Giovanni Donadoni

Defining the optimal biological dose of NGR-hTNF, a selective vascular targeting agent, in advanced solid tumours.

BACKGROUND NGR-hTNF consists of human tumour necrosis factor-alpha (hTNF-alpha) fused to the tumour-homing peptide NGR, a ligand of an aminopeptidase N/CD13 isoform, which is overexpressed on endothelial cells of newly formed tumour blood vessels. NGR-TNF showed a biphasic dose-response curve in preclinical models. This study exploring the low-dose range aimed to define safety and optimal biological dose of NGR-hTNF. PATIENTS AND METHODS Pharmacokinetics, plasma biomarkers and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were evaluated at baseline and after each cycle in 16 patients enrolled at four doubling-dose levels (0.2-0.4-0.8-1.6 microg/m(2)). NGR-hTNF was given intravenously as 1-h infusion every 3 weeks (q3w). Tumour response was assessed q6w. RESULTS Eighty-three cycles (median, 2; range, 1-29) were administered. Most frequent treatment-related toxicity was grade 1-2 chills (69%), occurring during the first infusions. Only one patient treated at 1.6 microg/m(2) had a grade 3 drug-related toxicity (chills and dyspnoea). Both C(max) and AUC increased proportionally with dose. No shedding of soluble TNF-alpha receptors was observed up to 0.8 microg/m(2). Seventy-five percent of DCE-MRI assessed patients showed a decrease over time of K(trans), which was more pronounced at 0.8 microg/m(2). Seven patients (44%) had stable disease for a median time of 5.9 months, including a colon cancer patient who experienced an 18-month progression-free time. CONCLUSION Based on tolerability, soluble TNF-receptors kinetics, anti-vascular effect and disease control, NGR-hTNF 0.8 microg/m(2) will be further developed either as single-agent or with standard chemotherapy.

Phase I Study of NGR-hTNF, a Selective Vascular Targeting Agent, in Combination with Cisplatin in Refractory Solid Tumors

Purpose: NGR-hTNF exploits the tumor-homing peptide asparagine-glycine-arginine (NGR) for selectively targeting TNF-α to an aminopeptidase N overexpressed on cancer endothelial cells. Preclinical synergism with cisplatin was displayed even at low doses. This study primarily aimed to explore the safety of low-dose NGR-hTNF combined with cisplatin in resistant/refractory malignancies. Secondary aims included pharmacokinetics (PKs), pharmacodynamics, and activity. Experimental Design: NGR-hTNF was escalated using a doubling-dose scheme (0.2–0.4–0.8–1.6 μg/m2) in combination with fixed-dose of cisplatin (80 mg/m2), both given intravenously once every three weeks. PKs and circulating TNF-receptors (sTNF-Rs) were assessed over the first three cycles. Results: Globally, 22 patients (12 pretreated with platinum) received a range of one to ten cycles. Consistently with the low-dose range tested, maximum-tolerated dose was not reached. No dose-limiting toxicities (DLTs) were observed at 0.2 (n = 4) and 0.4 μg/m2 (n = 3). One DLT (grade 3 infusion-related reaction) was observed at 0.8 μg/m2. This dose cohort was expanded to six patients without further DLTs. No DLTs were noted also at 1.6 μg/m2 (n = 3). NGR-hTNF exposure increased dose-proportionally without apparent PK interactions with cisplatin. No shedding of sTNF-Rs was detected up to 0.8 μg/m2. At the dose level of 0.8 μg/m2, expanded to 12 patients for activity assessment, a platinum-pretreated lung cancer patient achieved a partial response lasting more than six months and five patients maintained stable disease for a median time of 5.9 months. Conclusions: The combination of NGR-hTNF 0.8 μg/m2 with cisplatin 80 mg/m2 showed favorable toxicity profile and promising antitumor activity. Clin Cancer Res; 17(7); 1964–72. ©2011 AACR.

High Doses of Antimetabolites Followed by High-Dose Sequential Chemoimmunotherapy and Autologous Stem-Cell Transplantation in Patients With Systemic B-Cell Lymphoma and Secondary CNS Involvement: Final Results of a Multicenter Phase II Trial

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 × 10(6)/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.

Risk-tailored CNS prophylaxis in a mono-institutional series of 200 patients with diffuse large B-cell lymphoma treated in the rituximab era.

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.

Activity and safety of NGR-hTNF, a selective vascular-targeting agent, in previously treated patients with advanced hepatocellular carcinoma.

Background:Hepatocellular carcinoma (HCC) is a highly vascularised and poor-prognosis tumour. NGR-hTNF is a vascular-targeting agent consisting of human tumour necrosis factor-alpha fused to the tumour-homing peptide NGR, which is able to selectively bind an aminopeptidase N overexpressed on tumour blood vessels.Methods:Twenty-seven patients with advanced-stage disease resistant to either locoregional (59%; range, 1–3), systemic treatments (52%; range, 1–3) or both (33%) received NGR-hTNF 0.8 μg m−2 once every 3 weeks. The primary aim of the study was progression-free survival (PFS).Results:No grade 3–4 treatment-related toxicities were noted. Common toxicity included mild-to-moderate, short-lived chills (63%). Median PFS was 2.3 months (95% CI: 1.7–2.9). A complete response ongoing after 20 months was observed in a sorafenib-refractory patient and a partial response in a Child-Pugh class-B patient, yielding a response rate of 7%. Six patients (22%) experienced stable disease. The disease control rate (DCR) was 30% and was maintained for a median PFS time of 4.3 months. Median survival was 8.9 months (95% CI: 7.5–10.2). In a subset of 12 sorafenib-resistant patients, the response rate was 8% and the median survival was 9.5 months.Conclusion:NGR-hTNF was well tolerated and showed single-agent activity in HCC. Further investigation in HCC is of interest.

High-dose clarithromycin is an active monotherapy for patients with relapsed/refractory extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT): the HD-K phase II trial

BACKGROUND Clarithromycin displays immunomodulatory and antineoplastic properties. As single agent, this macrolide is associated with tumor responses in anecdotal cases of relapsed/refractory extranodal marginal zone lymphoma (rrEMZL), with a putative dose-dependent effect. Tolerability and activity of high-dose clarithromycin (HD-K) in patients with rrEMZL were addressed in a phase II trial (clinicaltrials.gov NCT01516606). METHODS HIV-negative adults with rrEMZL and at least one measurable/parametrable lesion were enrolled and treated with four courses of oral clarithromycin 2 g/day, days 1-14, every 21 days. Activity (overall response rate, ORR) was the primary end point. RESULTS Twenty-three patients were registered (median age 70 years, range 47-88 years; M:F ratio: 0.27). HD-K was given at greater than or equal to second relapse in 11 patients. Ocular adnexae were the most commonly involved organs. Five patients had hepatitis B virus/hepatitis C virus (HBV/HCV) infections; Helicobacter pylori and Chlamydophila psittaci infections were excluded at the time of patient registration.Tolerability was excellent, even among HBV/HCV-positive patients; only two patients had grade >2 toxicity (nausea). Six patients achieved a complete remission and six a partial response (ORR = 52%; 95% confidence interval 32% to 72%). Age, previous treatment and stage did not influence activity. At a median follow-up of 24 (16-33) months, only two patients with responsive disease experienced relapse, with a 2-year progression-free survival of 56 ± 10%; all patients are alive. CONCLUSIONS HD-K is a safe and active salvage treatment in EMZL patients. This macrolide deserves to be further investigated in EMZL and other lymphoma categories.

Safety and activity of a new intensive short-term chemoimmunotherapy in HIV-positive patients with Burkitt lymphoma

The treatment of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) patients with Burkitt lymphoma (HIV-BL) is a difficult challenge, requiring multidisciplinary efforts and demanding strategies. While the worldwide use of highly active antiretroviral therapy (HAART) resulted in improved tolerability and efficacy of standard chemotherapy in HIV-positive patients with diffuse large B-cell lymphomas, it has not been associated with better outcome in HIV-BL, with respect to the pre-HAART era, suggesting that more intensive treatments should be used (Lim et al, 2005). Currently, a few, small studies addressing feasibility and activity of dose-dense chemotherapeutic regimens in HIV-BL are available (Table S1). Reported regimens display high efficacy, but are often associated with important dose-limiting side-effects, prolonged hospitalization and treatment-related mortality (TRM) of 15–20%. A dose-dense, short-term chemotherapy program including seven active drugs and intrathecal drug delivery has showed excellent activity and safety profiles in HIV-negative patients with BL in the pre-rituximab era (Di Nicola et al, 2004). We introduced a few changes to this regimen to maintain efficacy and improve tolerability in HIV-BL. In particular, six doses of rituximab were added and methotrexate dose was reduced, from 150 and 250 mg/kg to 3 g/m, mostly to avoid mucositis, which constitutes an important route of access for infectious agents and one of the main causes of death in these patients (Galicier et al, 2007). We used this modified chemoimmunotherapy regimen in 15 consecutive HIV-BL (median age 42 years old, range 27–63) between July 2009 and July 2011 (Table S2). Treatment consisted of a 36-day induction phase including sequential doses of fractionated cyclophosphamide, high doses of methotrexate and cytarabine, doxorubicin, vincristine, and etoposide, rituximab and intrathecal prophylaxis/ treatment (Table I). Subsequent treatment was then tailored according to the objective response to induction phase (Fig. 1): patients in complete response (CR) were referred to a high-dose cytarabine-based consolidation phase (Table I); patients in partial response (PR) were referred to consolidation followed by BEAM (carmustine, etoposide, cytarabine, melphalan) plus autologous stem cell transplant (ASCT); patients with stable or progressive disease were referred to intensification phase, followed by BEAM + ASCT. At the end of chemoimmunotherapy, patients with initial bulky disease or with a residual positron emission tomography-positive single lesion were evaluated for 36-Gy involved-field irradiation. Treatment was safe and well tolerated. All patients but one completed the induction phase (median duration: 49 d; range 34–108); methotrexate and etoposide occasionally required delivery delay due to G3 transaminase increase or G4 neutropenia. Cytostatics dose reductions were recorded only in two patients. There was a single toxic death, which was due to pneumonia in a patient with extensive bone marrow infiltration and baseline CD4+ count of 0 017 9 10/l. As expected, haematological toxicity was common, but manageable (Table S3); with conventional antimicrobial prophylaxis and rHuG-CSF support, infective complications were mild and no systemic fungal infections occurred. The most relevant toxicity was recorded after consolidation: the original cytarabine-cisplatin consolidation regimen (Di Nicola et al, 2004) used in the first four patients was too toxic, with prolonged G4 neutropenia and severe infections in all cases. The exclusion of cisplatin, the change of cytarabine administration schedule and the addition of rituximab (Table I) were associated with a strikingly improved tolerability in subsequent patients, with only two cases of well-controlled febrile neutropenia. Of note, there was a single case of G4 non-haematological toxicity (transient diarrhoea). Patients with hepatitis B virus or hepatitis C virus positivity completed the planned treatment (ASCT in three), and experienced only transient G3 increase of transaminase serum level, without significant chemotherapy delay. HAART was discontinued during chemoimmunotherapy in four patients: three patients exhibited an increase of plasmatic HIV-RNA levels at day 45 followed by undetectable levels at day 90 in two cases, while the third patient needed for a further HAART line; the fourth patient was the toxic death. CD4+ cell counts remained unchanged in the three assessed patients, but were < 0 05 9 10/l in two of them. Response after induction phase was complete in six patients and partial in seven [overall response rate risk (ORR) = 87%; 95% confidence interval CI: 70–100%], one patient had meningeal dissemination and one died of sepsis (Fig. 1). Thirteen patients were referred to consolidation phase, 11 of them were referred to APBSC collection, which was successful in nine (median: 14 10 CD34+ cells/ kg; range 7 20–20 02). The six patients in CR after inducCorrespondence

Assessing “occult” cervical cord damage in patients with neuropsychiatric systemic lupus erythematosus using diffusion tensor MRI

Background: Whereas focal and diffuse brain damage on conventional MRI is seen in patients with neuropsychiatric systemic lupus erythematosus (NSLE), the spinal cord seems to be rarely involved. Diffusion tensor (DT) MRI provides information on the patterns of tissue disruption of the central nervous system, which may go undetected by conventional MRI. Objective: To quantify the extent of otherwise “occult” injury of the cervical cord in NSLE, and to improve our understanding of its nature. Subjects and methods: Conventional and DT MRI scans of the cervical cord and brain were acquired from 11 patients with NSLE and 10 healthy controls. Histograms of mean diffusivity (MD) and fractional anisotropy (FA) of the cervical cord and brain were analysed. Measures of cervical cord and brain atrophy and focal lesion loads were computed. Results: Only one patient had a single focal lesion of the cord whereas all had multiple brain lesions on conventional MRI scans. Cord and brain volumes did not differ between patients and controls. Mean peak height of the cervical cord MD histogram (p = 0.0001) and average brain FA (p = 0.001) were significantly lower in patients than in controls. Average cord MD was correlated with average brain MD (r = 0.69, p = 0.01) and FA (r = −0.81, p = 0.002). Conclusion: DT MRI shows mild and otherwise “occult” cord damage in NSLE, which might be secondary to Wallerian degeneration of long tract fibres passing trough damaged areas of the brain.

[The primary mediastinal lymphoma: state of the art and therapeutical perspectives].

Within diffuse large B-cell lymphomas, the Primary Mediastinal Large B-Cell Lymphoma has to be considered as a separate and well-defined clinico-pathological entity. Its tendency to target young adults makes its social impact particularly significant; hence, the General Practitioner carries the responsibility for an early diagnosis. On the contrary, the extreme complexity of the available therapies makes a quick referral to specialized Clinical Centres of outmost importance, since this remains the best way to enrol as many patients as possible in therapeutic protocols. Nowadays, good clinical results and a favourable outcome are achievable, but some questions remain open. The role of radiotherapy still has to be clarified, both as a complete remission consolidation, as well as a treatment of the residual disease. Conversely, a golden standard for the second line treatment has not been clearly established.

Predictive potential of angiogenic plasma biomarkers (PBs) in phase I trial with NGR-hTNF.

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 (Spearmans r=0.55, p=.04), baseline DCE-MRI values (r=0.86, p=.004) and ...