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

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ClinicalTrials.gov Identifier: NCT01098266

Recruitment Status : Completed

First Posted : April 2, 2010

Results First Posted : September 17, 2019

Last Update Posted : September 17, 2019

Sponsor:

Information provided by (Responsible Party):

MolMed S.p.A.

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition	Malignant Pleural Mesothelioma
Interventions	Drug: NGR-hTNF plus Best Investigator's Choice (BIC) Drug: Placebo plus Best Investigator's Choice (BIC)
Enrollment	400

Participant Flow

Recruitment Details	Study Period: April 12th, 2010(First enrolment); January 21st, 2013 (date of last enrolment); April 29th, 2014 (cut-off date). 15 clinical sites in Italy, 10 in UK, 7 in USA, 4 in Belgium, 2 in Canada, 2 in Netherland, 2 in Poland, 1 in Egypt, 1 in Ireland;1 in Sweden
Pre-assignment Details	Before randomization, the physician had to decide for each patient if he/she was candidate to either Best Supportive Care (BSC) alone or combined with single-agent chemotherapy.


Arm/Group Title	A: NGR-hTNF + BIC	B: Placebo+BIC
Arm/Group Description	NGR-hTNF plus Best Investigator's C...	Placebo plus Best Investigator's Ch...
Arm/Group Description	NGR-hTNF plus Best Investigator's Choice 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 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)
Period Title: Overall Study
Started	200	200
Completed	193	193
Not Completed	7	7
Reason Not Completed
Physician Decision	1	0
Death	3	2
Withdrawal by Subject	3	5

Baseline Characteristics

Arm/Group Title		A: NGR-hTNF + BIC	B: Placebo+BIC	Total
Arm/Group Description		NGR-hTNF plus Best Investigator's C...	Placebo plus Best Investigator's Ch...	Total of all reporting groups
Arm/Group Description		NGR-hTNF plus Best Investigator's Choice 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 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)	Total of all reporting groups
Overall Number of Baseline Participants		200	200	400
Baseline Analysis Population Description		...
Baseline Analysis Population Description		Patients ≥ 18 years with advanced malignant pleural mesothelioma previously treated with a pemetrexed based chemotherapy regimen for advanced or metastatic disease.
Age, Categorical Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	200 participants	200 participants	400 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	92 46.0%	87 43.5%	179 44.8%
	>=65 years	108 54.0%	113 56.5%	221 55.3%
Age, Continuous Median (Full Range) Unit of measure: Years
	Number Analyzed	200 participants	200 participants	400 participants
		65 (25 to 89)	67 (31 to 81)	66 (25 to 89)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	200 participants	200 participants	400 participants
	Female	44 22.0%	55 27.5%	99 24.8%
	Male	156 78.0%	145 72.5%	301 75.3%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	200 participants	200 participants	400 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	1 0.5%	1 0.3%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	2 1.0%	0 0.0%	2 0.5%
	White	198 99.0%	197 98.5%	395 98.8%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	2 1.0%	2 0.5%
Region of Enrollment Measure Type: Number Unit of measure: Participants	Number Analyzed	200 participants	200 participants	400 participants
Canada		3	5	8
Netherlands		5	2	7
Sweden		1	1	2
Belgium		5	8	13
United States		14	12	26
Ireland		3	1	4
Egypt		17	19	36
Poland		17	14	31
Italy		79	84	163
United Kingdom		49	46	95
France		4	6	10
Spain		3	2	5

Outcome Measures

1.Primary Outcome


Title	Overall Survival (OS)
Description	Defined as the time from the date of randomization until the date of d...
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	A: NGR-hTNF + BIC	B: Placebo+BIC
Arm/Group Description:	NGR-hTNF plus Best Investigator's C...	Placebo plus Best Investigator's Ch...
Arm/Group Description:	NGR-hTNF plus Best Investigator's Choice 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 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)
Overall Number of Participants Analyzed	200	200
Median (95% Confidence Interval) Unit of Measure: months
	8.5 (7.2 to 9.9)	8.0 (6.6 to 8.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	A: NGR-hTNF + BIC, B: Placebo+BIC
	Comments	Study with one control per experimental patient, an accrual interval of 24 months, and an additional FU after the accrual interval of 12 months.If the true HR of experimental relative to control patients was 0.726, then 195 experimental patients and 195 control patients were required to be able to reject the null hypothesis that the experimental and control survival curves were equal with probability (power)0.80 Type I error probability associated with this test of this null hypothesis was 0.05
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.58
	Comments	The log-rank test (unstratified) was used to compare the two treatment arms. In addition, a stratified version of the log-rank test was performed with the stratification factors used for randomization.
	Method	Log Rank
	Comments	Cox regression analyses (unstratified and stratified) were performed to assess the influence of baseline covariates in an exploratory manner.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95% 0.75 to 1.18
	Estimation Comments	[Not Specified]

2.Secondary Outcome


Title	Progression-Free Survival (PFS)
Description	Defined as the time from the date of randomization until disease progr...
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	A: NGR-hTNF + BIC	B: Placebo+BIC
Arm/Group Description:	NGR-hTNF plus Best Investigator's C...	Placebo plus Best Investigator's Ch...
Arm/Group Description:	NGR-hTNF plus Best Investigator's Choice 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 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)
Overall Number of Participants Analyzed	200	200
Median (95% Confidence Interval) Unit of Measure: months
	3.4 (2.7 to 4.1)	3.0 (2.3 to 3.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	A: NGR-hTNF + BIC, B: Placebo+BIC
	Comments	The log-rank test (unstratified and stratified) was used at an alpha level of 5% to test for differences in PFS between the two treatment arms. Kaplan-Meier curves and estimates were provided.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.65
	Comments	[Not Specified]
	Method	Log Rank
	Comments	Cox regression analyses (unstratified and stratified) was performed to assess the influence of baseline covariates in an exploratory manner.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 95% 0.78 to 1.17
	Estimation Comments	[Not Specified]

3.Secondary Outcome


Title	Disease Control Rate (DCR)
Description	Disease control rate (DCR), defined as the percentage of patients who ...
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	A: NGR-hTNF + BIC	B: Placebo+BIC
Arm/Group Description:	NGR-hTNF plus Best Investigator's C...	Placebo plus Best Investigator's Ch...
Arm/Group Description:	NGR-hTNF plus Best Investigator's Choice 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 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)
Overall Number of Participants Analyzed	200	200
Measure Type: Count of Participants Unit of Measure: Participants
Disease control rate (DCR)	114 57.0%	109 54.5%
Complete or partial response (CR o PR)	3 1.5%	6 3.0%
Stable disease (SD)	111 55.5%	103 51.5%
Progressive disease (PD)	51 25.5%	71 35.5%
Nonassessable (NA)	35 17.5%	20 10.0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	A: NGR-hTNF + BIC, B: Placebo+BIC
	Comments	Difference in DCR between the two treatment arms were tested using a chi-squared test with 95% confidence intervals calculated in each treatment arm.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.62
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.13
	Confidence Interval	(2-Sided) 95% 0.76 to 1.68
	Estimation Comments	Logistic regression analyses were performed to assess the influence of baseline covariates in an exploratory manner

4.Secondary Outcome


Title	Number of Partecipants With Disease Control for ≥ 6 Months
Description	Measured from the date of randomization until disease progression, or ...
Description	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

Outcome Measure Data

Analysis Population Description

Duration of disease control ≥ 6 months


Arm/Group Title	A: NGR-hTNF + BIC	B: Placebo+BIC
Arm/Group Description:	NGR-hTNF plus Best Investigator's C...	Placebo plus Best Investigator's Ch...
Arm/Group Description:	NGR-hTNF plus Best Investigator's Choice 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 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)
Overall Number of Participants Analyzed	200	200
Measure Type: Count of Participants Unit of Measure: Participants
	84 42.0%	76 38.0%

5.Secondary Outcome


Title	Number of Partecipants With Adverse Events
Description	All adverse events will be recorded according to CTC version 4.02 (CTC...
Description	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.
Time Frame	Assessed every 6-12 weeks, up to 100 weeks

Outcome Measure Data

Analysis Population Description

The safety data referred to patients of both arms who received at least one treatment and is termed as safety population (n=386)


Arm/Group Title	A: NGR-hTNF + BIC	B: Placebo+BIC
Arm/Group Description:	NGR-hTNF plus Best Investigator's C...	Placebo plus Best Investigator's Ch...
Arm/Group Description:	NGR-hTNF plus Best Investigator's Choice 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 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)
Overall Number of Participants Analyzed	193	193
Measure Type: Number Unit of Measure: participants
Study-emergent AEs of any grade	191	185
Study-emergent AEs of grade 3	102	86
Study-emergent AEs of grade 4	22	19
Study-emergent AEs of grade 5	12	13
Treatment-related AEs of grade 5	0	0
Treatment discontinuation due to AEs	31	24

6.Secondary Outcome


Title	Time to LCSS Symptomatic Progression
Description	Quality of life (QoL) assessment was performed by using a questionnair...
Description	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%.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

Participants with a worsening in the average symptom burden index by 25%.


Arm/Group Title	A: NGR-hTNF + BIC	B: Placebo+BIC
Arm/Group Description:	NGR-hTNF plus Best Investigator's C...	Placebo plus Best Investigator's Ch...
Arm/Group Description:	NGR-hTNF plus Best Investigator's Choice 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 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)
Overall Number of Participants Analyzed	175	185
Median (95% Confidence Interval) Unit of Measure: months
	3.2 (2.1 to 4.4)	3.0 (2.8 to 3.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	A: NGR-hTNF + BIC, B: Placebo+BIC
	Comments	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(the best score). The LCSS subscore is the average symptom burden index computed as the mean score for all 6 major symptoms. Symptomatic progression was defined as a worsening in the average symptom burden index by 25%.
	Type of Statistical Test	Other
	Comments	Two-sided log-rank test was used to compare time to symptomatic progression between treatment arms. Median and 95% confidence limits for the time to symptomatic progression were estimated using Kaplan-Meier survival methodology. Estimates of the treatment effect were expressed as hazard ratio including 95% confidence intervals.

Statistical Test of Hypothesis	P-Value	0.5806
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.92
	Confidence Interval	(2-Sided) 95% 0.68 to 1.26
	Estimation Comments	[Not Specified]

7.Secondary Outcome


Title	Evaluation of Medical Care Utilization in the Two Treatment Arms
Description	Medical resource use data collected will be used in health economic an...
Description	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.
Time Frame	Assessed every 6-12 weeks, up to 100 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	A: NGR-hTNF + BIC	B: Placebo+BIC
Arm/Group Description:	NGR-hTNF plus Best Investigator's C...	Placebo plus Best Investigator's Ch...
Arm/Group Description:	NGR-hTNF plus Best Investigator's Choice 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 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)
Overall Number of Participants Analyzed	200	200
Measure Type: Count of Participants Unit of Measure: Participants
ACE INHIBITORS, COMBINATIONS	0 0.0%	2 1.0%
ACE INHIBITORS, PLAIN	5 2.5%	2 1.0%
ADRENERGICS, INHALANTS	7 3.5%	10 5.0%
AMINOGLYCOSIDE ANTIBACTERIALS	2 1.0%	2 1.0%
ANESTHETICS, LOCAL	0 0.0%	4 2.0%
ANGIOTENSIN II ANTAGONISTS,COMBINATIONS	1 0.5%	4 2.0%
ANGIOTENSIN II ANTAGONISTS, plain	2 1.0%	5 2.5%
ANTACIDS	7 3.5%	3 1.5%
ANTERIOR PITUITARY LOBE HORMONES AND ANALOGUES	13 6.5%	7 3.5%
ANTIADRENERGIC AGENTS CENTRALLY ACTING	0 0.0%	2 1.0%
ANTIADRENERGIC AGENTS PERIPHERALLY ACTING	0 0.0%	2 1.0%
ANTIANDROGENS	0 0.0%	1 0.5%
ANTIARRHYTHMICS, CLASS I AND III	4 2.0%	3 1.5%
ANTIBIOTICS FOR TOPICAL USE	0 0.0%	4 2.0%
ANTIDEPRESSANTS	17 8.5%	2 1.0%
ANTIDIARRHEAL MICROORGANISMS	2 1.0%	1 0.5%
ANTIEMETICS AND ANTINAUSEANTS	107 53.5%	110 55.0%
ANTIEPILEPTICS	3 1.5%	2 1.0%
ANTIFIBRINOLYTICS	1 0.5%	0 0.0%
ANTIFUNGALS FOR TOPICAL USE	2 1.0%	0 0.0%
ANTIGLAUCOMA PREPARATIONS AND MIOTICS	0 0.0%	1 0.5%
ANTIGOUT PREPARATIONS	10 5.0%	12 6.0%
ANTIHISTAMINES FOR SYSTEMIC USE	66 33.0%	31 15.5%
ANTIINFECTIVES	0 0.0%	1 0.5%
ANTIINFLAMMATORY AGENTS AND ANTIINFECTIVES IN COM	0 0.0%	2 1.0%
ANTIINFLAMMATORY ANANTIRHEUMATIC PRODUCTSD	58 29.0%	65 32.5%
ANTIMETABOLITES	1 0.5%	1 0.5%
ANTIMYCOTICS FOR SYSTEMIC USE	15 7.5%	14 7.0%
ANTIPROPULSIVES	4 2.0%	8 4.0%
ANTIPRURITICS	3 1.5%	2 1.0%
ANTIPSYCHOTICS	7 3.5%	3 1.5%
ANTITHROMBOTIC AGENTS	41 20.5%	42 21.0%
ANTIVERTIGO PREPARATIONS	2 1.0%	1 0.5%
ANXIOLYTICS	24 12.0%	16 8.0%
ASCORBIC ACID (VITAMIN C)	0 0.0%	1 0.5%
BACTERIAL VACCINES	1 0.5%	0 0.0%
BELLADONNA AND DERIVATIVES	3 1.5%	4 2.0%
BETA BLOCKING AGENTS AND OTHER ANTIHYPERTENSIVES	11 5.5%	15 7.5%
BETA-LACTAM ANTIBACTERIALS, PENICILLINS	38 19.0%	29 14.5%
BILE THERAPY	1 0.5%	1 0.5%
BLOOD AND RELATED PRODUCTS	21 10.5%	26 13.0%
BLOOD GLUCOSE LOWERING DRUGS EXCL. INSULINS	2 1.0%	6 3.0%
CALCIUM	19 9.5%	12 6.0%
CAPILLARY STABILIZING	1 0.5%	0 0.0%
CARDIAC GLYCOSIDES	1 0.5%	3 1.5%
CARDIAC STIMULANTS EXCL CARDIAC GLYCOSIDES	1 0.5%	0 0.0%
CORTICOSTEROIDS FOR SYSTEMIC USE, PLAIN	138 69.0%	108 54.0%
CORTICOSTEROIDS, PLAIN	2 1.0%	1 0.5%
COUGH SUPPRESSANTS AND EXPECTORANTS, COMBINATIONS	2 1.0%	5 2.5%
COUGH SUPPRESSANTS, EXCL. COMBINATIONS WITH EXPEC	7 3.5%	17 8.5%
DECONGESTANTS AND ANTIALLERGICS	0 0.0%	1 0.5%
DIRECT ACTING ANTIVIRALS	2 1.0%	2 1.0%
DIURETICS AND POTASSIUM-SPARING AGENTS	6 3.0%	3 1.5%
DRUGS AFFECTING BONE	2 1.0%	3 1.5%
DRUGS FOR CONSTIPATION	39 19.5%	63 31.5%
DRUGS FOR FUNCTIONAL GASTROINTESTINAL DISORDERS	3 1.5%	5 2.5%
DRUGS FOR PEPTIC ULCER AND GASTRO-OESOPHAGEAL REF	74 37.0%	71 35.5%
DRUGS FOR TREATMENT OF TUBERCULOSIS	2 1.0%	0 0.0%
DRUGS USED IN BENIGN PROSTATIC HYPERTROPHY	4 2.0%	1 0.5%
ECTOPARASITICIDES, INC SCABICIDESL.	0 0.0%	1 0.5%
EMOLLIENTS AND PROTECTIVES	1 0.5%	0 0.0%
EXPECTORANTS EXCL COMBINATIONS WITH COUGH SUPPR.	14 7.0%	9 4.5%
HIGH-CEILING DIURETICS	19 9.5%	20 10.0%
HORMONES AND RELATED AGENTS	0 0.0%	1 0.5%
HYPNOTICS AND SEDATIVES	14 7.0%	14 7.0%
HYPOTHALAMIC HORMONES	0 0.0%	1 0.5%
I.V. SOLUTION ADDITIVES	17 8.5%	21 10.5%
I.V. SOLUTIONS	6 3.0%	10 5.0%
IMMUNOSTIMULANTS	20 10.0%	19 9.5%
INSULINS AND ANALOGUES	5 2.5%	0 0.0%
INTESTINAL ANTIINFECTIVES	3 1.5%	2 1.0%
IRON PREPARATIONS	14 7.0%	9 4.5%
LIPID MODIFYING AGENTS, PLAIN	4 2.0%	4 2.0%
LOW-CEILING DIURETICS, EXCL THIAZIDES	1 0.5%	0 0.0%
MACROLIDES, LINCOSAMIDES AND STREPTOGRAMINS	8 4.0%	14 7.0%
MULTIVITAMINS, COMBINATIONS	1 0.5%	4 2.0%
MULTIVITAMINS, PLAIN	4 2.0%	5 2.5%
MUSCLE RELAXANTS, CENTRALLY ACTING AGENTS	0 0.0%	1 0.5%
MYDRIATICS AND CYCLOPLEGICS	2 1.0%	3 1.5%
OPIOIDS	135 67.5%	160 80.0%
OTHER ANALGESICS AND ANTIPYRETICSD	105 52.5%	93 46.5%
OTHER ANTIANEMIC PREPARATIONS	20 10.0%	20 10.0%
OTHER ANTIBACTERIALS	4 2.0%	5 2.5%
OTHER ANTIDIARRHEALS	1 0.5%	0 0.0%
OTHER ANTINEOPLASTIC AGENTS	0 0.0%	2 1.0%
OTHER BETA-LACTAM ANTIBACTERIALS	8 4.0%	9 4.5%
OTHER CARDIAC PREPARATIONS	3 1.5%	0 0.0%
OTHER DRUGS FOR ACID RELATED DISORDERS	0 0.0%	1 0.5%
OTHER DRUGS FOR OBSTRUCTIVE	7 3.5%	8 4.0%
OTHER MINERAL SUPPLEMENTS	4 2.0%	5 2.5%
OTHER NUTRIENTS	4 2.0%	7 3.5%
OTHER OPHTHALMOLOGICALS	0 0.0%	1 0.5%
OTHER PLAIN VITAMIN PREPARATIONS	2 1.0%	0 0.0%
OTHER RESPIRATORY SYSTEM PRODUCTS	2 1.0%	0 0.0%
OTHER SYSTEMIC DRUGS FOR OBSTRUCTIVE AIRWAY DISEA	3 1.5%	1 0.5%
OTHER VITAMIN PRODUCTS, COMBINATIONS	1 0.5%	2 1.0%
PERIPHERAL VASODILATORS	0 0.0%	1 0.5%
POTASSIUM	4 2.0%	5 2.5%
POTASSIUM-SPARING AGENTS	1 0.5%	5 2.5%
PROPULSIVES	68 34.0%	87 43.5%
PSYCHOLEPTICS AND PSYCHOANALEPTICS	0 0.0%	1 0.5%
PSYCHOSTIMULANTS,	0 0.0%	1 0.5%
QUINOLONE ANTIBACTERIALS	31 15.5%	36 18.0%
SELECTIVE CALCIUM CHANNEL BLOCKERS WITH MAINLY VA	1 0.5%	6 3.0%
STOMATOLOGICAL PREPARATIONS	20 10.0%	19 9.5%
SULFONAMIDES AND TRIMETHOPRIM	2 1.0%	0 0.0%
TETRACYCLINES	0 0.0%	4 2.0%
THYROID PREPARATIONS	2 1.0%	0 0.0%
TOPICAL PRODUCTS FOR JOINT AND MUSCULAR PAIN	1 0.5%	2 1.0%
UROLOGICALS	3 1.5%	1 0.5%
VASODILATORS USED IN CARDIAC DISEASES	0 0.0%	2 1.0%
VIRAL VACCINES	1 0.5%	0 0.0%
VITAMIN A AND D	0 0.0%	5 2.5%
VITAMIN B1, PLAIN AND IN COMBINATION WITH VITAMIN	0 0.0%	3 1.5%
VITAMIN B12 AND FOLIC ACID	7 3.5%	11 5.5%
VITAMIN K AND OTHER HEMOSTATICS	1 0.5%	3 1.5%
SELECTIVE CALCIUM CHANNEL BLOCKERS WITH DIRECT CA	3 1.5%	4 2.0%

Adverse Events

Time Frame	Through study completation, an average of 2 years
Adverse Event Reporting Description	[Not Specified]

Arm/Group Title	A: NGR-hTNF + BIC		B: Placebo+BIC
Arm/Group Description	NGR-hTNF plus Best Investigator's C...		Placebo plus Best Investigator's Ch...
Arm/Group Description	NGR-hTNF plus Best Investigator's Choice 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 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)
All-Cause Mortality
	A: NGR-hTNF + BIC		B: Placebo+BIC
	Affected / at Risk (%)		Affected / at Risk (%)
Total	12/193 (6.22%)		13/193 (6.74%)
Serious Adverse Events Serious Adverse Events
	A: NGR-hTNF + BIC		B: Placebo+BIC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	56/193 (29.02%)		54/193 (27.98%)
Blood and lymphatic system disorders
Neutropenia ^† 1	2/193 (1.04%)	3	4/193 (2.07%)	5
Thrombocytopenia ^† 1	1/193 (0.52%)	1	0/193 (0.00%)	0
Leukopenia ^† 1	0/193 (0.00%)	0	1/193 (0.52%)	1
Neutropenic fever ^† 1	0/193 (0.00%)	0	2/193 (1.04%)	2
Anaemia ^† 1	0/193 (0.00%)	0	1/193 (0.52%)	1
Cardiac disorders
Pericardial effusion ^† 1	1/193 (0.52%)	1	2/193 (1.04%)	2
Atrial fibrillation ^† 1	1/193 (0.52%)	1	1/193 (0.52%)	1
Cardiac disorder ^† 1	1/193 (0.52%)	1	0/193 (0.00%)	0
Cardiac failure ^† 1	1/193 (0.52%)	1	0/193 (0.00%)	0
Myocardial infarction ^† 1	0/193 (0.00%)	0	1/193 (0.52%)	1
Pericarditis ^† 1	0/193 (0.00%)		1/193 (0.52%)
Cardiac arresr ^† 1	0/193 (0.00%)	0	1/193 (0.52%)	1
Gastrointestinal disorders
Intestinal obstruction ^† 1	0/193 (0.00%)	0	1/193 (0.52%)	1
Diarrhoea ^† 1	2/193 (1.04%)	2	0/193 (0.00%)	0
Pancreatitis ^† 1	0/193 (0.00%)	0	1/193 (0.52%)	1
Constipation ^† 1	2/193 (1.04%)	2	1/193 (0.52%)	1
Abdominal pain ^† 1	0/193 (0.00%)	0	2/193 (1.04%)	2
Abdominal ascites ^† 1	1/193 (0.52%)	1	1/193 (0.52%)	1
Dysphagia ^† 1	1/193 (0.52%)	1	0/193 (0.00%)	0
Vomiting ^† 1	2/193 (1.04%)		0/193 (0.00%)
General disorders
Chills ^† 1	2/193 (1.04%)	2	0/193 (0.00%)	0
Mucositis ^† 1	0/193 (0.00%)		1/193 (0.52%)
Pyrexia ^† 1	2/193 (1.04%)	2	2/193 (1.04%)	2
Death ^† 1	3/193 (1.55%)	3	2/193 (1.04%)	2
Hyperpyrexia ^† 1	1/193 (0.52%)		0/193 (0.00%)
Ischaemic ulcer to left heel ^† 1	0/193 (0.00%)	0	1/193 (0.52%)	1
Chest pain ^† 1	3/193 (1.55%)	3	3/193 (1.55%)	3
Deterioration of clinical status ^† 1	1/193 (0.52%)	1	1/193 (0.52%)	1
Admitted for pain control ^† 1	1/193 (0.52%)	1	0/193 (0.00%)	0
Fatigue ^† 1	0/193 (0.00%)	0	1/193 (0.52%)	1
Condition aggraveted ^† 1	4/193 (2.07%)	4	5/193 (2.59%)	5
Hepatobiliary disorders
Acute hepatitis ^† 1	0/193 (0.00%)	0	1/193 (0.52%)	1
Immune system disorders
Brain mets ^† 1	1/193 (0.52%)	1	0/193 (0.00%)	0
Infections and infestations
Cellulitis ^† 1	0/193 (0.00%)	0	1/193 (0.52%)	1
Pneumonia ^† 1	0/193 (0.00%)	0	3/193 (1.55%)	3
Neutropenic sepsis ^† 1	1/193 (0.52%)	1	1/193 (0.52%)	1
Appendiceal abscess ^† 1	0/193 (0.00%)	0	1/193 (0.52%)	1
Sepsis ^† 1	2/193 (1.04%)	2	1/193 (0.52%)	1
Infection - source unknown ^† 1	1/193 (0.52%)	1	0/193 (0.00%)	0
Viral gastroenteritis ^† 1	1/193 (0.52%)	1	0/193 (0.00%)	0
Lower Respiratory Tract Infection ^† 1	2/193 (1.04%)	2	1/193 (0.52%)	1
Lung Infection ^† 1	0/193 (0.00%)	0	1/193 (0.52%)	1
. Respiratory Tract Infection ^† 1	0/193 (0.00%)	0	1/193 (0.52%)	1
Injury, poisoning and procedural complications
Uncertain study medication dose delivered ^† 1	4/193 (2.07%)	4	9/193 (4.66%)	9
Drug infusion reaction ^† 1	2/193 (1.04%)	2	0/193 (0.00%)	0
Overdose ^† 1	1/193 (0.52%)	1	0/193 (0.00%)	0
Humerus fracture ^† 1	1/193 (0.52%)	1	0/193 (0.00%)	0
Hip fracture ^† 1	1/193 (0.52%)	1	0/193 (0.00%)	0
Occipital trauma ^† 1	1/193 (0.52%)	1	0/193 (0.00%)	0
Metabolism and nutrition disorders
Hyperglycaemia ^† 1	1/193 (0.52%)	1	0/193 (0.00%)	0
Cachexia ^† 1	1/193 (0.52%)	1	1/193 (0.52%)	1
Pleural Mesothelioma ^† 1	1/193 (0.52%)	1	0/193 (0.00%)	0
Musculoskeletal and connective tissue disorders
Pain right chest wall + right shoulder ^† 1	0/193 (0.00%)		1/193 (0.52%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Paraneoplastic fever ^† 1	1/193 (0.52%)	1	0/193 (0.00%)	0
Brain mets ^† 1	0/193 (0.00%)	0	1/193 (0.52%)	1
Nervous system disorders
Transient ischaemic attack ^† 1	0/193 (0.00%)	0	1/193 (0.52%)	1
Superior sagittal sinus thrombosis ^† 1	0/193 (0.00%)	0	1/193 (0.52%)	1
Right hemispheric cerebrovascular accident ^† 1	1/193 (0.52%)	1	0/193 (0.00%)	0
Encephalopathy ^† 1	1/193 (0.52%)	1	0/193 (0.00%)	0
Jacksonian seizure ^† 1	1/193 (0.52%)	1	0/193 (0.00%)	0
Renal and urinary disorders
Abnormal renal function ^† 1	1/193 (0.52%)	1	0/193 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism ^† 1	2/193 (1.04%)	2	2/193 (1.04%)	2
Dyspnoea ^† 1	4/193 (2.07%)	7	1/193 (0.52%)	1
Respiratory failure ^† 1	2/193 (1.04%)	2	2/193 (1.04%)	2
Bronchospasm ^† 1	1/193 (0.52%)	1	0/193 (0.00%)	0
Pneumonitis ^† 1	0/193 (0.00%)	0	1/193 (0.52%)	1
Infection (chest) with normal ANC ^† 1	0/193 (0.00%)	0	1/193 (0.52%)	1
Pleural effusion ^† 1	2/193 (1.04%)	2	0/193 (0.00%)	0
Pleural pain ^† 1	0/193 (0.00%)	0	1/193 (0.52%)	1
Pneumothorax ^† 1	1/193 (0.52%)	1	0/193 (0.00%)	0
Haemoptysis ^† 1	0/193 (0.00%)	0	1/193 (0.52%)	1
1 Term from vocabulary, MedDRA 18.1 † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	A: NGR-hTNF + BIC		B: Placebo+BIC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	190/193 (98.45%)		185/193 (95.85%)
Blood and lymphatic system disorders
Neutropenia ^† 1	57/193 (29.53%)	162	60/193 (31.09%)	119
Anaemia ^† 1	34/193 (17.62%)	58	42/193 (21.76%)	79
Thrombocytopenia ^† 1	26/193 (13.47%)	56	23/193 (11.92%)	47
Leukopenia ^† 1	24/193 (12.44%)	85	20/193 (10.36%)	24
Gastrointestinal disorders
Nausea ^† 1	61/193 (31.61%)	122	62/193 (32.12%)	130
Constipation ^† 1	42/193 (21.76%)	65	45/193 (23.32%)	65
Vomiting ^† 1	33/193 (17.10%)	61	38/193 (19.69%)	81
Diarrhoea ^† 1	20/193 (10.36%)	39	36/193 (18.65%)	58
Dyspepsia ^† 1	10/193 (5.18%)	12	11/193 (5.70%)	13
Abdominal disconfort ^† 1	1/193 (0.52%)	1	11/193 (5.70%)	12
General disorders
Chills ^† 1	104/193 (53.89%)	462	23/193 (11.92%)	29
Fatigue ^† 1	93/193 (48.19%)	166	94/193 (48.70%)	180
Pain ^† 1	91/193 (47.15%)	179	89/193 (46.11%)	184
Pyrexia ^† 1	48/193 (24.87%)	103	39/193 (20.21%)	67
Oedema ^† 1	26/193 (13.47%)	31	25/193 (12.95%)	29
Mucosal inflammation ^† 1	20/193 (10.36%)	29	17/193 (8.81%)	23
Infections and infestations
Respiratory tract infection ^† 1	13/193 (6.74%)	15	10/193 (5.18%)	13
Investigations
Transaminases Increased ^† 1	14/193 (7.25%)	37	7/193 (3.63%)	20
Metabolism and nutrition disorders
Decreased appetite ^† 1	46/193 (23.83%)	68	51/193 (26.42%)	76
Hypocalcaemia ^† 1	12/193 (6.22%)	21	5/193 (2.59%)	6
Nervous system disorders
Dizziness ^† 1	11/193 (5.70%)	12	12/193 (6.22%)	14
Dysgeusia ^† 1	10/193 (5.18%)	10	6/193 (3.11%)	7
Headache ^† 1	15/193 (7.77%)	16	13/193 (6.74%)	15
Pheripheral neuropathy ^† 1	12/193 (6.22%)	20	12/193 (6.22%)	15
Psychiatric disorders
Insomnia ^† 1	11/193 (5.70%)	12	12/193 (6.22%)	12
Respiratory, thoracic and mediastinal disorders
Dysponoea ^† 1	63/193 (32.64%)	94	56/193 (29.02%)	80
Cough ^† 1	39/193 (20.21%)	59	47/193 (24.35%)	71
Skin and subcutaneous tissue disorders
Alopecia ^† 1	12/193 (6.22%)	12	4/193 (2.07%)	4
Pruritus ^† 1	11/193 (5.70%)	15	8/193 (4.15%)	8
Vascular disorders
Hypertension ^† 1	12/193 (6.22%)	16	12/193 (6.22%)	15
Hypotension ^† 1	10/193 (5.18%)	12	7/193 (3.63%)	9
1 Term from vocabulary, MedDRA 18.1 † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Clinical Operations
Organization:	Molmed S.p.A
Phone:	003902212771
EMail:	clinical.operations@molmed.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Gregorc V, Gaafar RM, Favaretto A, Grossi F, Jassem J, Polychronis A, Bidoli P, Tiseo M, Shah R, Taylor P, Novello S, Muzio A, Bearz A, Greillier L, Fontana F, Salini G, Lambiase A, O'Brien M. NGR-hTNF in combination with best investigator choice in previously treated malignant pleural mesothelioma (NGR015): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2018 Jun;19(6):799-811. doi: 10.1016/S1470-2045(18)30193-1. Epub 2018 May 9.

Layout table for additonal information

Responsible Party:	MolMed S.p.A.
ClinicalTrials.gov Identifier:	NCT01098266 History of Changes
Other Study ID Numbers:	NGR015 2009-016879-29 ( EudraCT Number )
First Submitted:	March 17, 2010
First Posted:	April 2, 2010
Results First Submitted:	June 5, 2019
Results First Posted:	September 17, 2019
Last Update Posted:	September 17, 2019

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