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Clinical Trial Results:
Randomized phase II trial on primary chemotherapy with high-dose methotrexate and high-dose cytarabine with or without thiotepa, and with or without rituximab, followed by brain irradiation vs. high-dose chemotherapy supported by autologous stem cells transplantation for immunocompetent patients with newly diagnosed primary cns lymphoma.

Summary
EudraCT number	2009-012432-32
Trial protocol	IT DE GB DK
Global end of trial date	19 Dec 2024

Results information
Results version number	v1(current)
This version publication date	02 Jan 2026
First version publication date	02 Jan 2026
Other versions
Summary report(s)	IELSG32 Synopsis

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

Top of page

Sponsor protocol code

IELSG 32

ISRCTN number

US NCT number

NCT01011920

WHO universal trial number (UTN)

Sponsor organisation name

International Extranodal Lymphoma Study Group (IELSG)

Sponsor organisation address

Via Vincenzo Vela 6, Bellinzona, Switzerland, 6500

Public contact

Operations Office, IELSG, +41 58 666 73 21, ielsg@ior.usi.ch

Scientific contact

Operations Office, IELSG , +41 58 666 73 21, ielsg@ior.usi.ch

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

13 Nov 2025

Is this the analysis of the primary completion data?

Yes

Primary completion date

19 Dec 2024

Global end of trial reached?

Yes

Global end of trial date

19 Dec 2024

Was the trial ended prematurely?

Main objective of the trial

Primary objective at first randomization: to compare in a prospective, randomized phase II trial the activity of primary chemotherapy containing high-dose methotrexate (HD-MTX) + high-dose cytarabine (HD-araC) vs. HD-MTX + HD-araC + rituximab vs. HD-MTX + HD-araC + rituximab + thiotepa, in patients with newly diagnosed PCNSL. Primary objective at second randomization: to compare the efficacy of two consolidation strategies: conventional whole-brain radiotherapy (WBRT) vs. high-dose chemotherapy supported by autologous stem cell transplantation (HDC+ASCT) in patients with newly diagnosed PCNSL.

Protection of trial subjects

In case of hematological toxicity, dose modifications of primary chemotherapy were foreseen. In case of inadequate bone marrow recovery on the intended day of re-treatment, the start of the next cycle could be delayed for a maximum of 2 weeks. Thereafter, chemotherapy has to be discontinued, and patient referred to WBRT 40 Gy plus boost 9 Gy. The dose of cytostatic drug were determined according to the nadir neutrophil or platelet counts of the previous course. Ara-C dose reduction consisted of the omission of the 4th dose of the drug (2nd dose of the day 3). No dose reductions were required in case of CTC grade 1 or 2 non-hematological toxicities. In case of CTC grade 3-4 non-hematological toxicity, the total dose of drugs to be administered in the subsequent course was reduced as foreseen in the study protocol. Rituximab infusion reactions were managed according to international guidelines.

Background therapy

The following drugs: antiemetics, analgesics, antibiotics, anticonvulsants, sedatives, anti-hyperuricemic agents as well as other therapies to control metabolic and malnutrition disturbances were delivered. Additional cytotoxic therapy, biological responsive modifiers and drugs possibly interfering in the action or pharmacokinetics of MTX, Ara-C, rituximab, BCNU or thiotepa were avoided. The type and doses of anticonvulsants and corticosteroids had to be accurately registered. Antimicrobial prophylaxis followed Institutional guidelines since the variability in endemic or epidemic distribution of infectious agents. However, oral antiviral (Acyclovir 400 mg x 2/d), antifungine (Fluconazole 400 mg/d per os once weekly), antipneumocystic (Trimethoprim 160 mg and sulfamethoxazole 800 mg; three times per week) were suggested. Conventional doses of rHuG-CSF from day 7th - 14th of every course associated with antibiotic prophylaxis with Levofloxacin 500 mg/day (same period) was strongly suggested. Antimicrobial drugs were interrupted during chemotherapy administration to avoid potential negative pharmacological interactions.

Evidence for comparator

Actual start date of recruitment

19 Feb 2010

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Switzerland: 2

Country: Number of subjects enrolled

United Kingdom: 39

Country: Number of subjects enrolled

Denmark: 11

Country: Number of subjects enrolled

Germany: 82

Country: Number of subjects enrolled

Italy: 93

Worldwide total number of subjects

227

EEA total number of subjects

186

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

187

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Recruitment lasted from 19 February 2010 to 07 October 2014

Screening details

227 patients were screened and enrolled

Period 1 title

First randomization

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Arm A

Arm description

At the first randomization, patients were allocated to receive one of three different chemo(immuno)therapy combinations as an induction phase. Patients in Arm A received: Methotrexate 3.5 g/m2 on day 1 + Cytarabine 2g/m2 on days 2 and 3. Treatment was repeated on a 21 day cycle for 4 cycles.

Arm type

Active comparator

Investigational medicinal product name

Methotrexate

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

3.5 mg/m2 (0.5 g/m2 in 15 min, followed by 3 g/m2 in 3-hour infusion) in combination with Cytarabine on day 1 of a 3 week cycle, for 4 cycles

Investigational medicinal product name

Cytarabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

2 g/m2 (1-hour infusion, twice a day, every 12 h) in combination with Methotrexate, on days 2 and 3 of a 21 days cycle for 4 cycles

Arm B

Arm description

At the first randomization, patients were allocated to receive one of three different chemo(immuno)therapy combinations as an induction phase. Patients in Arm B received: Methotrexate 3.5 g/m2 on day 1 + Cytarabine 2g/m2 on days 2 and 3 + Rituximab 375 mg/m2 on days - 5 and 0. Treatment was repeated on a 21 day cycle for 4 cycles

Arm type

Experimental

Investigational medicinal product name

Methotrexate

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Methotrexate was administered at the dosage of 3.5 mg/m2 (0.5 g/m2 in 15 min, followed by 3 g/m2 in 3-hour infusion) in combination with Cytarabine and Rituximab on day 1 of a 3 week cycle, for 4 cycles

Investigational medicinal product name

Cytarabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Cytarabine was administered at the dosage of 2 g/m2 (1-hour infusion, twice a day, every 12 h) in combination with Methotrexate and Rituximab, on days 2 and 3 of a 21 days cycle for 4 cycles

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Rituximab was administered at the dosage of 375 mg/m2 (conventional infusion) on days - 6 and 0, in combination with Methotrexate and Cytarabine, in a 21 days cycle for 4 cycles

Arm C

Arm description

At the first randomization, patients were allocated to receive one of three different chemo(immuno)therapy combinations as an induction phase. Patients in Arm C received: Methotrexate 3.5 g/m2 on day 1 + Cytarabine 2g/m2 on days 2 and 3 + Rituximab 375 mg/m2 on days - 5 and 0. Treatment was repeated on a 21 day cycle for 4 cycles less

Arm type

Experimental

Investigational medicinal product name

Methotrexate

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Methotrexate was administered at the dosage of 3.5 mg/m2 (0.5 g/m2 in 15 min, followed by 3 g/m2 in 3-hour infusion) in combination with Cytarabine, Rituximab and Thiotepa on day 1 of a 3 week cycle, for 4 cycles

Investigational medicinal product name

Cytarabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Cytarabine was administered at the dosage of 2 g/m2 (1-hour infusion, twice a day, every 12 h) in combination with Methotrexate, Rituximab and Thiotepa, on days 2 and 3 of a 21 days cycle for 4 cycles

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Rituximab was administered at the dosage of 375 mg/m2 (conventional infusion) on days - 6 and 0, in combination with Methotrexate, Cytarabine and Thiotepa, in a 21 days cycle for 4 cycles

Investigational medicinal product name

Thiotepa

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Thiotepa was administered at the dosage of 30 mg/m2 (30 minutes infusion) on day 4 of a 21 days cycle for 4 cycles

Number of subjects in period 1 ^[1]	Arm A	Arm B	Arm C
Started	75	69	75
Completed	46	55	66
Not completed	29	14	9
Adverse event, serious fatal	7	3	3
Progressive Disease	22	11	6

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Two hundreds and twenty seven patients were enrolled and treated in the IELSG32 study. Eight patients were excluded (five from arm B and three from arm C) because of misdiagnosis, systemic lymphoma, or concomitant cancer.

Period 2 title

Second Randomization

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Arm D

Arm description

Patients responsive, Complete Response (CR) or Partial Response (PR) or with Stable Disease (SD) after primary chemotherapy (patients treated either with Arm A, B, or C ) were randomly assigned to Arm D or Arm E. Patients in Arm D were treated with conventional whole-brain radiotherapy (WBRT) with 36 Gy in the case of CR to primary chemotherapy or the same WBRT dose followed by a tumor-bed boost of 9 Gy with 1-2 cm of margin surrounding enhanced residual lesion (total tumor-bed dose 45 Gy) in patients who achieved a PR or SD after primary chemotherapy.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Arm E

Arm description

Patients responsive, Complete Response (CR) or Partial Response (PR), or with Stable Disease (SD) after primary chemotherapy (patients treated either with Arm A, B, or C ) were randomly assigned to Arm D or Arm E. Treatment regimen for Arm E corresponds to the conditioning phase for autologous stem cell transplantation (ASCT).

Arm type

Experimental

Investigational medicinal product name

Carmustine

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Carmustine was administered at the dosage of 400 mg/m2 on day - 6 before re-infusion of Peripheral Blood Stem Cells

Investigational medicinal product name

Thiotepa

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Thiotepa was administered at the dosage of 5 mg/Kg on days - 5 and -4 before re-infusion of Peripheral Blood Stem Cells

Number of subjects in period 2 ^[2]	Arm D	Arm E
Started	55	58
Completed	52	54
Not completed	3	4
Adverse event, serious fatal	-	2
Progressive Disease	3	2

Notes
[2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: A total of 167 patients with responsive or stable disease were observed. Eighteen patients experienced PD before the second randomization, 12 were deemed unfit, and 15 had no harvest. Consequently, 122 patients were eligible and assessable for second randomization. Four patients refused the second randomization, leaving 59 patients allocated to Arm D and 59 to Arm E. Of these, five patients refused consolidation resulting in 113 patients proceeding.

Baseline characteristics

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Reporting group title

Arm A

Reporting group description

Reporting group title

Arm B

Reporting group description

Reporting group title

Arm C

Reporting group description

Reporting group values	Arm A	Arm B	Arm C	Total
Number of subjects	75	69	75	219
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	59	56	64	179
From 65-84 years	16	13	11	40
85 years and over	0	0	0	0
Gender categorical
Units: Subjects
Female	29	25	29	83
Male	46	44	46	136
Performance Status (ECOG)
Units: Subjects
ECOG 0 - 1	48	46	51	145
ECOG > 1	27	23	24	74
Increased LDH
Increased serum lactate dehydrogenase concentration
Units: Subjects
Increased LDH	37	26	25	88
No increased LDH	38	43	50	131
Deep lesions
Units: Subjects
Deep lesions	58	52	64	174
No deep lesions	17	17	11	45
Increased CSF protein
Increased cerebrospinal fluid (CSF) protein
Units: Subjects
Increased CSF protein	33	33	35	101
No increased CSF protein	23	20	18	61
Not recorded	19	16	22	57
IELSG risk score
International Extranodal Lymphoma Study Group (IELSG) risk score
Units: Subjects
Low	14	12	13	39
Intermediate	47	44	47	138
High	14	13	15	42
Intraocular disease
Units: Subjects
Intraocular disease	5	1	1	7
No Intraocular disease	70	68	74	212
Meningeal involvement
Units: Subjects
Meningeal involvement	11	10	13	34
No meningeal involvement	45	43	40	128
Not recorded	19	16	22	57
Multiple lesions
Units: Subjects
Multiple lesions	45	40	41	126
No Multiple lesions	30	29	34	93

End points

Top of page

Reporting group title

Arm A

Reporting group description

Reporting group title

Arm B

Reporting group description

Reporting group title

Arm C

Reporting group description

Reporting group title

Arm D

Reporting group description

Reporting group title

Arm E

Reporting group description

Primary: Complete Remission (CR) Rate

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End point title

Complete Remission (CR) Rate ^[1]

End point description

End point type

Primary

End point timeframe

After primary chemotherapy

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal comparison was planned among the groups involved and the randomised active control group (Arm A) was used for calibration purposes.

End point values	Arm A	Arm B	Arm C
Number of subjects analysed	75	69	75
Units: Percentage
number (confidence interval 95%)	23 (14 to 31)	30 (21 to 42)	49 (38 to 60)

No statistical analyses for this end point

Primary: 2-year failure-free survival (2-yr FFS)

Top of page

End point title

2-year failure-free survival (2-yr FFS) ^[2]

End point description

End point type

Primary

End point timeframe

From the time of study entry until disease progression or death from any cause until 2 years

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal comparison was planned between groups D and E. The randomised active control group was used for calibration purposes.

End point values	Arm D	Arm E
Number of subjects analysed	55	58
Units: Percentage
number (confidence interval 95%)	76 (65 to 87)	75 (64 to 86)

No statistical analyses for this end point

Secondary: 2 year Progression Free survival (PFS)

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End point title

2 year Progression Free survival (PFS)

End point description

End point type

Secondary

End point timeframe

From the time of study entry until disease progression or death from any cause until 2 years

End point values	Arm A	Arm B	Arm C
Number of subjects analysed	75	69	75
Units: Percentage
number (confidence interval 95%)	36 (31 to 41)	46 (40 to 52)	61 (55 to 67)

No statistical analyses for this end point

Secondary: 2 year overall survival (OS)

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End point title

2 year overall survival (OS)

End point description

End point type

Secondary

End point timeframe

From treatment starts until 2 years after

End point values	Arm A	Arm B	Arm C	Arm D	Arm E
Number of subjects analysed	75	69	75	55	58
Units: Percentage
number (confidence interval 95%)	42 (36 to 48)	56 (50 to 62)	69 (64 to 74)	76 (65 to 87)	75 (64 to 86)

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

From the signature of the informed consent to 30 days after the last dose of the study drug

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

5.1

Reporting group title

Arm A

Reporting group description

Reporting group title

Arm B

Reporting group description

Reporting group title

Arm C

Reporting group description

Reporting group title

Arm D

Reporting group description

Reporting group title

Arm E

Reporting group description

Serious adverse events	Arm A	Arm B	Arm C	Arm D	Arm E
Total subjects affected by serious adverse events
subjects affected / exposed	39 / 75 (52.00%)	38 / 69 (55.07%)	39 / 75 (52.00%)	5 / 55 (9.09%)	10 / 58 (17.24%)
number of deaths (all causes)	56	41	33	30	23
number of deaths resulting from adverse events	7	3	3	0	2
Vascular disorders
Epistaxis
subjects affected / exposed	1 / 75 (1.33%)	1 / 69 (1.45%)	1 / 75 (1.33%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Embolism
subjects affected / exposed	1 / 75 (1.33%)	0 / 69 (0.00%)	0 / 75 (0.00%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral arterial ischemia
subjects affected / exposed	1 / 75 (1.33%)	0 / 69 (0.00%)	0 / 75 (0.00%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hemorrhage, CNS
subjects affected / exposed	0 / 75 (0.00%)	0 / 69 (0.00%)	1 / 75 (1.33%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
Haemorrhage, pulmonary
subjects affected / exposed	0 / 75 (0.00%)	0 / 69 (0.00%)	0 / 75 (0.00%)	0 / 55 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
Thrombosis
subjects affected / exposed	0 / 75 (0.00%)	1 / 69 (1.45%)	0 / 75 (0.00%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Fever
subjects affected / exposed	6 / 75 (8.00%)	1 / 69 (1.45%)	4 / 75 (5.33%)	1 / 55 (1.82%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	6 / 6	1 / 1	2 / 4	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Pain general
subjects affected / exposed	0 / 75 (0.00%)	2 / 69 (2.90%)	1 / 75 (1.33%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
pain abdomen
subjects affected / exposed	0 / 75 (0.00%)	1 / 69 (1.45%)	0 / 75 (0.00%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 75 (0.00%)	0 / 69 (0.00%)	1 / 75 (1.33%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower extremity gait
subjects affected / exposed	0 / 75 (0.00%)	1 / 69 (1.45%)	0 / 75 (0.00%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Multi-organ failure
subjects affected / exposed	0 / 75 (0.00%)	1 / 69 (1.45%)	0 / 75 (0.00%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Pelvic pain
subjects affected / exposed	0 / 75 (0.00%)	0 / 69 (0.00%)	1 / 75 (1.33%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sudden death
subjects affected / exposed	0 / 75 (0.00%)	0 / 69 (0.00%)	1 / 75 (1.33%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
Disease progression
subjects affected / exposed	0 / 75 (0.00%)	1 / 69 (1.45%)	0 / 75 (0.00%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Immune system disorders
Allergy
subjects affected / exposed	0 / 75 (0.00%)	0 / 69 (0.00%)	1 / 75 (1.33%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Respiratory increased
subjects affected / exposed	1 / 75 (1.33%)	0 / 69 (0.00%)	0 / 75 (0.00%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory insufficiency
subjects affected / exposed	0 / 75 (0.00%)	0 / 69 (0.00%)	1 / 75 (1.33%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	3 / 75 (4.00%)	0 / 69 (0.00%)	2 / 75 (2.67%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Mood alteration
subjects affected / exposed	0 / 75 (0.00%)	1 / 69 (1.45%)	0 / 75 (0.00%)	0 / 55 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Confusion
subjects affected / exposed	1 / 75 (1.33%)	0 / 69 (0.00%)	0 / 75 (0.00%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychosis
subjects affected / exposed	0 / 75 (0.00%)	0 / 69 (0.00%)	1 / 75 (1.33%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 75 (0.00%)	1 / 69 (1.45%)	0 / 75 (0.00%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 75 (0.00%)	1 / 69 (1.45%)	0 / 75 (0.00%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular Ischemia
subjects affected / exposed	0 / 75 (0.00%)	2 / 69 (2.90%)	1 / 75 (1.33%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	1 / 1	0 / 0	0 / 0
Seizure
subjects affected / exposed	2 / 75 (2.67%)	4 / 69 (5.80%)	1 / 75 (1.33%)	0 / 55 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 2	3 / 5	2 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 75 (0.00%)	1 / 69 (1.45%)	0 / 75 (0.00%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
cerebellar toxicity
subjects affected / exposed	1 / 75 (1.33%)	2 / 69 (2.90%)	1 / 75 (1.33%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	1 / 1	2 / 2	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
Hydrocephalus
subjects affected / exposed	0 / 75 (0.00%)	0 / 69 (0.00%)	1 / 75 (1.33%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Leukoencephalopathy
subjects affected / exposed	0 / 75 (0.00%)	0 / 69 (0.00%)	1 / 75 (1.33%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	1 / 75 (1.33%)	0 / 69 (0.00%)	0 / 75 (0.00%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	2 / 75 (2.67%)	0 / 69 (0.00%)	0 / 75 (0.00%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sensory neuropathy
subjects affected / exposed	1 / 75 (1.33%)	0 / 69 (0.00%)	0 / 75 (0.00%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Depressed level of consciousness
subjects affected / exposed	1 / 75 (1.33%)	0 / 69 (0.00%)	0 / 75 (0.00%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Pancytopenia
subjects affected / exposed	0 / 75 (0.00%)	1 / 69 (1.45%)	0 / 75 (0.00%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhea
subjects affected / exposed	0 / 75 (0.00%)	2 / 69 (2.90%)	1 / 75 (1.33%)	0 / 55 (0.00%)	2 / 58 (3.45%)
occurrences causally related to treatment / all	0 / 0	2 / 2	1 / 1	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hemorrhoids
subjects affected / exposed	1 / 75 (1.33%)	0 / 69 (0.00%)	0 / 75 (0.00%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mucositis
subjects affected / exposed	0 / 75 (0.00%)	0 / 69 (0.00%)	0 / 75 (0.00%)	0 / 55 (0.00%)	2 / 58 (3.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
Enteritis
subjects affected / exposed	0 / 75 (0.00%)	1 / 69 (1.45%)	0 / 75 (0.00%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea/Vomiting
subjects affected / exposed	0 / 75 (0.00%)	0 / 69 (0.00%)	0 / 75 (0.00%)	0 / 55 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 75 (0.00%)	0 / 69 (0.00%)	0 / 75 (0.00%)	1 / 55 (1.82%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Perforation
subjects affected / exposed	0 / 75 (0.00%)	1 / 69 (1.45%)	0 / 75 (0.00%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal failure
subjects affected / exposed	2 / 75 (2.67%)	3 / 69 (4.35%)	1 / 75 (1.33%)	1 / 55 (1.82%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	2 / 2	3 / 3	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Fracture
subjects affected / exposed	0 / 75 (0.00%)	0 / 69 (0.00%)	0 / 75 (0.00%)	1 / 55 (1.82%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	2 / 75 (2.67%)	1 / 69 (1.45%)	0 / 75 (0.00%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	2 / 2	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Febrile Neutropenia
subjects affected / exposed	8 / 75 (10.67%)	8 / 69 (11.59%)	16 / 75 (21.33%)	1 / 55 (1.82%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	8 / 8	8 / 8	22 / 22	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Viral Encephalitis
subjects affected / exposed	1 / 75 (1.33%)	0 / 69 (0.00%)	0 / 75 (0.00%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	12 / 75 (16.00%)	5 / 69 (7.25%)	5 / 75 (6.67%)	0 / 55 (0.00%)	3 / 58 (5.17%)
occurrences causally related to treatment / all	12 / 12	5 / 5	4 / 5	0 / 0	3 / 3
deaths causally related to treatment / all	6 / 6	2 / 2	0 / 0	0 / 0	1 / 1
Pneumonia
subjects affected / exposed	5 / 75 (6.67%)	6 / 69 (8.70%)	8 / 75 (10.67%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	5 / 5	5 / 7	8 / 8	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	3 / 3	0 / 0	0 / 0	0 / 0
Aspergillosis
subjects affected / exposed	1 / 75 (1.33%)	1 / 69 (1.45%)	0 / 75 (0.00%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections general
subjects affected / exposed	9 / 75 (12.00%)	7 / 69 (10.14%)	15 / 75 (20.00%)	1 / 55 (1.82%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	7 / 9	7 / 10	12 / 16	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cytomegalovirus infection
subjects affected / exposed	0 / 75 (0.00%)	1 / 69 (1.45%)	2 / 75 (2.67%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 75 (1.33%)	0 / 69 (0.00%)	2 / 75 (2.67%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholangitis
subjects affected / exposed	0 / 75 (0.00%)	0 / 69 (0.00%)	0 / 75 (0.00%)	0 / 55 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 75 (0.00%)	0 / 69 (0.00%)	1 / 75 (1.33%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal infection
subjects affected / exposed	0 / 75 (0.00%)	1 / 69 (1.45%)	0 / 75 (0.00%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pseudomonas infection
subjects affected / exposed	0 / 75 (0.00%)	0 / 69 (0.00%)	1 / 75 (1.33%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
ALT increased
subjects affected / exposed	3 / 75 (4.00%)	1 / 69 (1.45%)	0 / 75 (0.00%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	3 / 4	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	1 / 75 (1.33%)	1 / 69 (1.45%)	0 / 75 (0.00%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Creatinine increased
subjects affected / exposed	0 / 75 (0.00%)	0 / 69 (0.00%)	1 / 75 (1.33%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	3 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Arm A	Arm B	Arm C	Arm D	Arm E
Total subjects affected by non serious adverse events
subjects affected / exposed	75 / 75 (100.00%)	68 / 69 (98.55%)	74 / 75 (98.67%)	38 / 55 (69.09%)	49 / 58 (84.48%)
Vascular disorders
Coagulation disorders
subjects affected / exposed	9 / 75 (12.00%)	11 / 69 (15.94%)	7 / 75 (9.33%)	5 / 55 (9.09%)	7 / 58 (12.07%)
occurrences all number	16	18	11	5	7
Nervous system disorders
Neurological toxicity
subjects affected / exposed	13 / 75 (17.33%)	18 / 69 (26.09%)	13 / 75 (17.33%)	10 / 55 (18.18%)	4 / 58 (6.90%)
occurrences all number	34	38	27	10	4
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	66 / 75 (88.00%)	65 / 69 (94.20%)	71 / 75 (94.67%)	9 / 55 (16.36%)	40 / 58 (68.97%)
occurrences all number	187	207	261	9	40
Neutropenia
subjects affected / exposed	68 / 75 (90.67%)	65 / 69 (94.20%)	69 / 75 (92.00%)	7 / 55 (12.73%)	49 / 58 (84.48%)
occurrences all number	129	158	198	7	58
Thrombocytopenia
subjects affected / exposed	67 / 75 (89.33%)	65 / 69 (94.20%)	70 / 75 (93.33%)	2 / 55 (3.64%)	49 / 58 (84.48%)
occurrences all number	177	203	248	2	58
General disorders and administration site conditions
Fatigue
subjects affected / exposed	4 / 75 (5.33%)	0 / 69 (0.00%)	0 / 75 (0.00%)	6 / 55 (10.91%)	0 / 58 (0.00%)
occurrences all number	5	0	0	6	0
Pain
subjects affected / exposed	0 / 75 (0.00%)	0 / 69 (0.00%)	3 / 75 (4.00%)	0 / 55 (0.00%)	4 / 58 (6.90%)
occurrences all number	0	0	6	0	4
Fever
subjects affected / exposed	0 / 75 (0.00%)	0 / 69 (0.00%)	0 / 75 (0.00%)	0 / 55 (0.00%)	4 / 58 (6.90%)
occurrences all number	0	0	0	0	4
Immune system disorders
Allergic reaction
subjects affected / exposed	0 / 75 (0.00%)	2 / 69 (2.90%)	7 / 75 (9.33%)	0 / 55 (0.00%)	0 / 58 (0.00%)
occurrences all number	0	6	10	0	0
Ear and labyrinth disorders
Hearing impairment
subjects affected / exposed	0 / 75 (0.00%)	0 / 69 (0.00%)	0 / 75 (0.00%)	4 / 55 (7.27%)	0 / 58 (0.00%)
occurrences all number	0	0	0	4	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	13 / 75 (17.33%)	22 / 69 (31.88%)	50 / 75 (66.67%)	1 / 55 (1.82%)	19 / 58 (32.76%)
occurrences all number	16	44	30	1	19
Nausea/Vomiting
subjects affected / exposed	13 / 75 (17.33%)	29 / 69 (42.03%)	30 / 75 (40.00%)	7 / 55 (12.73%)	16 / 58 (27.59%)
occurrences all number	20	68	61	7	16
Stomatisis/Mucositis
subjects affected / exposed	18 / 75 (24.00%)	20 / 69 (28.99%)	20 / 75 (26.67%)	2 / 55 (3.64%)	30 / 58 (51.72%)
occurrences all number	23	41	46	2	30
Hepatobiliary disorders
Hepatotoxicity
subjects affected / exposed	41 / 75 (54.67%)	42 / 69 (60.87%)	39 / 75 (52.00%)	4 / 55 (7.27%)	19 / 58 (32.76%)
occurrences all number	97	104	97	4	19
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	18 / 75 (24.00%)	22 / 69 (31.88%)	28 / 75 (37.33%)	16 / 55 (29.09%)	17 / 58 (29.31%)
occurrences all number	18	22	28	16	17
Erithema
subjects affected / exposed	0 / 75 (0.00%)	0 / 69 (0.00%)	0 / 75 (0.00%)	7 / 55 (12.73%)	0 / 58 (0.00%)
occurrences all number	0	0	0	7	0
Renal and urinary disorders
Nephrotoxicity
subjects affected / exposed	14 / 75 (18.67%)	18 / 69 (26.09%)	11 / 75 (14.67%)	2 / 55 (3.64%)	6 / 58 (10.34%)
occurrences all number	31	35	20	2	6
Infections and infestations
Infections
subjects affected / exposed	22 / 75 (29.33%)	18 / 69 (26.09%)	28 / 75 (37.33%)	0 / 55 (0.00%)	13 / 58 (22.41%)
occurrences all number	22	18	32	0	13

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Were there any global substantial amendments to the protocol? Yes

31 Aug 2009

Amendment N. 1 The main purposes of this amendment were: • A section on monitoring and audit has been added. • A section on “Publication policy” has been modified. • A pregnancy test has been added to the work-up procedures. • Anonymization procedures have been included. • The use of PET in staging procedures has been better specified

06 Jul 2011

Amendment N. 2 In the section Statistical Design and Sample Size, the wording The A’Hern-Fleming Single stage Phase II design was used was reported. It has been better specified that the clinical trial design used to assess the effectiveness of treatment is a "single-stage" design, meaning that all participants are enrolled and observed for a fixed period before an assessment of the treatment's efficacy is made. The "A'Hern-Fleming" part refers to the statistical methods used to analyze the data and make decisions about whether the treatment is promising enough to warrant further investigation in larger, more definitive phase III trials.

02 Jan 2013

Amendment N. 4 The statistical design for the second randomisation was reviewed to optimise power and precision of the estimates after the first 100 patients were enrolled. The design of the study was not changed. Accordingly, 52 patients per arm at the second randomisation were needed, and a new sample size for trial registration was estimated to be more than 200 patients.

30 Oct 2015

Amendment N. 6 This amendment included the following changes: • Modification of an inclusion criterion regarding the hepatic function • Change of definition of lethal SAE

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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