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

Primary Outcome Measures:

• Overall Survival (OS) [ Time Frame: every 6-12 weeks ] [ Designated as safety issue: No ]
  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

Secondary Outcome Measures:

• Progression-Free Survival (PFS) [ Time Frame: every 6-12 weeks ] [ Designated as safety issue: No ]
  Defined as the time from the date of randomization until disease progression, or death
• Disease Control Rate (DCR) [ Time Frame: every 6-12 weeks ] [ Designated as safety issue: No ]
  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 ] [ Designated as safety issue: No ]
  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 ] [ Designated as safety issue: Yes ]
• Quality of life (QoL) according to Lung Cancer Symptom Scale [ Time Frame: every 6-12 weeks ] [ Designated as safety issue: No ]
• Evaluation of medical care utilization in the two treatment arms [ Time Frame: every 6-12 weeks ] [ Designated as safety issue: No ]
  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.

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.

Criteria

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
• 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 and radiation therapy: wash-out period of 14 days
  2. Systemic 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. 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 childbearing potential must provide a negative pregnancy test (serum or urine) within 14 days before the enrollment