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

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.

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