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Patients with primary central nervous system lymphoma (PCNSL) are treated with high-dose methotrexate-based chemotherapy, which requires hospitalization and extensive expertise to manage related toxicity. The use of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) could overcome these difficulties, but blood-brain barrier (BBB) penetration of related drugs is poor. Tumor necrosis factor-α coupled with NGR (NGR-hTNF), a peptide targeting CD13+ vessels, induces endothelial permeabilization and improves tumor access of cytostatics. We tested the hypothesis that NGR-hTNF can break the BBB, thereby improving penetration and activity of R-CHOP in patients with relapsed/refractory PCNSL (NCT03536039). Patients received six R-CHOP21 courses, alone at the first course and preceded by NGR-hTNF (0.8 μg/m2) afterward. This trial included 2 phases: an “explorative phase” addressing the effect of NGR-hTNF on drug pharmacokinetic parameters and on vessel permeability, assessed by dynamic contrast-enhanced magnetic resonance imaging and 99mTc-diethylene-triamine-pentacetic acid–single-photon emission computed tomography, and the expression of CD13 on tumor tissue; and an “expansion phase” with overall response rate as the primary end point, in which the 2-stage Simon Minimax design was used. At the first stage, if ≥4 responses were observed among 12 patients, the study accrual would have continued (sample size, 28). Herein, we report results of the explorative phase and the first-stage analysis (n = 12). CD13 was expressed in tumor vessels of all cases. NGR-hTNF selectively increased vascular permeability in tumoral/peritumoral areas, without interfering with drug plasma/cerebrospinal fluid concentrations. The NGR-hTNF/R-CHOP combination was well tolerated: there were only 2 serious adverse events, and grade 4 toxicity was almost exclusively hematological, which were resolved without dose reductions or interruptions. NGR-hTNF/R-CHOP was active, with 9 confirmed responses (75%; 95% confidence interval, 51-99), 8 of which were complete. In conclusion, NGR-hTNF/R-CHOP was safe in these heavily pretreated patients. NGR-hTNF enhanced vascular permeability specifically in tumoral/peritumoral areas, which resulted in fast and sustained responses.

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard treatment of diffuse large B-cell lymphoma (DLBCL). Primary DLBCL of the central nervous system (CNS) (primary central nervous system lymphoma [PCNSL]) is an exception because of the low CNS bioavailability of related drugs. NGR–human tumor necrosis factor (NGR-hTNF) targets CD13+ vessels, enhances vascular permeability and CNS access of anticancer drugs, and provides the rationale for the treatment of PCNSL with R-CHOP. Herein, we report activity and safety of R-CHOP preceded by NGR-hTNF in patients with PCNSL relapsed/refractory to high-dose methotrexate-based chemotherapy enrolled in a phase 2 trial. Overall response rate (ORR) was the primary endpoint. A sample size of 28 patients was considered necessary to demonstrate improvement from 30% to 50% ORR. NGR-hTNF/R-CHOP would be declared active if ≥12 responses were recorded. Treatment was well tolerated; there were no cases of unexpected toxicities, dose reductions or interruptions. NGR-hTNF/R-CHOP was active, with confirmed tumor response in 21 patients (75%; 95% confidence interval, 59%-91%), which was complete in 11. Seventeen of the 21 patients with response to treatment received consolidation (ASCT, WBRT, and/or lenalidomide maintenance). At a median follow-up of 21 (range, 14-31) months, 5 patients remained relapse-free and 6 were alive. The activity of NGR-hTNF/R-CHOP is in line with the expression of CD13 in both pericytes and endothelial cells of tumor vessels. High plasma levels of chromogranin A, an NGR-hTNF inhibitor, were associated with proton pump inhibitor use and a lower remission rate, suggesting that these drugs should be avoided during TNF-based therapy. Further research on this innovative approach to CNS lymphomas is warranted. The trial was registered as EudraCT: 2014-001532-11.

Introduction: Primary central nervous system lymphoma (PCNSL) retains peculiar biological and clinical characteristics and a worse prognosis with respect to other comparable lymphomas. The need for...

Primary CNS lymphomas (PCNSL) represent a subgroup of malignancies with specific characteristics, aggressive course, and unsatisfactory outcome in contrast with other lymphomas comparable for tumour burden and/or histological type. Despite a high chemo- and radiosensitivity, remissions are frequently shortlasting, mainly because the blood brain-barrier limits the access of many drugs to the CNS. Moreover, survivor patients are at high risk of developing severe treatment-related toxicity, mainly disabling neurotoxicity, raising the question of how to balance therapy intensification with side-effects control. Although the prognosis remains poor, it has significantly improved over the past two decades as a result of better treatment strategies with a curative aim. Surgery has no impact on survival, and is reserved to diagnosis by stereotactic biopsy. Actual front-line therapy consists of high-dose methotrexate-based poly-chemotherapy. The optimal drugs combination has not yet been identified even if there is a suggestion for a synergistic role for the adjunction of cytarabine, thiotepa, and rituximab. Radiotherapy retains an important role as salvage therapy in refractory/relapsing patients, while its use is more debated in the setting of response consolidation in patients who achieve a complete remission after induction chemotherapy. High-dose chemotherapy supported by autologous stem-cell transplantation is increasingly used as an effective method aimed to control microscopic disease, and the pros and contras of this approach are outlined.

Background: The NGR-hTNF (asparagine–glycine–arginine–human tumour necrosis factor) is able to promote antitumour immune responses and to improve the intratumoural doxorubicin uptake by selectively damaging tumour blood vessels. Methods: Patients progressing after ⩾1 platinum/taxane-based regimen received NGR-hTNF 0.8 μg m−2 and doxorubicin 60 mg m−2 every 3 weeks. Primary endpoint was a Response Evaluation Criteria in Solid Tumors-defined response rate with a target of more than 6 out of 37 responding patients. Results: A total of 37 patients with platinum-free interval lower than 6 months (PFI

Background NGR-hTNF consists of human tumour necrosis factor (hTNF) fused with the tumour-homing peptide Asp-Gly-Arg (NGR), which is able to selectively bind an aminopeptidase N overexpressed on tumour blood vessels. Preclinical antitumour activity was observed even at low doses. We evaluated the activity and safety of low-dose NGR-hTNF in colorectal cancer (CRC) patients failing standard therapies. Patients and methods Thirty-three patients with progressive disease at study entry received NGR-hTNF 0.8μg/m 2 given intravenously every 3weeks. The median number of prior treatment regimens was three (range, 2–5). One-quarter of patients had previously received four or more regimens and two-thirds targeted agents. Progression-free survival (PFS) was the primary study objective. Results NGR-hTNF was well tolerated. No treatment-related grade 3 to 4 toxicities were detected, most common grade 1 to 2 adverse events being short-lived, infusion-time related chills (50.0%). One partial response and 12 stable diseases were observed, yielding a disease control rate of 39.4% (95% CI, 22.9–57.8%). Median PFS and overall survival were 2.5months (95% CI, 2.1–2.8) and 13.1months (95% CI, 8.9–17.3), respectively; whereas in patients who achieved disease control the median PFS and overall survival were 3.8 and 15.4months, respectively. In an additional cohort of 13 patients treated at same dose with a weekly schedule, there was no increased toxicity and 2 patients experienced PFS longer than 10months. Conclusion Based on tolerability and preliminary evidence of disease control in heavily pretreated CRC patients, NGR-hTNF deserves further evaluation in combination with standard chemotherapy.

Purpose NGR-hTNF consists of human tumor necrosis factor α (hTNF-α) fused to the tumor-homing peptide asparagine-glycine-arginine (NGR) able to selectively bind an aminopeptidase N isoform overexpressed on tumor blood vessels. Hypervascularity is a prominent and poor-prognosis feature of malignant pleural mesothelioma (MPM). Currently, there are no standard options for patients with MPM who are failing a front-line pemetrexed-based regimen. We explored safety and efficacy of NGR-hTNF in this setting. Patients and Methods Eligible patients had radiologically documented tumor progression and performance status ≤ 2. Primary study aim was progression-free survival (PFS). NGR-hTNF 0.8 μg/m2 was given intravenously every 3 weeks. A subsequent cohort of patients received 0.8 μg/m2 on a weekly basis. Results In the triweekly cohort (n = 43), only one grade 3 drug-related toxicity was noted, and the most common grades 1 to 2 were short-lived chills (71%). The median PFS was 2.8 months (95% CI, 2.3 to 3.3 months). Nineteen patients (44%) had disease control (one had partial response, and 18 had stable diseases) and experienced a median progression-free time of 4.4 months. In the weekly cohort (n = 14), there was no higher toxicity, and median PFS was 3.0 months (95% CI, 1.9 to 4.1 months). Seven patients (50%) had disease control (all stable diseases) and had a median progression-free interval of 9.1 months. In the overall study population (N = 57), median PFS was 2.8 months. Median progression-free time was 4.7 months in twenty-six patients (46%) who achieved disease control. Median survival was 12.1 months. Conclusion The tolerability and disease control of NGR-hTNF 0.8 μg/m2 weekly warrant additional evaluation in patients with advanced MPM.

Summary: The most effective strategy to prevent central nervous system (CNS) dissemination in diffuse large B-cell lymphoma (DLBCL) remains an important, unmet clinical need. Herein, we report a retrospective analysis of risk-tailored CNS prophylaxis in 200 human immunodeficiency virus-negative adults with DLBCL treated with rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or similar. High risk of CNS relapse was defined by involvement of specific extranodal organs, or simultaneous presence of advanced stage and high serum lactate dehydrogenase level; CNS prophylaxis with high-dose methotrexate ± intrathecal chemotherapy (IT) was routinely used in high-risk patients diagnosed after 2007. CNS relapse risk was low in 93 patients and high in 107; 40 high-risk patients received prophylaxis, which consisted of IT alone in 7. At a median follow-up of 60 months, one low-risk and nine high-risk patients (1% vs. 8%; P = 0·01) experienced CNS relapse. In the high-risk group, CNS relapses occurred in 8/67 (12%) patients who did not receive prophylaxis and in 1/40 (2·5%) patients who did; the latter occurred in a patient managed with IT alone. CNS relapse rate was 12% (9/74) for patients treated with "inadequate" prophylaxis (none or IT only) and 0% (0/33) for patients managed with intravenous prophylaxis (P = 0·03). In conclusion, high-dose methotrexate-based prophylaxis significantly reduces CNS failures in high-risk patients stratified by involvement of specific extranodal sites and International Prognostic Index.

Purpose Treatment of secondary CNS dissemination in patients with aggressive lymphomas remains an important, unmet clinical need. Herein, we report the final results of a multicenter phase II trial addressing a new treatment for secondary CNS lymphoma based on encouraging experiences with high doses of antimetabolites in primary CNS lymphoma and with rituximab plus high-dose sequential chemoimmunotherapy (R-HDS) in relapsed aggressive lymphoma. Patients and Methods HIV-negative patients with aggressive B-cell lymphoma and secondary CNS involvement at diagnosis or relapse, age 18 to 70 years, and Eastern Cooperative Oncology Group performance status ≤ 3 were enrolled and treated with high-doses of methotrexate and cytarabine, followed by R-HDS (cyclophosphamide, cytarabine, and etoposide) supported by autologous stem-cell transplantation (ASCT). Treatment included eight doses of rituximab and four doses of intrathecal liposomal cytarabine. The primary end point was 2-year event-free survival; the planned accrual was 38 patients. Results Thirty-eight patients were enrolled; CNS disease was detected at presentation in 16 patients. Toxicity was usually hematologic and manageable, with grade 4 febrile neutropenia in 3% of delivered courses and grade 4 nonhematologic toxicity in 2% of delivered courses. Four patients died because of toxicity. Autologous stem cells were successfully collected in 24 (89%) of 27 patients (median, 10 × 106/kg); 20 patients underwent ASCT. Complete response was achieved in 24 patients (complete response rate, 63%; 95% CI, 48% to 78%). At a median follow-up of 48 months, 17 patients remained relapse free, with a 2-year event-free survival rate of 50% ± 8%. At 5 years, 16 patients were alive, with a 5-year overall survival rate of 41% ± 8% for the whole series and 68% ± 11% for patients who received transplantation. Systemic (extra-CNS) and/or meningeal disease did not affect outcome. Conclusion The combination of high doses of antimetabolites, R-HDS, and ASCT is feasible and effective in patients age 18 to 70 years old with secondary CNS lymphoma, and we propose it as a new standard therapeutic option.

Background The purpose of the present study was to investigate the therapeutic effectiveness of interleukin-2 (IL-2) and interferon (IFN), either alone or in combination, in comparable groups of patients affected by advanced renal cell carcinoma (RCC). Patients and methods In order to limit selection biases, treatment was allocated on a random basis. Patients randomized to IL-2 alone were scheduled to receive eight rIL-2 24-hour i.v. infusion cycles, days 1 to 4, at a daily dose of 18 x 106 IU/m2 for a total of 25 weeks. Patients randomized to IFN alone were scheduled to receive rIFN-α at a daily dose of 6 x 106 IU/m2, days 1, 3 and 5, every week for a total of 52 weeks. Patients randomized to the combination of IFN and IL-2 were given the same drugs at the same daily doses for a total of 24 weeks. Drug dose was modified according to toxicity. Results Twenty-three percent (95% CI: ± 17.5) of patients treated with IL-2 alone showed an objective response to treatment (9% CR). The corresponding figures in patients treated with IFN alone or IFN plus IL-2 were 9% (95% CI: ± 11.9) and 9% (95% CI: ± 11.9), respectively. Complete responses were observed only in patients treated with IL-2. The median duration of response in the IL-2 arm was 18 months (range, 9.5-24). The duration of the two responses achieved by IFN alone was seven and nine, months, respectively. The corresponding figures in the two patients responding to the combination of IFN with IL-2 were 19 and 27 months, respectively. Total IL-2 dose appeared to be a major predictor of response. Only a minority of patients experienced grade 3-4 toxicity, the incidence being higher in those treated with IL-2 or IL-2 plus IFN. Conclusions Neither IFN nor IL-2 or the combination of the two appear to be very active in patients with advanced RCC, even when trial entry was restricted to patients with relatively indolent disease. This stresses the need for the development of new approaches.

OBJECTIVE Metastatic renal cell cancer (RCC) portends a bad prognosis, but survival is quite different among different patients. The objective of this study was to determine prognostic factors for survival with the aim to offer patients proper therapeutic options. METHODS A consecutive series of 109 metastatic RCC patients admitted to our department since 1988 was reviewed, and survival from the time of diagnosis with metastases recognition was considered. The role of age, sex, disease-free interval (DFI), ECOG performance status (PS), stage at diagnosis, grading, number and type of metastatic sites, nephrectomy, blood levels of hemoglobin, creatinine, albumin, calcium, lactate dehydrogenase (LDH), ferritin, alkaline phosphatase, triglycerides was assessed in univariate and multivariate analysis. RESULTS In our study, the following variables were found to be statistically significant at the univariate analysis (p < 0.01): DFI, ECOG PS, stage at diagnosis, grading, nephrectomy, sites of metastases, blood hemoglobin, serum albumin, calcium, LDH, alkaline phosphatase. Indeed, only an ECOG PS of 2-3 (relative risk 1.82; p = 0.003) and blood hemoglobin levels < or = 10 g/100 ml (relative risk 1.20; p = 0.017) retained their value as independent risk factors for poor survival at multivariate analysis. According to the number of independent risk factors, three groups of patients were identified, with significantly different median survival (21.7 vs. 8.6 vs. 3.5 months; log-rank test: p = 0.00004, p = 0.04126 and p = 0.00047, respectively). CONCLUSIONS Poor performance status and anemia at diagnosis of metastatic RCC predict the worst outcome in our series. These factors could be taken into account to stratify patients in clinical trails and to select the proper treatment option in oncological practice.

High-dose methotrexate (HD-MTX)-based chemotherapy is the current first-line therapy for primary CNS lymphoma. Whole-brain radiotherapy (WBRT) plays an important role in the management of primary CNS lymphoma and is indicated in patients with contraindication to chemotherapy, in patients with unusual histologic subtypes as curative treatment, as complementary therapy for patients failing to achieve complete remission after systemic chemotherapy and as salvage therapy for refractory or relapsing patients when systemic chemotherapy is no longer advisable. The two major pitfalls in WBRT use are transitory efficacy and neurotoxicity with deterioration of quality of life. Accordingly, WBRT administration as consolidation therapy in complete remission patients after first-line chemotherapy is controversial. In the present review, indications of WBRT will be outlined with emphasis on consolidation therapy, treatment-related neurotoxicity and efforts aimed at reducing toxicity.

In 40 out of 99 patients (40.4%) with solid tumours of different tissue, but the same stage (IV), elevated serum levels of interleukin-10 were observed. The mean levels of the cytokine in patients with malignant melanoma (24.3 ng/ml), pancreatic (6.8 ng/ml) or gastric (6.3 ng/ml) adenocarcinoma were significantly higher than in healthy subjects (3.4 ng/ml) or in patients with uterine fibroma (1.7 ng/ml). Patients with colon (6.8 ng/ml) and renal (5.7 ng/ml) carcinoma had similar values of interleukin-10 but did not significantly differ from controls. Interleukin-10 is known to suppress the functions of both T lymphocytes and macrophages, working as a general dampener of the immune and inflammatory responses. The observation of increased circulating levels of interleukin-10 in cancer patients may have important implications for future investigations, immunological monitoring and therapeutic intervention on neoplastic patients, and suggests a mechanism for tumour cells escaping from immune surveillance.

Interleukin-2 (IL-2) is a cytokine with proven activity against metastatic renal cell carcinoma (RCC) and malignant melanoma (MM). The intravenous administration of high-dose IL-2 is limited by important cardiovascular side effects such as hypotension, fluid retention, arrhythmias, and myocardial ischemia, which often cause dose reduction and/or treatment withdrawal. The occurrence of these toxic events is not predicted by routine pretreatment examinations. The aim of the present study was to test the reliability of serial echocardiography in predicting subsequent cardiac adverse effects in patients undergoing IL-2 administration. In 19 patients (15 men, 4 women; median age: 51 years, range 27-71 years; 10 affected by metastatic RCC and 9 affected by MM) we performed two-dimensional and Doppler echocardiography before and immediately after 28 continuous intravenous infusions (CIVI) of IL-2 at the dose of 18 MIU/m2/day for 4 days. Left ventricular systolic function and the diastolic transmitral flow pattern were assessed before and after IL-2 administration. Significant changes of two indexes of left ventricular filling were noted: a decrease of the ratio of maximal flow velocity in early diastole to that in late diastole (E/A) (basal: 1.12 +/- 0.46, mean +/- SD; posttreatment: 0.83 +/- 0.27; p < 0.01) and an increase of the percentage of the atrial contribution to left ventricular filling (basal: 37.75 +/- 11.58%; posttreatment: 49.43 +/- 16.48%; p < 0.01). Eight major cardiovascular events causing IL-2 infusion withdrawal were observed (two ischemic electrocardiographic modifications, three grade III-IV hypotension, one atrial fibrillation, one pericardial effusion, one acute heart failure). These major cardiovascular events were observed more often when an abnormal basal E/A ratio < 1.0 (p < 0.05) was found. We conclude that Doppler transmitral flow pattern analysis before and subsequent to IL-2 infusion is a useful and easily available procedure for the monitoring of cardiac modifications during CIVI IL-2 administration. It might also predict a major cardiovascular event during IL-2 administration. Patients with basal E/A ratio < 1.0 should be more carefully monitored during treatment and/or should be treated with lower IL-2 doses to avoid cardiovascular toxicity.

Nitric oxide (NO), a biologically active mediator generated in many cell types by the enzyme NO synthase, may play an important role in cardiovascular toxicity that is frequently observed in cancer patients during intravenous (i.v.) interleukin 2 (IL-2) therapy. The induction of NO synthase and the production of NO seem to be involved in the pathogenesis of the vascular leakage syndrome, as well as in the regulation of myocardial contractility. In the present study, we evaluated the pattern of plasmatic NO changes during multiple cycles of continuous i.v. infusion (CIVI) of IL-2 in ten advanced cancer patients (five males, five females, median age 59 years, range 33-67 years; eight affected by renal cell cancer and two affected by malignant melanoma). The patients received IL-2 at 18 MIU m-2 day-1 (14 cycles) or 9 MIU m-2 day-1 (seven cycles) for 96 h, repeated every 3 weeks. Interferon alpha (IFN alpha) was also administered subcutaneously (s.c) during the 3 week interval between IL-2 cycles. For each cycle, plasma samples were collected before treatment (t0), 24 h (t1), 48 h (t2), 72 h (t3) and 96 h (t4) after the start of IL-2 infusion, and 24 h after the end of the cycle. NO concentration was determined spectrophotometrically by measuring the accumulation of both nitrite and nitrate (after reduction to nitrite). The following observations may be drawn from data analysis: (1) plasma nitrate + nitrite significantly raised during treatment (P = 0.0226 for t0 vs t3), but statistical significance was retained only when cycles administered with IL-2 18 MIU m-2 day-1 are considered (P = 0.0329 for t0 vs t3; P = 0.0354 for t0 vs t2 vs t4) (dose-dependent pattern); (2) during subsequent cycles a significant trend toward a progressive increase of plasma nitrate + nitrite levels, with increasing cumulative dose of IL-2, was observed (linear regression coefficient r = 0.62, P = 0.0141 for t0; r = 0.80, P = 0.0003 for t1; r = 0.62, P = 0.013 for t2; r = 0.69, P = 0.045 for t3); (3) plasma nitrate + nitrite levels peaked earlier in subsequent cycles than in the first cycle; (4) all patients experienced hypotension. The mean of the systolic blood pressure values was significantly lower at the time of plasma nitrate + nitrite peak than at t0 (P = 0.0004); (5) the two cases of grade III hypotension occurred in patients with the higher mean and peak plasma nitrate + nitrite values. We conclude that determination of plasma nitrate + nitrite levels during CIVI IL-2 can usefully estimate, in a dose-dependent pattern, the degree of peripheral vascular relaxation and capillary leakage associated with cytokine action, clinically manifested as hypotension. However, isolated cardiac toxicity that continues to represent a relevant problem during IL-2 therapy, does not appear to correlate with plasma nitrate + nitrite levels; therefore, further studies are required to understand adequately the mechanisms underlying IL-2-induced cardiac toxicity.

e20077Background: In the NGR015 trial, patients failing a pemetrexed-based regimen were randomly assigned to weekly NGR-hTNF (N; n = 200) or placebo (P; n = 200), both given with BIC that included ...

Advanced renal cell cancer (RCC) has a very poor prognosis, but a minority of patients can achieve objective responses after Interleukin-2 (IL-2)-based immunotherapy. When the drug is administered intravenously (i.v.), either by boluses or by continuous infusion, the presence of even asymptomatic cerebral metastases of any size is regarded as a major exclusion criterion, since the vascular leakage determined by IL-2 might contribute to an increase in perilesional oedema and therefore to elicit or to enhance neurologic toxicity, namely confusion, lethargy or seizures (1).

Background CNS dissemination is an uncommon but lethal event in non-Hodgkin lymphomas. Early detection of CNS disease and a timely and effective CNS prophylaxis are the main strategies to reduce related mortality. However, both the criteria for recognition of lymphoma patients (pts) with increased risk of CNS involvement and the most effective prophylaxis modality remain important, unmet clinical needs. Some international guidelines recommend intrathecal chemotherapy by lumbar injection as exclusive prophylaxis; however, this strategy results in erratic, short-lived drug bioavailability and does not prevent brain parenchymal relapses. Herein, we report a retrospective analysis of the value of clinical variables and immunohistochemical ontogenic stratification in predicting CNS dissemination and of risk-tailored CNS prophylaxis in a mono-institutional series of 194 pts with DLBCL treated in the rituximab era. Methods Consecutive HIV- adults with DLBCL without CNS involvement at diagnosis treated with first-line rituximab-CHOP or similar ± radiotherapy were considered. Primary CNS, mediastinal and cutaneous leg-type lymphomas were excluded. ‘High risk’ of CNS relapse was defined by the involvement of the testis, spine, skull, orbit, nasopharynx, kidney, and/or breast or by IPI ≥2 (including two among extranodal sites ≥2, advanced stage and high serum LDH). DLBCLs were ontogenically subclassified in ‘germinal-centre B-cell-like’ (GCB) and ‘non-germinal-centre B-cell-like’ (non-GC) by immunohistochemistry following the Hans algorithm. Results 194 patients were analyzed (median age 65, range 18-89; M:F ratio 1.1). Risk of CNS relapse was low in 90 pts and high in 104. Low-risk pt did not receive CNS prophylaxis, while 40/104 (38%) high-risk pts received 3-4 courses of methotrexate 3 g/m2 ± intrathecal (IT) liposomal cytarabine (n=30), cytarabine 16 g/m2 in 4 days (n=2) or IT chemotherapy (n=8). In the high-risk group, IPI ≥2 was more common among pts who did not receive prophylaxis (89% vs. 68%; p=0.006), while “high-risk” extranodal lymphomas were more common among pts who did (88% vs. 33%; p= 0.0001). One hundred and forty-one cases were assessable for Hans algorithm: 74 (52%) were GCB and 67 (48%) were non-GCB DLBCL. GCB DLBCLs were significantly associated with low CNS risk (55% vs. 31%; p= 0.004), and normal LDH levels (57% vs. 36%; p= 0.02); ontogenic stratification was not associated with high-risk extranodal sites, IPI ≥2, bone marrow infiltration, stage and systemic symptoms. After first-line treatment, 160 pts achieved a CR (82%; 95%CI= 77-87%), 34 pts had PD. At a median follow-up of 60 months (13-156), a single low-risk pt and 9 high-risk pts (1% vs. 9%; p= 0.016) experienced CNS relapse (exclusive site in all cases; brain in 5 pts, meninges in 5), with a median TTP of 12 months (7-55). CNS relapses occurred in 3 pts with IPI ≥2, in 1 pt with extranodal disease (testis) and in 5 pts with both features (kidney 3; testis, orbit). Ontogenic stratification was not associated with CNS recurrence, which was 5% for GCB and 6% for non-GCB; these figures were confirmed when analysis was limited to high-risk pts managed without prophylaxis. In the high-risk group, CNS relapses occurred in 7/64 (11%) pts who did not receive prophylaxis, in 2/8 (25%) pts who received only IT chemotherapy, whereas no CNS relapses were detected in the 32 pts treated with intravenous (IV) prophylaxis. CNS relapse rate was 13% for pts treated with “inadequate” prophylaxis (none or IT only) and 0% (p= 0.03) for pts managed with IV prophylaxis. Eight pts with CNS relapses died of lymphoma after 7-37 months (median 12), which represented 28% of all lymphoma-related deaths (n=29) in the high-risk group. Pts treated with IV prophylaxis had a significantly better OS than the other high-risk pts (5-yr: 94 ± 7% vs. 49 ± 6%; p= 0.001). Conclusions Stratification by specific extranodal sites and IPI is superior to ontogenic stratification to recognize CNS risk groups in DLBCL. However, the low sensitivity of predictive clinical variables suggests that molecular studies focused on the predictive and pathogenic role of molecules involved in CNS tropism will contribute to a more accurate definition of lymphoma candidates for CNS-directed strategies. In this context, IV high-dose methotrexate-based prophylaxis may significantly reduce CNS failures in high-risk pts. Disclosures: No relevant conflicts of interest to declare.

8035 Background: NGR-hTNF, a selective antivascular agent, induces at low dose an initial vascular normalization that greatly enhances the intratumoral chemotherapy uptake, with synergistic effects that were noted especially in combination with cisplatin and gemcitabine. Methods: Chemo-naive patients (pts) with advanced NSCLC were stratified by histology (nonsquamous or squamous) and PS (0 or 1) and randomly assigned to receive cisplatin 80 mg/m2/d1 plus either pemetrexed 500 mg/m2/d1 (nonsquamous) or gemcitabine 1,250 mg/m2/d1+8 (squamous) every 3 weeks (q3w) for 6 cycles, with (arm A) or without (arm B) NGR-hTNF given at 0.8 μg/m2/d1/q3w until progression. Progression-free survival (PFS) was primary aim (1-β=80%, 1-sided α=10%, n=102). Secondary aims comprised adverse events (AEs), response rate (RR), and overall survival (OS). Results: Baseline characteristics in arm A (n=62) vs B (n=59) were: median age: 62 vs 63 years; men: 37 vs 39; PS 1: 23 vs 23; squamous: 18 v 17; smokers: 41 vs 43. For the nonsquamous stratum, 299 cycles were given in arm A (mean 7.0; range 1-20) and 192 in arm B (4.8; 1-6), while for the squamous stratum, 113 in arm A (6.7; 1-31) and 52 in arm B (3.5; 1-6). Rates of grade 3/4 AEs were similar (arm A vs B): neutropenia 13% vs 18%, anaemia 7% vs 4% and fatigue 7% vs 11%. No grade 3/4 AEs related to NGR-hTNF or bleeding/pulmonary hemorrhage events were reported in the squamous subset. With median follow-up time of 24.2 months, median PFS (5.8 vs 5.6 months; HR=0.92), RR (25% vs 21%) and 1-year OS (53% vs 53%) were similar between the two treatment arms. However, by predefined analysis in the squamous stratum, median PFS was 5.6 months for arm A and 4.3 months for arm B (hazard ratio, HR=0.75) and median OS was 14.2 months for arm A and 9.7 months for arm B (HR=0.49; p=0.07). In pts with squamous histology, RR was 38% for arm A and 27% for arm B (odds ratio=1.6), while the median changes in tumor size on treatment from baseline to 2nd, 4th and 6th cycle for arm A vs B were -32% vs -20%, -41% vs -19%, and -42% vs -14%, respectively. Conclusions: Clinical tolerability and benefit were noted in squamous NSCLC with NGR-hTNF plus cisplatin and gemcitabine, which deserve further investigation. Clinical trial information: NCT00994097.

7581 Background: NGR-hTNF (asparagine-glycine-arginine human tumor necrosis factor) is a selective vascular targeting agent able to improve intratumoral chemotherapy uptake. Methods: Chemo-naive, stage IIIb-IV NSCLC patients (pts), stratified by histology (nonsquamous or squamous) and PS (0 or 1), were randomized to cisplatin 80 mg/m2/day(d)1 plus either pemetrexed 500 mg/m2/d1 (nonsquamous) or gemcitabine 1,250 mg/m2/d1+8 (squamous) every 3 weeks (q3w) up to 6 cycles with (arm A) or without (arm B) NGR-hTNF 0.8 μg/m2/d1 q3w until progression. Progression free survival (PFS) was primary end point of this phase 2 trial (β=20%, α=20%, HR=0.62, and n=102). Secondary end points included adverse events (AEs), response rate (RR) and overall survival (OS). Results: 59 pts were assigned to arm A and 57 to arm B. Baseline characteristics in arm A/B were: median age 62/63; male 34/37; PS 1 21/21; squamous 15/15; nonsmokers 14/12; EGFR mutations 5/5. For the nonsquamous group, 281 cycles (mean 6.5; range 1-18) were given in arm A and 190 (mean 4.7; range 1-6) in arm B, while for the squamous group, 88 (mean 6.3; range 1-19) in arm A and 48 (mean 3.7; range 1-6) in arm B. Most common grade 3/4 AEs were neutropenia 14% vs 17% and fatigue 7% vs 11% in arm A and B, respectively. No grade 3/4 AEs related to NGR-hTNF or bleeding in pts with squamous histology were noted. Median follow-up was 12.4 months. In the whole study population, median (m)PFS was 5.8 vs 5.7 months (HR=0.95), RR was 23% vs 19%, and 1-year OS was 62% vs 62% in arm A and B, respectively. In the nonsquamous subset, a trend toward longer mPFS in arm A compared to arm B was noted in pts with a PS of 1 (6.7 vs 4.6 months, respectively), nonsmoking history (6.2 vs 3.4), younger age (6.5 vs 3.4), and EGFR mutations (7.2 vs 3.3). In the squamous subset, mPFS was 5.1 vs 3.9 months (HR=0.71) and mOS was 14.2 vs 10.8 months (HR=0.73) in arm A and B, respectively. In these pts, ORR was 36% in arm A and 23% in arm B, while median changes from baseline in target tumor size after 2, 4, and 6 cycles were -29%, -45%, and -41%, respectively in arm A, and -18%, -22%, and -14%, respectively in arm B. Conclusions: Regardless of histology, NGR-hTNF can be safely given with standard chemotherapy, showing tolerability and hint of activity in squamous NSCLC.

Systemic chemotherapy is the treatment of choice for patients with small cell lung cancer (sclc), Myelosuppression is the limiting toxicity related to most comnbination regimens in sclc, inducing substantial morbidity, frequent dose reductions, and delay in administrating subsequent cycles. Vp-16, Ifosfamide and Carboplatin are all highly active as single agents against sclc, with a ramge of objective response between 60 % and 75 %, A combination of these 3 drugs (with concurrent chest radiotherapy) showed impressive activity) > 90 % objective response rate) in a previous report by another group (Smith, 1990), at the cost of a 100 % incidence of grade III-IV neutropenia, with 7 % therapyrelated deaths and dose reductions required for 72 % of patients. The association of recombinant human granolocyte-macrophage colony stimulating factor (r-hu-gm-csf) to a chemotherapy regimen consisting of Carboplatin and Vp-16 could allow higher doses of cytotoxic drugs to be given, possibly resulting in much higher complete response rates, even in extended disease (Morstyn, 1989). Basing on these data, we designed a pilot study on the association of r-hu-gm-csf to intensive chemotherapy.

e13612 Background: NGR-hTNF is a vascular targeting agent consisting of TNF fused with the peptide NGR, a ligand of a CD13 overexpressed on tumor blood vessels. Methods: Fifteen refractory patients (pts) received 83 cycles (range, 1-29) of NGR-hTNF (0.2-1.6 μg/m2) given every 3 weeks until progression. Median progression-free (PFS) and overall survival (OS) were 3.4 and 6.9 months, respectively. Ninety PBs were tested at baseline and 2-h after first cycle (post-dosing). Significant post-dosing changes in IL1/IL8/IL10/MCP1/MIP1b were noted. Based on their angiogenic role, an additional four PBs were selected: VEGF, matrix metalloproteinase-9 (MMP9), vascular-cell and inter-cellular adhesion molecule-1 (VCAM1 and ICAM1). The associations between these nine PBs and treatment duration (TD; ≤2 v >2 cycles), OS and maximal changes in tumour vascularity (assessed every cycle by DCE-MRI) were investigated. Results: TD was associated with OS (Spearman's r=0.55, p=.04), baseline DCE-MRI values (r=0.86, p=.004) and ...

e15500 Background: NGR-hTNF is a VTA exploiting a tumor-homing peptide (NGR) that selectively binds to aminopeptidase N (CD13) overexpressed on tumor blood vessels. In preclinical models, NGR-hTNF has shown potent anti-vascular and antitumor activity, both at low and at high doses. Methods: Patients with recurrent or metastatic HCC were treated with NGR-hTNF given intravenously at 0.8 μg/m2 as 1-hour infusion every 3 weeks (q3w). This phase II trial had a 2-stage design with 16 and a total of 27 patients to be enrolled after first and second stage, respectively. Progression-free survival (PFS) was the primary endpoint with reassessment performed q6w according to WHO criteria. Results: 27 patients with progressive disease following prior loco- regional treatment (59%), systemic therapy (56%), or both (33%) were evaluated over 86 cycles (range, 1 to 14). Patient characteristics were: median age 67 years (range, 53 to 79); M/F 21/6; PS 0/1 18/9; Child-Pugh class A/B: 21/6. No grade 3–4 treatment-related adverse events were observed. Main grade 1–2 toxicities were short-lasting infusion-related constitutional symptoms, including chills (55%). Median PFS was 2.3 months (95% CI, 1.7–2.9 months). One complete response (4%) lasting 9.0+ months was observed in a sorafenib-refractory patient and one partial response (4%) was reported in a Child-Pugh class B patient. Additionally, a 28% tumor shrinkage was detected in one out of six patients (22%) experiencing stable disease. The median PFS duration in stable or responder patients was 4.3 months (95% CI, 2.7–5.8 months). With a median follow-up of 7.6 months, the overall survival rates at 3 and 6 months were 82% and 60%, respectively. Conclusions: NGR-hTNF given at 0.8 μg/m2 every 3 weeks is well tolerated and appears to have promising antitumor activity in previously treated patients with advanced HCC. The drug will be further developed in this setting and, currently, an additional cohort of 12 patients has been enrolled and treated at same dose with a weekly schedule. [Table: see text]

15544 Background: NGR-hTNF is a VTA exploiting a tumor-homing peptide (NGR) that selectively binds to aminopeptidase N/CD13 highly expressed on tumour blood vessels. NGR-hTNF combines activity on t...

Cardiovascular toxicity related to i. v. administration of Interleukin2 (IL-2) is the main cause of treatment withdrawal and it is unpredictable on the base of standard pre-treatment evaluations including history, physical examination and EKG. We performed this study to investigate the value of Cardiac Ultra Sono Scan (CUSS) in the detection and prediction of such toxicity. The study included 19 patients (15 males, 4 females, median age: 51, tumor type: 10 advanced renal cell cancer, 9 malignant melanoma) scheduled to receive multiple cycles of IL-2 by continuous i. v. infusion at the dose of 18 MIU/m 2 /day for 96 hours. Data were recorded from 31 IL-2 infusions: a marked impairment of diastolic function was observed in all cases, but in a subset of cycles (12/31) this function was already impaired at the pre-treatment determination, and this was significantly correlated with the onset of major cardiovascular side-effects conditioning treatment discontinuation ( P P