Resminostat plus sorafenib as second-line therapy of advanced hepatocellular carcinoma - The SHELTER study.

BACKGROUND & AIMS: No established therapies for patients with hepatocellular carcinoma (HCC) and progression on first-line sorafenib treatment currently exist. This phase I/II trial investigated safety, pharmacokinetics and potential biomarkers of the histone deacetylase inhibitor resminostat and a combination therapy with resminostat and sorafenib. METHODS: Patients with HCC and radiologically confirmed progression on sorafenib were treated in an exploratory, multi-center, open-label, uncontrolled, non-randomized, parallel group phase I/II study. In the combination group (n=38) four dose levels ranged from daily 200 to 600mg resminostat plus 400 to 800mg sorafenib. The monotherapy group (n=19) received 600mg resminostat. RESULTS: 57 patients received treatment. Most common adverse events were gastrointestinal disorders, thrombocytopenia and fatigue. Median maximal histone deacetylase inhibition and highest increase in H4-acetylation matched Tmax of resminostat. Sorafenib or the Child-Pugh score did not affect typical pharmacokinetics characteristics of resminostat. Efficacy assessment as progression-free survival-rate after 6 treatment cycles (12weeks, primary endpoint) was 12.5% for resminostat and 62.5% for resminostat plus sorafenib. Median time to progression and overall survival were 1.8 and 4.1months for resminostat and 6.5 and 8.0months for the combination, respectively. Zinc finger protein 64 (ZFP64) baseline expression in blood cells was found to correlate with overall survival. CONCLUSIONS: The combination of sorafenib and resminostat in HCC patients was safe and showed early signs of efficacy. Sorafenib did not alter the pharmacokinetic profile of resminostat or its histone deacetylase inhibitory activity in vivo. A prognostic and potentially predictive role of ZFP64 for treatment with resminostat should be further investigated in HCC and possibly other cancer indications. LAY SUMMARY: No established therapy for patients with advanced hepatocellular carcinoma and progression under first-line systemic treatment with sorafenib currently exists. Epigenetic modulation by inhibition of histone deacetylases might be able to overcome therapy resistance. This exploratory phase I/II clinical study in patients with radiologically confirmed progression under first-line treatment with sorafenib investigated the histone deacetylases inhibitor resminostat as single agent or in combination with continued application of sorafenib. CLINICAL TRIAL REGISTRATION: The clinical trial has been registered at www.clinicaltrials.gov as NCT00943449.

FOLFIRI and sunitinib as first-line treatment in metastatic colorectal cancer patients with liver metastases--a CESAR phase II study including pharmacokinetic, biomarker, and imaging data.

BACKGROUND: The aim of this study was the evaluation of pharmacokinetic parameters, biomarkers, clinical outcome, and imaging parameters in metastatic colorectal cancer (mCRC) patients treated with FOLFIRI plus sunitinib. METHODS: mCRC patients with liver metastases were treated with FOLFIRI and sunitinib as 1st line therapy. At protocol-defined time points, multicontrast magnetic resonance imaging (MRI)measurements, computed tomography (CT) scans, pharmacokinetics (PK), and biomarker analyses were performed during the first and second treatment cycle. Thereafter, patients were treated until tumor progression, investigator’s decision due to toxicity, or patient withdrawal. RESULTS: 28 patients were screened, 26 were included, and 23 received at least one study medication. Full safety analysis was performed in 23 patients. Full PK and biomarker analyses were performed in 21 patients. Strong responses in tumor size reduction forced a change from the original imaging timing scheme. This unforeseen change in the timing scheme resulted in subgroups too small for meaningful statistical analysis of most imaging parameters. Thus, only a descriptive analysis of the MRI data was possible. In 21/22 patients, MRI showeda decrease of the liver metastases. Best response was partial remission (PR) in 8/17 patients. Plasma concentrations of sVEGFR-2 and sVEGFR-3 decreased in all patients. The majority of the patients developed some kind of toxicity not always deducible to FOLFIRI or sunitinib. CONCLUSIONS: Due to the observed side effect profile, FOLFIRI plus sunitinib 37.5 mg per day cannot be recommended for previously untreated mCRC.

Preemptive tumor profiling for biomarker-stratified early clinical drug development in metastatic breast cancer patients.

Biomarker-stratified cancer pharmacotherapy was pioneered in the care of breast cancer patients. The utility of agents modulating hormone receptors, synthesis of steroid hormones, or HER2-targeting agents has been greatly enhanced by the detection of predictive biomarkers in diagnostic tumor samples. Based on deeper understanding of breast cancer biology multiple drug candidates have been developed to modulate additional molecular targets which may associate with specific biomarker profiles. Accordingly, exploratory biomarkers are increasingly incorporated in early clinical trials, thus demanding a new process of patient selection. Here, we describe the implementation of preemptive, multiplexed biomarker profiling linked to standard diagnostic algorithms for metastatic breast cancer patients treated at the West German Cancer Center. Profiling for experimental biomarkers was prospectively offered to patients with metastatic breast cancer who met generic clinical trial inclusion criteria. Formalin-fixed, paraffin-embedded tumor samples were retrieved and studied for potentially "actionable" biomarkers related to active clinical trials by immunohistochemistry, amplicon sequencing, and in situ hybridization. The clinical course of those "profiled" patients was closely monitored to offer trial participation whenever applicable. Here, we report results from the first 131 patients enrolled in this program. PIK3CA mutations (23 %) and amplifications (2 %), loss of PTEN expression (13 %), and FGFR1 amplifications (8 %) were detected next to established biomarkers such as estrogen (67 %) and progesterone receptor expression (52 %), and HER2 overexpression or amplification (23 %). So far 16 "profiled" patients (12 %) have been enrolled in biomarker-stratified early clinical trials. Preemptive profiling of investigational biomarkers can be integrated into the diagnostic algorithm of a large Comprehensive Cancer Center. Extensive administrative efforts are required to successfully enroll "profiled" patients with metastatic breast cancer in early clinical trials stratified by exploratory biomarkers.

A randomized, double-blind, placebo-controlled study to assess QTc interval prolongation of standard dose aflibercept in cancer patients treated with docetaxel.

: The effect of repeated doses of aflibercept on ventricular repolarization in cancer patients was evaluated in an intensive electrocardiogram trial. This randomized, placebo-controlled, double-blind trial was conducted in 87 treated solid tumor patients. Treatment was with 6 mg/kg aflibercept, 1-hour intravenous (n = 43), or placebo (n = 44), combined with ≤75 mg/m docetaxel, every 3 weeks. Electrocardiograms were collected for 6 hours posttreatment using digital 12-lead Holter recorders, at day 1, in cycles 1 and 3. Free and vascular endothelial growth factor-bound aflibercept concentrations were assessed at similar time points. Eighty-four patients (43 placebo and 41 aflibercept) were evaluable for QT interval, Fridericia correction (QTcF) at cycle 1 and 59 (31 placebo and 28 aflibercept) at cycle 3. During cycle 3, from 30 minutes to 6 hours after the start of aflibercept, the maximum observed upper limit of the QTcF 90% confidence interval was 16 ms, for a mean of 8.4 ms. QTcF prolongation above 480 ms and 60 ms above baseline was observed in 1 aflibercept patient (2%). The slope of the relationship between free aflibercept concentration and QTcF was 0.048 (95% confidence interval, 0.013-0.082), corresponding to a 5-ms increase per 100 µg/mL increase in concentration. These results exclude a clinically important effect of aflibercept on ventricular repolarization.

Chemosensitivity of conjunctival melanoma cell lines to target-specific chemotherapeutic agents.

OBJECTIVE: In conjunctival melanoma, local chemotherapy has been based so far on clinical evidence and limited to the therapy of melanoma in situ. Our aim was to define substances that may have the potential to add to therapeutic options in extended local growth and metastatic disease. Two conjunctival cell lines (CRMM-1 and CRMM-2) have been established from recurrent conjunctival melanoma. In this study, we examined the chemosensitivity of these cell lines to different cytotoxic substances. MATERIALS AND METHODS: The cell lines CRMM-1 and CRMM-2 were exposed to chemotherapeutics for 24 h and the IC50 was generated. Sulforhodamin-B assays were used for quantification of in vitro efficacy. Time of exposure and escalating concentrations of the substances were adapted to the experimental setting. RESULTS: Bortezomib, clusianone 502 (nemorosone), ranpirnase, and sorafenib were efficient in inhibiting the growth of conjunctival melanoma cell lines. The IC50 achieved concentrations below or around 10 µM for these substances. CONCLUSIONS: Bortezomib, clusianone 502, ranpirnase, and sorafenib inhibited growth in conjunctival melanoma cell lines efficiently. The new substances may be a suitable alternative for local therapy. New therapeutic options with highly specific targeted agents for metastatic disease have to be evaluated in further experiments.

Relationship between baseline hepatic status and outcome, and effect of sorafenib on liver function: SHARP trial subanalyses.

BACKGROUND & AIMS: Hepatic markers are utilized in many classification systems of patients with hepatocellular carcinoma and, by measuring organ damage and tumor stage, can influence treatment. Moreover, elevated serum concentrations of aminotransferases and alpha-fetoprotein are indicators of poor prognosis in patients with hepatocellular carcinoma. We examined the effects of sorafenib on hepatic markers by performing exploratory subset analyses of the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial in patients categorized by baseline concentrations of alanine aminotransferase/aspartate aminotransferase, alpha-fetoprotein, and bilirubin; and by evaluating the effects of sorafenib on bilirubin concentrations during treatment. METHODS: Patients (n=602) were grouped by baseline concentrations of alanine aminotransferase/aspartate aminotransferase (not significantly elevated, mildly elevated, or moderately elevated), alpha-fetoprotein (normal or elevated), and bilirubin (normal or elevated). Bilirubin was measured at baseline and on day 1 of each cycle. RESULTS: Patients with elevated baseline concentrations of alanine aminotransferase/aspartate aminotransferase, alpha-fetoprotein, or bilirubin had shorter overall survival (OS) than those with normal baseline concentrations, irrespective of treatment group. No notable differences in safety profiles were observed between patients with normal vs. elevated alanine aminotransferase/aspartate aminotransferase, alpha-fetoprotein, or bilirubin. Median changes from baseline in bilirubin concentration at the last cycle of treatment were +0.17 and +0.19 mg/dl in the sorafenib and placebo groups, respectively. CONCLUSIONS: These subset analyses suggest that sorafenib is safe and effective for hepatocellular carcinoma, irrespective of baseline alanine aminotransferase/aspartate aminotransferase, alpha-fetoprotein, or bilirubin concentration and that hepatic function remains stable over the course of sorafenib therapy.

Results of a phase II trial of S-1 as first-line treatment of metastatic pancreatic cancer (CESAR-study group).

PURPOSE: S-1, an oral fluoropyrimidine derivative, has previously demonstrated anticancer efficacy in pancreatic cancer (PC), predominantly in Asian populations. This study evaluated the antitumor effect and safety of S-1 in Caucasian patients with metastatic PC. METHODS: Chemotherapy-naïve patients received S-1 orally at 30 mg/m(2) twice daily (BID) for 2 weeks, repeated every 3 weeks. Primary endpoint was ORR. Secondary endpoints included PFS, OS and safety assessment. The trial had a Simon's two-stage design with 22 patients evaluable for efficacy in stage 1 and an additional 18 patients in stage 2, if ≥3/22 patients had a confirmed response at the first stage. RESULTS: Three out of 27 patients showed PR, however, detection of asymptomatic brain metastases in one of them prevented this study from proceeding to stage 2. The median PFS and OS for all patients was 3.5 and 9.1 months, respectively. The median duration of disease control for patients with SD or PR (n = 17) was 4.3 months. S-1 was well tolerated; fatigue was the most frequent grade 3/4 adverse event. CONCLUSIONS: Efficacy data of PFS and OS are at least comparable to gemcitabine, the current standard of care. S-1 is active in Caucasian patients with metastatic PC.

Assessment of sorafenib induced changes in tumor perfusion of uveal melanoma metastases with dynamic contrast-enhanced ultrasound (DCE-US).

PURPOSE: Dynamic contrast-enhanced ultrasound (DCE-US) was used to monitor early response to sorafenib therapy in patients with liver metastases from uveal melanoma. METHODS: In total, 21 patients with liver metastases were recruited within a prospective trial and underwent daily sorafenib therapy. DCE-US of a target lesion was performed before initiation of treatment, on day 15 and 56. Two independent blinded investigators performed software analysis for DCE-US parameters and inter-observer-correlation was calculated. Response to treatment was evaluated on day 56. DCE-US parameters were correlated with clinical response and RECIST1.1 criteria. RESULTS: Inter-observer-correlation (r) of DCE-US parameters [time-to-peak (TTP), mean-transit-time (MTT), peak intensity (PI), regional blood volume (RBV), regional blood flow (RBF)] at baseline, day 15, and day 56 was highly significant (r-range 0.73-0.97, all p < 0.001). Out of 17 evaluable patients, 12 patients survived day 56 (clinical responders, cRE), whereas, five patients died before day 56 and were classified as non-responders (cNR). TTP values significantly increased in the cRE group 15 days after initiation of treatment for investigator 1 (p = 0.034) and at day 56 for both investigators (p = 0.028/0.028). MTT had increased significantly in the cRE group on day 56 (p = 0.037/0.022). In the cNR group changes for TTP and MTT remained insignificant. Thus, increase of the DCE-US parameters TTP and MTT are associated with response to treatment and prognosis. CONCLUSION: An increase of TTP and MTT at frequent intervals could serve as a surrogate marker for early response evaluation to anti-angiogenic treatment of metastatic uveal melanoma.

Improved survival in metastatic breast cancer: results from a 20-year study involving 1033 women treated at a single comprehensive cancer center.

PURPOSE: Diagnosis and treatment of breast cancer have changed profoundly over the past 25 years. The outcome improved dramatically and was well quantified for early stage breast cancer (EBC). However, progress in the treatment of metastatic disease has been less convincingly demonstrated. We have studied survival data of patients with metastatic breast cancer (MBC) from a large academic cancer center over a period of 20 years. METHODS: Data from 1033 consecutive MBC patients who were treated at the Department of Medical Oncology of the West German Cancer Center from January 1990 to December 2009 were retrospectively analyzed for overall survival (OS) and risk factors. Patients were grouped in 5-year cohorts, and survival parameters of each cohort were compared before and after adjustment for risk factors. RESULTS: Overall survival of patients with MBC treated at specialized center has significantly improved from 1990 to 2010 (hazard ratio 0.7, 95%CI 0.58-0.84). The increments in OS have become less profound over time (median OS 1990-1994: 24.2 months, 1995-1999: 29.6 months, 2000-2004: 36.5 months, 2005-2009: 37.8 months). CONCLUSION: Survival of patients with MBC has improved between 1990 and 2004, but less from 2005 to 2009. Either this suggests an unnoticed shift in the patient population, or a lesser impact of therapeutic innovations introduced in the most recent period.

Pharmacokinetics of a novel anticancer ruthenium complex (KP1019, FFC14A) in a phase I dose-escalation study.

A phase I and pharmacokinetic study was carried out with the new ruthenium complex indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019, FFC14A). Seven patients with various types of solid tumours refractory to standard therapy were treated with escalating doses of KP1019 (25-600 mg) twice weekly for 3 weeks. No dose-limiting toxicity occurred. Ruthenium plasma concentration-time profiles after the first dose and under multiple-dose conditions were analysed using a compartmental approach. The pharmacokinetic disposition was characterised by a small volume of distribution, low clearance and long half-life. Only a small fraction of ruthenium was excreted renally. The area under the curve values increased proportionally with dose indicating linear pharmacokinetics.

Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors.

PURPOSE: BAY 43-9006 is a novel dual-action Raf kinase and vascular endothelial growth factor receptor inhibitor that inhibits tumor cell proliferation and angiogenesis. This study established the safety and pharmacokinetics of BAY 43-9006 in 69 patients with advanced refractory solid tumors. PATIENTS AND METHODS: BAY 43-9006 (50 to 800 mg) was administered once or twice daily on a varying weekly schedule. Pharmacokinetic sampling was performed in all patients; preliminary tumor response was also assessed. The effect of BAY 43-9006 on phorbol myristate acetate-stimulated ERK phosphorylation in peripheral blood lymphocytes was studied using flow cytometry. RESULTS: Mild to moderate diarrhea was the most common (55%) treatment-related adverse event. The maximum-tolerated dose was 400 mg bid continuous. Dose-limiting toxicities were grade 3 diarrhea and fatigue at 800 mg bid, and grade 3 skin toxicity at 600 mg bid. BAY 43-9006 pharmacokinetics were highly variable for single and multiple dosing, and toxicity did not appear to be dose dependent. Significant decreases of phorbol myristate acetate-stimulated ERK phosphorylation (P < .01) were identified at doses >/= 200 mg bid continuous. Forty-five patients were assessable for efficacy; one patient had a partial response (hepatocellular carcinoma at 400 mg bid continuous), 25 patients had stable disease, with eight lasting > 6 months and five for >12 months. Eighteen patients had progressive disease, and tumor response could not be evaluated in one patient. CONCLUSION: Oral BAY 43-9006 was well tolerated and appeared to provide some clinical benefits. Based on the results of this study, BAY 43-9006 at 400 mg bid continuous is recommended for ongoing and future studies.

Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer.

PURPOSE: In this study, two doses of temsirolimus (CCI-779), a novel inhibitor of the mammalian target of rapamycin, were evaluated for efficacy, safety, and pharmacokinetics in patients with locally advanced or metastatic breast cancer who had been heavily pretreated. PATIENTS AND METHODS: Patients (n = 109) were randomly assigned to receive 75 or 250 mg of temsirolimus weekly as a 30-minute intravenous infusion. Patients were evaluated for tumor response, time to tumor progression, adverse events, and pharmacokinetics of temsirolimus. RESULTS: Temsirolimus produced an objective response rate of 9.2% (10 partial responses) in the intent-to-treat population. Median time to tumor progression was 12.0 weeks. Efficacy was similar for both dose levels but toxicity was more common with the higher dose level, especially grade 3 or 4 depression (10% of patients at the 250-mg dose level, 0% at the 75-mg dose level). The most common temsirolimus-related adverse events of all grades were mucositis (70%), maculopapular rash (51%), and nausea (43%). The most common, clinically important grade 3 or 4 adverse events were mucositis (9%), leukopenia (7%), hyperglycemia (7%), somnolence (6%), thrombocytopenia (5%), and depression (5%). CONCLUSION: In heavily pretreated patients with locally advanced or metastatic breast cancer, 75 and 250 mg temsirolimus showed antitumor activity and 75 mg temsirolimus showed a generally tolerable safety profile.

A phase I study of BI 811283, an Aurora B kinase inhibitor, in patients with advanced solid tumors.

PURPOSE: This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and antitumor activity of the Aurora B kinase inhibitor BI 811283 in patients with advanced solid tumors. METHODS: BI 811283 was administered via 24-h infusion on Days 1 and 15 of a 4-week cycle (schedule A) or Day 1 of a 3-week cycle (schedule B) in a modified 3 + 3 dose-escalation design. Pharmacodynamic assessments included immunohistochemistry for phosphorylated histone H3 (pHH3) on skin biopsies to determine Aurora B kinase inhibition and plasma concentrations of caspase-cleaved CK-18 (apoptosis marker). RESULTS: A total of 121 patients were treated. The MTDs of BI 811283 were 125 mg (schedule A) and 230 mg (schedule B). Dose-limiting toxicities were primarily hematological (febrile neutropenia and grade 4 neutropenia); the most common drug-related adverse effects included neutropenia, fatigue, leukopenia, nausea, alopecia, diarrhea, and decreased appetite. A trend toward a decrease in pHH3 was observed, with increasing BI 811283 doses, indicating target engagement; there was no consistent trend regarding caspase-cleaved CK-18 levels. No objective response was observed although 19 patients in each schedule achieved clinical benefit (stable disease). CONCLUSIONS: BI 811283 demonstrated a generally manageable safety profile and disease stabilization in some patients. TRIAL REGISTRATION: EudraCT No: 2007-000191-17, ClinicalTrials.gov Identifier: NCT00701324.

Results of a phase I trial of sorafenib (BAY 43-9006) in combination with oxaliplatin in patients with refractory solid tumors, including colorectal cancer.

BACKGROUND: Sorafenib (BAY 43-9006), a multiple kinase inhibitor, has been shown to inhibit tumor growth and tumor angiogenesis by targeting Raf kinase, vascular endothelial growth factor receptor, and platelet-derived growth factor receptor. In phase I studies, sorafenib demonstrated single-agent activity in patients with advanced solid tumors and was successfully combined with oxaliplatin in preclinical studies. This phase I study investigated the safety, pharmacokinetics, and efficacy of sorafenib in combination with oxaliplatin. PATIENTS AND METHODS: Twenty-seven patients with refractory solid tumors were enrolled in the initial dose-escalation part (cohorts 1, 2A, and 2B) and 10 additional patients with oxaliplatin-refractory colorectal cancer were subsequently enrolled in an extension part (cohort 3). Oxaliplatin 130 mg/m2 was given on day 1 of a 3-week cycle and oral sorafenib was administered continuously from day 4 of cycle 1 at 200 mg twice daily (cohort 1) or 400 mg twice daily (cohorts 2A, 2B, and 3). RESULTS: Adverse events were generally mild to moderate and the maximum tolerated dose was not reached. Common adverse events were diarrhea (52% of patients in the dose-escalation part and 20% in the extension part), sensory neuropathy (44% and 20%), and dermatologic toxicities (41% and 80%). No pharmacokinetic interaction between sorafenib and oxaliplatin was detectable. Two patients with gastric cancer had a partial response. Forty-three percent of patients in cohorts 1 and 2A/B and 78% of patients in cohort 3 exhibited stable disease for >or=10 weeks. CONCLUSION: Continuous oral sorafenib 400 mg twice daily was safely combined with oxaliplatin without detectable drug interactions and showed preliminary antitumor activity in this phase I study. This dose is recommended for phase II studies.

Phase II trial of cisplatin, gemcitabine and treosulfan in patients with metastatic uveal melanoma.

Gemcitabine plus treosulfan (GeT) is under investigation in metastatic uveal melanoma. In this phase II trial, cisplatin was added to a GeT regimen to investigate the efficacy and toxicity of two alkylating agents in combination with gemcitabine. Patients received 30 or 40 mg/m of cisplatin, 1000 mg/m of gemcitabine and 3000 mg/m of treosulfan on days 1 and 8. Therapy was repeated on day 29. A maximum of six cycles was administered. Nineteen patients were included in the trial, of whom 17 were evaluable for response. No objective response was observed; seven patients (41%) had stable disease and 10 (59%) progressed. The median progression-free survival of all 19 patients was 3.0 months [95% confidence interval (CI), 1.8-3.1]; the median overall survival was 7.7 months (95% CI, 1.9-13.8). Grade 3 and 4 thrombopenia and leucopenia occurred in eight and nine of the 19 patients, respectively. The addition of cisplatin to the GeT regimen results in excessive haematological toxicity without improvement in efficacy.

Impact of the expression of P glycoprotein, the multidrug resistance-related protein, bcl-2, mutant p53, and heat shock protein 27 on response to induction therapy and long-term survival in patients with de novo acute myeloid leukemia.

OBJECTIVE: Resistance to chemotherapy-induced apoptosis and a multidrug-resistance phenotype is the major problem in the treatment of acute myeloid leukemia (AML). PATIENTS AND METHODS: We recently demonstrated that the coexpression of at least two proteins, including P glycoprotein, multidrug resistance-related protein, bcl-2 (flow cytometry), p53 (luminometric immunoassay), and heat shock protein 27 (Western blotting), was predictive for response to induction therapy in de novo AML comparing leukemic blasts of 20 responders with 20 nonresponders. After long-term follow-up, we now present our evaluation on the prognostic significance of these proteins in leukemic blasts of 124 untreated AML patients with regard to the probability of remission (PoR) and overall survival (OS). RESULTS: Analyzing leukemic blasts obtained from bone marrow samples, we found that no single protein significantly correlated with PoR or OS. In contrast, the coexpression of at least two of these proteins was predictive for reduced OS in univariate as well as multivariate analysis. Although we could not identify any particular protein combination predictive for reduced OS, those patients with no or only one protein expressed in their leukemic blasts had a survival probability of 48% in contrast to 24% in those patients with the coexpression of two or more proteins. Among the clinical markers, only response to chemotherapy had a significant effect on OS and age was of prognostic relevance for PoR. CONCLUSION: We conclude that overexpression of only one protein possibly involved in resistance, is not sufficient to influence the prognosis for long-term survival in AML, whereas the expression of more than one protein is predictive for reduced OS. Protein combination seems to be individually different, and targeting only one protein in further clinical trials may not help to overcome multifactorial resistance.

Clinical Benefit and Health-Related Quality of Life Assessment in Patients Treated with Cisplatin/S-1 Versus Cisplatin/5-FU: Secondary End Point Results From the First-Line Advanced Gastric Cancer Study (FLAGS).

PURPOSE: Patient-reported outcomes (PRO) of health-related quality of life (HRQoL) and time to worsening of clinical benefit parameters were evaluated as secondary end points in the phase 3 first-line advanced gastric cancer study (FLAGS) trial of cisplatin/S-1 versus cisplatin/5-fluorouracil (5-FU) in patients with previously untreated advanced gastric cancer. METHODS: The primary PRO end point was the Trial Outcome Index of the Functional Assessment of Cancer Therapy-Gastric (FACT-Ga). FACT-Ga was completed at the beginning of the first 4 cycles, cycle 6, and then every 3 cycles thereafter. The Chemotherapy Convenience and Satisfaction Questionnaire (CCSQ) was administered before the first 4 cycles; clinical benefit parameters (performance status, weight loss, and anorexia) were assessed at baseline, prior to study drug administration on day 1 of each cycle after cycle 1, and at the end of study treatment. RESULTS: Compliance to questionnaire fulfillment was more than 80 % through cycle 9. Significantly, fewer patients treated with cisplatin/S-1 reported worsened physical well-being (PWB) scores (45.1 versus 51.7 %, p = 0.044) and experienced significantly longer time to worsening in PWB scores, with a median of 4.5 months (95 % confidence interval (CI), 3.1-5.1) compared to 3.0 months (2.8-4.6) with cisplatin/5-FU (CF) (p = 0.01). Patients receiving cisplatin/S-1 also reported significantly higher best and worst score of PWB as well as CCSQ scores and a longer median time to worsening in clinical benefit parameters. CONCLUSIONS: Differences in secondary end points of PWB, CCSQ scores, and clinical benefit parameters favoring the cisplatin/S-1 arm provide further evidence for considering this combination a standard therapeutic option for first-line treatment of advanced gastric cancer.

Phase I clinical study of the toll-like receptor 9 agonist MGN1703 in patients with metastatic solid tumours.

PURPOSE: This study was initiated to evaluate safety, toxicity, pharmacokinetics, and pharmacodynamics of treatment with MGN1703, a novel synthetic DNA-based toll-like receptor 9 (TLR9)-immunomodulator. METHODS: The study consisted of an escalating single dose regimen followed by a multiple dose part. Dose levels of 0.25, 2, 10, 30, and 60 mg of MGN1703 were administered subcutaneously over 6 weeks twice weekly. Patients with at least stable disease (SD) could participate in the extension phase of the study for six further weeks. Effects on the immune status were monitored. RESULTS: 28 patients with metastatic solid tumours were included. Fatigue and activated partial thromboplastin time (aPTT) prolongation were the only two cases of drug-related grade 3 Common Terminology Criteria adverse events (CTCAE). The most frequently reported drug-related adverse events were of CTC Grade ⩽2. There was no relationship between toxicity and dose and no patient was withdrawn from the study due to drug-related AE. No drug-related serious AE (SAE) were reported. Six out of 24 patients had SD after 6 weeks of treatment and three of those remained in SD after a total of 12 weeks. Four patients were further treated in a compassionate use programme showing long-term disease stabilisation for up to 18 months. Immune assessment of cell compartments showed a non-significant increase of TLR9 expressing naïve B cells during therapy. CONCLUSION: Twice weekly subcutaneous applications of MGN1703 in a dose of up to 60 mg are safe and well tolerated without dose-limiting toxicities. MGN1703 shows immune activation and anti-tumour efficacy in heavily pretreated patients. The recommended dose of 60 mg twice weekly is currently used in a phase II trial in small cell lung cancer and a phase III trial in colorectal cancer patients.

A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas.

BACKGROUND: Trametinib, an oral mitogen/extracellular signal-related kinase (MEK)1/2 inhibitor, holds promise for malignancies with rat sarcoma (RAS) mutations, like pancreas cancer. This phase II study was designed to determine overall survival (OS) in patients with pancreas cancer treated with trametinib and gemcitabine. Secondary end-points included progression-free survival (PFS), overall response rate (ORR) and duration of response (DOR); safety end-points were also assessed. METHODS: Adults with untreated metastatic adenocarcinoma of the pancreas were randomised (1:1) to receive intravenous gemcitabine 1000 mg/m(2) (weekly × 7 for 8 weeks, then days 1, 8 and 15 of 28-day cycles) plus trametinib or placebo 2mg daily. RAS mutations were determined in circulating free DNA (cfDNA) and archival tumour tissue. OS was evaluated in kirsten rat sarcoma viral oncogene homolog (KRAS) mutant and wild-type subgroups. RESULTS: Baseline characteristics for 160 patients were similar in both treatment arms. There was no significant difference in OS (hazard ratio (HR) 0.98; 95% confidence interval (CI), 0.67-1.44; P=.453); median OS was 8.4 months with gemcitabine plus trametinib and 6.7 months with gemcitabine plus placebo. Median PFS (16 versus 15 weeks), ORR (22% versus 18%) and median DOR (23.9 versus 16.1 weeks) were also similar for trametinib and placebo arms, respectively. KRAS mutation-positive patients (n=103) showed no difference in OS between arms. Thrombocytopenia, diarrhoea, rash and stomatitis were more frequent with trametinib, as was grade 3 anaemia. CONCLUSIONS: The addition of trametinib to gemcitabine did not improve OS, PFS, ORR or DOR in patients with previously untreated metastatic pancreas cancer. Outcomes were independent of KRAS mutations determined by cfDNA.

Ultradeep sequencing detects GNAQ and GNA11 mutations in cell-free DNA from plasma of patients with uveal melanoma.

Elevated levels of cell-free DNA (cfDNA) are frequently observed in tumor patients. Activating mutations in exon 4 (R183) and exon 5 (Q209) of GNAQ and GNA 11 are almost exclusively found in uveal melanoma, thus providing a highly specific marker for the presence of circulating tumor DNA (ctDNA). To establish a reliable, noninvasive assay that might allow early detection and monitoring of metastatic disease, we determined the proportion of GNAQ or GNA 11 mutant reads in cfDNA of uveal melanoma patients by ultradeep sequencing. Cell-free DNA from 28 uveal melanoma patients with metastases or extraocular growth was isolated and quantified by real-time polymerase chain reaction (PCR) (7-1550 ng DNA/mL plasma). GNAQ and GNA 11 regions of interest were amplified in 22 of 28 patients and ultradeep sequencing of amplicons was performed to detect even low proportions of mutant reads. We detected Q209 mutations (2-38% mutant reads) in either GNAQ or GNA 11 in the plasma of 9 of 22 metastasized patients. No correlation between the proportion of mutant reads and the concentration of cfDNA could be detected. Among the nine ctDNA-positive patients, four had metastases in bone, whereas no metastases were detected in the 13 ctDNA-negative patients at this location (P = 0.025). Furthermore, ctDNA-positive patients tended to be younger at initial diagnosis and show larger metastases. The results show that ultradeep amplicon sequencing can be used to detect tumor DNA in plasma of metastasized uveal melanoma patients. It remains to be shown if this approach can be used for early detection of disseminated tumor disease.