Cancer
Conditions
Keywords
NGR-hTNF, doxorubicin, solid tumors
Brief summary
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 ).
Detailed description
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.
Interventions
DRUGNGR-hTNF
0.2, 0.4, 0.8 and 1.6 μg/m²as 60-minute intravenous infusion every 3 weeks
DRUGDoxorubicin
75 mg/m² intravenous infusion over 15 minutes (starting 1 hour after the end of NGR-hTNF infusion)
Sponsors
AGC Biologics S.p.A.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Dose-escalating study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients ≥18 years old with proven advanced or metastatic solid tumor not amenable to any clinical improvement by current standard treatments and previously treated with a non cumulative dose of anthracyclines (\<300 mg/sqm) or chemotherapy naïve. * Life expectancy more than 3 months. * ECOG performance status 0 - 2. * Normal cardiac function (left ventricular ejection fraction \[LVEF\] ≥55%) and absence of uncontrolled hypertension. * Absence of any conditions involving hypervolemia and its consequences. * Adequate baseline bone marrow, hepatic and renal function, defined as follows: 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: * Chemo, radio, hormonal, immuno or anti-vascular therapy: wash-out period of 28 days. * Surgery: wash-out period of 14 days. * Patients must give written informed consent to participate in the study.
Exclusion criteria
* Concurrent anticancer therapy * Patients must not receive any other investigational agents while on study * Patients with a LVEF \<55% * New York Heart Association class III or IV cardiac disease * Acute angina * Patients with myocardial infarction within the last six (6) months * Patient with significant peripheral vascular disease * Thrombosis of main portal vein * Previous signs of severe toxicity doxorubicin related * Previous signs of cardiotoxicity doxorubicin related * Patients previously treated with a cumulative dosage of anthracyclines ≥300 mg/m\^2 * Clinical signs of CNS involvement * Patients with active or uncontrolled systemic disease/infections or with serious illness or medical conditions, which is incompatible with the protocol * Known hypersensitivity/allergic reaction to human albumin preparations or to any of the excipients * Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol * Pregnancy or lactation. Patients - both males and females - with reproductive potential (i.e. menopausal for less than 1-year and not surgically sterilized) must practice effective contraceptive measures throughout the study. Women of child-bearing potential must provide a negative pregnancy test (serum or urine) within 14 days prior to registration
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Adverse Events From Escalating Doses of NGR-hTNF in Combination With a Fixed Dose of Doxorubicin | Through study completion, an average of 1 year | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Tmax) | 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 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 Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (AUC0-t(Last)) | 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 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): |
| sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes | 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) |
| sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes | 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) |
| Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Cmax) | 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 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): |
| sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes | 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) |
| 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 | 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. | 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 |
| sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes | 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) |
Countries
Italy, Netherlands
Participant flow
Recruitment details
Study Period: 28 February 2006 (first enrollment); 8 May 2007 (last completed). 3 investigational centres in Italy and 1 in Netherlands.
Pre-assignment details
Screening details: Planned sample size: 20-25 patients; Patients screened n.: 15; Patients screening failure n.: 0.
Participants by arm
| Arm | Count |
|---|---|
| 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) | 3 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 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) | 3 |
| 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) | 3 |
| 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) | 3 |
| 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) | 3 |
| Total | 15 |
Baseline characteristics
| Characteristic | Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | Cohort 3: NGRhTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | Cohort 4: NGRhTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | Cohort 5: NGRhTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 3 Participants | 2 Participants | 3 Participants | 2 Participants | 13 Participants |
| Region of Enrollment Italy | 2 participants | 1 participants | 3 participants | 2 participants | 2 participants | 10 participants |
| Region of Enrollment Netherlands | 1 participants | 2 participants | 0 participants | 1 participants | 1 participants | 5 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 5 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 3 Participants | 2 Participants | 3 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 1 / 3 | 2 / 3 | 0 / 3 | 2 / 3 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 2 / 3 | 1 / 3 | 2 / 3 | 3 / 3 | 1 / 3 |
Outcome results
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.
Time frame: Through study completion, an average of 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | Number of Adverse Events From Escalating Doses of NGR-hTNF in Combination With a Fixed Dose of Doxorubicin | 59 Adverse event |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | Number of Adverse Events From Escalating Doses of NGR-hTNF in Combination With a Fixed Dose of Doxorubicin | 142 Adverse event |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | Number of Adverse Events From Escalating Doses of NGR-hTNF in Combination With a Fixed Dose of Doxorubicin | 67 Adverse event |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | Number of Adverse Events From Escalating Doses of NGR-hTNF in Combination With a Fixed Dose of Doxorubicin | 101 Adverse event |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | Number of Adverse Events From Escalating Doses of NGR-hTNF in Combination With a Fixed Dose of Doxorubicin | 124 Adverse event |
Comparison: All data regarding safety were registered and analyzed by descriptive analyses. Summary table were generated to document the safety
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):
Time frame: prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes
Population: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (AUC0-t(Last)) | Cycle1_AUC0-t(last)_NGR-hTNF | 1.94 pg⋅h/mL | Standard Deviation 0.27 |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (AUC0-t(Last)) | Cycle3_AUC0-t(last)_NGR-hTNF | 4.35 pg⋅h/mL | Standard Deviation 0.4 |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (AUC0-t(Last)) | Cycle2_AUC0-t(last)_ NGR-hTNF | 7.84 pg⋅h/mL | Standard Deviation 7.06 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (AUC0-t(Last)) | Cycle2_AUC0-t(last)_ NGR-hTNF | 2.74 pg⋅h/mL | Standard Deviation 1.63 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (AUC0-t(Last)) | Cycle1_AUC0-t(last)_NGR-hTNF | 1.99 pg⋅h/mL | Standard Deviation 1.42 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (AUC0-t(Last)) | Cycle3_AUC0-t(last)_NGR-hTNF | 2.71 pg⋅h/mL | Standard Deviation 1.11 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (AUC0-t(Last)) | Cycle2_AUC0-t(last)_ NGR-hTNF | 4.53 pg⋅h/mL | Standard Deviation 5.95 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (AUC0-t(Last)) | Cycle1_AUC0-t(last)_NGR-hTNF | 11.8 pg⋅h/mL | Standard Deviation 4.13 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (AUC0-t(Last)) | Cycle3_AUC0-t(last)_NGR-hTNF | 10.6 pg⋅h/mL | Standard Deviation 7.13 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (AUC0-t(Last)) | Cycle1_AUC0-t(last)_NGR-hTNF | 12.0 pg⋅h/mL | Standard Deviation 0.7 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (AUC0-t(Last)) | Cycle3_AUC0-t(last)_NGR-hTNF | 18.2 pg⋅h/mL | Standard Deviation 7.49 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (AUC0-t(Last)) | Cycle2_AUC0-t(last)_ NGR-hTNF | 20.5 pg⋅h/mL | Standard Deviation 13 |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (AUC0-t(Last)) | Cycle2_AUC0-t(last)_ NGR-hTNF | 46.4 pg⋅h/mL | Standard Deviation 28.9 |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (AUC0-t(Last)) | Cycle1_AUC0-t(last)_NGR-hTNF | 25.7 pg⋅h/mL | Standard Deviation 19.4 |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (AUC0-t(Last)) | Cycle3_AUC0-t(last)_NGR-hTNF | 64.0 pg⋅h/mL | — |
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):
Time frame: prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes
Population: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Cmax) | Cycle1_Cmax NGR-hTNF | 2.22 pg/mL | Standard Deviation 0.58 |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Cmax) | Cycle3_Cmax NGR-hTNF | 2.28 pg/mL | Standard Deviation 0.21 |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Cmax) | Cycle2_Cmax NGR-hTNF | 3.10 pg/mL | Standard Deviation 1.54 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Cmax) | Cycle2_Cmax NGR-hTNF | 2.31 pg/mL | Standard Deviation 1.69 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Cmax) | Cycle1_Cmax NGR-hTNF | 1.82 pg/mL | Standard Deviation 0.9 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Cmax) | Cycle3_Cmax NGR-hTNF | 3.04 pg/mL | Standard Deviation 2.14 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Cmax) | Cycle2_Cmax NGR-hTNF | 2.74 pg/mL | Standard Deviation 2.94 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Cmax) | Cycle1_Cmax NGR-hTNF | 4.44 pg/mL | Standard Deviation 1.7 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Cmax) | Cycle3_Cmax NGR-hTNF | 8.91 pg/mL | Standard Deviation 8.7 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Cmax) | Cycle1_Cmax NGR-hTNF | 8.10 pg/mL | Standard Deviation 1.5 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Cmax) | Cycle3_Cmax NGR-hTNF | 11.2 pg/mL | Standard Deviation 5.9 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Cmax) | Cycle2_Cmax NGR-hTNF | 18.0 pg/mL | Standard Deviation 15.6 |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Cmax) | Cycle2_Cmax NGR-hTNF | 34.4 pg/mL | Standard Deviation 22.5 |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Cmax) | Cycle1_Cmax NGR-hTNF | 15.7 pg/mL | Standard Deviation 8.34 |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Cmax) | Cycle3_Cmax NGR-hTNF | 25.4 pg/mL | — |
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):
Time frame: prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes
Population: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Tmax) | Cycle2_tmax NGR-hTNF | 0.87 h | Standard Deviation 0.29 |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Tmax) | Cycle1_tmax_NGR-hTNF | 0.25 h | Standard Deviation 0 |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Tmax) | Cycle3_tmax NGR-hTNF | 1.04 h | Standard Deviation 0.057 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Tmax) | Cycle1_tmax_NGR-hTNF | 2.50 h | Standard Deviation 3.04 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Tmax) | Cycle3_tmax NGR-hTNF | 4.08 h | Standard Deviation 3.32 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Tmax) | Cycle2_tmax NGR-hTNF | 2.42 h | Standard Deviation 3.13 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Tmax) | Cycle1_tmax_NGR-hTNF | 2.50 h | Standard Deviation 3.04 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Tmax) | Cycle2_tmax NGR-hTNF | 1.03 h | Standard Deviation 0.46 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Tmax) | Cycle3_tmax NGR-hTNF | 0.83 h | Standard Deviation 0.29 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Tmax) | Cycle3_tmax NGR-hTNF | 0.67 h | Standard Deviation 0.29 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Tmax) | Cycle1_tmax_NGR-hTNF | 0.78 h | Standard Deviation 0.39 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Tmax) | Cycle2_tmax NGR-hTNF | 0.75 h | Standard Deviation 0.35 |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Tmax) | Cycle2_tmax NGR-hTNF | 0.83 h | Standard Deviation 0.29 |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Tmax) | Cycle1_tmax_NGR-hTNF | 2.83 h | Standard Deviation 3.18 |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Tmax) | Cycle3_tmax NGR-hTNF | 6.00 h | — |
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
Time frame: 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.
Population: disease progression or until the start of another treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Stable Disease_follow-up 4 | 1 participants |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Partial Response follow-up 2 | 0 participants |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Partial Response follow-up 6 | 0 participants |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Progression Disease_follow-up 6 | 0 participants |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Stable Disease_follow-up 6 | 1 participants |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Progression Disease_follow-up 2 | 1 participants |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Stable Disease_follow-up 2 | 2 participants |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Partial Response follow-up 4 | 0 participants |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Progression Disease_follow-up 4 | 1 participants |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Progression Disease_follow-up 2 | 0 participants |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Stable Disease_follow-up 2 | 3 participants |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Partial Response follow-up 2 | 0 participants |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Stable Disease_follow-up 4 | 2 participants |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Progression Disease_follow-up 4 | 1 participants |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Partial Response follow-up 4 | 0 participants |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Stable Disease_follow-up 6 | 1 participants |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Progression Disease_follow-up 6 | 0 participants |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Partial Response follow-up 6 | 1 participants |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Stable Disease_follow-up 8 | 1 participants |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Progression Disease_follow-up 8 | 1 participants |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Partial Response follow-up 8 | 0 participants |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Stable Disease_follow-up 2 | 3 participants |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Stable Disease_follow-up 4 | 1 participants |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Stable Disease_follow-up 6 | 0 participants |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Progression Disease_follow-up 2 | 0 participants |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Progression Disease_follow-up 6 | 1 participants |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Partial Response follow-up 6 | 0 participants |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Partial Response follow-up 4 | 0 participants |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Progression Disease_follow-up 4 | 1 participants |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Partial Response follow-up 2 | 0 participants |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Progression Disease_follow-up 2 | 0 participants |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Progression Disease_follow-up 4 | 0 participants |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Partial Response follow-up 4 | 1 participants |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Progression Disease_follow-up 8 | 2 participants |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Stable Disease_follow-up 6 | 2 participants |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Stable Disease_follow-up 2 | 2 participants |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Stable Disease_follow-up 8 | 1 participants |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Progression Disease_follow-up 6 | 0 participants |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Partial Response follow-up 8 | 0 participants |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Partial Response follow-up 2 | 1 participants |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Stable Disease_follow-up 4 | 2 participants |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Partial Response follow-up 6 | 1 participants |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Partial Response follow-up 4 | 0 participants |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Stable Disease_follow-up 4 | 1 participants |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Partial Response follow-up 2 | 0 participants |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Progression Disease_follow-up 2 | 0 participants |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Stable Disease_follow-up 6 | 1 participants |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Partial Response follow-up 6 | 0 participants |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Progression Disease_follow-up 6 | 0 participants |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Stable Disease_follow-up 2 | 3 participants |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria | N. of Progression Disease_follow-up 4 | 0 participants |
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)
Time frame: prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes
Population: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Cycle 1_ARC sTNF-R1 | 0.1 ng⋅h/mL | Standard Deviation 0.24 |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Cycle 1_ARC sTNF-R2 | -1.04 ng⋅h/mL | Standard Deviation 1.12 |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Cycle 2_ARC sTNF-R1 | 0.75 ng⋅h/mL | Standard Deviation 0.27 |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Cycle 2_ARC sTNF-R2 | 0.35 ng⋅h/mL | Standard Deviation 1.16 |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Cycle 3_ARC sTNF-R1 | 0.32 ng⋅h/mL | Standard Deviation 0.29 |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Cycle 3_ARC sTNF-R2 | -1.08 ng⋅h/mL | Standard Deviation 0.09 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Cycle 3_ARC sTNF-R1 | 0.11 ng⋅h/mL | Standard Deviation 1.56 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Cycle 3_ARC sTNF-R2 | -3.30 ng⋅h/mL | Standard Deviation 2.06 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Cycle 1_ARC sTNF-R1 | -3.52 ng⋅h/mL | Standard Deviation 3.71 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Cycle 2_ARC sTNF-R1 | -0.57 ng⋅h/mL | Standard Deviation 0.58 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Cycle 2_ARC sTNF-R2 | -2.89 ng⋅h/mL | Standard Deviation 0.28 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Cycle 1_ARC sTNF-R2 | -1.58 ng⋅h/mL | Standard Deviation 1.17 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Cycle 2_ARC sTNF-R2 | 0.28 ng⋅h/mL | Standard Deviation 1.03 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Cycle 3_ARC sTNF-R1 | 0.85 ng⋅h/mL | Standard Deviation 0.37 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Cycle 1_ARC sTNF-R1 | -0.64 ng⋅h/mL | Standard Deviation 0.86 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Cycle 2_ARC sTNF-R1 | 0.74 ng⋅h/mL | Standard Deviation 1.38 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Cycle 1_ARC sTNF-R2 | -1.36 ng⋅h/mL | Standard Deviation 2.22 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Cycle 3_ARC sTNF-R2 | 0.61 ng⋅h/mL | Standard Deviation 0.34 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Cycle 2_ARC sTNF-R2 | 2.95 ng⋅h/mL | Standard Deviation 0.04 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Cycle 1_ARC sTNF-R2 | 2.10 ng⋅h/mL | Standard Deviation 1.41 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Cycle 2_ARC sTNF-R1 | 1.76 ng⋅h/mL | Standard Deviation 1.01 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Cycle 3_ARC sTNF-R2 | 3.25 ng⋅h/mL | Standard Deviation 1 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Cycle 3_ARC sTNF-R1 | 2.49 ng⋅h/mL | Standard Deviation 0.66 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Cycle 1_ARC sTNF-R1 | 2.11 ng⋅h/mL | Standard Deviation 1.72 |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Cycle 3_ARC sTNF-R1 | 2.55 ng⋅h/mL | — |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Cycle 2_ARC sTNF-R1 | 3.38 ng⋅h/mL | Standard Deviation 2.85 |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Cycle 1_ARC sTNF-R2 | 6.08 ng⋅h/mL | Standard Deviation 3.4 |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Cycle 3_ARC sTNF-R2 | 5.58 ng⋅h/mL | — |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Cycle 2_ARC sTNF-R2 | 9.08 ng⋅h/mL | Standard Deviation 7.17 |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) | Cycle 1_ARC sTNF-R1 | 3.38 ng⋅h/mL | Standard Deviation 0.81 |
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)
Time frame: prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes
Population: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Cycle 1_Eav sTNF-R1 | 0.02 ng/mL | Standard Deviation 0.04 |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Cycle 1_Eav sTNF-R2 | -0.17 ng/mL | Standard Deviation 0.19 |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Cycle 2_Eav sTNF-R1 | 0.13 ng/mL | Standard Deviation 0.05 |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Cycle 2_Eav sTNF-R2 | 0.06 ng/mL | Standard Deviation 0.19 |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Cycle 3_Eav sTNF-R1 | 0.05 ng/mL | Standard Deviation 0.05 |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Cycle 3_Eav sTNF-R2 | -0.18 ng/mL | Standard Deviation 0.02 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Cycle 3_Eav sTNF-R1 | 0.02 ng/mL | Standard Deviation 0.26 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Cycle 3_Eav sTNF-R2 | -0.55 ng/mL | Standard Deviation 0.34 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Cycle 1_Eav sTNF-R1 | -0.59 ng/mL | Standard Deviation 0.62 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Cycle 2_Eav sTNF-R1 | -0.10 ng/mL | Standard Deviation 0.1 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Cycle 2_Eav sTNF-R2 | -0.48 ng/mL | Standard Deviation 0.05 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Cycle 1_Eav sTNF-R2 | -0.26 ng/mL | Standard Deviation 0.2 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Cycle 2_Eav sTNF-R2 | 0.003 ng/mL | Standard Deviation 0.17 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Cycle 3_Eav sTNF-R1 | 0.14 ng/mL | Standard Deviation 0.06 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Cycle 1_Eav sTNF-R1 | -0.11 ng/mL | Standard Deviation 0.14 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Cycle 2_Eav sTNF-R1 | 0.12 ng/mL | Standard Deviation 0.23 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Cycle 1_Eav sTNF-R2 | -0.23 ng/mL | Standard Deviation 0.37 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Cycle 3_Eav sTNF-R2 | 0.10 ng/mL | Standard Deviation 0.06 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Cycle 2_Eav sTNF-R2 | 0.49 ng/mL | Standard Deviation 0.01 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Cycle 1_Eav sTNF-R2 | 0.35 ng/mL | Standard Deviation 0.24 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Cycle 2_Eav sTNF-R1 | 0.29 ng/mL | Standard Deviation 0.17 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Cycle 3_Eav sTNF-R2 | 0.54 ng/mL | Standard Deviation 0.17 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Cycle 3_Eav sTNF-R1 | 0.42 ng/mL | Standard Deviation 0.11 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Cycle 1_Eav sTNF-R1 | 0.35 ng/mL | Standard Deviation 0.29 |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Cycle 3_Eav sTNF-R1 | 0.43 ng/mL | — |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Cycle 2_Eav sTNF-R1 | 0.56 ng/mL | Standard Deviation 0.48 |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Cycle 1_Eav sTNF-R2 | 1.01 ng/mL | Standard Deviation 0.57 |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Cycle 3_Eav sTNF-R2 | 0.93 ng/mL | — |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Cycle 2_Eav sTNF-R2 | 1.51 ng/mL | Standard Deviation 1.2 |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) | Cycle 1_Eav sTNF-R1 | 0.56 ng/mL | Standard Deviation 0.14 |
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)
Time frame: prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes
Population: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Cycle 3_Emax sTNF-R2 | 0.11 ng/mL | Standard Deviation 0.04 |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Cycle 1_Emax sTNF-R2 | 0.01 ng/mL | Standard Deviation 0.07 |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Cycle 3_Emax sTNF-R1 | 0.44 ng/mL | Standard Deviation 0.13 |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Cycle 2_Emax sTNF-R2 | 0.31 ng/mL | Standard Deviation 0.4 |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Cycle 2_Emax sTNF-R1 | 0.49 ng/mL | Standard Deviation 0.11 |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Cycle 1_Emax sTNF-R1 | 0.34 ng/mL | Standard Deviation 0.08 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Cycle 1_Emax sTNF-R2 | 0.26 ng/mL | Standard Deviation 0.1 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Cycle 1_Emax sTNF-R1 | -0.19 ng/mL | Standard Deviation 0.6 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Cycle 2_Emax sTNF-R1 | 0.21 ng/mL | Standard Deviation 0.31 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Cycle 2_Emax sTNF-R2 | -0.12 ng/mL | Standard Deviation 0.25 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Cycle 3_Emax sTNF-R1 | 0.51 ng/mL | Standard Deviation 0.48 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Cycle 3_Emax sTNF-R2 | -0.13 ng/mL | Standard Deviation 0.12 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Cycle 1_Emax sTNF-R1 | 0.21 ng/mL | Standard Deviation 0.26 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Cycle 3_Emax sTNF-R1 | 0.38 ng/mL | Standard Deviation 0.13 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Cycle 1_Emax sTNF-R2 | 0.13 ng/mL | Standard Deviation 0.14 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Cycle 2_Emax sTNF-R1 | 0.45 ng/mL | Standard Deviation 0.33 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Cycle 3_Emax sTNF-R2 | 0.37 ng/mL | Standard Deviation 0.17 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Cycle 2_Emax sTNF-R2 | 0.33 ng/mL | Standard Deviation 0.21 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Cycle 3_Emax sTNF-R2 | 1.10 ng/mL | Standard Deviation 0.24 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Cycle 2_Emax sTNF-R1 | 0.69 ng/mL | Standard Deviation 0.46 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Cycle 2_Emax sTNF-R2 | 1.31 ng/mL | Standard Deviation 0.79 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Cycle 1_Emax sTNF-R2 | 0.56 ng/mL | Standard Deviation 0.4 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Cycle 3_Emax sTNF-R1 | 0.84 ng/mL | Standard Deviation 0.11 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Cycle 1_Emax sTNF-R1 | 0.59 ng/mL | Standard Deviation 0.46 |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Cycle 3_Emax sTNF-R1 | 0.88 ng/mL | Standard Deviation 1 |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Cycle 1_Emax sTNF-R2 | 2.23 ng/mL | Standard Deviation 0.8 |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Cycle 3_Emax sTNF-R2 | 1.44 ng/mL | Standard Deviation 1 |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Cycle 1_Emax sTNF-R1 | 1.64 ng/mL | Standard Deviation 0.69 |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Cycle 2_Emax sTNF-R2 | 2.62 ng/mL | Standard Deviation 1.64 |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) | Cycle 2_Emax sTNF-R1 | 1.21 ng/mL | Standard Deviation 0.8 |
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)
Time frame: prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes
Population: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Cycle 1_Tmax sTNF-R1 | 5.47 h | Standard Deviation 1.17 |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Cycle 1_Tmax sTNF-R2 | 3.19 h | Standard Deviation 3 |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Cycle 2_Tmax sTNF-R1 | 4.71 h | Standard Deviation 1.25 |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Cycle 2_Tmax sTNF-R2 | 4.71 h | Standard Deviation 1.25 |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Cycle 3_Tmax sTNF-R1 | 6.09 h | Standard Deviation 0.12 |
| Cohort 1: NGRhTNF 0.2 μg/m^2+ Doxorubicin 60 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Cycle 3_Tmax sTNF-R2 | 6.09 h | Standard Deviation 0.12 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Cycle 3_Tmax sTNF-R1 | 2.33 h | Standard Deviation 3.18 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Cycle 3_Tmax sTNF-R2 | 2.33 h | Standard Deviation 3.18 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Cycle 1_Tmax sTNF-R1 | 2.17 h | Standard Deviation 3.32 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Cycle 2_Tmax sTNF-R1 | 6.00 h | Standard Deviation 0 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Cycle 2_Tmax sTNF-R2 | 1.42 h | Standard Deviation 1.42 |
| Cohort 2: NGRhTNF 0.2 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Cycle 1_Tmax sTNF-R2 | 0.25 h | Standard Deviation 0 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Cycle 2_Tmax sTNF-R2 | 3.67 h | Standard Deviation 2.52 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Cycle 3_Tmax sTNF-R1 | 5.33 h | Standard Deviation 1.16 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Cycle 1_Tmax sTNF-R1 | 4.33 h | Standard Deviation 2.89 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Cycle 2_Tmax sTNF-R1 | 4.33 h | Standard Deviation 2.89 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Cycle 1_Tmax sTNF-R2 | 3.67 h | Standard Deviation 2.52 |
| Cohort 3: NGR-hTNF 0.4 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Cycle 3_Tmax sTNF-R2 | 3.50 h | Standard Deviation 2.78 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Cycle 2_Tmax sTNF-R2 | 1.50 h | Standard Deviation 0.71 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Cycle 1_Tmax sTNF-R2 | 1.78 h | Standard Deviation 0.32 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Cycle 2_Tmax sTNF-R1 | 4.12 h | Standard Deviation 2.67 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Cycle 3_Tmax sTNF-R2 | 1.18 h | Standard Deviation 0.31 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Cycle 3_Tmax sTNF-R1 | 1.84 h | Standard Deviation 1.04 |
| Cohort 4: NGR-hTNF 0.8 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Cycle 1_Tmax sTNF-R1 | 3.78 h | Standard Deviation 3.15 |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Cycle 3_Tmax sTNF-R1 | 6.00 h | — |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Cycle 2_Tmax sTNF-R1 | 1.17 h | Standard Deviation 0.29 |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Cycle 1_Tmax sTNF-R2 | 2.83 h | Standard Deviation 3.18 |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Cycle 3_Tmax sTNF-R2 | 1.00 h | — |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Cycle 2_Tmax sTNF-R2 | 1.17 h | Standard Deviation 0.29 |
| Cohort 5:NGR-hTNF 1.6 μg/m^2+ Doxorubicin 75 mg/m^2 | sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) | Cycle 1_Tmax sTNF-R1 | 2.83 h | Standard Deviation 3.18 |
Secondary
To Evaluate Phenotype Analysis and Adaptative Immune Response
Time frame: during the study
Population: No analysis was performed. No biopsy was preformed.