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

• ClinicalTrials.gov Identifier: NCT00305084
• Recruitment Status: Completed
• First Posted: March 21, 2006
• Results First Posted: October 4, 2019
• Last Update Posted: October 4, 2019
• Sponsor: AGC Biologics S.p.A.
• Information provided by: AGC Biologics S.p.A.

Study Description

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 ).

Condition or disease	Intervention/treatment	Phase
Cancer	Drug: NGR-hTNF; Drug: Doxorubicin	Phase 1

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 15 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Dose-escalating study
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase IB Study of NGR-hTNF in Combination With Doxorubicin in Patients Affected by Advanced or Metastatic Solid Tumors
• Study Start Date: February 28, 2006
• Actual Primary Completion Date: May 8, 2007
• Actual Study Completion Date: May 8, 2007

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Number of Adverse Events From Escalating Doses of NGR-hTNF in Combination With a Fixed Dose of Doxorubicin [ Time Frame: 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 Outcome Measures :

1. Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Cmax) [ Time Frame: 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):
2. Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Tmax) [ Time Frame: 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):
3. Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (AUC0-t(Last)) [ Time Frame: 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):
4. sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax) [ Time Frame: 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)
5. sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax) [ Time Frame: 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)
6. sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC) [ Time Frame: 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)
7. sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav) [ Time Frame: 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)
8. To Evaluate Phenotype Analysis and Adaptative Immune Response [ Time Frame: during the study ]
9. Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria [ 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. ]
   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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

Italy

Istituto Clinico Humanitas

Rozzano, Milan, Italy, 20089

Azienda Ospedaliera Universitaria "San Martino"

Genova, Italy, 16132

Fondazione San Raffaele del Monte Tabor

Milan, Italy, 20132

Netherlands

University Medical Centre, Nijmegen

Nijmegen, Netherlands

Sponsors and Collaborators

AGC Biologics S.p.A.

Investigators

• Principal Investigator: Federico Caligaris Cappio, MD; Fondazione San Raffaele del Monte Tabor

More Information

Publications:

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.

• Responsible Party: Molmed
• ClinicalTrials.gov Identifier: NCT00305084
• Other Study ID Numbers: NGR003; EUDRACT Number: 2005-004846-15
• First Posted: March 21, 2006
• Results First Posted: October 4, 2019
• Last Update Posted: October 4, 2019
• Last Verified: September 2019

Keywords provided by AGC Biologics S.p.A.:

NGR-hTNF; doxorubicin; solid tumors

Additional relevant MeSH terms:

Doxorubicin; Antibiotics, Antineoplastic; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action