BACKGROUND:Panobinostat, a pan-deacetylase inhibitor, overcomes imatinib resistance in preclinical models of gastrointestinal stromal tumours (GIST). Here we determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of panobinostat in combination with imatinib (IM) for treatment of patients with refractory GIST.METHODS:Following a 7-day run-in phase of IM (400 mg per day), escalating doses of panobinostat were added following a '3 plus 3' design. Twelve heavily pretreated GIST patients were enrolled in two dose levels.RESULTS:Most common adverse events were thrombocytopenia, anaemia, fatigue, creatinine elevation, nausea, emesis and diarrhoea. Twenty micrograms of panobinostat and 400 mg IM were declared the MTD. Pharmacologically active concentrations of panobinostat and IM were achieved as evidenced by histone H3 acetylation in blood mononuclear cells in vivo and inhibition of the IM-resistant KIT (D816) mutation in vitro. In FDG-PET-CT scans after IM run-in and following 3 weeks panobinostat treatment, 1 out of 11 evaluable patients showed a metabolic partial response, 7 patients were metabolically stable and 3 patients progressed. Longest treatment duration was 17 weeks (median 6).CONCLUSION:Panobinostat and IM can be administered at doses achieving target inhibition in vivo. Further clinical exploration of patients with treatment-refractory GIST is warranted. Correlative studies in this trial may help to optimise dosing schedules in GIST.

4035 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumours, but PDAC is still associated with a poor prognosis in advanced disease with an overall 5-year survival of only about 15%. Therefore there is a need for new treatment strategies. To improve the standard therapy with gemcitabine we initiated a prospective randomized phase-II trial with gemcitabine (GEM) vs. gemcitabine plus sunitinib (SUNGEM) based on data of in vitro trials and phase-I data for the combination treatment. Methods: Patients (N=113) with locally advanced or metastatic PDAC were prospectively randomized to receive gemcitabine alone (GEM) at a dosage of 1000 mg/m² day 1, 8, 15 q28 or to a combination of gemcitabine and sunitinib (SUNGEM) at a dosage of GEM 1000 mg/m² d1+8 and sunitinib 50mg p.o. d1-14, qd21 (based on a phase-I trial). The primary endpoint was progression-free survival (PFS), secondary endpoints were overall survival (OS), time to progression (TTP), overall response rate (ORR) and toxicity. Results: The confirmatory analysis of PFS was based on the ITT population (N=106). The median PFS was 13.3 weeks (95 %-Cl: 10.4-18.1 weeks) in the GEM group and 11.6 weeks in the SUNGEM arm (95 %-Cl: 7.0-18.0 weeks) (one-sided logrank: p=0.74). The 6-month PFS rate was 26.8 % (95 %-Cl: 15.4-39.5 %) in GEM arm and 25.0 % in SUNGEM arm (95 %-Cl: 14.0-37.8 %). The overall response rate was 6.1 % (95 %-Cl: 0.7-20.2 %) in the GEM arm and was a slightly but not significantly higher for the SUNGEM arm with 7.1% (95%-Cl: 0.9 – 23.5%).The median time to progression (TTP) was 14.0 weeks (95 %-Cl: 12.4-22.3 weeks) for the GEM arm and 18.0 weeks (95 %-Cl: 11.3-19.3 weeks) for the SUNGEM arm (two-sided logrank: p=0.60). The median OS was 30.4 weeks (95 %-Cl: 18.1-37.6 weeks) for the SUNGEM and 36.7 weeks (95 %-Cl: 20.6-49.0 weeks) for the GEM arm (two-sided logrank: p=0.44). With regard to toxicities, at least one AE of grade 3 or 4 was reported in 78.8% in the SUNGEM arm and 72.2% in the GEM arm. Conclusions: The combination of gemcitabine plus sunitinib (SUNGEM) did not improve the PFS in locally advanced or metastatic PDAC compared to gemcitabine alone. Clinical trial information: NCT00673504.

Tivozanib is a potent selective tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. This Phase Ib study investigated the safety/tolerability, pharmacokinetics (PK), and activity of tivozanib with weekly paclitaxel in metastatic breast cancer (MBC). MBC patients with no prior VEGFR TKI treatment received daily oral tivozanib (3 weeks on, 1 week off) with weekly paclitaxel 90 mg/m(2). Standard 3 + 3 dose escalation was used; tivozanib cohorts (C) included C1 0.5 mg, C2 1.0 mg, and C3 1.5 mg. Assessments included Response Evaluation Criteria in Solid Tumors response, PK, and vascular function. Eighteen patients enrolled. Toxicities in >20 % of patients included fatigue, alopecia, nausea, diarrhea, peripheral sensory neuropathy, and hypertension. Grade 3/4 toxicities in >15 % of patients included fatigue and neutropenia. Maximum tolerated dose was tivozanib 1.5 mg with paclitaxel 90 mg/m(2). Four patients withdrew because of toxicity and one due to progressive disease. Thirteen patients were evaluable for response: four (30.8 %) had confirmed partial response; four had stable disease ≥6 months (30.8 %). PK data suggest no influence of paclitaxel on tivozanib concentrations. Tivozanib plus weekly paclitaxel was tolerable at all dose levels, supporting their combination at full dose. Activity in this small population was encouraging.

BI 2536, a novel Polo-like kinase 1 inhibitor, was assessed in patients with unresectable advanced exocrine adenocarcinoma of the pancreas. The study employed a two-stage design. Randomised first-line patients received BI 2536 200 mg on day 1 (n=43) or 60 mg on days 1–3 (n=43) every 21 days. Recruitment of second-line patients was planned for a second stage dependent on an interim analysis demonstrating ⩾2 responses in the first 18 evaluable patients following 12 weeks of treatment and/or tumour control ⩾12 weeks in 5 patients per schedule. Primary end point was objective response rate (ORR). By independent review, ORR was 2.3% (all partial) and 24.4% had stable disease as confirmed best response. The second stage was not initiated. Median overall and progression-free survivals were 149 (95% confidence interval (CI), 91–307) and 46 days (95% CI, 44–56). Most common drug-related adverse events were neutropenia (37.2%), leukopenia (29.1%), fatigue (29.1%) and nausea (22.1%); most common grade 3/4-related events were neutropenia (36.0%), leukopenia (27.9%) and thrombocytopenia (8.1%). Given the low ORR and poor survival, further development of BI 2536 monotherapy is not warranted in this population.

Aims: Resminostat (4SC–201), an orally taken pan-HDAC inhibitor, is currently under investigation in various oncological indications. The Phase I/II SHELTER study aims to evaluate safety, tolerability and efficacy in HCC patients (pts) exhibiting progressive disease under sorafenib (S) first-line therapy.

In a phase I dose-escalation study, regorafenib demonstrated tolerability and antitumour activity in solid tumour patients. The study was expanded to focus on patients with metastatic colorectal cancer (CRC). Patients received oral regorafenib 60–220 mg daily (160 mg daily in the extension cohort) in cycles of 21 days on, 7 days off treatment. Assessments included toxicity, response, pharmacokinetics and pharmacodynamics. Thirty-eight patients with heavily pretreated CRC (median 4 prior lines of therapy, range 0–7) were enrolled in the dose-escalation and extension phases; 26 patients received regorafenib 160 mg daily. Median treatment duration was 53 days (range 7–280 days). The most common treatment-related toxicities included hand–foot skin reaction, fatigue, voice change and rash. Twenty-seven patients were evaluable for response: 1 achieved partial response and 19 had stable disease. Median progression-free survival was 107 days (95% CI, 66–161). At steady state, regorafenib and its active metabolites had similar systemic exposure. Pharmacodynamic assessment indicated decreased tumour perfusion in most patients. Regorafenib showed tolerability and antitumour activity in patients with metastatic CRC. This expanded-cohort phase I study provided the foundation for further clinical trials of regorafenib in this patient population.

1Tumor Biology Center at the Albert-Ludwigs-University Freiburg, 2Magnetic Resonance Development & Application Center (MRDAC) of the University Freiburg, Freiburg, 3Institute of Pharmacy, Clinical Pharmacy, University Bonn, Bonn, 4Innere Klinik (Tumorforschung), West German Cancer Center, Universitatsklinikum Essen, Essen, 5Department Hematology and Oncology, University Hospital Herne, University Bochum, Bochum, Germany, 6CESAR Central European Society for Anticancer Drug Research-EWIV, Vienna, Austria, and 7Department of Gastroenterology, University Hospital Freiburg, Germany

Abstract Background: Anticalins are a new class of therapeutic small protein (20kDa) antibody mimetics based on human lipocalins which can be engineered to bind key molecules involved in tumor progression with high affinity and specificity. PRS-050 (40kDa PEGylated Anticalin) targets VEGF-A. The first clinical trial of this putative therapeutic drug is reported. Methods: This Phase I study is a dose-escalation trial in patients with solid tumors according to the 3+3 escalation scheme investigating the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of PRS-050 given via a 5–20 min iv infusion/bolus on days 1, 22, 29, 36, and 43 and in 2-weeks intervals thereafter until toxicity or tumor progression. PK was assessed after the first administration. Anti-PRS-050 antibodies and PD markers including target engagement (PRS-050:VEGF-A complex), free plasma VEGF-A, serum MMP-2 levels, and DCE-MRI were assessed repetitively. Tumor response was evaluated at day 43 according to RECIST. Results: Twenty-six patients (pts) with progressive solid tumors were enrolled and treated with doses ranging from 0.1 to 10 mg/kg. Tumor types included CRC (46%), malignant melanoma (12%), and pancreatic cancer (8%). The median treatment duration was 43 days (min. 1, max. 251). Drug-related adverse events (AEs) of all grades reported in >20% of pts were chills (46%, G3 4%), fever (23%, G3 4%), hypertension (39%, G3 12%), which were responsive to pretreatment with steroids, antipyretics, and/or H1/H2 blockers, or antihypertensive medication. DLT's include 1 G3 hypertension at 1.5mg/kg and 1 G3 infusion reaction at 10mg/kg. As a result, infusion time was increased to 2 hrs in 4 pts and there was no further infusion reaction. There was one nonfatal intestinal perforation after dose 9. Anti-PRS-050 antibodies were not detected at day 43 (21 pts) or at day 71 (16 pts). PRS-050 showed a dose-dependent increase in exposure up to 10 mg/kg with a terminal half-life of 6 days. No patient achieved an objective response (PR/CR). Stable disease was observed in 9 pts with the longest duration, to date, of 8.5 months in a patient with melanoma. Free VEGF-A levels were detectable at baseline in 8/22 pts, becoming undetectable after 15 min subsequent to the infusion of PRS-050, and remained so for 21 days. PRS-050:VEGF-A complex formation was detectable for up to 3 weeks at all dose levels (22/22 pts) including pts with no detectable free VEGF-A at baseline. Furthermore, circulating MMP-2 levels and changes in the DCE-MRI response at day 2 suggest an anti-angiogenic effect. Conclusions: PRS-050 a small selective high affinity antibody mimetics is well-tolerated when administered with premedication as a 2 hour infusion at doses up to 10mg/kg. No formally defined MTD was reached. The recommended dose of PRS-050 for phase II is 6 mg/kg every 2 weeks, with premedication and 2 hour infusion time, based on results in preclinical xenograft models, preclinical and clinical PK/PD data of this phase I study. Most important, the drug demonstrates the intended PD effects and is ready for Phase II studies in patients with solid tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A212.

3017 Background: Mutations of Ras/Raf lead to a sustained and constitutive activation of ERK pathway. MEK1/2 is the only enzyme that activates ERK1/2; consequently MEK1/2 is a potential target to inhibit in cancers with an activated ERK pathway. RO4987655, a potent, highly selective ATP non-competitive MEK1i with an excellent selectivity profile, was tested in a 3+3 Ph1 study design. Objectives were determination of maximum tolerated dose (MTD), recommended Ph2 dose (RP2D), dose limiting toxicities (DLTs), safety/tolerability, PK/ PD and clinical activity. Methods: Patients (pts) with advanced/metastatic solid tumors received oral RO4987655 administered on a continuous daily dosing (QD) from 1-2.5 mg then twice daily (BID) from 3-21 mg total daily dose in 28 days (D) cycles. Blood PK samples were collected on cycle 1 (C1) [D 1, 8, 15 and 22]. Molecular target suppression was measured by pERKi in PBMC on C1 (D1, D15). Paired skin and tumor biopsies (optional) (baseline, C1D15) and sequential FDG-PET scans (baseline, C1D15, C3D1) were taken. Efficacy was measured as per RECIST. Results: 49 pts in 12 cohorts were enrolled at 4 sites. Mean age 52 y, ECOG 0-1, previous chemotherapy lines median 3 (0-10). Common tumor types included melanoma (27), CRC (11) and NSCLC (3). Four reversible DLTs were observed: CPK elevation (17 mg (n=1), 21 mg (n=2) and blurred vision (21 mg). MTD and RP2D were defined as 17 mg. Most commonly related adverse events included skin (91%), GI (57%), eye (26%) and CPK disorders (44%). PK profiles showed dose-linearity, a half-life of 4 to 6 hrs and drug accumulation ~ 2 fold at steady-state. High (mean 75%) and sustained (90% of time >IC50) pERKi was observed in PBMC at RP2D. FDG PET showed large decrease in SUV at RP2D (-47%, -90% to +29%) (mean, range) which correlated with PBMC pERKi in melanoma pts. PRs and SDs (>=4 mo) were observed in 2 and 5 melanoma, respectively. Conclusions: RO4987655 showed acceptable and manageable safety profile. PK was linear for the tested dose range with moderate inter-pt variability. PD activity in PBMC associated with large metabolic FDG-PET response and preliminary encouraging antitumor activity were demonstrated at the RP2D.

1092 Background: Tivozanib (T; AV-951) is a potent and selective oral small molecule tyrosine kinase inhibitor (TKI) of VEGFR-1, -2, and -3. This phase Ib open-label, multicenter study investigated the safety/tolerability, pharmacokinetics (PK), and activity of T in combination with weekly paclitaxel (P) in metastatic breast cancer (MBC). Methods: Eligible patients (pts) had evaluable MBC with normal organ function, ECOG PS 0-2, ≤4 prior lines of chemotherapy for MBC, including taxanes, and no limit on prior endocrine/biologic therapies. Prior bevacizumab (B) was permitted; prior VEGFR TKIs were excluded. Unstable brain metastases, grade >1 baseline neuropathy, uncontrolled hypertension (HTN), and symptomatic heart failure were excluded. Standard 3+3 dose escalation was used: P 90 mg/m2 3 of 4 weeks (28 days = 1 cycle); escalation cohorts of T: 0.5 mg, 1.0 mg, and 1.5 mg. Maximum tolerated dose (MTD) was defined as the maximum dose at which ≤1 of 6 pts experienced dose-limiting toxicity (DLT). Response was assessed every 2 cycles. PK was evaluated on Day -5 and Cycles 1-2. Results: Eighteen pts enrolled: median age was 48 years (32-65); median ECOG PS was 0 (0-1). 56% were hormone receptor–positive, 22% HER2-positive, and 39% triple negative. Median of 2 (0-4) prior lines of therapy for MBC. 100% had prior taxane exposure: 61% adjuvant, 17% neo-adjuvant, and 22% for MBC. 56% had prior B exposure. Therapy was well tolerated; toxicities (all grades) occurring in ≥20% of pts: fatigue (72%), diarrhea (44%), nausea (44%), HTN (33%), cough (33%) and vomiting (28%). Grade 3 toxicities: diarrhea (11%), fatigue (11%), HTN (11%), neutropenia (11%), and neuropathy (6%); no grade 4 toxicity was observed. The MTD was T 1.5 mg with P 90 mg/m2. All pts were evaluable for response: 5 pts (28%) had a partial response, 2 with prior B exposure; 3 pts (17%) had stable disease ≥24 weeks. PK data suggest no influence of P on circulating levels of T. Conclusions: The combination of T and weekly P was tolerable at all dose levels, supporting combination at full dose and schedule of both agents. In this small patient population with prior taxane exposure, encouraging evidence of clinical activity was observed, supporting further evaluation.

1Institute of Pharmacy, Clinical Pharmacy, University of Bonn, 2IBMP, Institute for Biomedical and Pharmaceutical Research, Nurnberg-Heroldsberg, 3Department of Hematology and Oncology, Marienhospital Herne, University Hospital of Bochum, 4Innere Klinik (Tumorforschung), West German Cancer Center, Universitatsklinikum Essen, 5Tumor Biology Center at the Albert-Ludwigs-University Freiburg, 6University Hospital of Freiburg, Department of Gastroenterology, Freiburg, Germany, and 7CESAR, Central European Society for Anticancer Drug Research, EWIV, Vienna, Austria

In this paper, we prove that the derivability problems for product-free Lambek calculus and product-free Lambek calculus allowing empty premises are NP-complete. Also we introduce a new derivability characterization for these calculi.

Introduction Nimotuzumab is a humanized monoclonal antibody that binds to the EGFR. Based on phase I data, the recommended dose has been established at 200 mg weekly. This study was aimed at evaluating the safety and efficacy of nimotuzumab monotherapy in patients (pts) with locally advanced or metastatic pancreatic cancer. Methods Pts who failed first line standard chemotherapy for advanced disease and had at least one measurable lesion were eligible for the study. Nimotuzumab was given intravenously at 200 mg once weekly for 6 weeks (wks). Follow up by CT scan was performed after 8 weeks. Pts continued receiving treatment 3-weekly until disease progression or unacceptable toxicity occurred. Endpoints included tumor response (RECIST), progression-free survival (PFS), and safety. Results A total of 56 pts were enrolled for treatment (ECOG status of 1 [n = 41] or 0 [n = 15]), the majority (47 pts) had metastatic disease. Nearly half of the pts [n = 26] received ≥2 regimens. Pts evaluable for response: n = 36; CR: 0; PR: 0; SD: 6 pts. Median PFS for pts with SD was 19.2 weeks, for all pts 6.7 weeks (95% CI: 6.43–7.14 weeks). PFS after 1 year was 10.3% with a median overall survival of 18.1 weeks. Treatment-related adverse events were generally mild including rash grade 1 in 5 pts. After a single dose of 200 mg, the t1/2 was calculated to 45 h. Conclusion These data confirm that nimotuzumab is safe and very well tolerated. To improve efficacy, a randomized, placebo-controlled trial with Gem has been initiated.