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Summary Background. Mitomycin C and etoposide have both demonstrated activity against gastric carcinoma. Etoposide is a topoisomerase II inhibitor with evidence for phase-specific and schedule-dependent activity. Patients and method: Twenty-eight consecutive patients with advanced upper gastrointestinal adenocarcinoma were treated with intravenous (i.v.) bolus mitomycin C 6 mg/m2 on day 1 every 21 days to a maximum of four courses. Oral etoposide capsules 50 mg b.i.d. (or 35 mg b.i.d. liquid) were administered days 1 to 10 extending to 14 days in subsequent courses if absolute neutrophil count > 1.5 x 10 9/l on day 14 of first course, for up to six courses. Results: Twenty-six patients were assessed for response of whom 12 had measurable disease and 14 evaluable disease. Four patients had a documented response (one complete remission, three partial remissions) with an objective response rate of 15% (95% confidence interval (95% CI) 4%-35%). Eight patients had stable disease and 14 progressive disease. The median survival was six months. The schedule was well tolerated with no treatment-related deaths. Nine patients experienced leucopenia (seven grade II and two grade III). Nausea and vomiting (eight grade II, one grade III), fatigue (eight grade II, two grade III) and anaemia (seven grade II, two grade III) were the predominant toxicities. Conclusion: This out-patient schedule is well tolerated and shows modest activity in the treatment of advanced upper gastrointestinal adenocarcinoma. Further studies using protracted schedules of etoposide both orally and as infusional treatment should be developed.

Δ9-Tetrahydrocannabinol (THC) is the active metabolite of cannabis. THC causes cell death in vitro through the activation of complex signal transduction pathways. However, the role that the cannabinoid 1 and 2 receptors (CB1-R and CB2-R) play in this process is less clear. We therefore investigated the role of the CB-Rs in mediating apoptosis in 3 leukemic cell lines and performed microarray and immunoblot analyses to establish further the mechanism of cell death. We developed a novel flow cytometric technique of measuring the expression of functional receptors and used combinations of selective CB1-R and CB2-R antagonists and agonists to determine their individual roles in this process. We have shown that THC is a potent inducer of apoptosis, even at 1 × IC50 (inhibitory concentration 50%) concentrations and as early as 6 hours after exposure to the drug. These effects were seen in leukemic cell lines (CEM, HEL-92, and HL60) as well as in peripheral blood mononuclear cells. Additionally, THC did not appear to act synergistically with cytotoxic agents such as cisplatin. One of the most intriguing findings was that THC-induced cell death was preceded by significant changes in the expression of genes involved in the mitogen-activated protein kinase (MAPK) signal transduction pathways. Both apoptosis and gene expression changes were altered independent of p53 and the CB-Rs.

The recombinant growth factors (GFs) erythropoietin (Epo) and granulocyte–macrophage colony stimulating factor (GM-CSF) have important roles in the management of cancer patients. However, the effects of these GFs at a cellular level are not well understood. We examined the effect of GFs alone, and in combination with cytotoxic chemotherapy, in a panel of seven cell lines. Flow cytometric analysis showed varying levels of receptor expression, which correlated with phosphorylated MAPK expression. Additionally, there were also concomitant increases in BCL-2 protein levels in those cells with high levels of MAPK activation. Although culturing cells with Epo or GM-CSF did not alter cell viability by themselves, GF pretreatment in cell lines expressing higher receptor levels resulted in a reduced magnitude of cell kill following exposure to cytotoxic IC50 concentrations of cisplatin. Subsequent co-culture with either the MEK inhibitor U0126 or the GM-CSF antagonist E21R negated this induced resistance to cytotoxic chemotherapy, confirming the importance of the GF receptor as well as MAPK in mediating these effects. These results suggest that the use of GFs during chemotherapy may be detrimental in those cancers expressing higher levels of the specific receptor. Conversely, our results also suggest that GFs are safe to use in chemotherapeutic regimens if the cancer cells do not overexpress the particular receptor.

4121 Background: The TeloVac trial randomized 1,062 patients with advanced pancreatic cancer to a control chemotherapy Arm1, using GemCap; sequential chemoimmunotherapy Arm 2, GemCap for 8 wks foll...

Purpose: To develop, using dacarbazine as a model, reliable techniques for measuring DNA damage and repair as pharmacodynamic endpoints for patients receiving chemotherapy. Methods: A group of 39 patients with malignant melanoma were treated with dacarbazine 1 g/m2 i.v. every 21 days. Tamoxifen 20 mg daily was commenced 24 h after the first infusion and continued until 3 weeks after the last cycle of chemotherapy. DNA strand breaks formed during dacarbazine-induced DNA damage and repair were measured in individual cells by the alkaline comet assay. DNA methyl adducts were quantified by measuring urinary 3-methyladenine (3-MeA) excretion using immunoaffinity ELISA. Venous blood was taken on cycles 1 and 2 for separation of peripheral blood lymphocytes (PBLs) for measurement of DNA strand breaks. Results: Wide interpatient variation in PBL DNA strand breaks occurred following chemotherapy, with a peak at 4 h (median 26.6 h, interquartile range 14.75–40.5 h) and incomplete repair by 24 h. Similarly, there was a range of 3-MeA excretion with peak levels 4–10 h after chemotherapy (median 33 nmol/h, interquartile range 20.4–48.65 nmol/h). Peak 3-MeA excretion was positively correlated with DNA strand breaks at 4 h (Spearman's correlation coefficient, r=0.39, P=0.036) and 24 h (r=0.46, P=0.01). Drug-induced emesis correlated with PBL DNA strand breaks (Mann Whitney U-test, P=0.03) but not with peak 3-MeA excretion. Conclusions: DNA damage and repair following cytotoxic chemotherapy can be measured in vivo by the alkaline comet assay and by urinary 3-MeA excretion in patients receiving chemotherapy.

ANovartisPharmaAG, Basle, Switzerland Summary Background: MKT 077 is a rhodacyanine dye analogue which preferentially accumulates in tumour cell mitochondria. It is cytotoxic to a range of tumours. In this phase I study, MKT 077 was administered as a five-day infusion once every three weeks. Patients and methods: Ten patients, median age 59 (38-70) years, with advanced solid cancers were treated at three dose levels: 30, 40 and 50 mg/m 2 /day for a total of 18 cycles. 31 Phosphorus magnetic resonance spectroscopy (MRS) was used to evaluate the effect of MKT077 on skeletal muscle mitochondrial function. Results: The predominant toxicity was recurrent reversible functional renal impairment (grade 2, two patients). One patient with renal cancer attained stable disease and the remainder progressive disease. There were no MRS changes in the first or second treatment cycles but one patient received 11 treatment cycles and developed changes consistent with a mitochondrial myopathy. Mean values for all pharmacokinetic parameters were at sub micromolar levels and did not exceed IC50 values (>1 uM). Conclusions: Because of the renal toxicity, and animal studies showing MKT 077 causes eventual irreversible renal toxicity, further recruitment was halted. The study shows, however, that it is feasible to target mitochondria with rhodacyanine analogues, if drugs with higher therapeutic indices could be developed.

Bryostatin 1 is a protein kinase C partial agonist which has both antineoplastic and immune-stimulatory properties, including the induction of cytokine release and expansion of tumour-specific lymphocyte populations. In phase I studies, tumour responses have been observed in patients with malignant melanoma, lymphoma and ovarian carcinoma. The dose-limiting toxicity is myalgia. Sixteen patients (age 35-76 years, median 57 years) with malignant melanoma were treated. All had received prior chemotherapy. In each cycle of treatment, patients received bryostatin 25 degrees g m(-2) weekly for three courses followed by a rest week. The drug was given in PET diluent (10 microg bryostatin ml(-1) of 60% polyethylene glycol, 30% ethanol, 10% Tween 80) and infused in normal saline over 1 h. The principal toxicities were myalgia (grade 2, eight patients and grade 3, six patients) and grade 2 phlebitis (four patients), fatigue (three patients) and vomiting (one patient). Of 15 patients evaluable for tumour response, 14 developed progressive disease. One patient developed stable disease for 9 months after bryostatin treatment. In conclusion, single-agent bryostatin appears ineffective in the treatment of metastatic melanoma in patients previously treated with chemotherapy. It should, however, be investigated further in previously untreated patients.

LBA4004 Background: GV1001, a promiscuous class II epitope encompassing aa 611-626 of hTERT led to the development of CD4+ clones recognizing hTERT in patients with advanced pancreatic cancer (APC). Preclinically gemcitabine increases antigen cross-presentation, enhances T cell trafficking/activation, and reduces MDSCs and Tregs. Methods: Patients with APC were randomized 1:1:1 to: Arm 1 GemCap; 2 GemCap for 8/52 followed by GV1001 followed by further GemCap if no PD at week 8; 3 concurrent administration of GemCap and GV1001. 735 (69.2%) had metastatic disease and 948 (89.3%) had ECOG PS=0 or 1. Randomization was stratified by stage and PS. Primary endpoint was overall survival (OS); secondary endpoints included ORR, TTP, and AEs. Recruitment target was 1,110 patients (780 deaths) to permit detection of a hazard ratio of 0.748 between either GV1001 arm and Arm 1 using a 2-sided α=0.025 level of significance with at least 80% power. Results: 1,062 pts from 51 centers were randomized. Trial maturity was high (72.7% patients died): median follow-up was 6.11 months. The overall response rates were Arm 1=17.6%; Arm 2=8.9% (p=0.001); Arm 3: 15.5% (p=0.460 compared with Arm 1). Conclusions: OS with concurrent GemCap/GV1001 was not different to that with GemCap alone. OS with sequential GV1001 was not statistically different to GemCap alone as it did not meet the criterion for statistical significance (p

Introduction Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor, is approved in combination with gemcitabine for advanced pancreatic cancer. As the use of biomarkers to guide treatment decisions for targeted therapies is an area of increasing interest, a post-approval commitment was made to investigate potential biomarkers for erlotinib in pancreatic cancer. This randomised, placebo-controlled, multicentre, phase II study examined whether any biomarkers were predictive of differential outcomes with erlotinib monotherapy in advanced pancreatic cancer. The primary data for this study have been presented previously and showed no correlation between any of the pre-specified biomarkers investigated and the primary endpoint of progression-free survival (PFS) with erlotinib. Here we present the results of exploratory analyses on serum biomarkers. Methods Serum samples were collected from patients at baseline, 3 weeks, and after treatment discontinuation. Randomisation was stratified by ECOG PS, region and smoking status, and the initial estimation of hazard ratio for the treatment effect was by unadjusted Cox regression. After observing imbalances in some baseline characteristics, additional post-hoc analyses using a stepwise model selection algorithm were performed to assess for any impact on PFS and OS. Serum biomarker analyses were conducted on amphiregulin, EGF, TGF-a, and sHer-2. Exploratory analyses of efficacy were performed in ‘low’ and ‘high’ subgroups, as compared to the median of each soluble marker in the overall population. Efficacy was analysed in subgroups using both the initial unadjusted analysis, as well as the post-hoc model that was developed in the overall population. Results Data on baseline serum markers were available for 199 out of 207 patients for amphiregulin and TGF-a, and 202 out of 207 patients for EGF and sHer-2. The adjusted post-hoc analysis of serum biomarkers showed that erlotinib provided a significant benefit in terms of PFS and OS in patients with high levels of amphiregulin (Table). Validation of results for other markers is ongoing and data will be presented. Conclusion Exploratory adjusted analyses of serum markers showed that patients with high serum amphiregulin concentrations achieved a significant benefit in both PFS and OS. The observation that patients with elevated baseline levels of amphiregulin obtained benefits in both PFS and OS with erlotinib may suggest potential for this biomarker in pancreatic cancer. Table 1 .

e14137 Background: Colorectal cancer (CRC) is the third most common cancer in the UK with approximately 20% of patients (pts) presenting with metastatic disease. In 2008 there were over 16,000 deat...

2613^ Background: Afatinib (BIBW 2992) is an oral, irreversible ErbB family blocker. This trial prospectively evaluated the possible proarrhythmic potential of afatinib by assessing QTc interval, as well as its PK and clinical efficacy. Methods: Patients (pts) with tumors known to overexpress EGFR or HER2, including those with brain metastases and GBM were eligible for treatment with daily afatinib 50mg. Pts with a QTcF-interval >470 ms, a PR-interval >230 ms, a QRS-interval >120 ms and ST-segment and T/U-wave abnormalities at screening, as assessed by central cardiology review, were excluded. 60 pts were treated. Time-matched 24-h ECGs were performed prior to drug exposure, after single dose and at steady state. Pharmacokinetic (PK) samples were drawn on days coincident with ECGs. Results: 49 of 60 pts were analyzed for the QTcF. The largest mean time matched QTcF change from baseline to Day 14 was 1.6 ms (90% CI –2.1, 5.2) at 1 h post dosing. The analysis of the relationship between the afatinib concent...

TPS187 Background: BIBW 2992 is an oral, irreversible inhibitor of EGFR/HER1 and HER2. EGFR and HER2 are amplified and overexpressed in most epithelial cancers as well as 50%–60% of GBMs. In a phase I study, one patient with NSCLC and brain metastases showed a response in both systemic and CNS disease. Preclinical and retrospective ECG analyses did not suggest an effect of BIBW 2992 on QTc, although this has not been prospectively assessed according to ICH E14 Cardiac Assessment of New Drugs Guidelines. The primary objectives of this study are to evaluate the effect of BIBW 2992 on QTc interval and the efficacy in patients with GBM, and patients with eligible tumors with and without brain metastases. Methods: In this phase II open label study, patients ≥18 years, with tumors known to historically overexpress EGFR or HER2, including those with brain metastases, and GBM at 1st recurrence, adequate organ function and ECOG PS 0–2, are eligible for treatment with BIBW 2992 50 mg PO OD q28. Patients with a QTcF...

Background: When cure is impossible, cancer treatment should focus on both length and quality of life. Maximisation of time without toxic effects could be one effective strategy to achieve both of these goals. The COIN trial assessed preplanned treatment holidays in advanced colorectal cancer to achieve this aim. Methods: COIN was a randomised controlled trial in patients with previously untreated advanced colorectal cancer. Patients received either continuous oxaliplatin and fluoropyrimidine combination (arm A), continuous chemotherapy plus cetuximab (arm B), or intermittent (arm C) chemotherapy. In arms A and B, treatment continued until development of progressive disease, cumulative toxic effects, or the patient chose to stop. In arm C, patients who had not progressed at their 12-week scan started a chemotherapy-free interval until evidence of disease progression, when the same treatment was restarted. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and B is described in a companion paper. Here, we compare arms A and C, with the primary objective of establishing whether overall survival on intermittent therapy was non-inferior to that on continuous therapy, with a predefined non-inferiority boundary of 1·162. Intention-to-treat (ITT) and per-protocol analyses were done. This trial is registered, ISRCTN27286448. Findings: 1630 patients were randomly assigned to treatment groups (815 to continuous and 815 to intermittent therapy). Median survival in the ITT population (n=815 in both groups) was 15·8 months (IQR 9·4–26·1) in arm A and 14·4 months (8·0–24·7) in arm C (hazard ratio [HR] 1·084, 80% CI 1·008–1·165). In the per-protocol population (arm A, n=467; arm C, n=511), median survival was 19·6 months (13·0–28·1) in arm A and 18·0 months (12·1–29·3) in arm C (HR 1·087, 0·986–1·198). The upper limits of CIs for HRs in both analyses were greater than the predefined non-inferiority boundary. Preplanned subgroup analyses in the per-protocol population showed that a raised baseline platelet count, defined as 400 000 per μL or higher (271 [28%] of 978 patients), was associated with poor survival with intermittent chemotherapy: the HR for comparison of arm C and arm A in patients with a normal platelet count was 0·96 (95% CI 0·80–1·15, p=0·66), versus 1·54 (1·17–2·03, p=0·0018) in patients with a raised platelet count (p=0·0027 for interaction). In the per-protocol population, more patients on continuous than on intermittent treatment had grade 3 or worse haematological toxic effects (72 [15%] vs 60 [12%]), whereas nausea and vomiting were more common on intermittent treatment (11 [2%] vs 43 [8%]). Grade 3 or worse peripheral neuropathy (126 [27%] vs 25 [5%]) and hand–foot syndrome (21 [4%] vs 15 [3%]) were more frequent on continuous than on intermittent treatment. Interpretation: Although this trial did not show non-inferiority of intermittent compared with continuous chemotherapy for advanced colorectal cancer in terms of overall survival, chemotherapy-free intervals remain a treatment option for some patients with advanced colorectal cancer, offering reduced time on chemotherapy, reduced cumulative toxic effects, and improved quality of life. Subgroup analyses suggest that patients with normal baseline platelet counts could gain the benefits of intermittent chemotherapy without detriment in survival, whereas those with raised baseline platelet counts have impaired survival and quality of life with intermittent chemotherapy and should not receive a treatment break. Funding: Cancer Research UK.

PURPOSE: N-Benzoyl staurosporine (PKC412) is a protein kinase C inhibitor with antitumor activity in laboratory models. We determined the toxicity of oral PKC412 administered daily for repeat cycles of 28 days. PATIENTS AND METHODS: Thirty-two patients with advanced solid cancers were treated at seven dose levels (12.5 to 300 mg daily) for a total of 68 cycles. RESULTS: The most frequent treatment-related toxicities were nausea, vomiting, fatigue, and diarrhea. At the two top dose levels (225 and 300 mg/d), 15 of 16 patients experienced nausea/vomiting (common toxicity criteria [CTC], version 1), grade 2 in nine of 16 and grade 3 in three of 16 patients; and six of 16 patients developed CTC grade 2 diarrhea. After 1 month of treatment, there were significant reductions in circulating lymphocyte (P < .02) and monocyte (P < .01) counts in patients receiving doses ≥ 100 mg/d. Nevertheless, only two patients developed myelosuppression (both grade 2). Of two patients with progressive cholangiocarcinoma, one attained stable disease lasting 4.5 months and one a partial response lasting 4 months. There was a linear relationship between PKC412 dose and area under the curve0-24 hours and maximum plasma concentration with marked interpatient variability. The estimated median elimination half-life was 1.6 days (range, 0.9 to 4.0 days), and a metabolite with a median half-life of 36 days was detected. Steady-state PKC412 plasma levels at the top three dose cohorts (150 to 300 mg) were five to 10 times the cellular 50% inhibitory concentration for PKC412 of 0.2 to 0.7 μmol/L. CONCLUSION: PKC412 can be safely administered by chronic oral therapy, and 150 mg/d is suitable for phase II studies. The pharmacokinetics and lack of conventional toxicity indicate that pharmacodynamic measures may be additionally needed to optimize the drug dose and schedule.