Clinical trial NCT00305084: Study of NGR-hTNF in Combination With Doxorubicin in Solid Tumors
Official title: A Phase IB Study of NGR-hTNF in Combination With Doxorubicin in Patients Affected by Advanced or Metastatic Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Cancer
Keywords: NGR-hTNF
doxorubicin
solid tumors
Lead sponsor: AGC Biologics S.p.A.
Sponsor class: INDUSTRY
First posted: 2006-03-21
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Dose-escalating study
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Number of Adverse Events From Escalating Doses of NGR-hTNF in Combination With a Fixed Dose of Doxorubicin
timeFrame: Through study completion, an average of 1 year
Secondary outcomes:
measure: Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Cmax)
timeFrame: prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes
measure: Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (Tmax)
timeFrame: prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes
measure: Pharmacokinetic Profiles of NGR-hTNF Administrated in Combination With Doxorubicin (AUC0-t(Last))
timeFrame: prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes
measure: sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Emax)
timeFrame: prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes
measure: sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Tmax)
timeFrame: prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes
measure: sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (ARC)
timeFrame: prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes
measure: sTNFRs and Anti-NGR-hTNF Antibody Plasma Levels (Eav)
timeFrame: prior to infusion and 15', 30', 60', 90', 120', 134' [1 minute before the end of doxorubicin administration], 180', 240', 360' minutes
measure: To Evaluate Phenotype Analysis and Adaptative Immune Response
timeFrame: during the study
measure: Signs of Anticancer Activity by Standard Imaging or Clinically; When Possible Tumor Response Will be Documented According to RECIST Criteria
timeFrame: 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.
Other outcomes:
Locations:
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
state: Milan
city: Genova
country: Italy
facility: Azienda Ospedaliera Universitaria "San Martino"
city: Milan
country: Italy
facility: Fondazione San Raffaele del Monte Tabor
city: Nijmegen
country: Netherlands
facility: University Medical Centre, Nijmegen
Study officials:
affiliation: Fondazione San Raffaele del Monte Tabor
name: Federico Caligaris Cappio, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sacchi A, Gasparri A, Gallo-Stampino C, Toma S, Curnis F, Corti A. Synergistic antitumor activity of cisplatin, paclitaxel, and gemcitabine with tumor vasculature-targeted tumor necrosis factor-alpha. Clin Cancer Res. 2006 Jan 1;12(1):175-82. doi: 10.1158/1078-0432.CCR-05-1147.