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| ID | Type | Description | Link |
|---|---|---|---|
| EUDRACT Number: 2005-004846-15 |
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The main objective of the trial is to document the safety of the combination (escalation doses of NGR-hTNF, from 0.2 mcg/sqm to 1.6 mcg/sqm , with a fixed dose of doxorubicin, 75 mg/sqm). Safety will be established by clinical and laboratory assessment according to National Cancer Institute Common Toxicity Criteria (NCI-CTC ).
This is a phase IB, open-label, non-randomized, dose-escalation study that will be conducted in sequential cohorts of patients. Three patients per each cohort are planned.
Patients, with advanced or metastatic solid tumor previously treated with a non cumulative dose of doxorubicin (<300 mg/sqm in order to allow an adequate number of cycles) or chemotherapy naïve will be enrolled.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| A | Experimental |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| NGR-hTNF | Drug | 0.2, 0.4, 0.8 and 1.6 μg/m²as 60-minute intravenous infusion every 3 weeks |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Adverse Events From Escalating Doses of NGR-hTNF in Combination With a Fixed Dose of Doxorubicin | An Adverse Event (AE) is any untoward medical occurrence or experience in a patient or clinical investigation subject treated administered a pharmaceutical product and which does not necessarily have to have a casual relationship with this treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. | Through study completion, an average of 1 year |
| Measure | Description | Time Frame |
|---|---|---|
| Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Cmax) | Pharmacokinetic profiles of NGR-hTNF and doxorubicin was conducted in 4 sequential cohorts of patients (Three patients per each cohort were planned). The first 3 patients of the first cohort were treated with 0.2 μg/m2 of NGR-hTNF in combination with a suboptimal dose (minus 20%) of doxorubicin (60 mg/m2).Following 4 cohorts were treated with escalating dose of NGR-hTNF (0.2, 0.4, 0.8 and 1.6 μg/m2) in combination with a standard dose of doxorubicin (75 mg/m2): |
Not provided
Inclusion Criteria:
Neutrophils > 1.5 x 10^9/L and platelets >100 x 10^9/L Bilirubin < 1.5 x ULN AST and/or ALT < 2 x ULN Serum creatinine < 1.5 x ULN
Patients may have had prior therapy providing the following conditions are met:
Patients must give written informed consent to participate in the study.
Exclusion Criteria:
Not provided
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| Name | Affiliation | Role |
|---|---|---|
| Federico Caligaris Cappio, MD | Fondazione San Raffaele del Monte Tabor | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Istituto Clinico Humanitas | Rozzano | Milan | 20089 | Italy | ||
| Azienda Ospedaliera Universitaria "San Martino" |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 16397040 | Background | Sacchi A, Gasparri A, Gallo-Stampino C, Toma S, Curnis F, Corti A. Synergistic antitumor activity of cisplatin, paclitaxel, and gemcitabine with tumor vasculature-targeted tumor necrosis factor-alpha. Clin Cancer Res. 2006 Jan 1;12(1):175-82. doi: 10.1158/1078-0432.CCR-05-1147. |
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Screening details:
Planned sample size: 20-25 patients; Patients screened n.: 15; Patients screening failure n.: 0.
Study Period: 28 February 2006 (first enrollment); 8 May 2007 (last completed). 3 investigational centres in Italy and 1 in Netherlands.
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | Cohort 1: NGR-hTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | NGR-hTNF: 0.2 μg/m^2 as 60-minute intravenous infusion every 3 weeks Doxorubicin: 60 mg/m^2 intravenous infusion over 15 minutes (starting 1 hour after the end of NGR-hTNF infusion) |
| FG001 | Cohort 2: NGR-hTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | NGR-hTNF: 0.2 μg/m^2 as 60-minute intravenous infusion every 3 weeks Doxorubicin: 75 mg/m^2 intravenous infusion over 15 minutes (starting 1 hour after the end of NGR-hTNF infusion) |
| FG002 | Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | NGR-hTNF: 0.4 μg/m^2 as 60-minute intravenous infusion every 3 weeks Doxorubicin: 75 mg/m^2 intravenous infusion over 15 minutes (starting 1 hour after the end of NGR-hTNF infusion) |
| FG003 | Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | NGR-hTNF: 0.8 μg/m^2 as 60-minute intravenous infusion every 3 weeks Doxorubicin: 75 mg/m^2 intravenous infusion over 15 minutes (starting 1 hour after the end of NGR-hTNF infusion) |
| FG004 | Cohort 5: NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | NGR-hTNF: 1.6 μg/m^2 as 60-minute intravenous infusion every 3 weeks Doxorubicin: 75 mg/m^2 intravenous infusion over 15 minutes (starting 1 hour after the end of NGR-hTNF infusion) |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | NGR-hTNF: 0.2 μg/m^2as 60-minute intravenous infusion every 3 weeks Doxorubicin: 60 mg/m^2 intravenous infusion over 15 minutes (starting 1 hour after the end of NGR-hTNF infusion) |
| BG001 | Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Adverse Events From Escalating Doses of NGR-hTNF in Combination With a Fixed Dose of Doxorubicin | An Adverse Event (AE) is any untoward medical occurrence or experience in a patient or clinical investigation subject treated administered a pharmaceutical product and which does not necessarily have to have a casual relationship with this treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. | Posted | Number | Adverse event | Through study completion, an average of 1 year |
|
Through study completion, an average of 1 year
Not provided
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | NGR-hTNF: 0.2 μg/m^2 as 60-minute intravenous infusion every 3 weeks Doxorubicin: 60 mg/m² intravenous infusion over 15 minutes (starting 1 hour after the end of NGR-hTNF infusion) |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Deep vein thrombosis | Vascular disorders | MedDRA 22.0 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA 22.0 | Systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| MolMed S.p.A. | Clinical Operations | 0039 02212771 | clinical.operations@molmed.com |
Not provided
| ID | Term |
|---|---|
| D009369 | Neoplasms |
Not provided
Not provided
Not provided
| ID | Term |
|---|---|
| C464839 | tumor necrosis factor-alpha, CNGRC fusion protein, human |
| D004317 | Doxorubicin |
| ID | Term |
|---|---|
| D003630 | Daunorubicin |
| D018943 | Anthracyclines |
| D009279 | Naphthacenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
Not provided
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Dose-escalating study
Not provided
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| Doxorubicin |
| Drug |
75 mg/m² intravenous infusion over 15 minutes (starting 1 hour after the end of NGR-hTNF infusion) |
|
| prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes |
| Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Tmax) | Pharmacokinetic profiles of NGR-hTNF and doxorubicin was conducted in 4 sequential cohorts of patients (Three patients per each cohort were planned). The first 3 patients of the first cohort were treated with 0.2 μg/m2 of NGR-hTNF in combination with a suboptimal dose (minus 20%) of doxorubicin (60 mg/m2).Following 4 cohorts were treated with escalating dose of NGR-hTNF (0.2, 0.4, 0.8 and 1.6 μg/m2) in combination with a standard dose of doxorubicin (75 mg/m2): | prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes |
| Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (AUC0-t(Last)) | Pharmacokinetic profiles of NGR-hTNF and doxorubicin was conducted in 4 sequential cohorts of patients (Three patients per each cohort were planned). The first 3 patients of the first cohort were treated with 0.2 μg/m2 of NGR-hTNF in combination with a suboptimal dose (minus 20%) of doxorubicin (60 mg/m2).Following 4 cohorts were treated with escalating dose of NGR-hTNF (0.2, 0.4, 0.8 and 1.6 μg/m2) in combination with a standard dose of doxorubicin (75 mg/m2): | prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes |
| sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Pharmacodynamic calculations for sTNF-R1 and sTNF-R2 were performed on the plasma concentrations from which the baseline concentrations were subtracted (i.e. on positive and negative values). At all doses, Emax, i.e. the maximal stimulatory effect, and tmax were estimated as the coordinates of the highest point of the plasma profile (y, x axis, respectively) | prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes |
| sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Pharmacodynamic calculations for sTNF-R1 and sTNF-R2 were performed on the plasma concentrations from which the baseline concentrations were subtracted (i.e. on positive and negative values). At all doses, Emax, i.e. the maximal stimulatory effect, and tmax were estimated as the coordinates of the highest point of the plasma profile (y, x axis, respectively) | prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes |
| sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Pharmacodynamic calculations for sTNF-R1 and sTNF-R2 were performed on the plasma concentrations from which the baseline concentrations were subtracted (i.e. on positive and negative values). At all doses, Emax, i.e. the maximal stimulatory effect, and tmax were estimated as the coordinates of the highest point of the plasma profile (y, x axis, respectively) | prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes |
| sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Pharmacodynamic calculations for sTNF-R1 and sTNF-R2 were performed on the plasma concentrations from which the baseline concentrations were subtracted (i.e. on positive and negative values). At all doses, Emax, i.e. the maximal stimulatory effect, and tmax were estimated as the coordinates of the highest point of the plasma profile (y, x axis, respectively) | prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes |
| To Evaluate Phenotype Analysis and Adaptative Immune Response | during the study |
| Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | Response to treatment was assessed on a set of target lesions(TL) chosen before the 1st treatment administration, the list of TL must be reported on the initial measurement form before the start of treatment. Lesions had to have clearly defined borders and initially were measured in at least one dimension, and had to be repeated at each evaluation of the disease by the same method. Sum of the longest diameter (LD) was calculated as the baseline sum LD Complete Response(CR): Disappearance of all TL Partial Response(PR): At least a 30% decrease in the sum of the LD of TL, taking as reference the base line sum LD Progressive Disease(PD): At least a 20% increase in the sum of LD of TL, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions Stable Disease (SD):Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started | after the first 2 cycles(Follow-up 2) of treatment and then every 2 cycles (Follow-up 4,6..). In case of detection of a complete or partial response, a confirmation assessment must be performed ≥ 4 weeks after the first documentation of the response. |
| Genova |
| 16132 |
| Italy |
| Fondazione San Raffaele del Monte Tabor | Milan | 20132 | Italy |
| University Medical Centre, Nijmegen | Nijmegen | Netherlands |
NGR-hTNF: 0.2 μg/m^2as 60-minute intravenous infusion every 3 weeks Doxorubicin: 75 mg/m^2 intravenous infusion over 15 minutes (starting 1 hour after the end of NGR-hTNF infusion) |
| BG002 | Cohort 3: NGRhTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | NGR-hTNF: 0.4 μg/m^2as 60-minute intravenous infusion every 3 weeks Doxorubicin: 75 mg/m^2 intravenous infusion over 15 minutes (starting 1 hour after the end of NGR-hTNF infusion) |
| BG003 | Cohort 4: NGRhTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | NGR-hTNF: 0.8 μg/m^2as 60-minute intravenous infusion every 3 weeks Doxorubicin: 75 mg/m^2 intravenous infusion over 15 minutes (starting 1 hour after the end of NGR-hTNF infusion) |
| BG004 | Cohort 5: NGRhTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | NGR-hTNF: 1.6 μg/m^2as 60-minute intravenous infusion every 3 weeks Doxorubicin: 75 mg/m^2 intravenous infusion over 15 minutes (starting 1 hour after the end of NGR-hTNF infusion) |
| BG005 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | NGR-hTNF: 0.2 μg/m^2 as 60-minute intravenous infusion every 3 weeks Doxorubicin: 75 mg/m^2 intravenous infusion over 15 minutes (starting 1 hour after the end of NGR-hTNF infusion) |
| OG002 | Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | NGR-hTNF: 0.4 μg/m^2 as 60-minute intravenous infusion every 3 weeks Doxorubicin:75 mg/m^2 intravenous infusion over 15 minutes (starting 1 hour after the end of NGR-hTNF infusion) |
| OG003 | Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | NGR-hTNF: 0.8 μg/m^2 as 60-minute intravenous infusion every 3 weeks Doxorubicin: 75 mg/m^2 intravenous infusion over 15 minutes (starting 1 hour after the end of NGR-hTNF infusion) |
| OG004 | Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | NGR-hTNF: 1.6 μg/m^2 as 60-minute intravenous infusion every 3 weeks Doxorubicin: 75 mg/m^2 intravenous infusion over 15 minutes (starting 1 hour after the end of NGR-hTNF infusion) |
|
|
|
| Secondary | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Cmax) | Pharmacokinetic profiles of NGR-hTNF and doxorubicin was conducted in 4 sequential cohorts of patients (Three patients per each cohort were planned). The first 3 patients of the first cohort were treated with 0.2 μg/m2 of NGR-hTNF in combination with a suboptimal dose (minus 20%) of doxorubicin (60 mg/m2).Following 4 cohorts were treated with escalating dose of NGR-hTNF (0.2, 0.4, 0.8 and 1.6 μg/m2) in combination with a standard dose of doxorubicin (75 mg/m2): | Pharmacokinetic of NGR-hTNF was conducted in 5 sequential cohorts of patients, 3 patients per each cohort were planned). All the patients treated on Cycle 1 were still in the study on Cycle2. On Cycle3 twelve out of fifteen patients were still in the study. Subjects no more included in the study were 1 patient in cohort 1 and 2 patients in cohort 5 | Posted | Mean | Standard Deviation | pg/mL | prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes |
|
|
|
| Secondary | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Tmax) | Pharmacokinetic profiles of NGR-hTNF and doxorubicin was conducted in 4 sequential cohorts of patients (Three patients per each cohort were planned). The first 3 patients of the first cohort were treated with 0.2 μg/m2 of NGR-hTNF in combination with a suboptimal dose (minus 20%) of doxorubicin (60 mg/m2).Following 4 cohorts were treated with escalating dose of NGR-hTNF (0.2, 0.4, 0.8 and 1.6 μg/m2) in combination with a standard dose of doxorubicin (75 mg/m2): | Pharmacokinetic of NGR-hTNF was conducted in 5 sequential cohorts of patients, 3 patients per each cohort were planned). All the patients treated on Cycle 1 were still in the study on Cycle2. On Cycle3 twelve out of fifteen patients were still in the study. Subjects no more included in the study were 1 patient in cohort 1 and 2 patients in cohort 5 | Posted | Mean | Standard Deviation | h | prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes |
|
|
|
| Secondary | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (AUC0-t(Last)) | Pharmacokinetic profiles of NGR-hTNF and doxorubicin was conducted in 4 sequential cohorts of patients (Three patients per each cohort were planned). The first 3 patients of the first cohort were treated with 0.2 μg/m2 of NGR-hTNF in combination with a suboptimal dose (minus 20%) of doxorubicin (60 mg/m2).Following 4 cohorts were treated with escalating dose of NGR-hTNF (0.2, 0.4, 0.8 and 1.6 μg/m2) in combination with a standard dose of doxorubicin (75 mg/m2): | Pharmacokinetic of NGR-hTNF was conducted in 5 sequential cohorts of patients, 3 patients per each cohort were planned). All the patients treated on Cycle 1 were still in the study on Cycle2. On Cycle3 twelve out of fifteen patients were still in the study. Subjects no more included in the study were 1 patient in cohort 1 and 2 patients in cohort 5 | Posted | Mean | Standard Deviation | pg⋅h/mL | prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes |
|
|
|
| Secondary | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Pharmacodynamic calculations for sTNF-R1 and sTNF-R2 were performed on the plasma concentrations from which the baseline concentrations were subtracted (i.e. on positive and negative values). At all doses, Emax, i.e. the maximal stimulatory effect, and tmax were estimated as the coordinates of the highest point of the plasma profile (y, x axis, respectively) | Pharmacodynamic of NGR-hTNF was conducted in 5 sequential cohorts of patients, 3 patients per each cohort were planned). All the patients treated on Cycle 1 were still in the study on Cycle2. On Cycle3 twelve out of fifteen patients were still in the study. Subjects no more included in the study were 1 patient in cohort 1 and 2 patients in cohort 5 | Posted | Mean | Standard Deviation | ng/mL | prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes |
|
|
|
| Secondary | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Pharmacodynamic calculations for sTNF-R1 and sTNF-R2 were performed on the plasma concentrations from which the baseline concentrations were subtracted (i.e. on positive and negative values). At all doses, Emax, i.e. the maximal stimulatory effect, and tmax were estimated as the coordinates of the highest point of the plasma profile (y, x axis, respectively) | Pharmacodynamic of NGR-hTNF was conducted in 5 sequential cohorts of patients, 3 patients per each cohort were planned). All the patients treated on Cycle 1 were still in the study on Cycle2. On Cycle3 twelve out of fifteen patients were still in the study. Subjects no more included in the study were 1 patient in cohort 1 and 2 patients in cohort 5 | Posted | Mean | Standard Deviation | h | prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes |
|
|
|
| Secondary | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Pharmacodynamic calculations for sTNF-R1 and sTNF-R2 were performed on the plasma concentrations from which the baseline concentrations were subtracted (i.e. on positive and negative values). At all doses, Emax, i.e. the maximal stimulatory effect, and tmax were estimated as the coordinates of the highest point of the plasma profile (y, x axis, respectively) | Pharmacodynamic of NGR-hTNF was conducted in 5 sequential cohorts of patients, 3 patients per each cohort were planned). All the patients treated on Cycle 1 were still in the study on Cycle2. On Cycle3 twelve out of fifteen patients were still in the study. Subjects no more included in the study were 1 patient in cohort 1 and 2 patients in cohort 5 | Posted | Mean | Standard Deviation | ng⋅h/mL | prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes |
|
|
|
| Secondary | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Pharmacodynamic calculations for sTNF-R1 and sTNF-R2 were performed on the plasma concentrations from which the baseline concentrations were subtracted (i.e. on positive and negative values). At all doses, Emax, i.e. the maximal stimulatory effect, and tmax were estimated as the coordinates of the highest point of the plasma profile (y, x axis, respectively) | Pharmacodynamic of NGR-hTNF was conducted in 5 sequential cohorts of patients, 3 patients per each cohort were planned). All the patients treated on Cycle 1 were still in the study on Cycle2. On Cycle3 twelve out of fifteen patients were still in the study. Subjects no more included in the study were 1 patient in cohort 1 and 2 patients in cohort 5 | Posted | Mean | Standard Deviation | ng/mL | prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes |
|
|
|
| Secondary | To Evaluate Phenotype Analysis and Adaptative Immune Response | No analysis was performed. No biopsy was preformed. | Posted | during the study |
|
|
| Secondary | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | Response to treatment was assessed on a set of target lesions(TL) chosen before the 1st treatment administration, the list of TL must be reported on the initial measurement form before the start of treatment. Lesions had to have clearly defined borders and initially were measured in at least one dimension, and had to be repeated at each evaluation of the disease by the same method. Sum of the longest diameter (LD) was calculated as the baseline sum LD Complete Response(CR): Disappearance of all TL Partial Response(PR): At least a 30% decrease in the sum of the LD of TL, taking as reference the base line sum LD Progressive Disease(PD): At least a 20% increase in the sum of LD of TL, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions Stable Disease (SD):Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started | disease progression or until the start of another treatment | Posted | Number | participants | after the first 2 cycles(Follow-up 2) of treatment and then every 2 cycles (Follow-up 4,6..). In case of detection of a complete or partial response, a confirmation assessment must be performed ≥ 4 weeks after the first documentation of the response. |
|
|
|
| 2 |
| 3 |
| 2 |
| 3 |
| 3 |
| 3 |
| EG001 | Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | NGR-hTNF: 0.2 μg/m^2 as 60-minute intravenous infusion every 3 weeks Doxorubicin: 75 mg/m² intravenous infusion over 15 minutes (starting 1 hour after the end of NGR-hTNF infusion) | 1 | 3 | 1 | 3 | 3 | 3 |
| EG002 | Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | NGR-hTNF: 0.4 μg/m^2 as 60-minute intravenous infusion every 3 weeks Doxorubicin: 75 mg/m² intravenous infusion over 15 minutes (starting 1 hour after the end of NGR-hTNF infusion) | 2 | 3 | 2 | 3 | 3 | 3 |
| EG003 | Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | NGR-hTNF: 0.8 μg/m^2 as 60-minute intravenous infusion every 3 weeks Doxorubicin: 75 mg/m² intravenous infusion over 15 minutes (starting 1 hour after the end of NGR-hTNF infusion) | 0 | 3 | 3 | 3 | 3 | 3 |
| EG004 | Cohort 5: NGR-hTNF: 1.6 μg/m^2 + Doxorubicin 75 mg/m^2 | NGR-hTNF: 1.6 μg/m^2 as 60-minute intravenous infusion every 3 weeks Doxorubicin: 75 mg/m² intravenous infusion over 15 minutes (starting 1 hour after the end of NGR-hTNF infusion) | 2 | 3 | 1 | 3 | 3 | 3 |
| Febrile neutropenia | Blood and lymphatic system disorders | MedDRA 22.0 | Systematic Assessment |
|
| Pulmonary embolism | Vascular disorders | MedDRA 22.0 | Systematic Assessment |
|
| Acute myocardial infarction | Cardiac disorders | MedDRA 22.0 | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Sacral pain | Musculoskeletal and connective tissue disorders | MedDRA 22.0 | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Leukopenia | Blood and lymphatic system disorders | MedDRA 22.0 | Systematic Assessment |
|
| Anaemia | Blood and lymphatic system disorders | MedDRA 22.0 | Systematic Assessment |
|
| Febrile neutropenia | Blood and lymphatic system disorders | MedDRA 22.0 | Systematic Assessment |
|
| Leukopenia | Blood and lymphatic system disorders | MedDRA 22.0 | Systematic Assessment |
|
| Lymphopenia | Blood and lymphatic system disorders | MedDRA 22.0 | Systematic Assessment |
|
| Neutropenia | Blood and lymphatic system disorders | MedDRA 22.0 | Systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA 22.0 | Systematic Assessment |
|
| Asystole | Cardiac disorders | MedDRA 22.0 | Systematic Assessment |
|
| Cardio-respiratory arrest | Cardiac disorders | MedDRA 22.0 | Systematic Assessment |
|
| Extrasystoles | Cardiac disorders | MedDRA 22.0 | Systematic Assessment |
|
| Mitral valve incompetence | Cardiac disorders | MedDRA 22.0 | Systematic Assessment |
|
| Mitral valve sclerosis | Cardiac disorders | MedDRA 22.0 | Systematic Assessment |
|
| Sinus bradycardia | Cardiac disorders | MedDRA 22.0 | Systematic Assessment |
|
| Tricuspid valve incompetence | Cardiac disorders | MedDRA 22.0 | Systematic Assessment |
|
| Ventricular dysfunction | Cardiac disorders | MedDRA 22.0 | Systematic Assessment |
|
| Ventricular fibrillation | Cardiac disorders | MedDRA 22.0 | Systematic Assessment |
|
| Tinnitus | Ear and labyrinth disorders | MedDRA 22.0 | Systematic Assessment |
|
| Abnormal sensation in eye | Eye disorders | MedDRA 22.0 | Systematic Assessment |
|
| Dry eyes | Eye disorders | MedDRA 22.0 | Systematic Assessment |
|
| Keratitis | Eye disorders | MedDRA 22.0 | Systematic Assessment |
|
| Lacrimation increased | Eye disorders | MedDRA 22.0 | Systematic Assessment |
|
| Abdominal distension | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Aptyalism | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Ascites | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Dry mouth | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Dysphagia | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Eructation | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Faeces discoloured | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Gastritis | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Intestinal obstruction | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Oesophagitis | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Pruritus ani | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Stomatitis | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Teething | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Asthenia | General disorders | MedDRA 22.0 | Systematic Assessment |
|
| Chest pain | General disorders | MedDRA 22.0 | Systematic Assessment |
|
| Chills | General disorders | MedDRA 22.0 | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA 22.0 | Systematic Assessment |
|
| Mucosal inflammation | General disorders | MedDRA 22.0 | Systematic Assessment |
|
| Oedema peripheral | General disorders | MedDRA 22.0 | Systematic Assessment |
|
| Pain | General disorders | MedDRA 22.0 | Systematic Assessment |
|
| Pyrexia | General disorders | MedDRA 22.0 | Systematic Assessment |
|
| Hyperbilirubinaemia | Hepatobiliary disorders | MedDRA 22.0 | Systematic Assessment |
|
| Jaundice | Hepatobiliary disorders | MedDRA 22.0 | Systematic Assessment |
|
| Bacterial infection | Infections and infestations | MedDRA 22.0 | Systematic Assessment |
|
| Escherichia infection | Infections and infestations | MedDRA 22.0 | Systematic Assessment |
|
| Infection | Infections and infestations | MedDRA 22.0 | Systematic Assessment |
|
| Mycosis fungoides | Infections and infestations | MedDRA 22.0 | Systematic Assessment |
|
| Onychomycosis | Infections and infestations | MedDRA 22.0 | Systematic Assessment |
|
| Graft complication | Injury, poisoning and procedural complications | MedDRA 22.0 | Systematic Assessment |
|
| Post procedural pain | Injury, poisoning and procedural complications | MedDRA 22.0 | Systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | MedDRA 22.0 | Systematic Assessment |
|
| Aspartate aminotransferase increased | Investigations | MedDRA 22.0 | Systematic Assessment |
|
| Blood alkaline phosphatase increased | Investigations | MedDRA 22.0 | Systematic Assessment |
|
| Blood lactate dehydrogenase increased | Investigations | MedDRA 22.0 | Systematic Assessment |
|
| Gamma-glutamyltransferase increased | Investigations | MedDRA 22.0 | Systematic Assessment |
|
| Troponin I | Investigations | MedDRA 22.0 | Systematic Assessment |
|
| Weight decreased | Investigations | MedDRA 22.0 | Systematic Assessment |
|
| Acidosis | Metabolism and nutrition disorders | MedDRA 22.0 | Systematic Assessment |
|
| Anorexia | Metabolism and nutrition disorders | MedDRA 22.0 | Systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | MedDRA 22.0 | Systematic Assessment |
|
| Hyperuricaemia | Metabolism and nutrition disorders | MedDRA 22.0 | Systematic Assessment |
|
| Hypokalaemia | Metabolism and nutrition disorders | MedDRA 22.0 | Systematic Assessment |
|
| Hyponatremia | Metabolism and nutrition disorders | MedDRA 22.0 | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 22.0 | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 22.0 | Systematic Assessment |
|
| Chest wall pain | Musculoskeletal and connective tissue disorders | MedDRA 22.0 | Systematic Assessment |
|
| Groin pain | Musculoskeletal and connective tissue disorders | MedDRA 22.0 | Systematic Assessment |
|
| Muscle cramp | Musculoskeletal and connective tissue disorders | MedDRA 22.0 | Systematic Assessment |
|
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA 22.0 | Systematic Assessment |
|
| Neck pain | Musculoskeletal and connective tissue disorders | MedDRA 22.0 | Systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA 22.0 | Systematic Assessment |
|
| Pain in limb | Musculoskeletal and connective tissue disorders | MedDRA 22.0 | Systematic Assessment |
|
| Sacral pain | Musculoskeletal and connective tissue disorders | MedDRA 22.0 | Systematic Assessment |
|
| Sciatica | Musculoskeletal and connective tissue disorders | MedDRA 22.0 | Systematic Assessment |
|
| Shoulder blade pain | Musculoskeletal and connective tissue disorders | MedDRA 22.0 | Systematic Assessment |
|
| Burning sensation | Nervous system disorders | MedDRA 22.0 | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA 22.0 | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 22.0 | Systematic Assessment |
|
| Hyperaesthesia | Nervous system disorders | MedDRA 22.0 | Systematic Assessment |
|
| Loss of consciousness | Nervous system disorders | MedDRA 22.0 | Systematic Assessment |
|
| Muscle tone abnormal | Nervous system disorders | MedDRA 22.0 | Systematic Assessment |
|
| Neuropathic pain | Nervous system disorders | MedDRA 22.0 | Systematic Assessment |
|
| Neuropathy | Nervous system disorders | MedDRA 22.0 | Systematic Assessment |
|
| Paraesthesia | Nervous system disorders | MedDRA 22.0 | Systematic Assessment |
|
| Agitation | Psychiatric disorders | MedDRA 22.0 | Systematic Assessment |
|
| Anxiety | Psychiatric disorders | MedDRA 22.0 | Systematic Assessment |
|
| Insomnia | Psychiatric disorders | MedDRA 22.0 | Systematic Assessment |
|
| Vaginal haemorrhage | Reproductive system and breast disorders | MedDRA 22.0 | Systematic Assessment |
|
| Bronchospasm | Respiratory, thoracic and mediastinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Hiccups | Respiratory, thoracic and mediastinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Hypoxia | Respiratory, thoracic and mediastinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Mediastinal disorder | Respiratory, thoracic and mediastinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Nasopharyngitis | Respiratory, thoracic and mediastinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Rhinorrhoea | Respiratory, thoracic and mediastinal disorders | MedDRA 22.0 | Systematic Assessment |
|
| Alopecia | Skin and subcutaneous tissue disorders | MedDRA 22.0 | Systematic Assessment |
|
| Nail disorder | Skin and subcutaneous tissue disorders | MedDRA 22.0 | Systematic Assessment |
|
| Peely skin | Skin and subcutaneous tissue disorders | MedDRA 22.0 | Systematic Assessment |
|
| Palmar-plantar erythrodysaesthesia syndrome | Skin and subcutaneous tissue disorders | MedDRA 22.0 | Systematic Assessment |
|
| Red face | Skin and subcutaneous tissue disorders | MedDRA 22.0 | Systematic Assessment |
|
| Deep vein thrombosis | Vascular disorders | MedDRA 22.0 | Systematic Assessment |
|
| Haematoma | Vascular disorders | MedDRA 22.0 | Systematic Assessment |
|
| Haemorrhoids | Vascular disorders | MedDRA 22.0 | Systematic Assessment |
|
| Head cold | Vascular disorders | MedDRA 22.0 | Systematic Assessment |
|
| Hypertension | Vascular disorders | MedDRA 22.0 | Systematic Assessment |
|
| Hypotension | Vascular disorders | MedDRA 22.0 | Systematic Assessment |
|
| Phlebitis | Vascular disorders | MedDRA 22.0 | Systematic Assessment |
|
| Pulmonary embolism | Vascular disorders | MedDRA 22.0 | Systematic Assessment |
|
| Renal vein thrombosis | Vascular disorders | MedDRA 22.0 | Systematic Assessment |
|
| Restless legs syndrome | Vascular disorders | MedDRA 22.0 | Systematic Assessment |
|
| Shock | Vascular disorders | MedDRA 22.0 | Systematic Assessment |
|
| Vena cava thrombosis | Vascular disorders | MedDRA 22.0 | Systematic Assessment |
|
Not provided
Not provided
| D006841 |
| Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D011083 | Polycyclic Compounds |
| D000617 | Aminoglycosides |
| D006027 | Glycosides |
| D002241 | Carbohydrates |
|
| Cycle2_Cmax NGR-hTNF |
|
|
| Cycle3_Cmax NGR-hTNF |
|
|
|
| Cycle2_tmax NGR-hTNF |
|
|
| Cycle3_tmax NGR-hTNF |
|
|
|
| Cycle2_AUC0-t(last)_ NGR-hTNF |
|
|
| Cycle3_AUC0-t(last)_NGR-hTNF |
|
|
|
| Cycle 1_Emax sTNF-R2 |
|
|
| Cycle 2_Emax sTNF-R1 |
|
|
| Cycle 2_Emax sTNF-R2 |
|
|
| Cycle 3_Emax sTNF-R1 |
|
|
| Cycle 3_Emax sTNF-R2 |
|
|
|
| Cycle 1_Tmax sTNF-R2 |
|
|
| Cycle 2_Tmax sTNF-R1 |
|
|
| Cycle 2_Tmax sTNF-R2 |
|
|
| Cycle 3_Tmax sTNF-R1 |
|
|
| Cycle 3_Tmax sTNF-R2 |
|
|
|
| Cycle 1_ARC sTNF-R2 |
|
|
| Cycle 2_ARC sTNF-R1 |
|
|
| Cycle 2_ARC sTNF-R2 |
|
|
| Cycle 3_ARC sTNF-R1 |
|
|
| Cycle 3_ARC sTNF-R2 |
|
|
|
| Cycle 1_Eav sTNF-R2 |
|
|
| Cycle 2_Eav sTNF-R1 |
|
|
| Cycle 2_Eav sTNF-R2 |
|
|
| Cycle 3_Eav sTNF-R1 |
|
|
| Cycle 3_Eav sTNF-R2 |
|
|
|
| N. of Progression Disease_follow-up 2 |
|
|
| N. of Partial Response follow-up 2 |
|
|
| N. of Stable Disease_follow-up 4 |
|
|
| N. of Progression Disease_follow-up 4 |
|
|
| N. of Partial Response follow-up 4 |
|
|
| N. of Stable Disease_follow-up 6 |
|
|
| N. of Progression Disease_follow-up 6 |
|
|
| N. of Partial Response follow-up 6 |
|
|
| N. of Stable Disease_follow-up 8 |
|
|
| N. of Progression Disease_follow-up 8 |
|
|
| N. of Partial Response follow-up 8 |
|
|