and 13 % (4/39) on CAPIRI and FOLFIRI, respectively. Median number of CT cycles: 3 (CAPIRI) and 5 (FOLFIRI). Median dose intensity for irinotecan: 83% (CAPIRI) and 85% (FOLFIRI). Response rate (RR): 5/23 (22%) in CAPIRI+C, 10/21 (48%) in CAPIRI+P, 6/19 (32%) in FOLFIRI+C and 10/22 (45%) in FOLFIRI+C. RR for CAPIRI vs FOLFIRI: 15/44 (34%) versus 16/41 (39%), RR for Celecoxib vs Placebo: 11/42 (26%) vs. 20/43 (46 %). Median PFS: 5.9 months (95% CI: 4.4–8.9) with CAPIRI vs 9.6 months (95% CI: 6.9–11.8) with FOLFIRI (HR=1.31, 95%CI: 0.8–2.1), and 6.9 months (95% CI: 5.5–10.4) with C vs 7.8 months (95% CI: 6.0–12.0) with P (HR=1.1, 95%CI: 0.7–1.8). Median OS: 14.8 months (95% CI: 10.7–18.3) with CAPIRI vs 19.9 months (95% CI: 18.9-n.a.) with FOLFIRI (HR=3.2, 95%CI: 1.4–7.3), and 18.3 months (95% CI: 10.2-n.a.) with C versus 19.9 months (95% CI: 16.7-n.a.) with P (HR=1.25, 95%CI: 0.6–2.6). Conclusions: The data suggest that celecoxib might reduce response to CT and this warrants further preclinical investigation. The stratified analysis failed to demonstrate the non-inferiority of CAPIRI as compared to FOLFIRI. Small sample size and confounding safety issues prevent us from drawing definitive conclusions. Results of larger studies would be needed.

No significant financial relationships to disclose.
Continuous versus intermittent chemotherapy in metastatic colorectal cancer
Authors: Alexopoulos C. G. , Kotsori A. A.
Published: March 2020

3582

Background: The current policy concerning the duration of chemotherapy in metastatic colorectal cancer (MCC) varies considerably (Clin Oncol 1997;9:248) while no benefit of continuous versus intermittent 5-FU was found in a published randomized study (Lancet 2003;361:457). Serious cumulative toxicity is not usually a problem with long-term 5-FU/FA, but this is not the case with contemporary triple regimens (FOLFIRI, FOLFOX). We, therefore, performed a randomized study of continuous versus intermittent FOLFIRI as first line chemotherapy in MCC. Methods: Patients with MCC and ECOG 0–2 were given 6 biweekly courses of FOLFIRI (Irinotecan 180mg/m2 + De Gramont). Patients with response or stable disease were randomized to continue with another 6 FOLFIRI (group A) or discontinue until relapse when 6 FOLFIRI were readministered (group B). Time to progression (TTP) was calculated from study entrance until 1st progression for group A, and 2nd progression for group B, and overall survival (OS) from study entrance until death. Results: Fifty eight (M=38, F=20) patients entered into the study. Two (3.4%) withdrew before evaluation, 1 (1.7%) died of stroke, 1 (1.7%) was lost to FU and 15 (26%) progressed before or at the completion of 6 FOLFIRI. Thirty nine (67%) patients (M=25, F=14), median age 69 (38–79) responded (21=54%) or had stable disease (18=46%) and were randomized: 19 (49%) to group A and 20 (51%) to group B. Median TTP was 8 months 95% CI: 5.3–10.7) for group A and 9 (95% CI: 7.8–10) for group B (p=NS). 10/19 (52%) in group A received 2nd line chemotherapy vs 7/20 (35%) in group B (p=NS). With a median follow-up of 13 months, 21 patients are alive (12 in group A and 9 in group B). Median OS was 21 months (95% CI: 15 - 26.7) in group A vs 15 (95% CI: 12.6 - 17.3) in group B (p=NS), and 18 months (95% CI: 15.5 - 21) for all 39 patients. Conclusions: In MCC, when response or stability has been achieved after 6 courses ofFOLFIRI there seemstobe little more benefit from continuing chemotherapy than from retreating patients at relapse

No significant financial relationships to disclose.
Phase II trial of depsipeptide (NSC-630176) in colorectal cancer patients who have received either one or two prior chemotherapy regimens for metastatic or locally advanced, unresectable disease: A Southwest Oncology Group study
Authors: Whitehead R. P. , McCoy S. , Wollner I. S. , Wong L. , Harker W. G. , Hoff P. M. , Gold P. J. , Billingsley K. G. , Blanke C. D.
Published: March 2020

3598

The treatment for metastatic colorectal cancer has markedly improved but the disease is still not curable, and additional active agents need to be found. Depsipeptide is a histone deacetylase inhibitor that has shown activity against human solid tumor cell lines and promising results in murine model systems. This phase II trial was undertaken to determine its activity in patients with advanced colorectal cancer. Eligibility requirements included measurable disease, either metastatic or locally advanced and not surgically resectable, Zubrod performance status of 0–1, and adequate renal, hepatic, hematologic and cardiac function. Prior surgery or radiation therapy was allowed and patients were required to have received either one or two prior chemotherapy regimens for advanced disease. A two-stage design was used designed to detect a difference in the null hypothesis of 5% response vs. an alternative 20% response, with 20 eligible patients to be accrued initially followed by an additional 20 patients if one or more confirmed responses were observed. The study closed after the first stage, with 28 patients registered. Three patients are ineligible, two who did not meet requirements for serum magnesium level, and one whose baseline labs were performed more than 14 days prior to registration. One eligible patient never received treatment and is not analyzable for any endpoint. For the 24 eligible and analyzable patients, median age was 58.6 years (range 31–84) with 14 males. Performance status was 0 in 16 patients and 1 in 8. Ten patients received 1 prior chemotherapy regimen and 14 received 2 prior regimens. There were no grade 4 or higher toxicities. The most common grade 2 or 3 toxicities were anorexia, fatigue, nausea, and dehydration. No objective responses were observed. Four patients had stable disease, 15 showed increasing disease, 3 had symptomatic deterioration, and 2 had assessment inadequate. The current Kaplan-Meier estimate of 6 month overall survival is 69% (95% CI 50%-88%) with a median survival of 8.4 months. Depsipeptide does not show significant anti-tumor activity in previously treated patients with advanced colorectal cancer.

No significant financial relationships to disclose.
Prognostic value of ERCC1, thymidylate synthase and glutathione S-transferase π for 5-FU/oxaliplatin chemotherapy in advanced colorectal cancer
Authors: Kwon H. , Roh M. S. , Oh S. Y. , Kim S. , Lee J. H. , Kim J. , Park J. I. , Park K. J. , Choi H. J. , Kim H.
Published: March 2020

3607

Background: The aim of this study was to determine whether expressions of the excision cross-complementing (ERCC1), thymidylate synthase (TS) and glutathione S-transferase π (GSTπ) predict clinical outcome in patients with advanced colorectal cancer treated with fluorouracil (5-FU)/oxaliplatin chemotherapy. Methods: The study population consisted of 70 advanced colorectal cancer patients (median age, 53 years). Patients were treated with oxaliplatin 85 mg/m2 as a 2-hour infusion at days 1 plus LV 20 mg/m2 over 10 minutes, followed by 5-FU bolus 400 mg/m2 and 22 hour continuous infusion of 600 mg/m2 at day 1–2. Treatment was repeated in 2 week intervals. The expressions of ERCC1, TS and GSTπ of primary tumors were examined by immunohistochemistry. Results: The positive rates of ERCC1, TS, and GSTπ were 55.7%, 68.6%, and 71.4%, respectively. The patients without TS expression were more likely to respond to chemotherapy (p=0.009). There were no significant differences between response and ERCC1 or GSTπ expression pattern (p=0.768, p=0.589, respectively). Median overall survival (OS) was significantly longer in patients without ERCC1 expression (p=0.0474). Patients with ERCC1 positive combined with TS positive, or those with ERCC1 positive combined with TS positive and GSTπ positive had poor OS (p=0.0017, p=0.0323, respectively). Multivariate analysis revealed that both ERCC1 and TS expression significantly impacted on OS (Hazard ratio 1.72, p=0.023). Conclusions: Immunohistochemical studies for ERCC1 and TS may be useful in prediction of the clinical outcome of advanced colorectal cancer patients treated with 5-FU and oxaliplatin.

No significant financial relationships to disclose.