Neoplasms

All Conditions

Respiratory Tract (Lung and Bronchial) Diseases

Rare Diseases

Mesothelioma

Mesothelioma, Malignant

Adenoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Mesothelial

Lung Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Pleural Neoplasms

Lung Diseases

Respiratory Tract Diseases

Malignant Mesothelioma

Antineoplastic Agents

All Drugs and Chemicals

Analgesics

Anti-Infective Agents

Antiemetics

Gastrointestinal Agents

Gemcitabine

Vinorelbine

Doxorubicin

Liposomal doxorubicin

Pemetrexed

Anti-Bacterial Agents

Antibiotics, Antitubercular

* NGR-hTNF: 0.8 mcg/m² as 60-minute intravenous infusion every week until confirmed evidence of disease progression or unacceptable toxicity occurs.
* Best Supportive Care: antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions, nutritional support, and focal external-beam radiation for control of pain, cough, dyspnea, or hemoptysis
* Investigator's Choice: one of the following single-agent chemotherapy might be administered in combination:

  1. Doxorubicin: 60-75 mg/m2 every 3 weeks, for a maximum of 6 cycles
  2. Gemcitabine: 1,000-1,250 mg/m2 on days 1 and 8, every 3 weeks, for a maximum of 6 cycles
  3. Vinorelbine: 25 mg/m2 iv (or 60 mg/m2 per os) on days 1 and 8, every 3 weeks, for a maximum of 6 cycles (or weekly for 12 weeks)

NGR-hTNF plus Best Investigator's Choice (BIC)

* Placebo: 0.8 mcg/m² as 60-minute intravenous infusion every week until confirmed evidence of disease progression or unacceptable toxicity occurs.
* Best Supportive Care: antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions, nutritional support, and focal external-beam radiation for control of pain, cough, dyspnea, or hemoptysis
* Investigator's Choice: one of the following single-agent chemotherapy might be administered in combination:

  1. Doxorubicin: 60-75 mg/m2 every 3 weeks, for a maximum of 6 cycles
  2. Gemcitabine: 1,000-1,250 mg/m2 on days 1 and 8, every 3 weeks, for a maximum of 6 cycles
  3. Vinorelbine: 25 mg/m2 iv (or 60 mg/m2 per os) on days 1 and 8, every 3 weeks, for a maximum of 6 cycles (or weekly for 12 weeks)

Placebo plus Best Investigator's Choice (BIC)

Antonio Lambiase, MD

The main objective of the trial is to document the efficacy of NGR-hTNF administered at low dose weekly in advanced Malignant Pleural Mesothelioma patients previously treated with a pemetrexed-based chemotherapy regimen.

Currently, there are no regulatory-approved or widely accepted treatment options for patients failing a standard pemetrexed-based chemotherapy regimen.

For this reason, the best supportive care (BSC) alone might be considered as a standard reference for a randomized phase III trial in this setting.

However, single-agent chemotherapeutic agents (such as doxorubicin,gemcitabine, or vinorelbine) with a well-documented safety profile and antitumor activity are also used in clinical practice.

Therefore, the best investigator's choice (BIC) between either best supportive care alone or combined with a few selected single-agent chemotherapy (including doxorubicin, gemcitabine, or vinorelbine) might be considered as an acceptable reference arm as well in this setting.

The current phase III study aims to show a superior efficacy in terms of overall survival duration of NGR-hTNF 0.8 µg/mq weekly plus BIC versus placebo plus BIC in advanced MPM patients progressing after a standard pemetrexed-based chemotherapy.

NGR015: Study in Second Line for Patient With Advanced Malignant Pleural Mesothelioma Pretreated With Pemetrexed

NGR015: Randomized Double-blind Phase III Study of NGR-hTNF Plus Best Investigator's Choice (BIC) Versus Placebo Plus BIC in Previously Treated Patients With Advanced Malignant Pleural Mesothelioma (MPM)

Defined as the time from the date of randomization until the date of death due to any cause or the last date the patient was known to be alive

Defined as the time from the date of randomization until disease progression, or deathdue to any couse or the last patient was konwn to be alive. Progression is defined usind Response Evaluation Criteria In Solid Tumors Criteria (Recist v1.1), as a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition torelative increase of 20% the sum must also demonstrate an absolute increase of at least 5 mm. In addition the appearance of one or more new lesions was also considered progression

Disease control rate (DCR), defined as the percentage of patients who have a best-response rating of complete or partial response or stable disease, according to MPM-modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria

Measured from the date of randomization until disease progression, or death due to any cause

All adverse events will be recorded according to CTC version 4.02 (CTC reference: http://ctep.cancer.gov/reporting/ctc.html) on the case report forms (CRFs); the investigator will decide if those events are drug related and his decision will be recorded on the forms for all adverse events.

Quality of life (QoL) assessment was performed by using a questionnaire according to The Lung Cancer Symptom Scale (LCSS) . The LCSS is designed as a disease and site-specific measure of QoL particularly for use in clinical trials. It evaluates six major symptoms (loss of appetite, fatigue, cough, dyspnea, hemoptysis, and pain) associated with lung malignancies and their effect on overall symptomatic distress, functional activities, and global QoL. Within this trial the questionnaire according to LCSS was only recorded by the patient (patient's scale). QoL assessment was performed by using a questionnaire according to LCSS, which consists of nine 100-mm visual analog scales, with scores reported from 0 to 100 (0 representing the best score). The LCSS subscore is the average symptom burden index computed as the mean score for all six major symptoms. Symptomatic progression was defined as a worsening in the average symptom burden index by 25%.

Medical resource use data collected will be used in health economic analyses where it may be combined with other data from other sources such as cost data or other clinical parameters.

AGC Biologics S.p.A.

NGR-hTNF plus Best Investigator's Choice

NGR-hTNF plus Best Investigator's Choice (BIC): - NGR-hTNF: 0.8 mcg/m² as 60-minute intravenous infusion every week until confirmed evidence of disease progression or unacceptable toxicity occurs.

* Best Supportive Care: antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions, nutritional support, and focal external-beam radiation for control of pain, cough, dyspnea, or hemoptysis
* Investigator's Choice: one of the following single-agent chemotherapy might be administered in combination:

  1. Doxorubicin: 60-75 mg/m2 every 3 weeks, for a maximum of 6 cycles
  2. Gemcitabine: 1,000-1,250 mg/m2 on days 1 and 8, every 3 weeks, for a maximum of 6 cycles
  3. Vinorelbine: 25 mg/m2 iv (or 60 mg/m2 per os) on days 1 and 8, every 3 weeks, for a maximum of 6 cycles (or weekly for 12 weeks)

A: NGR-hTNF + BIC

Placebo plus Best Investigator's Choice

Placebo plus Best Investigator's Choice (BIC): - Placebo: 0.8 mcg/m² as 60-minute intravenous infusion every week until confirmed evidence of disease progression or unacceptable toxicity occurs.

* Best Supportive Care: antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions, nutritional support, and focal external-beam radiation for control of pain, cough, dyspnea, or hemoptysis
* Investigator's Choice: one of the following single-agent chemotherapy might be administered in combination:

  1. Doxorubicin: 60-75 mg/m2 every 3 weeks, for a maximum of 6 cycles
  2. Gemcitabine: 1,000-1,250 mg/m2 on days 1 and 8, every 3 weeks, for a maximum of 6 cycles
  3. Vinorelbine: 25 mg/m2 iv (or 60 mg/m2 per os) on days 1 and 8, every 3 weeks, for a maximum of 6 cycles (or weekly for 12 weeks)

B: Placebo+BIC

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Canada

Netherlands

Sweden

Belgium

United States

Ireland

Egypt

Poland

Italy

United Kingdom

France

Spain

Region of Enrollment

Patients ≥ 18 years with advanced malignant pleural mesothelioma previously treated with a pemetrexed based chemotherapy regimen for advanced or metastatic disease.

Clinical Operations

Study with one control per experimental patient, an accrual interval of 24 months, and an additional FU after the accrual interval of 12 months.If the true HR of experimental relative to control patients was 0.726, then 195 experimental patients and 195 control patients were required to be able to reject the null hypothesis that the experimental and control survival curves were equal with probability (power)0.80 Type I error probability associated with this test of this null hypothesis was 0.05

Overall Survival (OS)

The log-rank test (unstratified and stratified) was used at an alpha level of 5% to test for differences in PFS between the two treatment arms. Kaplan-Meier curves and estimates were provided.

Progression-Free Survival (PFS)

Difference in DCR between the two treatment arms were tested using a chi-squared test with 95% confidence intervals calculated in each treatment arm.

Disease control rate (DCR)

Complete or partial response (CR o PR)

Stable disease (SD)

Progressive disease (PD)

Nonassessable (NA)

Disease Control Rate (DCR)

Number of Partecipants With Disease Control for ≥ 6 Months

Study-emergent AEs of any grade

Study-emergent AEs of grade 3

Study-emergent AEs of grade 4

Study-emergent AEs of grade 5

Treatment-related AEs of grade 5

Treatment discontinuation due to AEs

The safety data referred to patients of both arms who received at least one treatment and is termed as safety population (n=386)

Number of Partecipants With Adverse Events

QoL assessment was performed by using a questionnaire according to LCSS, which consists of nine 100-mm visual analog scales, with scores reported from 0 to 100(the best score). The LCSS subscore is the average symptom burden index computed as the mean score for all 6 major symptoms. Symptomatic progression was defined as a worsening in the average symptom burden index by 25%.

Participants with a worsening in the average symptom burden index by 25%.

Time to LCSS Symptomatic Progression

ACE INHIBITORS, COMBINATIONS

ACE INHIBITORS, PLAIN

ADRENERGICS, INHALANTS

AMINOGLYCOSIDE ANTIBACTERIALS

ANESTHETICS, LOCAL

ANGIOTENSIN II ANTAGONISTS,COMBINATIONS

ANGIOTENSIN II ANTAGONISTS, plain

ANTACIDS

ANTERIOR PITUITARY LOBE HORMONES AND ANALOGUES

ANTIADRENERGIC AGENTS CENTRALLY ACTING

ANTIADRENERGIC AGENTS PERIPHERALLY ACTING

ANTIANDROGENS

ANTIARRHYTHMICS, CLASS I AND III

ANTIBIOTICS FOR TOPICAL USE

ANTIDEPRESSANTS

ANTIDIARRHEAL MICROORGANISMS

ANTIEMETICS AND ANTINAUSEANTS

ANTIEPILEPTICS

ANTIFIBRINOLYTICS

ANTIFUNGALS FOR TOPICAL USE

ANTIGLAUCOMA PREPARATIONS AND MIOTICS

ANTIGOUT PREPARATIONS

ANTIHISTAMINES FOR SYSTEMIC USE

ANTIINFECTIVES

ANTIINFLAMMATORY AGENTS AND ANTIINFECTIVES IN COM

ANTIINFLAMMATORY ANANTIRHEUMATIC PRODUCTSD

ANTIMETABOLITES

ANTIMYCOTICS FOR SYSTEMIC USE

ANTIPROPULSIVES

ANTIPRURITICS

ANTIPSYCHOTICS

ANTITHROMBOTIC AGENTS

ANTIVERTIGO PREPARATIONS

ANXIOLYTICS

ASCORBIC ACID (VITAMIN C)

BACTERIAL VACCINES

BELLADONNA AND DERIVATIVES

BETA BLOCKING AGENTS AND OTHER ANTIHYPERTENSIVES

BETA-LACTAM ANTIBACTERIALS, PENICILLINS

BILE THERAPY

BLOOD AND RELATED PRODUCTS

BLOOD GLUCOSE LOWERING DRUGS EXCL. INSULINS

CALCIUM

CAPILLARY STABILIZING

CARDIAC GLYCOSIDES

CARDIAC STIMULANTS EXCL CARDIAC GLYCOSIDES

CORTICOSTEROIDS FOR SYSTEMIC USE, PLAIN

CORTICOSTEROIDS, PLAIN

COUGH SUPPRESSANTS AND EXPECTORANTS, COMBINATIONS

COUGH SUPPRESSANTS, EXCL. COMBINATIONS WITH EXPEC

DECONGESTANTS AND ANTIALLERGICS

DIRECT ACTING ANTIVIRALS

DIURETICS AND POTASSIUM-SPARING AGENTS

DRUGS AFFECTING BONE

DRUGS FOR CONSTIPATION

DRUGS FOR FUNCTIONAL GASTROINTESTINAL DISORDERS

DRUGS FOR PEPTIC ULCER AND GASTRO-OESOPHAGEAL REF

DRUGS FOR TREATMENT OF TUBERCULOSIS

DRUGS USED IN BENIGN PROSTATIC HYPERTROPHY

ECTOPARASITICIDES, INC SCABICIDESL.

EMOLLIENTS AND PROTECTIVES

EXPECTORANTS EXCL COMBINATIONS WITH COUGH SUPPR.

HIGH-CEILING DIURETICS

HORMONES AND RELATED AGENTS

HYPNOTICS AND SEDATIVES

HYPOTHALAMIC HORMONES

I.V. SOLUTION ADDITIVES

I.V. SOLUTIONS

IMMUNOSTIMULANTS

INSULINS AND ANALOGUES

INTESTINAL ANTIINFECTIVES

IRON PREPARATIONS

LIPID MODIFYING AGENTS, PLAIN

LOW-CEILING DIURETICS, EXCL THIAZIDES

MACROLIDES, LINCOSAMIDES AND STREPTOGRAMINS

MULTIVITAMINS, COMBINATIONS

MULTIVITAMINS, PLAIN

MUSCLE RELAXANTS, CENTRALLY ACTING AGENTS

MYDRIATICS AND CYCLOPLEGICS

OPIOIDS

OTHER ANALGESICS AND ANTIPYRETICSD

OTHER ANTIANEMIC PREPARATIONS

OTHER ANTIBACTERIALS

OTHER ANTIDIARRHEALS

OTHER ANTINEOPLASTIC AGENTS

OTHER BETA-LACTAM ANTIBACTERIALS

OTHER CARDIAC PREPARATIONS

OTHER DRUGS FOR ACID RELATED DISORDERS

OTHER DRUGS FOR OBSTRUCTIVE

OTHER MINERAL SUPPLEMENTS

OTHER NUTRIENTS

OTHER OPHTHALMOLOGICALS

OTHER PLAIN VITAMIN PREPARATIONS

OTHER RESPIRATORY SYSTEM PRODUCTS

OTHER SYSTEMIC DRUGS FOR OBSTRUCTIVE AIRWAY DISEA

OTHER VITAMIN PRODUCTS, COMBINATIONS

PERIPHERAL VASODILATORS

POTASSIUM

POTASSIUM-SPARING AGENTS

PROPULSIVES

Evaluation of Medical Care Utilization in the Two Treatment Arms

Overall Study

Spots Global Cancer Trial Database for placebo plus best investigator's choice (bic)