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

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ClinicalTrials.gov Identifier: NCT01098266
Recruitment Status : Completed
First Posted : April 2, 2010
Results First Posted : September 17, 2019
Last Update Posted : September 17, 2019
Sponsor:
Information provided by (Responsible Party):
MolMed S.p.A.

Tracking Information
First Submitted Date  ICMJE March 17, 2010
First Posted Date  ICMJE April 2, 2010
Results First Submitted Date  ICMJE June 5, 2019
Results First Posted Date  ICMJE September 17, 2019
Last Update Posted Date September 17, 2019
Actual Study Start Date  ICMJE April 12, 2010
Actual Primary Completion Date April 29, 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 28, 2019)
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
Original Primary Outcome Measures  ICMJE
 (submitted: April 1, 2010)
Overall Survival (OS) [ Time Frame: every 6-12 weeks ]
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
Change History Complete list of historical versions of study NCT01098266 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 28, 2019)
  • 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
  • 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
  • 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
  • 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.
  • 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%.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 1, 2010)
  • Progression-Free Survival (PFS) [ Time Frame: every 6-12 weeks ]
    Defined as the time from the date of randomization until disease progression, or death
  • Disease Control Rate (DCR) [ Time Frame: every 6-12 weeks ]
    Defined as the percentage of patients who have a best-response rating of complete response, partial response, or stable disease
  • Duration of Disease Control [ Time Frame: every 6-12 weeks ]
    Measured from the date of randomization until disease progression, or death due to any cause
  • Safety and Toxicity according to NCI-CTCAE criteria (version 4.02) [ Time Frame: every 6-12 weeks ]
  • Quality of life (QoL) according to Lung Cancer Symptom Scale [ Time Frame: every 6-12 weeks ]
  • Evaluation of Medical Care Utilization in the Two Treatment Arms [ Time Frame: every 6-12 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE NGR015: Study in Second Line for Patient With Advanced Malignant Pleural Mesothelioma Pretreated With Pemetrexed
Official Title  ICMJE 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)
Brief Summary 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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Malignant Pleural Mesothelioma
Intervention  ICMJE
  • 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 Name: NGR-hTNF+BIC
  • 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 Name: Placebo+BIC
Study Arms  ICMJE
  • Experimental: A: NGR-hTNF + BIC
    NGR-hTNF plus Best Investigator's Choice
    Intervention: Drug: NGR-hTNF plus Best Investigator's Choice (BIC)
  • Placebo Comparator: B: Placebo+BIC
    Placebo plus Best Investigator's Choice
    Intervention: Drug: Placebo plus Best Investigator's Choice (BIC)
Publications * Gregorc V, Gaafar RM, Favaretto A, Grossi F, Jassem J, Polychronis A, Bidoli P, Tiseo M, Shah R, Taylor P, Novello S, Muzio A, Bearz A, Greillier L, Fontana F, Salini G, Lambiase A, O'Brien M. NGR-hTNF in combination with best investigator choice in previously treated malignant pleural mesothelioma (NGR015): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2018 Jun;19(6):799-811. doi: 10.1016/S1470-2045(18)30193-1. Epub 2018 May 9.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 20, 2017)
400
Original Estimated Enrollment  ICMJE
 (submitted: April 1, 2010)
390
Actual Study Completion Date  ICMJE December 2017
Actual Primary Completion Date April 29, 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   Canada,   Egypt,   France,   Ireland,   Italy,   Netherlands,   Poland,   Spain,   Sweden,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01098266
Other Study ID Numbers  ICMJE NGR015
2009-016879-29 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party MolMed S.p.A.
Study Sponsor  ICMJE MolMed S.p.A.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Antonio Lambiase, MD MolMed S.p.A.
PRS Account MolMed S.p.A.
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP