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

AGC Biologics S.p.A.400 enrolled

Overview

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.

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

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

400

Conditions

Malignant Pleural Mesothelioma

Interventions

NGR-hTNF plus Best Investigator's Choice (BIC)DRUG

* 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)

Placebo plus Best Investigator's Choice (BIC)DRUG

* 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)

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (49)

Outcomes

Primary Outcomes

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

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

Secondary Outcomes

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

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

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

Time frame: Assessed every 6-12 weeks, up to 100 weeks

Number of Partecipants With Disease Control for ≥ 6 Months

Measured from the date of randomization until disease progression, or death due to any cause

Time frame: Assessed every 6-12 weeks, up to 100 weeks

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.

Data from ClinicalTrials.gov

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