Study of NGR-hTNF in Combination With Doxorubicin in Solid Tumors

Study Overview
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Brief Summary
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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 ).

Detailed Description
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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.

Official Title
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A Phase IB Study of NGR-hTNF in Combination With Doxorubicin in Patients Affected by Advanced or Metastatic Solid Tumors

Conditions
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Cancer

Intervention / Treatment
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* Drug: NGR-hTNF
* Drug: Doxorubicin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Dose-escalating study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br> | Drug: NGR-hTNF<br>* 0.2, 0.4, 0.8 and 1.6 μg/m²as 60-minute intravenous infusion every 3 weeks<br>Drug: Doxorubicin<br>* 75 mg/m² intravenous infusion over 15 minutes (starting 1 hour after the end of NGR-hTNF infusion)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | 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): | 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NGR-hTNF, doxorubicin, solid tumors