Optimal safety profile and anticancer activity of NGRhTNF coupled with doxorubicin (NGR003 modified phase I combo trial)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14056-14056
Author(s):  
G. Rizzardi ◽  
V. Gregorc ◽  
G. Vitali ◽  
C. Gallo Stampino ◽  
C. van Herpen ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Vascular Permeability ◽  
Safety Profile ◽  
Low Dose ◽  
Specific Binding ◽  
Cytotoxic Agents ◽  
Dynamic Interactions ◽  
Grade Ii ◽  
Pretreated Patients ◽  
Combination Studies

14056 Background: NGRhTNF is a vascular targeting agent (VTA) exploiting a tumour homing peptide (CNGRCG) selectively binding angiogenic vessels in solid tumors, where NGRhTNF specific binding relies on dynamic interactions with TNF-receptors and aminopeptidase N (CD13). NGRhTNF combines activity on tumour vascular permeability and direct anticancer activity. At low dose, NGRhTNF increases tumour vascular permeability. Consistently, mouse preclinical data indicate significant synergy between low dose NGRhTNF and cytotoxic agents. Thus, we tested NGRhTNF in combination with doxorubicin. Methods: 4 doses of NGRhTNF (0.2, 0.4, 0.8 and 1.6 μg/m2) in combination with doxorubicin (75 mg/m2) have been administered every 3 weeks in 15 patients.Main end- points included safety, anticancer activity and pharmacokinetic. Measurement of circulating tumour (CTC) and endothelial cells, sTNF receptors, along with plasma chemokine profile are being performed. Results: All patients were enrolled (5F/10M). Toxicity was limited to constitutional symptoms, most frequently chills. After a median follow-up of 12 weeks (range 3–28), 5 episodes of chills (1 grade I and 4 grade II) were reported in 4/15 patients.One episode of grade I hypertension was reported. Of note, the toxicity profile commonly-associated to doxorubicin has not been exacerbated. Stabilization of disease occurred in 10/15 patients lasting 13 weeks (range 6–28 with 5 patients still ongoing at December 2006). In addition, partial response was achieved in 2 patients, lasting 23 and 14 (still ongoing) weeks, respectively. It is worth noting that anticancer activity was observed in 12/15 patients of whom 9 had previously received anthracycline-containing regimens and 5 were anthracycline-resistant suggesting a role of NGRhTNF in inducing tumour sensitivity to doxorubicin. Finally, changes in CTC levels over time consistently matched the clinical outcome. Conclusions: Coupling NGRhTNF with doxorubicin induced anticancer activity along with an optimal safety profile in pretreated patients providing support for the phase II combination studies addressing diseases suitable for anthracycline treatment such as sarcoma and ovarian cancer, and planned to start in early 2007. No significant financial relationships to disclose.

Safety and anticancer activity of low dose regimen of NGRhTNF, a new vascular targeting agent, in solid advanced malignancies (NGR002 phase I trial)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3540-3540 ◽  
Author(s):  
C. Gallo-Stampino ◽  
G. Rizzardi ◽  
S. Toma ◽  
A. Corti ◽  
P. Scifo ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Vascular Permeability ◽  
Drug Exposure ◽  
Low Dose ◽  
Biological Effects ◽  
Cytotoxic Agents ◽  
Vascular Targeting ◽  
Frequent Event ◽  
Over Time ◽  
Vascular Targeting Agent

3540 Background: NGRhTNF is a vascular targeting agent (VTA) exploiting a tumour homing peptide (CNGRCG) selectively binding angiogenic vessels in solid tumours where NGRhTNF specific binding relies on dynamic interactions with TNF-receptors and aminopeptidase N (CD13). NGRhTNF combines activity on tumour vascular permeability and direct anticancer activity. Consistently, mouse preclinical data indicate significant synergy between low dose NGRhTNF and cytotoxic agents. Methods: 4 dose levels of NGRhTNF (0.2 up to 1.6 mcg/sqm) have been administered q 3 w in 16 patients. Main end-points included safety, anticancer activity and pharmacokinetic.Measurement of circulating tumor and endothelial cells (CTC and CEC), sTNFRI and s TNFRII, along with plasma cyto-chemokine profile have been performed. Results: 16 patients were enrolled (6F/10M);median age 60,range 43–73). Toxicity was limited to constitutional symptoms, and chills were the most frequent event (40%). Over a median follow-up of 15 weeks, stable disease was achieved in 44% of patients, with long lasting disease control in 2 cases (27 and 75 weeks, with establishment of indication to radical surgery after 75 weeks, presently tumor free after removal of the residual tumor mass). In these 2 patients, VEGF, MMP-9, CA125, significantly decreased over time. DCE-MRI indicates that NGRhTNF increases vascular permeability after first drug exposure, particularly at the dose of 0.4 mcg/sqm, while following multiple infusions it exerts an antivascular effect, as demonstrated by the decrease of Ktrans values. Moreover NGRhTNF is able to elicit inflammatory and immune responses over time, as indicated by the modulation of expression of multiple cyto-chemokines. Finally, changes in CTC levels over time consistently matched the clinical outcome. Conclusions: Low dose NGRhTNF has an optimal safety profile along with anticancer activity acting on tumour vasculature and inducing relevant biological effects, thus rendering the agent suitable for a development both as monotherapy and in combination with chemotherapeutics. The phase II program is due to start in early 2007. [Table: see text]

NGRhTNF, a new vascular targeting agent with a dual mechanism of action: preliminary clinical results

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13052-13052
Author(s):  
C. Bordignon ◽  
F. Caligaris Capio ◽  
S. Toma ◽  
L. Manenti ◽  
P. Rizzardi ◽  
...  
Keyword(s):  
Phase I ◽  
Anticancer Activity ◽  
Vascular Permeability ◽  
Mechanism Of Action ◽  
Phase I Study ◽  
Low Dose ◽  
Moderate Intensity ◽  
Vascular Targeting ◽  
Dce Mri ◽  
Vascular Targeting Agent

13052 Background: NGRhTNF is a vascular targeting agent (VTA) exploiting a tumour homing peptide (CNGRCG) selectively binding solid tumor (lung, renal, and colorectal) neovasculature. NGRhTNF specific binding relies on dynamic interactions with TNF-receptors, aminopeptidase N (CD13) and a specific integrin: a combination of receptors expressed by the tumor neovasculature endothelium, but not on normal vessels. This combination provides NGRhTNF with unique biological properties: at low dose, increased tumor vascular permeability, and massive tumor necrosis at high dose. Mouse preclinical data confirmed these properties, revealing also strong synergy between low dose NGRhTNF and cytotoxic agents (antracyclines, platinum based compounds, etc.). Methods: Based on these data, a series of studies were designed. A multicentre phase I study with NGRhTNF as single agent -still in progress- aims at defining MTD and preliminary anticancer activity, within the EORTC network (EORTC 16041). A single center phase I study exploiting the low dose range (0.2–1.6 μg/m2) aims at defining safety and NGRhTNF activity on the tumor vascular permeability using DCE MRI (HSR NGR002). Results: Twelve advanced neoplastic patients were enrolled in the HSR NGR002 study. Up to the dose of 1.6 μg/m2, the only common toxicity was represented by constitutional symptoms such as infusion-associated chills (40%) of mild to moderate intensity. At the tested doses, NGRhTNF increased vascular permeability, as shown by changes in DCE MRI parameters (Ktrans and Kep), and modulated the expression of chemokines possessing antiangiogenic activity. NGRhTNF achieved stable disease in about 45% of highly refractory treated patients, and still ongoing long lasting disease control in 2 cases (7 and 9 months along with sharp decline of CA125 and VEGF). Conclusions: NGR-hTNF, a VTA with a unique mechanism of action, combines activity on tumor vascular permeability and direct anti-cancer effect. Preliminary data in humans confirm its favourable safety profile along with remarkable anticancer activity, thus rendering the agent suitable for a development program alone or in combination with chemotherapeutics. Phase II low dose combination studies will begin in 2006. [Table: see text]

CTIM-32. IMMUNE CHECKPOINT INHIBITOR NIVOLUMAB IN PEOPLE WITH RECURRENT SELECT RARE CNS CANCERS: RESULTS OF INTERIM ANALYSIS IN A HEAVILY PRETREATED COHORT

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi57-vi58
Author(s):  
Marta Penas-Prado ◽  
Ying Yuan ◽  
Kathleen Wall ◽  
Elizabeth Vera ◽  
Ukeme Ikiddeh-Barnes ◽  
...  
Keyword(s):  
Safety Profile ◽  
Interim Analysis ◽  
Cns Tumors ◽  
Myxopapillary Ependymoma ◽  
Investigational Drugs ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
Grade 3 ◽  
Total Accrual ◽  
Immune Profiling

Abstract INTRODUCTION Standard and experimental therapies for patients with rare CNS tumors are scarce. Nivolumab (PD-1 inhibitor) is approved for several non-CNS cancers. This ongoing Phase II trial (NCT03173950) will determine the efficacy of nivolumab in adults with recurrence/progression of one of 11 selected rare primary CNS tumors. Efficacy is measured by Disease Control Rate (DCR; confirmed CR/PR or durable SD for ≥ 6 months) in 2 cohorts: heavily and non-heavily pretreated patients (heavily pretreated: ≥ 3 prior therapies; non-heavily pretreated: ≤ 2). We report efficacy and safety results of a preplanned interim analysis in the heavily pretreated cohort. METHODS Eligibility includes recurrence/progression of an eligible tumor; age ≥ 18 years; tumor tissue available for histopathology, molecular and immune profiling; KPS ≥ 70; and no steroids at study entry. A total of 150 evaluable patients will be enrolled (75 to each cohort). Prior therapies include radiation and/or standard or investigational drugs. Nivolumab treatment is 240 mg IV every 2 weeks (4 doses); then 480 mg every 4 weeks (14 additional doses). Interim analysis was planned when sample size reached 32 in each cohort. RESULTS As of March 10, 2021, DCR exceeded the minimum required for interim analysis in the heavily pretreated cohort. Among 30 patients, 4 achieved SD > 6 months (medulloblastoma, anaplastic ependymoma, myxopapillary ependymoma, metastatic atypical meningioma). Safety profile (related AEs): grade 3 = 7; grade 4 = 1. Most frequent grade 3-5 AEs regardless of attribution: tumor progression (6); anemia, hydrocephalus, lymphopenia (3 each); cerebral edema, headache (2 each). CONCLUSION DCR exceeded the “go” boundary (i.e., > 2) in the heavily pretreated cohort. Nivolumab showed safety profile consistent with other studies. This cohort will continue to stage 2 and complete total accrual of 75 patients. The trial is currently being expanded to 10 additional sites across the BTTC/NCI-CONNECT consortium.

Roscovitine Sensitizes Leukemia and Lymphoma Cells to TRAIL-Induced Apoptosis and Enhances Cell-Mediated Cytotoxicity

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 596-596
Author(s):  
Jan Molinsky ◽  
Marie Markova ◽  
Magdalena Klanova ◽  
Michal Koc ◽  
Lenka Beranova ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cell Lines ◽  
Low Dose ◽  
Hematologic Malignancies ◽  
Additive Effect ◽  
Cytotoxic Agents ◽  
Potential Contribution ◽  
Primary Cells ◽  
Trail Receptors ◽  
Induced Apoptosis

Abstract Abstract 596 Roscovitine is a selective inhibitor of cyclin-dependent kinases (CDK) and it is under evaluation in several clinical trials in the treatment of diverse cancers. TNF-related apoptosis inducing ligand (TRAIL) is a death ligand important for tumor immunosurveillance with selective antitumor activity and minimal toxicity toward tissues. Soluble TRAIL is also under evaluation in several clinical trials. Unfortunatelly, many cancers are resistant to TRAIL. To circumvent TRAIL resistance, there is effort to combinate TRAIL with other cytotoxic agents. By measuring apoptosis and proliferation, we demonstrated that combination of low dose roscovitine and low dose TRAIL (low dose= up to 30% of apoptotic cells after 24h treatment) is synergistic in 20 of 21 tested hematologic cell lines including TRAIL resistant cell lines. Moreover, this combination was tested on primary cells from 9 patients with hematologic malignancies with synergism in 4 of 8 samples from patients with acute myeloid leukemia (AML) and 1 sample from patient with mantle cell lymphoma. Remaining 4 AML samples showed additive effect. Based on these results, we decided to explore molecular mechanisms responsible for the synergism between roscovitine and TRAIL using TRAIL-resistant K562 cells. Despite decreased mRNA, the surface expression of TRAIL receptors remained unaffected after 24h roscovitine treatment. Immunoprecipitation of death-inducing signaling complex (DISC) revealed distinct proapoptotic changes (enhanced CASP8 and 10, reduced FLIP at 12 and 24h). These proapoptotic changes suggested that roscovitine might synergize with other death ligands acting through the DISC, namely TNF and FASLG. Indeed, roscovitine significantly sensitized diverse cell lines (K562, DOHH2, RAMOS) to TNF or FASLG-induced apoptosis. We subsequently proved that pretreatment of the cells (K562, DOHH2, RAMOS) with roscovitine increased by approx. 20% the level of cell-mediated cytotoxicity (peripheral blood mononuclear cells from a healthy volunteer marked with carboxyfluorescein succinimidyl ester). Thus, proapoptotic changes of the DISC seem to play essential role in mediating roscovitine-induced sensitization to TRAIL. Despite detected alterations of the DISC, we decided to unveil additional potential changes in the protein levels of key apoptotic regulators by western blotting at 1.5, 3, 6, 12 and 24h timepoints. Like Ortiz-Ferron et al. we detected gradual downregulation of MCL1 that peaked at 12h, followed, however, by substantial upregulation at 24h. We proved that even at this point, i.e. at 24h exposure to roscovitine, the cells were sensitized to TRAIL-induced apoptosis. The role of MCL1 in mediating the proapoptotic change thus remains elusive. BCL-XL showed similar kinetics as MCL1. Several proapoptotic proteins were overexpressed (BAK and BAD at 1.5h, and PUMA at 1.5h and 24h). Gene-expression profiling unveiled additional changes that might contribute to sensitization to TRAIL, e.g. upregulation of proapoptotic death inducer-obliterator 1 (DIDO1) and downregulation of antiapoptotic DNA-damage-inducible transcript 4 (DDIT4). In contrast to TRAIL (and the other death ligands) roscovitine showed only additive effect or even antagonism with the tested genotoxic agents (cytarabine, doxorubicin, fludarabine, etoposide, cisplatin) probably due to the inhibition of CDK2 by roscovitine (Yu et al., Yanjun et al.). We demonstrated that combination of roscovitine and TRAIL is synergistic in hematologic cell lines and primary cells. In addition, roscovitine was shown to have potent immunostimulatory effect by increasing cell-mediated cytotoxicity. Based on our results we suggest that roscovitine-induced sensitization to TRAIL-triggered apoptosis was mediated by proapoptotic changes of the DISC with potential contribution of the proapoptotic changes in the protein expression of the apoptotic regulators (MCL1, BCL-XL, PUMA, BAK, BAD). We also suggest that roscovitine-induced increase in cell-mediated cytotoxicity, known to be mediated in part through death ligands, was also a consequence of the proapoptotic alteration of the DISC. Roscovitine, as a single agent, or in combination with TRAIL, might have a role in the experimental treatment of selected hematologic malignancies. Financial Support: LC 06044, MSM 0021620806, MSM 0021620808, GAUK 259211/110709, SVV-2010-254260507, IGA MZ NS/10287-3 Disclosures: No relevant conflicts of interest to declare.

Inhibition of immune-mediated low-dose streptozotocin diabetes by agents which reduce vascular permeability

1986 ◽  
Vol 12 (1) ◽  
pp. 17-21 ◽  
Author(s):  
Eckart Schwab ◽  
Volker Burkart ◽  
Götz Freytag ◽  
Ulrich Kiesel ◽  
Hubert Kolb
Keyword(s):  
Vascular Permeability ◽  
Low Dose ◽  
Streptozotocin Diabetes ◽  
Immune Mediated

Continuous Administration of Daily Low-Dose Temozolomide in Pretreated Patients with Advanced Non-Small Cell Lung Cancer: A Phase II Study

Oncology ◽  
2009 ◽  
Vol 76 (2) ◽  
pp. 112-117 ◽  
Author(s):  
Charalambos Kouroussis ◽  
Lambros Vamvakas ◽  
Nikolaos Vardakis ◽  
Athanasios Kotsakis ◽  
Antonia Kalykaki ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Phase Ii ◽  
Cell Lung Cancer ◽  
Low Dose ◽  
Phase Ii Study ◽  
Small Cell ◽  
Small Cell Lung ◽  
Continuous Administration ◽  
Pretreated Patients

scholarly journals Efficacy and Safety of Decitabine in Combination with G-CSF, Low-Dose Cytarabine and Mitoxantrone in Pediatric Refractory and Relapse Acute Myeloid Leukemia and MDS-Raebt

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5175-5175
Author(s):  
Liyan Fan ◽  
Aili Chen ◽  
Yixin Hu ◽  
Peifang Xiao ◽  
Jun Lu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Pediatric Patients ◽  
Efficacy And Safety ◽  
Hematopoietic Stem ◽  
Grade Ii ◽  
Acute Myeloid

Abstract Background: It is difficult for pediatric refractory and relapse acute myeloid leukemia (RR-AML) and MDS-RAEB/RAEBT patients to achieve complete remission (CR) and these patients develop recurrence and die of either disease progression or associated complications. The CAG regimen (cytarabine, aclarubicin and G-CSF) has been widely used in treating patients with MDS-EB and AML-MRC in Asia. Likely, Short term CAG derived regimens called low dose induction therapy, MAG regimen (Mitoxantrone for 3 doses, cytarabine and G-CSF for 10 days) also showed efficacy in De Novo AML. However, MAG regimen showed less efficacy in RR-AML and MDS-5(5q-). Purpose: To evaluate the clinical efficacy and safety of low-dose decitabine in combination with low-dose MAG regimen (D-MAG regimen) in the treatment of RR-AML and MDS-RAEB/RAEBT. Method A total of 17 patients with MDS-RAEB/RAEBT and RR-AML((2 cases of MDS-RAEB, 3 cases of MDS-RAEBT, 10 cases for refractory AML, and 2 cases for relapse AML) from June 2017 to April 2018 in our center were included in the retrospective study. All the patients were treated with decitabine of 20 mg/m2 for 5 days and followed by 10 days of MAG regimen (cytarabine of 10mg/m2 q12h for 10 days, mitoxantrone of 5 mg/ m2.d for 3 days, and G-CSF of 5μg/kg.d for 10 days),called D-CAG regimen. After two cycles of induction chemotherapy, the patients who obtained CR received consolidation chemotherapy or hematopoietic stem cell transplantation (HSCT). Results Among a total of 17 patients, the median age was the median age was 102 months (32-200 months) and 64.71 % of them were male. Characteristic features of these patients were illustrated in Table 1. Only 2 cases died of severe lung infection due to continuous agranulocytosis who had been received high dose induction therapy (Daunorubicin of 50mg/M2.d for 3 days, cytarabine of 100mg/m2 q12h for 10 days, and Etoposide of 150mg/m2.d for 5 days) for 2 cycles with poor physical condition before D-MAG. In the other 15 cases, 10 of them had complete remission (CR) after the first course of treatment, 4 cases were partial remission (PR), 1 case with a high blast cells at 25% indicated a poor response to D-MAG, and the effective rate was 93.3%. Among 4 children with PR, one case reached CR after the second courses of treatment. The most common adverse reactions in all children were hematological toxicity, grade III-IV. Liver damage was found in 2 cases, grade I and grade II respectively. There were 3 cases of oral side reactions, 1 case in grade I and 2 cases in grade II. The gastrointestinal reactions in all children were grade I - II. By July 2018, the median follow-up was 11 months (7-16months). Among 15 patients after D-MAG, 11 patients received HSCT. The twelve-month survival rate was 88.24% and the median leukemia-free survival (LFS) was 11 months. Conclusion The low-dose decitabine in combination with Low-dose MAG regimen improved CR rate for pediatric patients with MDS-RAEB and RR- AML, and is a promising treatment for pediatric patients with MDS/RR-AML. Disclosures No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document