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

Malignant Pleural Mesothelioma Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01098266
• Other study ID #: NGR015
• Secondary ID: 2009-016879-29
• Status: Completed
• Phase: Phase 3
• Start date: April 12, 2010
• Est. completion date: December 2017

Study information

• Verified date: August 2019
• Source: MolMed S.p.A.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 400
• Est. completion date: December 2017
• Est. primary completion date: April 29, 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Malignant Pleural Mesothelioma
• Mesothelioma

Intervention

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: Doxorubicin: 60-75 mg/m2 every 3 weeks, for a maximum of 6 cycles Gemcitabine: 1,000-1,250 mg/m2 on days 1 and 8, every 3 weeks, for a maximum of 6 cycles 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)
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: Doxorubicin: 60-75 mg/m2 every 3 weeks, for a maximum of 6 cycles Gemcitabine: 1,000-1,250 mg/m2 on days 1 and 8, every 3 weeks, for a maximum of 6 cycles 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)

Locations

Country	Name	City	State
Belgium	Cliniques Universitarie St. Luc	Bruxelles
Belgium	Institut Jules Bordet	Bruxelles
Belgium	Antwerp University Hospital	Edegem	Antwerp
Belgium	Universitair Ziekenhuis	Gent
Belgium	Centre Hospitalier Universitaire de Liège	Liège	Liege
Canada	UAB - Alberta Cancer Board - Cross Cancer Institute	Edmonton	Alberta
Canada	University Health Network, Princess Margaret Hospital	Toronto	Ontario
Egypt	National Cancer Institute	Cairo
France	Hôpitaux de Marseille Hôpital Nord	Marseille
Ireland	St James's Hospital	Dublin
Italy	Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo di Alessandria	Alessandria
Italy	Centro di Riferimento Oncologico	Aviano
Italy	Ospedale Santo Spirito	Casale Monferrato	Alessandria
Italy	Ospedale Valduce	Como
Italy	Azienda Ospedaliero-Universitaria Careggi di Firenze	Firenze
Italy	Istituto Nazionale per la Ricerca sul Cancro	Genoa
Italy	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori-IRST	Meldola
Italy	Fondazione San Raffaele del Monte Tabor	Milan
Italy	Azienda Ospedaliera San Gerardo	Monza
Italy	Azienda Ospedaliera Universitaria San Luigi Gonzaga	Orbassano	Torino
Italy	Istituto Oncologico Veneto	Padova
Italy	Azienda Ospedaliero Universitaria di Parma	Parma
Italy	Azienda Unità Sanitaria locale di Ravenna	Ravenna
Italy	A.O. Salvini Garbagnate, Ospedale di Rho	Rho
Italy	Azienda Ospedaliera Senese	Siena
Netherlands	St. Jansdal Hospital	Harderwijk	Gelderland
Netherlands	St. Antonius Hospital	Nieuwegein	Utrecht
Poland	Medical University of Gdansk	Gdansk
Poland	Maria Sklodowska Memorial Cancer Center and Institute of Oncology	Warsaw
Spain	Hospital Universitari Germans Trias i Pujol	Badalona	Barcelona
Spain	Hospital Vall d'Hebron	Barcelona
Sweden	The University Hospital	Linkoping
United Kingdom	Castle Hill Hospital	Cottingham	Yorkshire
United Kingdom	Edinburgh Cancer Centre, Western General Hospital	Edinburgh	Scotland
United Kingdom	The Beatson West of Scotland Cancer Centre	Glasgow	Scotland
United Kingdom	University Hospitals of Leicester	Leicester	Leicestershire
United Kingdom	Guy's Hospital	London
United Kingdom	The Royal Marsden Hospital	London
United Kingdom	Kent Oncology Centre Maidstone Hospital	Maidstone	Kent
United Kingdom	Chest Clinic, Wythenshawe Hospital	Manchester	Greater Manchester
United Kingdom	Mount Vernon Cancer Centre	Middlesex	Northwood
United Kingdom	The Royal Marsden Hospital	Sutton	Surrey
United States	Johns Hopkins	Baltimore	Maryland
United States	Wilshire Oncology Medical Group	Corona	California
United States	UTsouthwestern medical center	Dallas	Texas
United States	City of Hope-Comprehensive Cancer Cente	Duarte	California
United States	Columbia University	New York	New York
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	H. Lee Moffitt ancer Center and Research Institute	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
MolMed S.p.A.

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  Egypt,  France,  Ireland,  Italy,  Netherlands,  Poland,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival (OS)	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	Progression-Free Survival (PFS)	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
Secondary	Disease Control Rate (DCR)	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
Secondary	Number of Partecipants With Disease Control for = 6 Months	Measured from the date of randomization until disease progression, or death due to any cause	Assessed every 6-12 weeks, up to 100 weeks
Secondary	Number of Partecipants With Adverse Events	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
Secondary	Time to LCSS Symptomatic Progression	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)
Secondary	Evaluation of Medical Care Utilization in the Two Treatment Arms	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