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Mutació del MET; Capmatinib Mutación del MET; Capmatinib MET mutation; Capmatinib Background Dysregulation of receptor tyrosine kinase MET by various mechanisms occurs in 3%–4% of non-small-cell lung cancer (NSCLC) and is associated with unfavorable prognosis. While MET is a validated drug target in lung cancer, the best biomarker strategy for the enrichment of a susceptible patient population still remains to be defined. Towards this end we analyze here primary data from a phase I dose expansion study of the MET inhibitor capmatinib in patients with advanced MET-dysregulated NSCLC. Patients and methods Eligible patients [≥18 years; Eastern Cooperative Oncology Group (ECOG) performance status ≤2] with MET-dysregulated advanced NSCLC, defined as either (i) MET status by immunohistochemistry (MET IHC) 2+ or 3+ or H-score ≥150, or MET/centromere ratio ≥2.0 or gene copy number (GCN) ≥5, or (ii) epidermal growth factor receptor wild-type (EGFRwt) and centrally assessed MET IHC 3+, received capmatinib at the recommended dose of 400 mg (tablets) or 600 mg (capsules) b.i.d. The primary objective was to determine safety and tolerability; the key secondary objective was to explore antitumor activity. The exploratory end point was the correlation of clinical activity with different biomarker formats. Results Of 55 patients with advanced MET-dysregulated NSCLC, 40/55 (73%) had received two or more prior systemic therapies. All patients discontinued treatment, primarily due to disease progression (69.1%). The median treatment duration was 10.4 weeks. The overall response rate per RECIST was 20% (95% confidence interval, 10.4–33.0). In patients with MET GCN ≥6 (n = 15), the overall response rate by both the investigator and central assessments was 47%. The median progression-free survival per investigator for patients with MET GCN ≥6 was 9.3 months (95% confidence interval, 3.8–11.9). Tumor responses were observed in all four patients with METex14. The most common toxicities were nausea (42%), peripheral edema (33%), and vomiting (31%). Conclusions MET GCN ≥6 and/or METex14 are suited to predict clinical activity of capmatinib in patients with NSCLC (NCT01324479). This study was funded by Novartis Pharmaceuticals Corporation.

Background This study evaluated tumor response to olaratumab (an anti-PDGFRα monoclonal antibody) in previously treated patients with metastatic gastrointestinal stromal tumor (GIST) with or without PDGFRα mutations (cohorts 1 and 2, respectively). Patients and methods Patients received olaratumab 20 mg/kg intravenously every 14 days until disease progression, death, or intolerable toxicity occurred. Outcome measures were 12-week tumor response, progression-free survival (PFS), overall survival (OS), and safety. Results Of 30 patients enrolled, 21 patients received ≥1 dose of olaratumab. In the evaluable population (cohort 1,n=6; cohort 2,n=14), no complete response (CR) or partial response (PR) was observed. Stable disease (SD) was observed in 3 patients (50.0%) in cohort 1 and 2 patients (14.3%) in cohort 2. Progressive disease (PD) was observed in 3 patients (50.0%) in cohort 1 and 12 patients (85.7%) in cohort 2. The 12-week clinical benefit rate (CR + PR + SD) (90% CI) was 50.0% (15.3–84.7%) in cohort 1 and 14.3% (2.6–38.5%) in cohort 2. SD lasted beyond 12 weeks in 5 patients (cohort 1,n=3; cohort 2,n=2). Median PFS (90% CI) was 32.1 (5.0–35.9) weeks in cohort 1 and 6.1 (5.7–6.3) weeks in cohort 2. Median OS was not reached in cohort 1 and was 24.9 (14.4–49.1) weeks in cohort 2. All patients in cohort 1 and 9 (64.3%) in cohort 2 experienced an olaratumab-related adverse event (AE), most commonly fatigue (38.1%), nausea (19.0%), and peripheral edema (14.3%). Two grade ≥3 olaratumab-related events were reported (cohort 1, syncope; cohort 2, hypertension). Conclusions Olaratumab had an acceptable AE profile in patients with GIST. While there was no apparent effect on PFS in patients without PDGFRα mutations, patients with PDGFRα-mutant GIST (all with D842V mutations) treated with olaratumab had longer disease control compared with historical data for this genotype. ClinicalTrials.gov Identifier NCT01316263.

Background Activating MET exon 14 skipping (METex14) mutations can be detected by liquid biopsy (LBx) or tumor biopsy (TBx) and are sensitive to MET inhibition. We report interim data from the phase II VISION study of tepotinib, a highly selective MET inhibitor, in NSCLC patients with METex14 mutations (NCT02864992). Methods Patients (pts) with advanced EGFR/ALK wild-type NSCLC harboring METex14 mutation identified by RNA-based testing with LBx or TBx (both ≥60 pts; overlap of LBx/TBx anticipated), enrolled at 113 sites in 8 countries (13 sites in Japan), receive tepotinib 500mg QD until progression, intolerable toxicity or withdrawal. Primary endpoint is ORR by independent review committee (IRC); secondary endpoints include investigator assessed ORR (INV) and safety. Results To date, 90 pts are enrolled, 15 are from Japan. At data cut-off (16/10/2018), in 35 evaluable LBx pts ORR (95% CI) was 51.4% (34.0, 68.6) by IRC with a median duration of response (mDoR) (range) of 9.8 months (1.1, 18.0) and 63.9% (46.2, 79.2) by INV with a mDOR of 17.1 months (1.3, 21.5). In 41 evaluable TBx pts, ORR was 41.5% (26.3, 57.9) by IRC and 58.5% (42.1, 73.7) by INV; mDoR was 12.4 months (1.1, 18.0; IRC) and 14.3 months (1.3, 21.5; INV). Of 11 evaluable Japanese pts, 6 were METex14 positive by LBx and 9 by TBx (overlap occurred). Confirmed responses were reported in 4/6 LBx pts and 3/9 TBx pts by IRC and in 4/6 LBx pts and 4/9 TBx pts by INV. Safety was evaluable in 69 pts. Main treatment-related adverse events (TRAEs; ≥15%) of any grade were peripheral edema (47.8%), diarrhea (18.8%), nausea (15.9%). The safety profile was similar in Japanese pts. TRAEs led to permanent discontinuation in 2 (2.9%) pts (1 ILD, 1 diarrhea & nausea). No TRAEs led to death. Conclusion In NSCLC pts with METex14 mutations, tepotinib had promising clinical efficacy. Similar activity was observed in Japanese pts. The safety profile was favorable. Recruitment, including a MET amplification cohort, is ongoing.

Background Forodesine is a potent inhibitor of purine nucleoside phosphorylase (PNP) that leads to intracellular accumulation of deoxyguanosine triphosphate (dGTP) in T and B cells, resulting in apoptosis. Forodesine has demonstrated impressive antitumor activity in early phase clinical trials in cutaneous T-cell lymphoma (CTCL). Patients and methods In this phase II study, patients with CTCL who had already failed three or more systemic therapies were recruited. We investigated the response rate, safety and tolerability of oral forodesine treatment in subjects with cutaneous manifestations of CTCL, stages IB, IIA, IIB, III and IVA. The safety population encompassing all stages was used for analysis of accountability, demographics and safety. The efficacy population differed from the safety population by exclusion of stage IB and IIA patients. Results All 144 patients had performance status 0–2. The median duration of CTCL from diagnosis was 53 months (5–516 months). The median number of pretreatments was 4 (range: 3–15). No complete remissions were observed. In the efficacy group of patients, 11% achieved partial remission and 50% had stable disease. The median time to response was 56 days and the median duration of response was 191 days. A total of 96% of all treated patients reported one or more adverse events (AEs) and 33% reported a serious AE. The majority of AEs were classified as mild or moderate in severity. The most commonly reported AEs (>10%) were peripheral edema, fatigue, insomnia, pruritus, diarrhea, headache and nausea. Overall eight patients died during the study: five due to sepsis and infections, one due to a second malignancy (esophageal cancer), one due to disease progression and one due to liver failure. Conclusion Oral forodesine at a dose of 200 mg daily is feasible and shows partial efficacy in this highly selected CTCL population and some durable responses.

Contains fulltext : 138254.pdf (Publisher’s version ) (Closed access) BACKGROUND: The randomized, double-blind phase III AFFIRM trial demonstrated that enzalutamide, an oral androgen receptor inhibitor, significantly prolonged overall survival (OS) [median 18.4 versus 13.6 months (hazard ratio, HR) 0.63 (95% confidence interval, CI, 0.53-0.75); P/=75 years) patients in the AFFIRM population. Statistics are presented by age group (/=75 years) for efficacy outcomes of OS, radiographic progression-free survival (rPFS), time to prostate-specific antigen (PSA) progression, PSA response, and safety. RESULTS: OS was significantly improved with enzalutamide over placebo in patients/=75 years [median 18.2 versus 13.3 months; HR 0.61 (95% CI 0.43-0.86), P=0.004], respectively. rPFS was similarly improved in both the younger [HR 0.45 (95% CI 0.38-0.53), P/=75 years in the rates of all grade peripheral edema (22.1% versus 12.5%), fatigue (39.7% versus 31.6%), and diarrhea (26.6% versus 19.6%). The overall grade>/=3 AE rates were low with no major difference in frequency or severity between age groups or treatment arms. Five patients were reported with seizure events; three patients/=75 years. CONCLUSIONS: Enzalutamide significantly improves outcomes in both younger (/=75 years), with comparable safety and tolerability.

Background: To explore the association between hydration volume and symptoms during the last 3 weeks of life in terminally ill cancer patients. Patients and methods: This was a multicenter, prospective, observational study of 226 consecutive terminally ill patients with abdominal malignancies. Primary responsible physicians and nurses evaluated the severity of membranous dehydration (dehydration score calculated from three physical findings), peripheral edema (edema score calculated from seven physical findings), ascites and pleural effusion (rated as physically undetectable to symptomatic), bronchial secretion, hyperactive delirium (Memorial Delirium Assessment Scale), communication capacity (Communication Capacity Scale), agitation (Agitation Distress Scale), myoclonus and bedsores. Results: Patients were classified into two groups: the hydration group (n = 59) who received 1 l or more of artificial hydration per day, 1 and 3 weeks before death, and the non-hydration group (n = 167). The percentage of patients with deterioration in dehydration score in the final 3 weeks was significantly higher in the non-hydration group than the hydration group (35% versus 14%; P = 0.002), while the percentages of patients whose symptom scores for edema, ascites and pleural effusion increased were significantly higher in the hydration group than the non-hydration group (44% versus 29%, P = 0.039; 29% versus 8.4%, P

Summary Background Current regimens for treatment of distant metastases of soft tissue sarcomas result in response rates of about 25%. Therefore the search for active drugs remains a task for investigationaJ groups. Taxoids offer a new class of cytostatic drugs. Docetaxel has been studied as a second line chemotherapy in advanced soft tissue sarcomas of the adult. Patients and methods In a multi-center non-randomized phase II study docetaxel was administered at a dose of 100 mg/m2 in a 1-hour i.v. infusion q 3 weeks. Results Twenty-nine patients (pts), median age 52 yr, performance status WHO 0: 16 pts, WHO 1: 11 pts, WHO 2: 2 pts, were eligible. One patient had early death due to malignant disease, 1 patient died due to toxicity and progression, 1 pt refused after 1 course. Five partial responses (5/29 – 17%, C.I. 6%–36%) have been observed. Grade ≥3 leucopenia occurred in 76% of patients and grade ≥3 thrombopenia did not occur. Median nadir of neutrophils was 0.23 × 109/1. Episodes of fever and documented infection have been observed in 10 and 5 pts respectively. Anaphylactoid type reactions occurred in 5 patients: ranging from flushing in 5 pts to cardiovascular symptoms in 1 pt. Sensory neurotoxicity was observed in 14 pts grade 1: 10 pts, grade 2: 3 pts, grade 3: 1 pt). Grade 1 motor neurotoxicity was experienced by 3 pts. Skin reactions (pruritus, erythema, urticaria, exfoliation grade 1: 11 pts, grade 2: 7 pts, grade 3: 1 pt, grade 4: 1 pt) in 20 pts, among them 9 patients with nail changes. Peripheral edema and fluid retention has been observed in 12 pts. Conclusion Taxotere has activity in adult soft tissue sarcoma in second line, warranting studies on first line efficacy.

Aim: Axitinib is approved globally in patients with advanced renal cell carcinoma (RCC) who failed one prior therapy. Although tyrosine kinase inhibitors have been available to treat RCC since 2005, long-term safety data are limited. Here we report long-term safety results with single-agent axitinib in advanced RCC, using pooled data from 14 clinical trials conducted from Apr 2002 to Oct 2013. Methods: In the 14 studies included, starting dose of oral axitinib was 5 mg twice daily continuously. Dose interruptions and modifications were allowed per protocols. Common, long-term, treatment-emergent adverse events (AEs) were identified in patients who received axitinib ≥2 yr; these AEs were then evaluated in all patients. Analyses conducted were 1) interval analysis of AEs over successive treatment periods (0– Results: As of Oct 2013, 1304 patients with solid tumours, including 672 with advanced RCC, received single-agent axitinib in phase I-III studies. Among patients with RCC, 108 (16%) received axitinib ≥2 yr. In these patients, common AEs were most frequently reported within the first 6 mo of treatment, with rates stable or decreasing over time (Table). Rates of proteinuria, peripheral oedema, and elevated blood creatinine increased over time. Similarly, by cumulative analysis, most AEs analysed were reported within the first 6 mo–1 yr of treatment, with few new cases reported thereafter. Based on interval analysis, rates of common grade ≥3 AEs decreased over time with the exception of increased amylase and myocardial infarction. Table. Interval analysis of the most common AEs in patients with advanced RCC treated with axitinib ≥2 yr (n = 108). AE 0– 6 mo– 1– ≥2 yr Diarrhoea 53% 53% 45% 32% Fatigue 38% 15% 19% 13% Proteinuria 11% 10% 19% 11% Decreased appetite 27% 16% 16% 9% Hypertension 58% 16% 19% 9% Weight loss 28% 27% 25% 9% Conclusions: In patients with RCC, rates of most AEs were stable or declined after prolonged axitinib treatment. Results did not indicate that sustained exposure to axitinib is associated with unanticipated or more severe AEs. Disclosure: S. Hariharan, W.G. Roberts and Z. Askerova, J. Tarazi and B. Rosbrook: is an employee of and owns stock in Pfizer Inc.; B. Escudier has served as an advisor for Bayer, Pfizer, and Novartis, and has received honoraria from Bayer, Roche, Pfizer, Genentech, Novartis, and AVEO; R.J. Motzer: has served as an advisor for Pfizer, Genentech, and AVEO, received research funding from Pfizer, Novartis, and GlaxoSmithKline, and provided paid expert testimony for Pfizer; B.I. Rini: has served as an advisor for and received research funding from Pfizer.

Aim: Tumor immunosuppression and angiogenesis play a role in disease progression in HCC, OC, RCC and GC. Tasquinimod is a novel, small molecule compound that targets the tumor microenvironment by binding to S100A9, modulating accumulation and function of regulatory myeloid cells (myeloid derived suppressor cells [MDSCs] and tumor associated macrophages [TAMs]). Tasquinimod is an immunomodulator, antiangiogenic and antimetastatic agent. Antiangiogenic effects may be partly explained by action on MDSCs and TAMs, and through interaction with histone deacetylase-4, reducing the hypoxic response and down regulating HIF1a genes. Tasquinimod significantly improves median PFS (7.6 v 3.3 months) in patients with metastatic hormone resistant prostate cancer1 and is currently in late stage development in this indication. Its unique mode of action makes tasquinimod an attractive compound to be evaluated in other tumors. The primary objective was to determine the clinical activity of tasquinimod in advanced HCC pre-treated with sorafenib, platinum-resistant OC, RCC pre-treated with VEGF inhibitor and GC pre-treated with platinum therapy. Methods: The study design has been previously reported2. The primary endpoint was the PFS rate at a predefined time for each cohort. Secondary objectives included PFS, response rate, OS, safety, pharmacokinetics and biomarkers. Results: Cohort Pts PFS rate*, % Median PFS, w (95% CI) Pts with stable disease*, N (%) Median OS, w (95% CI) OC 55 24w: 7 8 (8-17) 27 (49) NR (31-NR) RCC 38 16w: 13 15 (8-17) 18 (47) 33 (26-41) GC 21 12w: 10 6 (5-7) 5 (24) 22 (14-33) HCC** 45 N/A *Central reading; **Ongoing; NA, not assessed; NR, not reached The most frequent treatment-emergent adverse events (all grade incidence >15%) were nausea (44%), vomiting (34%), constipation (32%), abdominal pain (32%), diarrhea (22%), fatigue (47%), decreased appetite (40%), back pain (27%), cough (22%), peripheral edema (20%), and insomnia (18%). Conclusions: The data did not support further development of tasquinimod mono therapy in heavily pretreated patients with OC, RCC and GC. Pharmacokinetic and biomarkers analyses are ongoing.HCC cohort is continuing with results expected 2015. Pili R et al, J Clin Oncol. 2011; 29:4022-8. Escudier B et al, J Clin Oncol. 2013;31(abstract TPS2622). Disclosure: R. Plummer: Ipsen funding to institution for present study; I.B. Vergote: Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Eisai, Eli Lilly, GE, GSK, Ipsen, Janssen, Menarini, MSD, Novartis, Novo Nordisk, Pfizer, Quintiles, Roche, Sanofi, Sandoz, Shering-Plough, Vifor, Wyett; R.J. Jones: Ipsen research funding GSK research funding, speaker honoraria, advisory board Pfizer research funding, speaker honoraria, advisory board Novartis research funding, speaker honoraria, advisory board Roche research funding; E. Van Cutsem: Ipsen funding to institution for present study; S. Faivre: Ipsen: research funding, advisory board; C. Descot: Ipsen employee; N. Germann: Ipsen employee. All other authors have declared no conflicts of interest.

Aim: Castleman's disese (CD) is a rare polyclonal lymphoproliferative disease that presents a variety of symptoms and clinical courses. Multicentric Castleman's disese (MCD) is defined by the involvement of at least two non-contiguous lymph node areas and commonly associated with poor clinical outcomes. We performed a retrospective analysis to reveal the clinical features and prognostic factors for patients with MCD. Methods: Between 1990 and 2013, 80 patients of biopsy proven CD were identified from the database of Asan Medical Center, Seoul, Korea. The data were collected retrospectively by reviewing medical records. Among them, 32 patients were classified into MCD. With the exclusion of 4 patients with unknown HIV infection status, a total of 28 HIV-negative patients with MCD were included in this analysis. Results: Most patients were male (76%) and median age was 54 years (range, 13-75) at diagnosis. Hyaline vascular variant was the most common subtype (39%) and followed by plasma cell variant (36%) and mixed cell variant (25%). Frequently reported symptoms and signs at diagnosis were hepatomegaly or splenomegaly (57%), fever (39%), edema (29%) and ascites (18%). As an initial therapy, cytotoxic chemotherapy, glucocorticoid alone, and interferon-a were given in 11 (39%), 6 (21%), and 1 (0.4%) patients, respectively. Remaining 10 (36%) patients were managed with ‘watch and wait’ strategy. With median follow-up of 67 months (range, 1-162), 10 (36%) patients died and 5-year overall survival rate was 77% (95% CI, 61%-93%). Patients who showed extravascular fluid accumulation (peripheral edema, ascites, pleural effusions) were significantly associated with poorer survival than those without those signs (5-year survival rate, 94% vs 56%; p = 0.04). Extent of involvement (same side vs both sides of diaphragm) was marginally associated with survival (p = 0.11). However, other clinicopathologic factors, including gender, age, histopathologic types, hepatosplenomegaly, anemia, thrombocytopenia, serum albumin and lactate dehydrogenase were not associated with survival (p > 0.1 for all comparisons). Conclusions: Clinicopathologic features of MCD in our cohort were consistent with previous reports. Our analyses showed that the signs of extravascular fluid accumulation at diagnosis were associated with poor overall survival in patients with MCD. Disclosure: All authors have declared no conflicts of interest.

Aim: To investigate safety and efficacy in four expansion cohorts treated with the combination of PIM and SAR. Methods: The recommended phase 2 dose (RP2D) for the combination of PIM and SAR has previously been defined in a dose escalation part of the same trial as 60 mg and 70 mg QD, respectively. Inclusion criteria included ECOG PS 0-1, and in the expansion cohorts prior MEK and/or PI3K inhibitor therapy was not allowed (NCT01390818). With an extract date of 25 March 2014, we carried out preliminary analyses for safety and efficacy using standard criteria (NCI CTCAE v4.0 and RECIST v1.1). Results: At the RP2D, 4 disease- and genotype-specific cohorts were recruited: RAS mutated non-small cell lung cancer (NSCLC, n = 24), triple-negative breast cancer (TNBC, n = 26), BRAF inhibitor resistant malignant melanoma (MEL, n = 15) and dual KRAS and PIK3CA mutated colorectal cancer (CRC, n = 18). The most frequent (≥20%) all grade treatment-emergent adverse events were: diarrhea (77.1%), fatigue (54.2%), nausea (50.6%), vomiting (47.0%), dermatitis acneiform (37.3%), maculo-papular rash (30.1%), decreased appetite (30.1%), peripheral edema (25.3%), pyrexia (25.3%), stomatitis (24.1%), dizziness (24.1%), dyspnea (21.7%), skin rash (21.7%), increased creatinine phosphokinase levels (21.7%), abdominal pain (20.5%) and pruritus (20.5%). Serous retinal detachment, which is a class effect of MEK inhibitors, was reported in 34.9% of pts and all cases were resolved without serious damage to the eyesight. Confirmed responses were observed in 2 of 18 evaluable NSCLC patients and in 1 of 13 evaluable MEL pts. Conclusions: Toxicities were manageable and improved or resolved with drug interruptions and/or dose reductions. Clinical activity was observed and an updated response evaluation will be presented at the meeting. We plan to evaluate whether there is a specific subset of pts who are more likely to benefit from the combination treatment with PIM and SAR. Disclosure: R.S. Heist: Research funding (for clinical trials) going to the institution at which I work (MGH), from the following companies: Genentech, GSK, Pfizer, Debiopharm, Infinity, Exelixis, EMD Serono, Sanofi F. Campana: Frank Campana is a Sanofi employee; C. Egile: Coumaran EGILE is a Sanofi employee; V. Jego: I am currently working for Cytel Inc, a CRO contracted by Merck KGaA. I do not have any stock ownership or advisory board or board of director membership or other substantial relationship beyond employment; L. Damstrup: I am an employer of Merck Serono, no other conflict of interest. All other authors have declared no conflicts of interest.

Aim: c-Met overexpression is associated with poor clinical prognosis. This dose-escalation study (3 + 3 design; NCT01014936) evaluates the selective c-Met inhibitor MSC2156119J in patients (pts) with advanced solid tumors. Methods: Primary endpoint is to assess an MTD. Secondary endpoints are antitumor activity, safety, pharmacokinetics (PK), and pharmacodynamics (Pd). Pts received 1x/d oral MSC2156119J (21-d cycles; 3 regimens [R]): d1–14 followed by 7-d rest (R1); 3x/wk (R2); or d1–21 (R3). An optimized formulation (OF) was introduced in Aug 2011, a 500-mg tablet in May 2013. An expansion cohort of 12 pts with c-Met amplification is ongoing at the recommended phase II dose (RP2D). Results: Up to 28 March 2014, 138 pts were analyzed (R1 = 42; R2 = 45; R3 = 51). On the initial formulation, doses were escalated from 30–230 mg/d in R1 and 30–115 mg/d in R2; on the OF (R1–3): 30–400 mg/d, 60–315 mg/d, and 300–1400 mg/d. AUC and Cmax increased with dose; bioavailability was higher with OF. An MTD was not reached. Treatment-related adverse events (trAEs) observed in ≥5% of pts across all regimens included fatigue (n = 21), peripheral edema (n = 16), decreased appetite (n = 10), nausea (n = 7), lipase and AST elevation (n = 6 and n = 4, resp.), and vomiting (n = 5); 76% of pts had no trAE >G1. Seven pts reported dose-limiting toxicities: fatigue, peripheral edema, nausea, vomiting and AST elevation (all n = 1), and lipase increase (n = 3). Pre- and on-therapy tumor biopsies showed target inhibition in 19/21 evaluable pts. 2 pts (esophageal adenocarcinoma and NSCLC) had confirmed partial response (PR); 2 pts (nasopharyngeal and colorectal carcinoma) had unconfirmed PRs. 22 pts showed stable disease (SD) ≥4 mo, incl. 1 pt with SD 32 mo. c-Met status, scored by immunohistochemistry, was high in 22/72 evaluable pts, of which 2 pts showed PR and 4 pts SD. Based on preclinical PK/Pd models and clinical Pd data, 500 mg was considered biologically active and able to reach ≥90% target inhibition. Conclusions: MSC2156119J was well tolerated and showed antitumor activity. The RP2D is 500 mg 1x/d. Dose escalation was stopped at 1400 mg/d. An MTD was not reached. Additional data from the expansion cohort will be presented. Disclosure: G.S. Falchook: Research funding from EMD Serono, Inc, Rockland, MA, USA.; H.M. Amin: Research funding from EMD Serono, Inc, Rockland, MA, USA.; H. Zheng: Employment by EMD Serono Inc, Rockland, MA, USA and stock ownership of Merck/EMD Serono.; F. Bladt: Employment by Merck KGaA, Darmstadt, Germany; A. Johne: Employment by Merck KGaA, Darmstadt, Germany; R. Kurzrock: Corporate-sponsored research: Merck Serono. All other authors have declared no conflicts of interest.

serious adverse events were observed in 72.2 % and 42.3 % of the pts (drug related in 41.3 % and 9.5% of the pts), respectively (n = 496). Most common drug-related toxicities (incidence ≥3%) of any grade were fatigue (7.3 %), rash (5.4 %), pruritus (5.4 %), nausea (4.0 %), diarrhoea (4.0 %), stomatitis (4.0 %), mucosal inflammation (3.8 %), anemia (7.5 %), thrombocytopenia (4.0 %) and peripheral oedema (3.6 %). Median progression-free survival for total patient population was 4.4 mo, for the subgroup of 1 st

Background Pemetrexed has been used as maintenance therapy for non-squamous non-small-cell lung cancer. Treatment period of pemetrexed is relatively longer than that of the other cytotoxic agents. Usually acute adverse events are mild and less frequent; however, it is still unknown if the long-term administration raised toxicities. There are several reports that pemetrexed caused eye lid or peripheral edema, which package insert also described the occurrences were 5 to 20%, 20%, respectively. We investigated if pemetrexed raised occurrence of peripheral edema that was treated with anti-diuretics during the maintenance therapy. Result One hundred sixty nine of NSCLC patients were treated with pemetrexed in our institution. Twelve patients were administered of pemetrexed more than 10 times. Anti-diuretics were used in 52 patients (30.2%) and pemetrexed probably induced peripheral edema in 12 patients (7.1%). The rate of administration of anti-diuretics due to the peripheral edema to the patients maintained with pemetrexed in less than 6 times, 6 times and more or 12 times and more was 4.3, 13.2 and 21.7, respectively. We concluded that long-term administration of pemetrexed raised the adverse event of peripheral edema.

Background EMD 525797 is a humanized monoclonal IgG2 antibody specifically targeting av integrins involved in tumor progression. Methods The safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of EMD 525797 were assessed in metastatic castrate-resistant prostate cancer (mCRPC) patients. 24 patients (43-80 years) were treated with IV infusions of 250, 500, 1000, or 1500 mg EMD 525797 given over 1 h and received 3 doses (weeks 1, 3, and 5) before response assessment at the end of week 6. Patients without progressive disease could receive further doses every 2 weeks. Dose-limiting toxic effects (DLTs) were assessed over the first 6 weeks and safety was monitored until 4 weeks after the last administration of EMD 525797. Results Final analysis showed that 13 of 24 patients had a longer exposure time than expected(≥84 days): 7 patients had exposure times ≥126 days, 3 patients ≥280 days and 1 patient received EMD 525797 for 534 days. All patients experienced adverse events (AEs), and in 11 patients AEs were considered related to EMD 525797. 4 patients had generalized pruritus, erythema, or rash and 3 patients experienced fatigue, mucosal inflammation, or peripheral edema, but no patient had administration site reactions. Changes in clinical lab values were consistent with basic disease. No DLTs occurred. EMD 525797 showed a dose-dependent, nonlinear PK profile in line with a target-mediated drug disposition. Two patients of the 500 mg cohort had a marked decrease in prostate specific antigen. One of them also had primary tumor shrinkage and normalization of lymph node size. These patients had long-term anti-integrin treatment (297 and 534 days, respectively). Both patients showed additional pain relief.

Introduction Temsirolimus (TEMS), an i.v. mTOR inhibitor, is approved in the EU for the first-line treatment of patients with a/mRCC who have at least 3 of 6 prognostic risk factors. A pivotal study had demonstrated significantly increased overall survival with TEMS in poor risk patients compared to the former standard Interferon (10.9 vs. 7.3 mo; p = 0.0078). To better identify the safety profile and efficacy of TEMS during clinical routine, collection of data in a postapproval non-interventional trial seems to be adequate. Methods A registry for a/mRCC patients treated with TEMS was started in Germany in January 2008 (NCT00700258). Primary objective: evaluation of the safety profile of TEMS. Secondary objectives: tolerability and anti-tumor activity of TEMS; profile of patients; sequence of systemic therapies. Inclusion criteria: histologically confirmed a/mRCC treated with TEMS and written informed consent by the patient. Results 118 active study centers recruited 455 patients from Feb. 2008 to April 2012. Preliminary data are available for 430 patients: 68.7% male, median age 68 years, median Karnofsky index 80%. Histological subtype: 75.3% clear cell, 10.9% papillary and 2.6% chromophobe RCC. According to modified MSKCC criteria 96.0% of patients (n = 323) were classified as poor risk and 4.0% as intermediate risk patients. Adverse events (AE) and serious adverse events (SAE) defined as drug related were observed in 41.2% and 10.2%, respectively. Skin disorders, fatigue, nausea, diarrhea, peripheral edema, anemia and dyspnea of any grade were the most frequent AEs. Median progression-free survival for the total patient population was 151 days (d), for the subgroup of 1st line patients 162 d, for patients ≥ 65 yrs 155 d. Median overall survival for all patients was 381 d. Conclusions Patient population in the registry represents the expected pattern in a/mRCC regarding distribution of age, sex, and histology. Safety profile and clinical efficacy of TEMS in the usual health care setting confirm the phase-III data. In addition, for patients ≥ 65 years safety and clinical efficacy of TEMS are comparable to results of the overall study population. Disclosure U. Mueller: Employment by Pfizer. G. Krekeler: Employment by Pfizer. L. Bergmann: Advisory boards: Bayer, GSK, Novartis, Pfizer, Roche, Astellas; Honoraria: Novartis, Pfizer, Roche. D. Kalanovic: Employment by Pfizer. All other authors have declared no conflicts of interest.

Introduction TH-302 is a cytotoxic prodrug designed to specifically target the hypoxic microenvironment of tumours. Combining TH-302 with gemcitabine may enable the targeting of both the normoxic and hypoxic regions of PAC. Methods Results from a Phase II open-label multi-center study of two dose levels of TH-302 (240 mg/m2 or 340 mg/m2) in combination with gemcitabine versus gemcitabine alone (randomized 1:1:1) are presented. 214 patients participated, 164 (77%) Stage IV and 50 (23%) Stage IIIB. Median age was 65 (range 29-86); M/F 59%/41% 40% ECOG 0 and 60% ECOG 1; 58% involved head of pancreas; 36% biliary stent. Median PFS was 3.6 months (mo) in gemcitabine vs 5.6 mo in combination with a HR of 0.61 (95% CI: 0.43 – 0.87), p-value 0.005. In patients with distant metastases the median PFS was 3.5 mo in gemcitabine and 5.1 mo in each of the combination arms with a HR of 0.62 (95% CI: 0.42 – 0.90). Results In patients with unresectable locally advanced disease the median PFS was 5.3 mo in gemcitabine, 8.5 mo in the 240 dose group and 9.5 mo in the 340 dose group with a HR for the two combination arms of 0.59 (95% CI: 0.25 – 1.38). RECIST best response was 12% in gemcitabine, 17% in 240 dose group and 27% in 340 dose group. The response rate in the 340 group was 24% in pts with distant metastases and 35% in pts with locally advanced disease. The most common adverse events were fatigue (49%), nausea (43%), constipation (34%) and peripheral edema (34%), similar across groups. Rash (45% in 340 group) and stomatitis (36% in 340 group) were greater in combination groups with no CTC G4 (4 pts with G3). G3/4 thrombocytopenia (11% gemcitabine, 39% 240 and 59% 340) and G3/4 neutropenia (28% gemcitabine, 56% 240 and 59% 340) were higher with the combination. Conclusion Data warrant further investigation of the compound in Phase III in advanced PAC regardless of disease stage.

POEMS is an acronym for a rare multisystemic syndrome encompassing polyneuropathy (P), organomegaly (O), endocrinopathy (E), monoclonal gammopathy (M), skin changes (S) and additional features variably expressed [1]. POEMS syndrome is associated with high vascular endothelial growth factor (VEGF) serum levels. This angiogenic factor likely plays a pathogenic role, in particular for neuropathy, possibly via alteration of endoneurial vessels [2]. Treatment options are still debated, but recently autologous stem-cell transplantation (ASCT) appears to be effective. This approach for POEMS patients, however, was associated with severe morbidity, mainly respiratory failures that appeared to be related to neuromuscular damage [3]. We report a 45-year-old woman presenting with a rapidly progressive sensorimotor polyneuropathy involving all extremities, multiple sclerotic bone lesions, skin hyperpigmentation and hemangiomas, hepatomegaly, peripheral edema and papilledema. A monoclonal immunoglobulin A k protein was detected (5 g/l) with a bone marrow plasmocytosis (15%). Platelets were 600 · 10/l and cerebrospinal fluid proteins were 30 g/l. Electromyographic and nerve conduction analyses confirmed neuropathy with axonal abnormalities. Within few months appeared walking impossibility, swallowing difficulties and respiratory distress. Serum VEGF was highly elevated at 9700 pg/ml (normal range: 62–707). Steroids treatment was declined by the patient. ASCT was considered at high risk because of her poor condition (Karnofsky score of 50%), neurological defects and respiratory failure. We hypothesized that VEGF inhibition may relieve neuropathy. Bevacizumab therapy was initiated at 10 mg/kg every 2 weeks. Pain relief was observed after two infusions, followed by major improvement in walking and breathing within 10 weeks. This was correlated with a drop in VEGF level (61 pg/ml) and a significant improvement in electromyographic and nerve conduction studies. Treatment was continued for 4 months, and further clinical improvement was observed, confirmed by electroneuromyography and pulmonary function tests. Hepatomegaly and skin abnormalities remained unchanged. Karnofsky score improved at 80%, allowing ASCT conditioned with melphalan (200 mg/m) to be realized in better conditions. The procedure was well tolerated, and clinical outcome was excellent with a Karnofsky score at 90% 1 year after the procedure. Rapidly evolving neuropathy may hamper to carry out ASCT in POEMS patients. Neurological defects in our POEMS patient has been partially reversed by bevacizumab therapy, further supporting the role of VEGF in this complication. The large biological and clinical heterogeneities of POEMS syndrome could explain variable sensitivities to anti-VEGF therapy [4, 5]. Our report indicates that some patients may benefit from bevacizumab to improve their clinical condition before applying more standard treatments.