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

August 28, 2019 updated by: AGC Biologics S.p.A.

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)

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

400

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Belgium
      • Bruxelles, Belgium, 1000
        • Institut Jules Bordet
      • Bruxelles, Belgium, 1200
        • Cliniques Universitarie St. Luc
      • Gent, Belgium, 9000
        • Universitair Ziekenhuis
    • Antwerp
      • Edegem, Antwerp, Belgium, B-2650
        • Antwerp University Hospital
    • Liege
      • Liège, Liege, Belgium, 4000
        • Centre Hospitalier Universitaire de Liège
  • Canada
    • Alberta
      • Edmonton, Alberta, Canada, T6G1Z2
        • UAB - Alberta Cancer Board - Cross Cancer Institute
    • Ontario
      • Toronto, Ontario, Canada, M5G2C4
        • University Health Network, Princess Margaret Hospital
  • Egypt
      • Cairo, Egypt, 11796
        • National Cancer Institute
  • France
      • Marseille, France, Cedex 20
        • Hôpitaux de Marseille Hôpital Nord
  • Ireland
      • Dublin, Ireland
        • St James's Hospital
  • Italy
      • Alessandria, Italy, 15100
        • Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo di Alessandria
      • Aviano, Italy
        • Centro di Riferimento Oncologico
      • Como, Italy
        • Ospedale Valduce
      • Firenze, Italy
        • Azienda Ospedaliero-Universitaria Careggi di Firenze
      • Genoa, Italy, 16132
        • Istituto Nazionale per la Ricerca sul Cancro
      • Meldola, Italy, 47014
        • Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori-IRST
      • Milan, Italy, 20132
        • Fondazione San Raffaele del Monte Tabor
      • Monza, Italy, 20052
        • Azienda Ospedaliera San Gerardo
      • Padova, Italy
        • Istituto Oncologico Veneto
      • Parma, Italy
        • Azienda Ospedaliero Universitaria di Parma
      • Ravenna, Italy, 48100
        • Azienda Unita Sanitaria Locale Di Ravenna
      • Rho, Italy
        • A.O. Salvini Garbagnate, Ospedale di Rho
      • Siena, Italy, 53100
        • Azienda Ospedaliera senese
    • Alessandria
      • Casale Monferrato, Alessandria, Italy, 15033
        • Ospedale Santo Spirito
    • Torino
      • Orbassano, Torino, Italy, 10043
        • Azienda Ospedaliera Universitaria San Luigi Gonzaga
  • Netherlands
    • Gelderland
      • Harderwijk, Gelderland, Netherlands, 3840
        • St. Jansdal Hospital
    • Utrecht
      • Nieuwegein, Utrecht, Netherlands, 3435
        • St. Antonius Hospital
  • Poland
      • Gdansk, Poland, 80211
        • Medical University of Gdansk
      • Warsaw, Poland, 02-781
        • Maria Sklodowska Memorial Cancer Center and Institute of Oncology
  • Spain
      • Barcelona, Spain, 08035
        • Hospital Vall d'Hebron
    • Barcelona
      • Badalona, Barcelona, Spain, 08916
        • Hospital Universitari Germans Trias I Pujol
  • Sweden
      • Linkoping, Sweden, 581 85
        • The University Hospital
  • United Kingdom
      • London, United Kingdom, SE1 9RT
        • Guy's Hospital
      • London, United Kingdom, SW3 6JJ
        • The Royal Marsden Hospital
    • Greater Manchester
      • Manchester, Greater Manchester, United Kingdom, M23 9LT
        • Chest Clinic, Wythenshawe Hospital
    • Kent
      • Maidstone, Kent, United Kingdom, ME16 9QQ
        • Kent Oncology Centre Maidstone Hospital
    • Leicestershire
      • Leicester, Leicestershire, United Kingdom, LE0116
        • University Hospitals of Leicester
    • Northwood
      • Middlesex, Northwood, United Kingdom, HA6 2RN
        • Mount Vernon Cancer Centre
    • Scotland
      • Edinburgh, Scotland, United Kingdom, EH4 2XU
        • Edinburgh Cancer Centre, Western General Hospital
      • Glasgow, Scotland, United Kingdom, G12
        • The Beatson West of Scotland Cancer Centre
    • Surrey
      • Sutton, Surrey, United Kingdom
        • The Royal Marsden Hospital
    • Yorkshire
      • Cottingham, Yorkshire, United Kingdom, HU16 5JQ
        • Castle Hill Hospital
  • United States
    • California
      • Corona, California, United States, 92879
        • Wilshire Oncology Medical Group
      • Duarte, California, United States, 91010
        • City of Hope-Comprehensive Cancer Cente
    • Florida
      • Tampa, Florida, United States, 33612
        • H. Lee Moffitt ancer Center and Research Institute
    • Maryland
      • Baltimore, Maryland, United States, 21231
        • Johns Hopkins
    • New York
      • New York, New York, United States, 10032
        • Columbia University
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • University of Pennsylvania
    • Texas
      • Dallas, Texas, United States, 75390
        • UTSouthwestern Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age ≥ 18 years
  • Histologically or cytological confirmed malignant pleural mesothelioma of any of the following subtype: epithelial, sarcomatoid, mixed, or unknown
  • Prior treatment with no more than one systemic pemetrexed-based chemotherapy regimen administered for advanced or metastatic disease. Prior use of a biological agent in combination with a pemetrexed-based regimen and prior administration of intrapleural cytotoxic agents are allowed. Patients who have previously received anthracyclines should not receive doxorubicin
  • ECOG Performance Status 0 - 2
  • Life expectancy of ≥ 12 weeks

  • Adequate baseline bone marrow, hepatic and renal function, defined as follows:

    1. Neutrophils ≥ 1.5 x 109/L; platelets ≥ 100 x 109/L; hemoglobin ≥ 9 g/dL
    2. Bilirubin ≤ 1.5 x ULN
    3. AST and/or ALT ≤ 2.5 x ULN in absence of liver metastasis or ≤ 5 x ULN in presence of liver metastasis
    4. Serum creatinine < 1.5 x ULN
  • Measurable or non-measurable disease according to MPM-modified RECIST criteria

  • Patients may have had prior therapy providing the following conditions are met:

    1. Surgery: wash-out period of 14 days
    2. Systemic and radiation anti-tumor therapy: wash-out period of 28 days
  • Patients must give written informed consent to participate in the study

Exclusion Criteria:

  • Patients must not receive any other investigational agents while on study
  • Patients with myocardial infarction within the last six months, unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, or serious cardiac arrhythmia requiring medication
  • Uncontrolled hypertension
  • QTc interval (congenital or acquired) > 450 ms
  • History or evidence upon physical examination of CNS disease unless adequately treated (e.g., primary brain tumor, any brain metastasis, seizure not controlled with standard medical therapy, or history of stroke)
  • 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: QUADRUPLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: A: NGR-hTNF + BIC
NGR-hTNF plus Best Investigator's Choice
Drug: 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)
Other Names:
  • NGR-hTNF+BIC
PLACEBO_COMPARATOR: B: Placebo+BIC
Placebo plus Best Investigator's Choice
Drug: 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)
Other Names:
  • Placebo+BIC

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Survival (OS)
Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, wichever came first, assesed up to 48 months
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
From date of randomization until the date of first documented progression or date of death from any cause, wichever came first, assesed up to 48 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression-Free Survival (PFS)
Time Frame: From the date of randomization until the date of first documented progression or date of death from any cause, wichever came first, assessed up to 48 months
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
From the date of randomization until the date of first documented progression or date of death from any cause, wichever came first, assessed up to 48 months
Disease Control Rate (DCR)
Time Frame: Assessed every 6-12 weeks, up to 100 weeks
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
Assessed every 6-12 weeks, up to 100 weeks
Number of Partecipants With Disease Control for ≥ 6 Months
Time Frame: Assessed every 6-12 weeks, up to 100 weeks
Measured from the date of randomization until disease progression, or death due to any cause
Assessed every 6-12 weeks, up to 100 weeks
Number of Partecipants With Adverse Events
Time Frame: Assessed every 6-12 weeks, up to 100 weeks
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.
Assessed every 6-12 weeks, up to 100 weeks
Time to LCSS Symptomatic Progression
Time Frame: from the date of randomization to the date of the LCSS assessment on which symptomatic progression was identified, assessed on cycle 2, cycle 4 and cycle 6 (each cycle lasted 21 days)
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%.
from the date of randomization to the date of the LCSS assessment on which symptomatic progression was identified, assessed on cycle 2, cycle 4 and cycle 6 (each cycle lasted 21 days)
Evaluation of Medical Care Utilization in the Two Treatment Arms
Time Frame: Assessed every 6-12 weeks, up to 100 weeks
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.
Assessed every 6-12 weeks, up to 100 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

AGC Biologics S.p.A.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

April 12, 2010

Primary Completion (ACTUAL)

April 29, 2014

Study Completion (ACTUAL)

December 1, 2017

Study Registration Dates

First Submitted

March 17, 2010

First Submitted That Met QC Criteria

April 1, 2010

First Posted (ESTIMATE)

April 2, 2010

Study Record Updates

Last Update Posted (ACTUAL)

September 17, 2019

Last Update Submitted That Met QC Criteria

August 28, 2019

Last Verified

August 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NGR015
  • 2009-016879-29 (EUDRACT_NUMBER)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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