NGR-hTNF in Combination With Standard Chemotherapy to Treat Patients With Advanced Non-small Cell Lung Cancer

NGR014: Randomized Phase II Study of NGR-hTNF in Combination With Standard Chemotherapy Versus Standard Chemotherapy Alone in Previously Untreated Patients With Advanced Non-small Cell Lung Cancer (NSCLC)

The main objective of this study is to demonstrate superiority in progression-free survival (PFS) when NGR-hTNF is added to standard chemotherapy regimen (cisplatin/gemcitabine or cisplatin/pemetrexed) in locally advanced (stage IIIb with supraclavicular lymph node metastases or malignant pleural or pericardial effusion), metastatic (stage IV) or recurrent non-small cell lung cancer (NSCLC).

Study Overview

• Status: Completed
• Conditions: Non-small Cell Lung Cancer
• Intervention / Treatment: Drug: NGR-hTNF; Drug: Cisplatin; Drug: Gemcitabine; Drug: Pemetrexed

Detailed Description

Eligible patients will be randomly assigned to a standard chemotherapy regimen plus low-dose (0.8 mcg/m^2) NGR-hTNF or standard chemotherapy alone, through a centralized randomization process using the following stratification factors: performance status (0 vs 1) and histology (squamous vs non-squamous). In both arms the choice between the two chemotherapy regimens will be based on the histologic subtype: in patients with squamous histology (including also generic diagnosis of NSCLC without further subtype classification) is recommended cisplatin/gemcitabine regimen, in patients with nonsquamous histology (including adenocarcinoma and large-cell carcinoma) is recommended cisplatin/pemetrexed regimen.

• Study Type: Interventional
• Enrollment (Actual): 121
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Genoa, Italy, 16132
    • Istituto Nazionale per la Ricerca sul Cancro
  • Milan, Italy, 20132
    • Fondazione San Raffaele del Monte Tabor
  • Milan, Italy
    • Istituto Europeo Oncologico
  • Milan, Italy, 20133
    • Istituto Nazionale Dei Tumori

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. Histologically or cytologically documented inoperable, locally advanced (stage IIIb with supraclavicular lymph node metastases or malignant pleural or pericardial effusion), metastatic (stage IV) or recurrent NSCLC. Mixed tumors should be categorized according to the predominant cell type.
2. Age ≥18 years
3. Life expectancy more than 3 months
4. ECOG performance status 0-1
5. At least one unidimensional measurable lesion (as per RECIST criteria)

6. Adequate baseline bone marrow, hepatic and renal function, defined as follows:

   • Neutrophils >1.5 x 10^9/L and platelets > 100 x 10^9/L
   • Bilirubin <1.5 x ULN
   • AST and/or ALT <2.5 x ULN in absence of liver metastasis
   • AST and/or ALT <5 x ULN in presence of liver metastasis
   • Serum creatinine <1.5 x ULN
   • Creatinine clearance (estimated according to Cockcroft-Gault formula) ≥ 50 ml/min

7. Patients may have had prior therapy providing the following conditions are met:

   • Radiation therapy: wash-out period of 28 days
   • Surgery: wash-out period of 14 days
8. Patients must give written informed consent to participate in the study

Exclusion criteria:

1. Prior chemotherapy or treatment with another systemic anti-cancer agent (for example monoclonal antibody, tyrosine kinase inhibitor).
2. Patients must not receive any other investigational agents while on study
3. Patients with myocardial infarction within the last six (6) months, unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, or serious cardiac arrhythmia requiring medication
4. Uncontrolled hypertension
5. Prolonged QTc interval (congenital or acquired)
6. Patient with significant peripheral vascular disease
7. 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).
8. Patients with active or uncontrolled systemic disease/infections or with serious illness or medical conditions, which is incompatible with the protocol
9. Known hypersensitivity/allergic reaction or contraindications to human albumin preparations or to any of the excipients
10. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol
11. 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 child-bearing potential must provide a negative pregnancy test (serum or urine) within 14 days prior to registration.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: A: NGR-hTNF + cisplatin/gemcitabine or cisplatin/pemetrexed; NGR-hTNF with cisplatin/gemcitabine regimen in patients with squamous histology or with cisplatin/pemetrexed regimen in patients with nonsquamous histology	Drug: NGR-hTNF; NGR-hTNF: 0.8 mcg/m² as 60-minute intravenous infusion every 3 weeks until confirmed evidence of disease progression or unacceptable toxicity occurs; Drug: Cisplatin; Cisplatin: 80 mg/m² intravenous infusion on day 1 every 3 weeks for a maximum of 6 cycles; Drug: Gemcitabine; Gemcitabine: 1,250 mg/m² intravenous infusion on days 1 and 8 every 3 weeks for a maximum of 6 cycles; Drug: Pemetrexed; Pemetrexed: 500 mg/m² intravenous infusion on day 1 every 3 weeks for a maximum of 6 cycles
ACTIVE_COMPARATOR: B: cisplatin/gemcitabine or cisplatin/pemetrexed; Cisplatin/gemcitabine regimen is administered in patients with squamous histology and cisplatin/pemetrexed regimen is administered in patients with nonsquamous histology	Drug: Cisplatin; Cisplatin: 80 mg/m² intravenous infusion on day 1 every 3 weeks for a maximum of 6 cycles; Drug: Gemcitabine; Gemcitabine: 1,250 mg/m² intravenous infusion on days 1 and 8 every 3 weeks for a maximum of 6 cycles; Drug: Pemetrexed; Pemetrexed: 500 mg/m² intravenous infusion on day 1 every 3 weeks for a maximum of 6 cycles

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)	PFS evaluated according to Response evaluation criteria in solid tumors (RECIST)	Every 6 weeks during study treatment and every 6 weeks during the follow-up before PD

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety according to NCI-CTCAE criteria (version 3)	To evaluate safety profile related to NGR-hTNF in combination with standard chemotherapy	from the date of randomization until 28 days after last treatment
Objective response rate	Antitumor activity defined as response rate evaluated according to Response evaluation criteria in solid tumors (RECIST)	Every 6 weeks during study treatment and every 6 weeks during the follow-up before PD
Duration of response (DR)	defined as the time that measurement criteria are met for complete response or partial response (whichever status is recorded first) until the progressive disease is objectively documented.	from the time of first recorded evidence of complete response or partial response until the progressive disease objectively documented
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 the randomization until to the date of patient death or discontinuation from the study

Collaborators and Investigators

• Sponsor: AGC Biologics S.p.A.

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 1, 2009
• Primary Completion (ACTUAL): March 1, 2017
• Study Completion (ACTUAL): March 1, 2017

Study Registration Dates

• First Submitted: October 13, 2009
• First Submitted That Met QC Criteria: October 13, 2009
• First Posted (ESTIMATE): October 14, 2009

Study Record Updates

• Last Update Posted (ACTUAL): September 27, 2018
• Last Update Submitted That Met QC Criteria: September 25, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: Gemcitabine; Randomized controlled trial; Cisplatin; Pemetrexed; NGR-hTNF; Carcinoma, non-small cell lung
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Folic Acid Antagonists; Gemcitabine; Cisplatin; Pemetrexed
• Other Study ID Numbers: NGR014; 2008-002703-20 (EUDRACT_NUMBER)