Download PDF

Clinical Trial Results:
EWING 2008

Summary
EudraCT number	2008-003658-13
Trial protocol	DE AT BE NL SE HU FI LT PL
Global end of trial date	30 Jun 2019

Results information
Results version number	v1(current)
This version publication date	12 Jan 2020
First version publication date	12 Jan 2020
Other versions

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

EWING2008

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Other trial identifiers

ClinicalTrials.gov: NCT00824083

Sponsor organisation name

Universitätsklinikum Münster

Sponsor organisation address

Albert-Schweitzer-Campus 1, Gebäude D5, Münster, Germany, 48149

Public contact

EWING 2008 Trial Office, Universitätsklinikum Münster, 49 2017238082, ewing@uk-essen.de

Scientific contact

EWING 2008 Trial Office, Universitätsklinikum Münster, 49 2017238082, ewing@uk-essen.de

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?

Yes

Analysis stage

Final

Date of interim/final analysis

30 Jun 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

30 Jun 2019

Global end of trial reached?

Yes

Global end of trial date

30 Jun 2019

Was the trial ended prematurely?

Main objective of the trial

Randomised trial to test for superiority regarding event-free survival (EFS) Standard Risk R1: in localised Ewing tumour (ET) with good histological response or initial tumour volume <200ml: fenretinide or bisphosphonates or bisphosphonates+fenretinide add-on to induction and maintenance chemotherapy versus no add-on treatment. High Risk R2: in localised Ewing tumour with unfavourable histological response or tumour volume>200ml (R2loc): busulfan/melphalan high dose chemotherapy (HDT) and autologous stem cell reinfusion versus standard chemotherapy. In pulmonary metastases: busulfan/melphalan HDT and autologous stem cell reinfusion (SCT) versus standard chemotherapy plus whole lung irradiation (R2pulm). Very High Risk R3: in primary disseminated disease: treosulfan-melphalan HDT and autologous SCT add-on to 8 cycles of standard adjuvant chemotherapy versus 8 cycles of standard adjuvant chemotherapy alone.

Protection of trial subjects

This study is conducted in accordance with applicable laws and regulations including, but not limited to, the ethical principles that have their origins in the Declaration of Helsinki and the International Conference on Harmonisation Guideline for Good Clinical Practice (GCP). Before any subjects are enrolled competent authorities and ethics committees concerned must grant authorisation and approval of this clinical trial. Before any procedures specified in this protocol are performed, the subject or subject’s parent(s)/legal guardian must sign and date the approved informed consent form according to requirements stated in national law.

Background therapy

Sufficient hydration (~ 2-3 L/m²/d), with appropriate electrolyte supplementation, during chemotherapy. Antiemetic therapy was administered according to institutional policy, e.g., ondansetron 5 mg/m² BSA (maximum single dose 8 mg) orally or IV every 12 hours for 5 days. Radiation of Blood Products: Due to the risk of graft-versus-host reactions in patients under chemotherapy, especially in case of high-dose therapy, all blood products (except fresh frozen plasma) were irradiated with at least 20 Gy prior to transfusion, according to national policies. The use of leukocyte filters for leukocyte depletion (CMV negativity) was advised. Red blood cells: Haemoglobin should be kept above 6 g/dl (haematocrit above 20 %). Platelets: Platelet substitution was advised when platelets are <10,000/μL or with clinical evidence of bleeding. Central Lines: The use of central lines was strongly recommended. In HDT patients, multi-lumen central lines should be used for PBPC sampling and supportive care. Pneumocystis carinii prophylaxis according to the recommendations of the national groups was mandatory. Treatment of Infections (especially neutropenic infection) according to accepted general principles of supportive care.

Evidence for comparator

EWING 2008 is a phase 3, open label, multi-centre, randomised controlled trial of international study groups with the intention of optimising treatment and treatment results in patients with localised and advanced Ewing sarcomas. The primary objective was to assess whether either of the randomised treatments is superior regarding 3-year event-free survival. The treatment was stratified according to prognostic factors as determined by previous studies. All patients received VIDE chemotherapy as induction treatment. Disease assessment was performed prior to treatment and after the 2nd (latest 3rd) and 5th (latest 6th) cycle of VIDE chemotherapy. Depending on the presentation at the time of diagnosis and on the histological response to induction chemotherapy, patients were stratified into to the risk groups.

Actual start date of recruitment

01 Oct 2009

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy, Safety

Long term follow-up duration

5 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 81

Country: Number of subjects enrolled

Poland: 8

Country: Number of subjects enrolled

Sweden: 19

Country: Number of subjects enrolled

Austria: 57

Country: Number of subjects enrolled

Belgium: 38

Country: Number of subjects enrolled

Czech Republic: 41

Country: Number of subjects enrolled

Finland: 7

Country: Number of subjects enrolled

Germany: 585

Country: Number of subjects enrolled

Hungary: 21

Country: Number of subjects enrolled

Lithuania: 1

Country: Number of subjects enrolled

Switzerland: 19

Country: Number of subjects enrolled

Australia: 30

Worldwide total number of subjects

907

EEA total number of subjects

858

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)

251

Adolescents (12-17 years)

399

Adults (18-64 years)

257

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

The patients were recruited from 120 trial sites in 12 countries. The recruitment period was from October 2009 to March 2018.

Screening details

The study included patients with histologically confirmed Ewing sarcoma of bone or soft tissue, either sex and age > 48 months (for Germany) and < 50 years at the date of diagnostic biopsy.

Number of subjects started

907

Number of subjects completed

441

Reason: Number of subjects

Other: 85

Reason: Number of subjects

Medical contraindication/toxicity: 47

Reason: Number of subjects

Organisational reasons: 40

Reason: Number of subjects

Progress: 20

Reason: Number of subjects

Not available: 2

Reason: Number of subjects

Consent withdrawn by patient/parents: 172

Reason: Number of subjects

Physician decision: 100

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

R1 Add-on

Arm description

Patients with localised disease and good histological response at surgery after induction chemotherapy and patients with initial surgery or in whom surgery was not feasible and who have small tumours < 200 mL at diagnosis were included in the risk group Standard Risk R1. Patients who were randomized into the R1 Add-on arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by 8 cycles of either VAI (vincristine, actinomycin-D, ifosfamide) or VAC (vincristine, actinomycin-D, cyclophosphamide). In addition to induction and maintenance chemotherapy, patients were treated with zoledronic acid (Add-on treatment).

Arm type

Experimental

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

VIDE chemotherapy (cycles 1-6 at 21-day intervals): Vincristine is given on day 1 in a dose of 1.5 mg/m²/d per cycle. VAI chemotherapy (cycles 7-14 at 21-day intervals): Vincristine is given on day 1 in a dose of 1.5 mg/m²/d per cycle. VAC chemotherapy (cycles 7-14 at 21-day intervals): Vincristine is given on day 1 in a dose of 1.5 mg/m²/d per cycle.

Investigational medicinal product name

Ifosfamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

VIDE chemotherapy (cycles 1-6 at 21-day intervals): Ifosfamide is given on day 1,2 and 3 in a dose of 3.0 g/m²/d per cycle. VAI chemotherapy (cycles 7-14 at 21-day intervals): Ifosfamide is given on day 1 and 2 in a dose of 3.0 g/m²/d per cycle.

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

VIDE chemotherapy (cycles 1-6 at 21-day intervals): Doxorubicin is given on day 1, 2 an 3 in a dose of 20 mg/m²/d per cycle.

Investigational medicinal product name

Etoposide

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

VIDE chemotherapy (cycles 1-6 at 21-day intervals): Etoposide is given on day 1, 2 an 3 in a dose of 150 mg/m²/d per cycle.

Investigational medicinal product name

Actinomycin D

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for injection

Routes of administration

Intravenous use

Dosage and administration details

VAI chemotherapy (cycles 7-14 at 21-day intervals): Actinomycin D is given on day 1 and 2 in a dose of 1.5 mg/m²/d per cycle. VAC chemotherapy (cycles 7-14 at 21-day intervals): Actinomycin D is given on day 1 and 2 in a dose of 1.5 mg/m²/d per cycle.

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

VAC chemotherapy (cycles 7-14 at 21-day intervals):Cyclophosphamide is given on day 1 in a dose of 1500 mg/m²/d per cycle.

Investigational medicinal product name

Zoledronic acid

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection

Routes of administration

Intracavernous use

Dosage and administration details

Patients randomised for zoledronic acid received zoledronic acid at 28-day intervals beginning with cycle 6 of VAC/VAI consolidation chemotherapy (cycle 12 from start of chemotherapy) for a maximum of nine cycles. Patients < 18 years received 0.05 mg/kg BW by IV infusion 30 min-1 h. In patients >= 18 years zoledronic acid was dosed according to body weight: Patients > 40kg received 4 mg by IV infusion 30 min–1 h. Patients 20-40 kg received 2 mg by IV infusion 30 min–1 h.

R1 No Add-on

Arm description

Patients with localised disease and good histological response at surgery after induction chemotherapy and patients with initial surgery or in whom surgery was not feasible and who have small tumours < 200 mL at diagnosis were included in the risk group Standard Risk R1. Patients who were randomized into the R1 No Add-on arm received only 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by 8 cycles of either VAI (vincristine, actinomycin-D, Ifosfamide) or VAC (vincristine, actinomycin-D, Cyclophosphamide). No additional treatment with zoledronic acid was administered to the patients (No Add-on treatment).

Arm type

Active comparator

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Ifosfamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

VIDE chemotherapy (cycles 1-6 at 21-day intervals): Doxorubicin is given on day 1, 2 an 3 in a dose of 20 mg/m²/d per cycle.

Investigational medicinal product name

Etoposide

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

VIDE chemotherapy (cycles 1-6 at 21-day intervals): Etoposide is given on day 1, 2 an 3 in a dose of 150 mg/m²/d per cycle.

Investigational medicinal product name

Actinomycin D

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for injection

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

VAC chemotherapy (cycles 7-14 at 21-day intervals):Cyclophosphamide is given on day 1 in a dose of 1500 mg/m²/d per cycle.

R2loc VAI

Arm description

Patients with localised disease and poor histological response at surgery after induction chemotherapy and patients with initial surgery or in whom surgery was not feasible and who have large tumours > 200 mL at diagnosis were included in the risk group High Risk localised disease R2loc. Patients who were randomized into the R2loc VAI arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by 8 cycles of standard chemotherapy VAI (vincristine, actinomycin-D, ifosfamide).

Arm type

Active comparator

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Ifosfamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

VIDE chemotherapy (cycles 1-6 at 21-day intervals): Doxorubicin is given on day 1, 2 an 3 in a dose of 20 mg/m²/d per cycle.

Investigational medicinal product name

Etoposide

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

VIDE chemotherapy (cycles 1-6 at 21-day intervals): Etoposide is given on day 1, 2 an 3 in a dose of 150 mg/m²/d per cycle.

Investigational medicinal product name

Actinomycin D

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for injection

Routes of administration

Intravenous use

Dosage and administration details

VAI chemotherapy (cycles 7-14 at 21-day intervals): Actinomycin D is given onday 1 and 2 in a dose of 1.5 mg/m²/d per cycle.

R2loc Bu-Mel

Arm description

Patients with localised disease and poor histological response at surgery after induction chemotherapy and patients with initial surgery or in whom surgery was not feasible and who have large tumours > 200 mL at diagnosis were included in the risk group High Risk localised disease R2loc. Patients who were randomized into the R2loc Bu-Mel arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by high-dose chemotherapy using busulfan-melphalan with autologous stem cell reinfusion.

Arm type

Experimental

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

VIDE chemotherapy (cycles 1-6 at 21-day intervals): Vincristine is given on day 1 in a dose of 1.5 mg/m²/d per cycle.

Investigational medicinal product name

Ifosfamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

VIDE chemotherapy (cycles 1-6 at 21-day intervals): Ifosfamide is given on day 1,2 and 3 in a dose of 3.0 g/m²/d per cycle.

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

VIDE chemotherapy (cycles 1-6 at 21-day intervals): Doxorubicin is given on day 1, 2 an 3 in a dose of 20 mg/m²/d per cycle.

Investigational medicinal product name

Etoposide

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

VIDE chemotherapy (cycles 1-6 at 21-day intervals): Etoposide is given on day 1, 2 an 3 in a dose of 150 mg/m²/d per cycle.

Investigational medicinal product name

Busulfan

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Busulfan–Melphalan High-Dose Chemotherapy with autologous stem cell reinfusion (cycle 8): Busulfan is given on day -6, -5, -4 and -3 before Stem cell reinfusion. Adults: 0.8 mg/kg body weight (BW), children and adolescents: <9 kg = 1 mg/kg BW, 9-<16 kg = 1.2 mg/kg BW, 16-23 kg = 1.1 mg/kg BW, >23-34 kg = 0.95 mg/kg BW, >34 kg = 0.8 mg/kg BW.

Investigational medicinal product name

Melphalan

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Busulfan–Melphalan High-Dose Chemotherapy with autologous stem cell reinfusion (cycle 8): Melphalan is given on day -2 before Stem cell reinfusion (140 mg/m² IV infusion, 30 min.).

Investigational medicinal product name

Adult haematopoietic stem cells

Investigational medicinal product code

Other name

Autologous adult haematopoietic stem cells

Pharmaceutical forms

Suspension for injection

Routes of administration

Intravenous use

Dosage and administration details

Busulfan–Melphalan High-Dose Chemotherapy with autologous stem cell reinfusion (cycle 8): Stem cell reinfusion (min. 3 x 1000000/kg CD 34+) after busulfan–melphalan Treatment (d 0).

R2pulm VAI

Arm description

Patients with a Ewing sarcoma metastatic to the lungs and/or pleura, but not to any other sites, at the time of diagnosis were included in the risk group High Risk primary lung metastases R2pulm. Patients who were randomized into the R2pulm VAI arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by 8 cycles of standard chemotherapy VAI (vincristine, actinomycin-D, ifosfamide) plus whole lung irradiation.

Arm type

Active comparator

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Ifosfamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

VIDE chemotherapy (cycles 1-6 at 21-day intervals): Doxorubicin is given on day 1, 2 an 3 in a dose of 20 mg/m²/d per cycle.

Investigational medicinal product name

Etoposide

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

VIDE chemotherapy (cycles 1-6 at 21-day intervals): Etoposide is given on day 1, 2 an 3 in a dose of 150 mg/m²/d per cycle.

Investigational medicinal product name

Actinomycin D

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for injection

Routes of administration

Intravenous use

Dosage and administration details

VAI chemotherapy (cycles 7-14 at 21-day intervals): Actinomycin D is given on day 1 and 2 in a dose of 1.5 mg/m²/d per cycle.

R2pulm Bu-Mel

Arm description

Patients with a Ewing sarcoma metastatic to the lungs and/or pleura, but not to any other sites, at the time of diagnosis were included in the risk group High Risk primary lung metastases R2pulm. Patients who were randomized into the R2pulm Bu-Mel arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by high dose busulfan-melphalan chemotherapy with autologous stem cell reinfusion.

Arm type

Experimental

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

VIDE chemotherapy (cycles 1-6 at 21-day intervals): Vincristine is given on day 1 in a dose of 1.5 mg/m²/d per cycle.

Investigational medicinal product name

Ifosfamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

VIDE chemotherapy (cycles 1-6 at 21-day intervals): Ifosfamide is given on day 1,2 and 3 in a dose of 3.0 g/m²/d per cycle.

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

VIDE chemotherapy (cycles 1-6 at 21-day intervals): Doxorubicin is given on day 1, 2 an 3 in a dose of 20 mg/m²/d per cycle.

Investigational medicinal product name

Etoposide

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

VIDE chemotherapy (cycles 1-6 at 21-day intervals): Etoposide is given on day 1, 2 an 3 in a dose of 150 mg/m²/d per cycle.

Investigational medicinal product name

Busulfan

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Melphalan

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Busulfan–Melphalan High-Dose Chemotherapy with autologous stem cell reinfusion (cycle 8): Melphalan is given on day -2 before Stem cell reinfusion (140 mg/m² IV infusion, 30 min.).

Investigational medicinal product name

Adult haematopoietic stem cells

Investigational medicinal product code

Other name

Autologous adult haematopoietic stem cells

Pharmaceutical forms

Suspension for injection

Routes of administration

Intravenous use

Dosage and administration details

Busulfan–Melphalan High-Dose Chemotherapy with autologous stem cell reinfusion (cycle 8): Stem cell reinfusion (min. 3 x 1000000/kg CD 34+) after busulfan–melphalan Treatment (d 0).

R3 VAC

Arm description

Patients with metastatic disease not confined to the lungs and/or pleura, i.e. patients with bone metastases, bone marrow metastases or other metastases (e.g. lymph nodes, liver, CNS, etc) with and without additional pulmonary metastases at the time of diagnosis were included in the risk group Very High Risk R3. Patients who were randomized into the R3 VAC arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by 8 cycles of VAC (vincristine, actinomycin-D, cyclophosphamide).

Arm type

Active comparator

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

VIDE chemotherapy (cycles 1-6 at 21-day intervals): Vincristine is given on day 1 in a dose of 1.5 mg/m²/d per cycle. VAC chemotherapy (cycles 7-14 at 21-day intervals): Vincristine is given on day 1 in a dose of 1.5 mg/m²/d per cycle.

Investigational medicinal product name

Ifosfamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

VIDE chemotherapy (cycles 1-6 at 21-day intervals): Ifosfamide is given on day 1,2 and 3 in a dose of 3.0 g/m²/d per cycle.

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

VIDE chemotherapy (cycles 1-6 at 21-day intervals): Doxorubicin is given on day 1, 2 an 3 in a dose of 20 mg/m²/d per cycle.

Investigational medicinal product name

Etoposide

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

VIDE chemotherapy (cycles 1-6 at 21-day intervals): Etoposide is given on day 1, 2 an 3 in a dose of 150 mg/m²/d per cycle.

Investigational medicinal product name

Actinomycin D

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for injection

Routes of administration

Intravenous use

Dosage and administration details

VAC chemotherapy (cycles 7-14 at 21-day intervals): Actinomycin D is given on day 1 and 2 in a dose of 1.5 mg/m²/d per cycle.

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

VAC chemotherapy (cycles 7-14 at 21-day intervals):Cyclophosphamide is given on day 1 in a dose of 1500 mg/m²/d per cycle.

R3 Treo-Mel

Arm description

Patients with metastatic disease not confined to the lungs and/or pleura, i.e. patients with bone metastases, bone marrow metastases or other metastases (e.g. lymph nodes, liver, CNS, etc) with and without additional pulmonary metastases at the time of diagnosis were included in the risk group Very High Risk R3. Patients who were randomized into the R3 Treo-Mel arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by high dose chemotherapy using treosulfan-melphalan and autologous stem cell reinfusion.

Arm type

Experimental

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

VIDE chemotherapy (cycles 1-6 at 21-day intervals): Vincristine is given on day 1 in a dose of 1.5 mg/m²/d per cycle.

Investigational medicinal product name

Ifosfamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

VIDE chemotherapy (cycles 1-6 at 21-day intervals): Ifosfamide is given on day 1,2 and 3 in a dose of 3.0 g/m²/d per cycle.

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

VIDE chemotherapy (cycles 1-6 at 21-day intervals): Doxorubicin is given on day 1, 2 an 3 in a dose of 20 mg/m²/d per cycle.

Investigational medicinal product name

Etoposide

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

VIDE chemotherapy (cycles 1-6 at 21-day intervals): Etoposide is given on day 1, 2 an 3 in a dose of 150 mg/m²/d per cycle.

Investigational medicinal product name

Treosulfan

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Treosulfan–Melphalan High-Dose Chemotherapy with autologous stem cell reinfusion: Treosulfan (12 g/m²/dose IV infusion, 2 hours) is given on day -5, -4 and -3 before Stem cell reinfusion.

Investigational medicinal product name

Melphalan

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Treosulfan–Melphalan High-Dose Chemotherapy with autologous stem cell reinfusion (cycle 8): Melphalan is given on day -2 before Stem cell reinfusion (140 mg/m² IV infusion, 30 min.).

Investigational medicinal product name

Adult haematopoietic stem cells

Investigational medicinal product code

Other name

Autologous adult haematopoietic stem cells

Pharmaceutical forms

Suspension for injection

Routes of administration

Intravenous use

Dosage and administration details

Treosulfan–Melphalan High-Dose Chemotherapy with autologous stem cell reinfusion (cycle 8): Stem cell reinfusion (min. 3 x 1000000/kg CD 34+) after treosulfan–melphalan Treatment (d 0).

Number of subjects in period 1 ^[1]	R1 Add-on	R1 No Add-on	R2loc VAI	R2loc Bu-Mel	R2pulm VAI	R2pulm Bu-Mel	R3 VAC	R3 Treo-Mel
Started	142	142	12	14	11	11	54	55
Completed	101	135	11	7	10	8	46	41
Not completed	41	7	1	7	1	3	8	14
Protocol deviation	41	7	1	7	1	3	8	14

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: 907 patients were eligible for the study and therefore study patients. Since 466 patients were not eligible for randomization or could not be randomized, only 441 started the randomized study. These patients are reported in the baseline period.

Baseline characteristics

Top of page

Reporting group title

R1 Add-on

Reporting group description

Reporting group title

R1 No Add-on

Reporting group description

Patients with localised disease and good histological response at surgery after induction chemotherapy and patients with initial surgery or in whom surgery was not feasible and who have small tumours < 200 mL at diagnosis were included in the risk group Standard Risk R1. Patients who were randomized into the R1 No Add-on arm received only 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by 8 cycles of either VAI (vincristine, actinomycin-D, Ifosfamide) or VAC (vincristine, actinomycin-D, Cyclophosphamide). No additional treatment with zoledronic acid was administered to the patients (No Add-on treatment).

Reporting group title

R2loc VAI

Reporting group description

Reporting group title

R2loc Bu-Mel

Reporting group description

Patients with localised disease and poor histological response at surgery after induction chemotherapy and patients with initial surgery or in whom surgery was not feasible and who have large tumours > 200 mL at diagnosis were included in the risk group High Risk localised disease R2loc. Patients who were randomized into the R2loc Bu-Mel arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by high-dose chemotherapy using busulfan-melphalan with autologous stem cell reinfusion.

Reporting group title

R2pulm VAI

Reporting group description

Reporting group title

R2pulm Bu-Mel

Reporting group description

Patients with a Ewing sarcoma metastatic to the lungs and/or pleura, but not to any other sites, at the time of diagnosis were included in the risk group High Risk primary lung metastases R2pulm. Patients who were randomized into the R2pulm Bu-Mel arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by high dose busulfan-melphalan chemotherapy with autologous stem cell reinfusion.

Reporting group title

R3 VAC

Reporting group description

Reporting group title

R3 Treo-Mel

Reporting group description

Patients with metastatic disease not confined to the lungs and/or pleura, i.e. patients with bone metastases, bone marrow metastases or other metastases (e.g. lymph nodes, liver, CNS, etc) with and without additional pulmonary metastases at the time of diagnosis were included in the risk group Very High Risk R3. Patients who were randomized into the R3 Treo-Mel arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by high dose chemotherapy using treosulfan-melphalan and autologous stem cell reinfusion.

Reporting group values	R1 Add-on	R1 No Add-on	R2loc VAI	R2loc Bu-Mel	R2pulm VAI	R2pulm Bu-Mel	R3 VAC	R3 Treo-Mel	Total
Number of subjects	142	142	12	14	11	11	54	55	441
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0	0	0
Children (2-11 years)	59	48	1	4	0	3	12	13	140
Adolescents (12-17 years)	50	66	6	3	5	5	24	23	182
Adults (18-64 years)	33	28	5	7	6	3	18	19	119
From 65-84 years	0	0	0	0	0	0	0	0	0
85 years and over	0	0	0	0	0	0	0	0	0
Gender categorical
Units: Subjects
Female	60	66	5	4	3	3	31	24	196
Male	82	76	7	10	8	8	23	31	245

End points

Top of page

Reporting group title

R1 Add-on

Reporting group description

Reporting group title

R1 No Add-on

Reporting group description

Patients with localised disease and good histological response at surgery after induction chemotherapy and patients with initial surgery or in whom surgery was not feasible and who have small tumours < 200 mL at diagnosis were included in the risk group Standard Risk R1. Patients who were randomized into the R1 No Add-on arm received only 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by 8 cycles of either VAI (vincristine, actinomycin-D, Ifosfamide) or VAC (vincristine, actinomycin-D, Cyclophosphamide). No additional treatment with zoledronic acid was administered to the patients (No Add-on treatment).

Reporting group title

R2loc VAI

Reporting group description

Reporting group title

R2loc Bu-Mel

Reporting group description

Patients with localised disease and poor histological response at surgery after induction chemotherapy and patients with initial surgery or in whom surgery was not feasible and who have large tumours > 200 mL at diagnosis were included in the risk group High Risk localised disease R2loc. Patients who were randomized into the R2loc Bu-Mel arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by high-dose chemotherapy using busulfan-melphalan with autologous stem cell reinfusion.

Reporting group title

R2pulm VAI

Reporting group description

Reporting group title

R2pulm Bu-Mel

Reporting group description

Patients with a Ewing sarcoma metastatic to the lungs and/or pleura, but not to any other sites, at the time of diagnosis were included in the risk group High Risk primary lung metastases R2pulm. Patients who were randomized into the R2pulm Bu-Mel arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by high dose busulfan-melphalan chemotherapy with autologous stem cell reinfusion.

Reporting group title

R3 VAC

Reporting group description

Reporting group title

R3 Treo-Mel

Reporting group description

Patients with metastatic disease not confined to the lungs and/or pleura, i.e. patients with bone metastases, bone marrow metastases or other metastases (e.g. lymph nodes, liver, CNS, etc) with and without additional pulmonary metastases at the time of diagnosis were included in the risk group Very High Risk R3. Patients who were randomized into the R3 Treo-Mel arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by high dose chemotherapy using treosulfan-melphalan and autologous stem cell reinfusion.

Subject analysis set title

R1 Add-on (First interim analysis)

Subject analysis set type

Full analysis

Subject analysis set description

The first interim analysis was performed after observing 17 events of 121 randomized patients in the Add-on group.

Subject analysis set title

R1 No Add-on (First interim analysis)

Subject analysis set type

Full analysis

Subject analysis set description

The first interim analysis was performed after observing 16 events of 121 randomized patients in the no Add-on group.

Subject analysis set title

R3 VAC (First interim analysis)

Subject analysis set type

Full analysis

Subject analysis set description

The first interim analysis was performed after observing 19 events of 32 randomized patients in the R3 VAC Group.

Subject analysis set title

R3 Treo-Mel (First interim analysis)

Subject analysis set type

Full analysis

Subject analysis set description

The first interim analysis was performed after observing 9 events of 30 randomized patients in the R3 Treo-Mel Group.

Subject analysis set title

R1 Add-on (Per protocol)

Subject analysis set type

Per protocol

Subject analysis set description

The per protocol collective is defined as all R1 Add-on patients completing the study without major protocol deviations.

Subject analysis set title

R1 No Add-on (Per protocol)

Subject analysis set type

Per protocol

Subject analysis set description

The per protocol collective is defined as all R1 No Add-on patients completing the study without major protocol deviations.

Subject analysis set title

R3 VAC (Per Protocol)

Subject analysis set type

Per protocol

Subject analysis set description

The per protocol collective is defined as all R3 VAC patients completing the study without major protocol deviations.

Subject analysis set title

R3 Treo-Mel (Per protocol)

Subject analysis set type

Per protocol

Subject analysis set description

The per protocol collective is defined as all R3 Treo-Mel patients completing the study without major protocol deviations.

Primary: R1: Event-free survival (EFS)

Top of page

End point title

R1: Event-free survival (EFS) ^[1]

End point description

The primary endpoint of event-free survival (EFS) was estimated according to the method of Kaplan and Meier (1958). EFS time starts at the date of randomisation and ends at the date of first event (progression of disease, relapse of disease, diagnosis of secondary malignancy, or death of the patient irrespective of its cause) or at the date of the patient's most recent consultation. Patients lost to follow-up without event were censored at the date of their last consultation. Progression of disease is defined as recurrent disease under active oncological therapy. Relapse of disease is defined as recurrent disease in patients with complete clinical remission after completion of active oncological therapy. The Primary Analysis was performed according to the Intention-to-treat (ITT) principle in the full analysis set.

End point type

Primary

End point timeframe

From randomisation to first event or last follow-up in case of no event.

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The R2 randomization of the EURO-E.W.I.N.G. 99 trial was continued in the EWING2008 Trial. The EWING2008 R2 data were transferred to the EURO-E.W.I.N.G. 99 data center and was analyzed by the EURO-E.W.I.N.G. Group. The results were already published (see online references).

End point values	R1 Add-on	R1 No Add-on	R1 Add-on (First interim analysis)	R1 No Add-on (First interim analysis)	R1 Add-on (Per protocol)	R1 No Add-on (Per protocol)
Number of subjects analysed	142	142	121	121	101	135
Units: Events	22	30	17	16	14	28

Final analysis (superiority)

Statistical analysis description

Because the number of the initially planned number of events (n=146) could not be reached, an adaptive design change was performed based on the data from the 1st interim analysis, according to which only an additional analysis is planned. The conditional rejection error probability (CREP) (Müller & Schäfer 2001) was calculated for each direction of the null hypothesis (superiority of Add-on ϵ+=0.0086 and inferiority of Add-on ϵ-=0.0126). The CREPs were used as new local significance levels.

Comparison groups

R1 Add-on v R1 No Add-on

Number of subjects included in analysis

284

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

= 0.0242 ^[3]

Method

Increment of the logrank test statistic

Parameter type

Hazard ratio (HR)

Point estimate

0.735

Confidence interval

level

95%

sides

2-sided

lower limit

0.424

upper limit

1.275

Notes
[2] - In the final analysis the one-sided null hypotheses was tested by calculating the approximately normally distributed independent increment of the logrank test statistic. The independent increment of the logrank test statistic was -1.0987, leading to the one-sided single-stage p-values p_end+=0.0242> 0.0086=ϵ+ and p_end-=0.9758> 0.0126=ϵ-.
[3] - The independent increment of the logrank test statistic was -1.0987, leading to the one-sided single-stage p-values p_end+=0.0242> 0.0086=ϵ+ and p_end-=0.9758> 0.0126=ϵ-.

First interim analysis

Statistical analysis description

The primary endpoint is event-free survival (EFS) starts at the date of randomization and ends at the date of first compound event (progression of disease, relapse of disease, diagnosis of secondary malignancy, or death of the patient irrespective of its cause) or at the date of the patient's most recent consultation. The EFS was analyzed using the intention-to-treat principle in the full-analysis set. A multiple type 1 error rate (significance level) of α = 5% (two-sided) was controlled.

Comparison groups

R1 Add-on (First interim analysis) v R1 No Add-on (First interim analysis)

Number of subjects included in analysis

242

Analysis specification

Pre-specified

Analysis type

superiority ^[4]

P-value

= 0.9058 ^[5]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.042

Confidence interval

level

95%

sides

2-sided

lower limit

0.526

upper limit

2.064

Notes
[4] - An adaptive two-sided group sequential design with four equally weighted stages using an inverse normal combination function and O’Brien & Fleming boundaries was applied (Wassmer 2006, O’Brien & Fleming 1979). The first interim analysis was performed based on data from 20 March 2017 after observing 33 events.
[5] - Stage I two-sided p-value is reported. Stage I p-value (one-sided) for superiority (H1: HR < 1) p=0.5471 and for inferiority (H1: HR > 1) p=0.4529.

Final analysis (inferiority)

Statistical analysis description

Comparison groups

R1 Add-on v R1 No Add-on

Number of subjects included in analysis

284

Analysis specification

Pre-specified

Analysis type

other ^[6]

P-value

= 0.0126 ^[7]

Method

Increment of the logrank test statistic

Parameter type

Hazard ratio (HR)

Point estimate

0.735

Confidence interval

level

95%

sides

2-sided

lower limit

0.424

upper limit

1.275

Notes
[6] - In the final analysis the one-sided null hypotheses was tested by calculating the approximately normally distributed independent increment of the logrank test statistic. The independent increment of the logrank test statistic was -1.0987, leading to the one-sided single-stage p-values p_end+=0.0242> 0.0086=ϵ+ and p_end-=0.9758> 0.0126=ϵ-.
[7] - The independent increment of the logrank test statistic was -1.0987, leading to the one-sided single-stage p-values p_end+=0.0242> 0.0086=ϵ+ and p_end-=0.9758> 0.0126=ϵ-.

Final analysis (Per protocol)

Comparison groups

R1 Add-on (Per protocol) v R1 No Add-on (Per protocol)

Number of subjects included in analysis

236

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1794

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.65

Confidence interval

level

95%

sides

2-sided

lower limit

0.34

upper limit

1.23

Primary: R3 trial: Event-free survival (EFS)

Top of page

End point title

R3 trial: Event-free survival (EFS) ^[8]

End point description

End point type

Primary

End point timeframe

From randomisation to first event or last follow-up in case of no event.

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The R2 randomization of the EURO-E.W.I.N.G. 99 trial was continued in the EWING2008 Trial. The EWING2008 R2 data were transferred to the EURO-E.W.I.N.G. 99 data center and was analyzed by the EURO-E.W.I.N.G. Group. The results were already published (see online references).

End point values	R3 VAC	R3 Treo-Mel	R3 VAC (First interim analysis)	R3 Treo-Mel (First interim analysis)	R3 VAC (Per Protocol)	R3 Treo-Mel (Per protocol)
Number of subjects analysed	54	55	32	30	46	41
Units: Events	43	39	19	9	35	31

Final analysis

Statistical analysis description

Because the number of the initially planned number of events (n=155) could not be reached, an adaptive design change was performed based on the data from the 1st interim analysis, according to which only an additional analysis is planned. The conditional rejection error probability (CREP) (Müller & Schäfer 2001) was calculated for the one-sided null hypothesis, resulting in ϵ+=0.0116. The CREP was used as new local significance level for the final analysis of the remaining trial.

Comparison groups

R3 Treo-Mel v R3 VAC

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

superiority ^[9]

P-value

= 0.1195 ^[10]

Method

Increment of the logrank test statistic

Parameter type

Hazard ratio (HR)

Point estimate

0.821

Confidence interval

level

95%

sides

2-sided

lower limit

0.532

upper limit

1.268

Notes
[9] - In the final analysis the one-sided null hypothesis was tested by calculating the approximately normally distributed independent increment of the logrank test statistic (Wassmer 2006). The final analysis was performed on data from 30th June 2019.
[10] - The independent increment of the logrank test statistic was -0.889, leading to the one-sided single-stage p-value p_end+=0.1195> 0.0116=ϵ+

First interim analysis

Statistical analysis description

Comparison groups

R3 VAC (First interim analysis) v R3 Treo-Mel (First interim analysis)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[11]

P-value

= 0.4737 ^[12]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.979

Confidence interval

level

95%

sides

2-sided

lower limit

0.52

upper limit

1.842

Notes
[11] - An adaptive one-sided group sequential design with four stages using an inverse normal combination function, O’Brien & Fleming boundaries, and equally spaced weights was applied (Wassmer 2006, O’Brien & Fleming 1979).
[12] - Stage I one-sided p-value is reported. The hypotheses that the randomization arm ‘R3: Treo-Mel’ differs in the full-analysis set from the randomization arm ‘R3: VAC' with respect to EFS could not be rejected.

Final analysis (Per protocol)

Comparison groups

R3 VAC (Per Protocol) v R3 Treo-Mel (Per protocol)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4463

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.83

Confidence interval

level

95%

sides

2-sided

lower limit

0.51

upper limit

1.35

Secondary: R1 trial: Overall survival (OS)

Top of page

End point title

R1 trial: Overall survival (OS) ^[13]

End point description

Overall survival time (OS) starts at the date of randomisation and ends at the date of death of the patient (irrespective of its cause) or at the date of the patient's most recent consultation. Patients lost to follow-up are censored at the date of their last consultation.

End point type

Secondary

End point timeframe

From randomisation to death.

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The R2 randomization of the EURO-E.W.I.N.G. 99 trial was continued in the EWING2008 Trial. The EWING2008 R2 data were transferred to the EURO-E.W.I.N.G. 99 data center and was analyzed by the EURO-E.W.I.N.G. Group. The results were already published (see online references).

End point values	R1 Add-on	R1 No Add-on	R1 Add-on (Per protocol)	R1 No Add-on (Per protocol)
Number of subjects analysed	142	142	101	135
Units: Deaths	13	12	9	10

R1 trial: OS (full analysis set)

Statistical analysis description

Comparision of overall survival between R1: Add-on and R1: No Add-on in the full analysis set (ITT principle).

Comparison groups

R1 Add-on v R1 No Add-on

Number of subjects included in analysis

284

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8445

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.08

Confidence interval

level

95%

sides

2-sided

lower limit

0.49

upper limit

2.37

R1 trial: OS (Per protocol)

Comparison groups

R1 Add-on (Per protocol) v R1 No Add-on (Per protocol)

Number of subjects included in analysis

236

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7441

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.16

Confidence interval

level

95%

sides

2-sided

lower limit

0.47

upper limit

2.86

Secondary: R3 trial: Overall survival (OS)

Top of page

End point title

R3 trial: Overall survival (OS) ^[14]

End point description

End point type

Secondary

End point timeframe

From randomisation to death or last follow-up.

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The R2 randomization of the EURO-E.W.I.N.G. 99 trial was continued in the EWING2008 Trial. The EWING2008 R2 data were transferred to the EURO-E.W.I.N.G. 99 data center and was analyzed by the EURO-E.W.I.N.G. Group. The results were already published (see online references).

End point values	R3 VAC	R3 Treo-Mel	R3 VAC (Per Protocol)	R3 Treo-Mel (Per protocol)
Number of subjects analysed	54	55	46	41
Units: Deaths	31	30	23	23

R3 trial: OS (full analysis set)

Statistical analysis description

Comparision of overall survival between R3: Treo-Mel and R3: VAC in the full analysis set (ITT principle).

Comparison groups

R3 VAC v R3 Treo-Mel

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.868

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.96

Confidence interval

level

95%

sides

2-sided

lower limit

0.58

upper limit

1.58

R3 trial: OS (Per protocol)

Comparison groups

R3 VAC (Per Protocol) v R3 Treo-Mel (Per protocol)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8779

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.59

upper limit

1.87

Adverse events

Top of page

Timeframe for reporting adverse events

from treatment initiation until 3 months following completion of active oncological therapy.

Adverse event reporting additional description

Expected toxicities, both severe (CTC grade >=3, hematologic: CTC grade = 4) and non-severe (CTC grade 1-2, hematologic: CTC grade 1-3), were recorded as pre-specified items according to CTCAE in the CRF. Severe toxicities were documented as SAE and non-severe toxicities as non-SAE. Toxicities collected as free text in the CRF were not documented.

Assessment type

Systematic

Dictionary name

CTCAE

Dictionary version

3.0

Reporting group title

Safety: R1 Add-on

Reporting group description

All randomized patients who received R1 add-on treatment (Safety set, as-treated). In this reporting group, 11 deaths occurred with the following causes: Cancer = 9, Secondary malignancy = 1, Pneumonia = 1. Because the deaths could not be assigned to any specific toxicity, 0 was entered under „Serious adverse event details and values“ for both „Fatalities number“ and „Fatalities causally related to treatment number“.

Reporting group title

Safety: R1 no Add-on

Reporting group description

All randomized patients who received R1 no Add-on treatment (Safety set, as-treated). In this reporting group, 14 deaths occurred with the following causes: Cancer = 14. Because the deaths could not be assigned to any specific toxicity, 0 was entered under „Serious adverse event details and values“ for both „Fatalities number“ and „Fatalities causally related to treatment number“.

Reporting group title

Safety: R2loc VAI

Reporting group description

All randomized patients who received R2loc VAI treatment (Safety set, as-treated). In this reporting group, 2 deaths occurred with the following causes: Cancer = 2. Because the deaths could not be assigned to any specific toxicity, 0 was entered under „Serious adverse event details and values“ for both „Fatalities number“ and „Fatalities causally related to treatment number“.

Reporting group title

Safety: R2loc Bu-Mel

Reporting group description

All randomized patients who received R2loc Bu-Mel treatment (Safety set, as-treated). In this reporting group, 1 death occurred with the following cause: Cancer = 1. Because the deaths could not be assigned to any specific toxicity, 0 was entered under „Serious adverse event details and values“ for both „Fatalities number“ and „Fatalities causally related to treatment number“.

Reporting group title

Safety: R2pulm VAI

Reporting group description

All randomized patients who received R2pulm VAI treatment (Safety set, as-treated). In this reporting group, 4 deaths occurred with the following causes: Cancer = 4. Because the deaths could not be assigned to any specific toxicity, 0 was entered under „Serious adverse event details and values“ for both „Fatalities number“ and „Fatalities causally related to treatment number“.

Reporting group title

Safety: R2pulm Bu-Mel

Reporting group description

All randomized patients who received R2pulm Bu-Mel treatment (Safety set, as-treated). In this reporting group, 2 deaths occurred with the following causes: Cancer = 1, Pulmonary veno-occlusive disease (Treatment-related) = 1. Because the deaths could not be assigned to any specific toxicity, 0 was entered under „Serious adverse event details and values“ for both „Fatalities number“ and „Fatalities causally related to treatment number“.

Reporting group title

Safety: R3 VAC

Reporting group description

All randomized patients who received R3 VAC treatment (Safety set, as-treated). In this reporting group, 35 deaths occurred with the following causes: Cancer = 34, Acute pulmonary embolism = 1. Because the deaths could not be assigned to any specific toxicity, 0 was entered under „Serious adverse event details and values“ for both „Fatalities number“ and „Fatalities causally related to treatment number“.

Reporting group title

Safety: R3 Treo-Mel

Reporting group description

All randomized patients who received R3 Treo-Mel treatment (Safety set, as-treated). In this reporting group, 25 deaths occurred with the following causes: Cancer = 24, Secondary malignancy = 1. Because the deaths could not be assigned to any specific toxicity, 0 was entered under „Serious adverse event details and values“ for both „Fatalities number“ and „Fatalities causally related to treatment number“.

Serious adverse events	Safety: R1 Add-on	Safety: R1 no Add-on	Safety: R2loc VAI	Safety: R2loc Bu-Mel	Safety: R2pulm VAI	Safety: R2pulm Bu-Mel	Safety: R3 VAC	Safety: R3 Treo-Mel
Total subjects affected by serious adverse events
subjects affected / exposed	124 / 124 (100.00%)	157 / 160 (98.13%)	18 / 18 (100.00%)	7 / 7 (100.00%)	12 / 12 (100.00%)	9 / 9 (100.00%)	62 / 64 (96.88%)	44 / 44 (100.00%)
number of deaths (all causes)	11	14	2	1	4	2	35	25
number of deaths resulting from adverse events
Investigations
Hemoglobin
subjects affected / exposed	66 / 124 (53.23%)	85 / 160 (53.13%)	8 / 18 (44.44%)	3 / 7 (42.86%)	7 / 12 (58.33%)	5 / 9 (55.56%)	31 / 64 (48.44%)	31 / 44 (70.45%)
occurrences causally related to treatment / all	145 / 145	180 / 180	14 / 14	3 / 3	13 / 13	9 / 9	64 / 64	66 / 66
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Leukocytes
subjects affected / exposed	123 / 124 (99.19%)	155 / 160 (96.88%)	15 / 18 (83.33%)	7 / 7 (100.00%)	12 / 12 (100.00%)	9 / 9 (100.00%)	58 / 64 (90.63%)	44 / 44 (100.00%)
occurrences causally related to treatment / all	1337 / 1337	1390 / 1390	125 / 125	41 / 41	86 / 86	58 / 58	504 / 504	425 / 425
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Granulocytes
subjects affected / exposed	114 / 124 (91.94%)	148 / 160 (92.50%)	15 / 18 (83.33%)	5 / 7 (71.43%)	10 / 12 (83.33%)	9 / 9 (100.00%)	55 / 64 (85.94%)	40 / 44 (90.91%)
occurrences causally related to treatment / all	1307 / 1307	1334 / 1334	107 / 107	25 / 25	81 / 81	57 / 57	459 / 459	393 / 393
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Platelets
subjects affected / exposed	107 / 124 (86.29%)	136 / 160 (85.00%)	11 / 18 (61.11%)	6 / 7 (85.71%)	11 / 12 (91.67%)	9 / 9 (100.00%)	54 / 64 (84.38%)	42 / 44 (95.45%)
occurrences causally related to treatment / all	652 / 652	711 / 711	62 / 62	23 / 23	41 / 41	33 / 33	269 / 269	256 / 256
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fever
subjects affected / exposed	9 / 124 (7.26%)	19 / 160 (11.88%)	1 / 18 (5.56%)	0 / 7 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)	5 / 64 (7.81%)	5 / 44 (11.36%)
occurrences causally related to treatment / all	10 / 10	28 / 28	1 / 1	0 / 0	0 / 0	1 / 1	5 / 5	5 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Creatinine
subjects affected / exposed	2 / 124 (1.61%)	2 / 160 (1.25%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)	1 / 64 (1.56%)	7 / 44 (15.91%)
occurrences causally related to treatment / all	2 / 2	7 / 7	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	10 / 10
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Proteinuria
subjects affected / exposed	0 / 124 (0.00%)	2 / 160 (1.25%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)	0 / 64 (0.00%)	2 / 44 (4.55%)
occurrences causally related to treatment / all	0 / 0	4 / 4	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hematuria
subjects affected / exposed	2 / 124 (1.61%)	0 / 160 (0.00%)	0 / 18 (0.00%)	1 / 7 (14.29%)	0 / 12 (0.00%)	0 / 9 (0.00%)	1 / 64 (1.56%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Glumerular filtration rate
subjects affected / exposed	1 / 124 (0.81%)	1 / 160 (0.63%)	0 / 18 (0.00%)	1 / 7 (14.29%)	0 / 12 (0.00%)	0 / 9 (0.00%)	0 / 64 (0.00%)	2 / 44 (4.55%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tubular phosphate reabsorption
subjects affected / exposed	19 / 124 (15.32%)	5 / 160 (3.13%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)	2 / 64 (3.13%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	71 / 71	15 / 15	0 / 0	0 / 0	0 / 0	0 / 0	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bilirubin
subjects affected / exposed	2 / 124 (1.61%)	1 / 160 (0.63%)	2 / 18 (11.11%)	0 / 7 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)	1 / 64 (1.56%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	3 / 3	1 / 1	3 / 3	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	0 / 0	0 / 0	0 / 0
S-GOT/S-GPT
subjects affected / exposed	16 / 124 (12.90%)	24 / 160 (15.00%)	3 / 18 (16.67%)	2 / 7 (28.57%)	2 / 12 (16.67%)	1 / 9 (11.11%)	12 / 64 (18.75%)	6 / 44 (13.64%)
occurrences causally related to treatment / all	41 / 41	45 / 45	6 / 6	2 / 2	6 / 6	1 / 1	19 / 19	10 / 10
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac function test
subjects affected / exposed	1 / 124 (0.81%)	2 / 160 (1.25%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)	1 / 64 (1.56%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	1 / 1	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ECHO: LV-SF
subjects affected / exposed	6 / 124 (4.84%)	4 / 160 (2.50%)	0 / 18 (0.00%)	0 / 7 (0.00%)	1 / 12 (8.33%)	2 / 9 (22.22%)	3 / 64 (4.69%)	3 / 44 (6.82%)
occurrences causally related to treatment / all	7 / 7	9 / 9	0 / 0	0 / 0	1 / 1	2 / 2	7 / 7	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mucous membrane
subjects affected / exposed	0 / 124 (0.00%)	0 / 160 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)	1 / 64 (1.56%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	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	0 / 0	0 / 0	0 / 0
Salivary gland
subjects affected / exposed	1 / 124 (0.81%)	0 / 160 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)	0 / 64 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pharynx and oesophagus
subjects affected / exposed	1 / 124 (0.81%)	2 / 160 (1.25%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)	1 / 64 (1.56%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	1 / 1	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Larynx
subjects affected / exposed	0 / 124 (0.00%)	0 / 160 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)	0 / 64 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper gastrointestinal tract
subjects affected / exposed	0 / 124 (0.00%)	1 / 160 (0.63%)	2 / 18 (11.11%)	0 / 7 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)	0 / 64 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung
subjects affected / exposed	0 / 124 (0.00%)	0 / 160 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)	1 / 64 (1.56%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Nervous system disorders
Central neurotoxicity
subjects affected / exposed	3 / 124 (2.42%)	4 / 160 (2.50%)	1 / 18 (5.56%)	0 / 7 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)	1 / 64 (1.56%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	3 / 3	4 / 4	1 / 1	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	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	6 / 124 (4.84%)	7 / 160 (4.38%)	1 / 18 (5.56%)	0 / 7 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)	2 / 64 (3.13%)	1 / 44 (2.27%)
occurrences causally related to treatment / all	6 / 6	8 / 8	1 / 1	0 / 0	0 / 0	1 / 1	2 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral neurotoxicity
subjects affected / exposed	2 / 124 (1.61%)	5 / 160 (3.13%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)	1 / 64 (1.56%)	2 / 44 (4.55%)
occurrences causally related to treatment / all	8 / 8	14 / 14	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
General physical condition
subjects affected / exposed	26 / 124 (20.97%)	43 / 160 (26.88%)	4 / 18 (22.22%)	0 / 7 (0.00%)	2 / 12 (16.67%)	5 / 9 (55.56%)	18 / 64 (28.13%)	18 / 44 (40.91%)
occurrences causally related to treatment / all	81 / 81	106 / 106	7 / 7	0 / 0	2 / 2	8 / 8	24 / 24	43 / 43
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 124 (0.00%)	1 / 160 (0.63%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)	0 / 64 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	39 / 124 (31.45%)	50 / 160 (31.25%)	3 / 18 (16.67%)	5 / 7 (71.43%)	4 / 12 (33.33%)	6 / 9 (66.67%)	19 / 64 (29.69%)	21 / 44 (47.73%)
occurrences causally related to treatment / all	87 / 87	137 / 137	3 / 3	6 / 6	8 / 8	15 / 15	35 / 35	40 / 40
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	20 / 124 (16.13%)	30 / 160 (18.75%)	2 / 18 (11.11%)	1 / 7 (14.29%)	1 / 12 (8.33%)	1 / 9 (11.11%)	13 / 64 (20.31%)	5 / 44 (11.36%)
occurrences causally related to treatment / all	27 / 27	69 / 69	4 / 4	2 / 2	1 / 1	1 / 1	19 / 19	10 / 10
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	7 / 124 (5.65%)	15 / 160 (9.38%)	0 / 18 (0.00%)	1 / 7 (14.29%)	1 / 12 (8.33%)	3 / 9 (33.33%)	7 / 64 (10.94%)	5 / 44 (11.36%)
occurrences causally related to treatment / all	10 / 10	17 / 17	0 / 0	1 / 1	1 / 1	3 / 3	9 / 9	7 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Changes in the skin
subjects affected / exposed	7 / 124 (5.65%)	9 / 160 (5.63%)	3 / 18 (16.67%)	0 / 7 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)	3 / 64 (4.69%)	7 / 44 (15.91%)
occurrences causally related to treatment / all	10 / 10	13 / 13	6 / 6	0 / 0	1 / 1	0 / 0	3 / 3	10 / 10
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Infection
subjects affected / exposed	45 / 124 (36.29%)	67 / 160 (41.88%)	8 / 18 (44.44%)	1 / 7 (14.29%)	5 / 12 (41.67%)	6 / 9 (66.67%)	27 / 64 (42.19%)	23 / 44 (52.27%)
occurrences causally related to treatment / all	97 / 97	122 / 122	12 / 12	2 / 2	6 / 6	8 / 8	45 / 45	39 / 39
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Safety: R1 Add-on	Safety: R1 no Add-on	Safety: R2loc VAI	Safety: R2loc Bu-Mel	Safety: R2pulm VAI	Safety: R2pulm Bu-Mel	Safety: R3 VAC	Safety: R3 Treo-Mel
Total subjects affected by non serious adverse events
subjects affected / exposed	124 / 124 (100.00%)	160 / 160 (100.00%)	18 / 18 (100.00%)	7 / 7 (100.00%)	12 / 12 (100.00%)	9 / 9 (100.00%)	63 / 64 (98.44%)	44 / 44 (100.00%)
Investigations
Hemoglobin
subjects affected / exposed	58 / 124 (46.77%)	75 / 160 (46.88%)	10 / 18 (55.56%)	4 / 7 (57.14%)	5 / 12 (41.67%)	4 / 9 (44.44%)	32 / 64 (50.00%)	13 / 44 (29.55%)
occurrences all number	1900	1865	207	47	130	55	675	494
Leukocytes
subjects affected / exposed	1 / 124 (0.81%)	4 / 160 (2.50%)	3 / 18 (16.67%)	0 / 7 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)	5 / 64 (7.81%)	0 / 44 (0.00%)
occurrences all number	807	662	91	12	55	12	204	137
Granulocytes
subjects affected / exposed	6 / 124 (4.84%)	5 / 160 (3.13%)	1 / 18 (5.56%)	1 / 7 (14.29%)	0 / 12 (0.00%)	0 / 9 (0.00%)	3 / 64 (4.69%)	0 / 44 (0.00%)
occurrences all number	461	403	51	12	32	4	113	69
Platelets
subjects affected / exposed	17 / 124 (13.71%)	22 / 160 (13.75%)	6 / 18 (33.33%)	1 / 7 (14.29%)	1 / 12 (8.33%)	0 / 9 (0.00%)	8 / 64 (12.50%)	2 / 44 (4.55%)
occurrences all number	867	913	90	21	78	23	282	219
Fever
subjects affected / exposed	109 / 124 (87.90%)	131 / 160 (81.88%)	15 / 18 (83.33%)	7 / 7 (100.00%)	11 / 12 (91.67%)	8 / 9 (88.89%)	55 / 64 (85.94%)	38 / 44 (86.36%)
occurrences all number	875	991	73	19	52	42	322	284
Creatinine
subjects affected / exposed	28 / 124 (22.58%)	34 / 160 (21.25%)	4 / 18 (22.22%)	2 / 7 (28.57%)	4 / 12 (33.33%)	0 / 9 (0.00%)	6 / 64 (9.38%)	12 / 44 (27.27%)
occurrences all number	100	83	7	3	9	0	10	38
Proteinuria
subjects affected / exposed	61 / 124 (49.19%)	60 / 160 (37.50%)	3 / 18 (16.67%)	2 / 7 (28.57%)	5 / 12 (41.67%)	4 / 9 (44.44%)	28 / 64 (43.75%)	18 / 44 (40.91%)
occurrences all number	238	194	5	2	9	8	62	52
Hematuria
subjects affected / exposed	59 / 124 (47.58%)	65 / 160 (40.63%)	5 / 18 (27.78%)	1 / 7 (14.29%)	5 / 12 (41.67%)	4 / 9 (44.44%)	26 / 64 (40.63%)	19 / 44 (43.18%)
occurrences all number	186	143	5	4	9	6	80	63
Glumerular filtration rate
subjects affected / exposed	30 / 124 (24.19%)	26 / 160 (16.25%)	2 / 18 (11.11%)	1 / 7 (14.29%)	2 / 12 (16.67%)	1 / 9 (11.11%)	2 / 64 (3.13%)	6 / 44 (13.64%)
occurrences all number	104	92	3	6	2	4	14	36
Tubular phosphate reabsorption
subjects affected / exposed	20 / 124 (16.13%)	29 / 160 (18.13%)	2 / 18 (11.11%)	2 / 7 (28.57%)	3 / 12 (25.00%)	1 / 9 (11.11%)	7 / 64 (10.94%)	6 / 44 (13.64%)
occurrences all number	141	67	3	2	4	1	17	8
Bilirubin
subjects affected / exposed	28 / 124 (22.58%)	40 / 160 (25.00%)	2 / 18 (11.11%)	1 / 7 (14.29%)	3 / 12 (25.00%)	3 / 9 (33.33%)	17 / 64 (26.56%)	12 / 44 (27.27%)
occurrences all number	84	79	12	1	6	3	41	23
S-GOT/S-GPT
subjects affected / exposed	97 / 124 (78.23%)	120 / 160 (75.00%)	15 / 18 (83.33%)	3 / 7 (42.86%)	10 / 12 (83.33%)	8 / 9 (88.89%)	48 / 64 (75.00%)	37 / 44 (84.09%)
occurrences all number	1071	996	104	29	78	58	318	248
ECHO: LV-SF
subjects affected / exposed	13 / 124 (10.48%)	17 / 160 (10.63%)	1 / 18 (5.56%)	0 / 7 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)	1 / 64 (1.56%)	3 / 44 (6.82%)
occurrences all number	33	45	1	0	0	2	6	8
ureter and bladder
subjects affected / exposed	1 / 124 (0.81%)	2 / 160 (1.25%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)	2 / 64 (3.13%)	2 / 44 (4.55%)
occurrences all number	1	2	0	0	0	0	2	4
Mucous membrane
subjects affected / exposed	5 / 124 (4.03%)	7 / 160 (4.38%)	1 / 18 (5.56%)	0 / 7 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)	3 / 64 (4.69%)	1 / 44 (2.27%)
occurrences all number	5	8	1	0	0	0	5	1
Salivary gland
subjects affected / exposed	1 / 124 (0.81%)	1 / 160 (0.63%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)	0 / 64 (0.00%)	0 / 44 (0.00%)
occurrences all number	1	1	0	0	0	1	0	0
Pharynx and oesophagus
subjects affected / exposed	2 / 124 (1.61%)	7 / 160 (4.38%)	1 / 18 (5.56%)	0 / 7 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)	3 / 64 (4.69%)	1 / 44 (2.27%)
occurrences all number	2	8	1	0	0	0	4	2
Larynx
subjects affected / exposed	2 / 124 (1.61%)	3 / 160 (1.88%)	0 / 18 (0.00%)	0 / 7 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)	0 / 64 (0.00%)	0 / 44 (0.00%)
occurrences all number	2	3	0	0	1	0	0	0
Upper gastrointestinal tract
subjects affected / exposed	4 / 124 (3.23%)	7 / 160 (4.38%)	1 / 18 (5.56%)	0 / 7 (0.00%)	2 / 12 (16.67%)	0 / 9 (0.00%)	9 / 64 (14.06%)	8 / 44 (18.18%)
occurrences all number	5	7	1	0	2	0	15	14
Lower gastrointestinal tract including pelvis
subjects affected / exposed	1 / 124 (0.81%)	5 / 160 (3.13%)	0 / 18 (0.00%)	0 / 7 (0.00%)	2 / 12 (16.67%)	1 / 9 (11.11%)	8 / 64 (12.50%)	7 / 44 (15.91%)
occurrences all number	1	5	0	0	2	1	16	14
Lung
subjects affected / exposed	2 / 124 (1.61%)	4 / 160 (2.50%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 12 (0.00%)	2 / 9 (22.22%)	3 / 64 (4.69%)	1 / 44 (2.27%)
occurrences all number	4	5	0	0	0	2	3	1
Cardiac disorders
Cardiac function test
subjects affected / exposed	13 / 124 (10.48%)	18 / 160 (11.25%)	1 / 18 (5.56%)	0 / 7 (0.00%)	2 / 12 (16.67%)	2 / 9 (22.22%)	6 / 64 (9.38%)	6 / 44 (13.64%)
occurrences all number	32	40	2	0	2	2	12	9
Nervous system disorders
Cantral neurotoxicity
subjects affected / exposed	19 / 124 (15.32%)	20 / 160 (12.50%)	2 / 18 (11.11%)	2 / 7 (28.57%)	0 / 12 (0.00%)	0 / 9 (0.00%)	17 / 64 (26.56%)	7 / 44 (15.91%)
occurrences all number	53	48	4	7	0	0	36	10
Seizure
subjects affected / exposed	12 / 124 (9.68%)	8 / 160 (5.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)	8 / 64 (12.50%)	2 / 44 (4.55%)
occurrences all number	17	9	0	0	0	0	9	2
Peripheral neurotoxicity
subjects affected / exposed	63 / 124 (50.81%)	50 / 160 (31.25%)	9 / 18 (50.00%)	2 / 7 (28.57%)	5 / 12 (41.67%)	3 / 9 (33.33%)	22 / 64 (34.38%)	18 / 44 (40.91%)
occurrences all number	290	144	51	9	17	6	85	75
General disorders and administration site conditions
General physical condition
subjects affected / exposed	89 / 124 (71.77%)	108 / 160 (67.50%)	13 / 18 (72.22%)	6 / 7 (85.71%)	9 / 12 (75.00%)	4 / 9 (44.44%)	44 / 64 (68.75%)	23 / 44 (52.27%)
occurrences all number	1404	1443	173	34	106	50	598	410
Headache
subjects affected / exposed	3 / 124 (2.42%)	2 / 160 (1.25%)	1 / 18 (5.56%)	0 / 7 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)	2 / 64 (3.13%)	3 / 44 (6.82%)
occurrences all number	4	2	1	0	0	0	2	5
Stomatitis
subjects affected / exposed	63 / 124 (50.81%)	83 / 160 (51.88%)	8 / 18 (44.44%)	2 / 7 (28.57%)	5 / 12 (41.67%)	3 / 9 (33.33%)	33 / 64 (51.56%)	22 / 44 (50.00%)
occurrences all number	407	469	45	16	35	8	172	149
Vomiting
subjects affected / exposed	91 / 124 (73.39%)	98 / 160 (61.25%)	9 / 18 (50.00%)	3 / 7 (42.86%)	8 / 12 (66.67%)	7 / 9 (77.78%)	38 / 64 (59.38%)	37 / 44 (84.09%)
occurrences all number	672	634	41	15	54	23	226	214
Diarrhoea
subjects affected / exposed	72 / 124 (58.06%)	66 / 160 (41.25%)	7 / 18 (38.89%)	2 / 7 (28.57%)	9 / 12 (75.00%)	3 / 9 (33.33%)	31 / 64 (48.44%)	27 / 44 (61.36%)
occurrences all number	214	199	12	3	23	12	90	87
Hepatobiliary disorders
VOD Bearman
subjects affected / exposed	0 / 124 (0.00%)	0 / 160 (0.00%)	0 / 18 (0.00%)	1 / 7 (14.29%)	0 / 12 (0.00%)	0 / 9 (0.00%)	0 / 64 (0.00%)	0 / 44 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Skin and subcutaneous tissue disorders
Changes in the skin
subjects affected / exposed	80 / 124 (64.52%)	85 / 160 (53.13%)	9 / 18 (50.00%)	5 / 7 (71.43%)	5 / 12 (41.67%)	4 / 9 (44.44%)	38 / 64 (59.38%)	29 / 44 (65.91%)
occurrences all number	263	221	36	11	18	7	126	98
Infections and infestations
Infection
subjects affected / exposed	75 / 124 (60.48%)	83 / 160 (51.88%)	9 / 18 (50.00%)	5 / 7 (71.43%)	7 / 12 (58.33%)	3 / 9 (33.33%)	32 / 64 (50.00%)	20 / 44 (45.45%)
occurrences all number	667	788	52	18	52	25	220	216

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

21 Feb 2011

- Member states were added: Belgium, Czech Republic and Spain joined study participation - Member state withdrawl trial participation: Slovenia - Changes in Datamanagement: Electronic data capture system is established. - Note regarding treatment with Treosulfan was added: In small children <20 kg BW the dose of treosulfan should be calculated per kg BW. 1 m² BSA = 30 kg BW - Changes in drug supply: In Germany study sites will be supplied with commercial drug from Novartis until 31 Dec 2011 - Changes in dosing of obese patients to ensure safety: In patients with BSA >2 m² dosing of chemotherapy may have to be adjusted to the individual patient’s requirements and tolerance. Note: Observe maximum single dose for vincristine: 2 mg. - Changes (due to typing error) in reportable AEs: Adverse Events not reportable on an SAE form are to be reported on the appropriate CRF (toxicity check list). This include: Neutropenia and neutropenic fever (CTCAE°1-4). Haematological toxicity: haemoglobin, WBC, granulocytes, platelets (CTCAE°1-4).

23 Apr 2013

- Changes in inclusion of patients: The option of registering patients to be observed is added into study design. These patients do not meet all inclusion criteria or meet one or more exclusion criteria. - Member states were added to participate in trial for recruiting patients to the R2 arm oft he trial: France, UK, USA - Member state was added: Hungary joined trial participation - Changes in Tresulfan IV administration: Infusion time was extended to 2 h - Changes in drug supply: In Germany study sites will be supplied with commercial drug from Novartis until 30 Sep 2013 - Clarification of drug administration which is relevant for patient safety: If SF remains below 29% then omit DOX and substitute ACT 0.75 mg/m2/d (d1, d2) (IV push) (1.5 mg/m2/cycle) (max. single dose/d: 1.5 mg/d).

18 Sep 2013

- Member states were added: Autralia and New Zealand joined trial participation. - Transformation of the original group sequential design into the corresponding inverse normal design: For the randomized risk groups R1 and R3 will be conducted, with 3 planned interim analyses and early stopping rules using the O’Brien and Fleming Design. For risk groups R2loc and R2pulm three interim analyses are intended to be performed using an inverse normal design corresponding to an equally spaced four step group sequential design according to O’Brien & Fleming (Wassmer 2006, O’Brien & Fleming 1979). After each interim analysis a data dependent sample size recalculation may be performed. Then, the accrual period, the observation time and the schedule of the next interim and final analysis (required number of events) can be adapted. If no adaptions are performed, the inverse normal design coincides with the underlying group sequential design. - Recommendation added for dose modifications of elderly patients to enhance paintent’s safety: Chemotherapy may have to be adjusted indivudual patient’s requirements. In these cases the EWING2008 Head Office should be contacted. - Recommandation added for dose medoifications in case of significant toxicities to enhance patient’s safety. Dose modicfications for ifosmamide, cyclophosphamide and actinomycin D

08 Dec 2014

- Member state was added: Finland joined trial participation. - Member state withdrawl trial participation: Spain - Changes in sample size, anticipated accrual time and recruitment period for risk groups: Recalculation of R2 (R2loc and R2pulm) with respect to conditional power was performed. - Clarification for patients who are not randomised and do not recieve the standard treatment was added: additional information for was provided each risk group in a guideline - Changes in drug supply: In Germany study sites will be supplied with commercial drug from Novartis until 31 Dec 2016 - SPC for all drugs are updated

19 Feb 2016

- Changes in study organisation: Retirement of Prof. Juergens; Prof. Dirksen is the new Coordinating Ivestigator - Changes in plannes study period: The overall study duration (incl. follow-up) was extended by one year as the accrual rate into the trials was slightly lower as expected. - Member state was added: Lithuania joined trial participation - Member state withdrawl trial participation: Slovakia - Changes in recruitment cohort: The study committee decided to close the R2loc arm and the R2pulm arm because of low accrual rate into the randomized arms. The study will be analyzed. - Changes in medication of Standard Risk R1 patients: Fenretinide will not be available, therefore the arm, that included fenretinide was deleted from the protocol for clarification. This results also on changes of the primary and secondary objecitves and oft he sample size. - Changes in inclusion criteria: for Germany patients either sex, age <48 months may be included. - Changes in Key time points: Response evaluation prior to add-on in R1 was changed to optional at the respective time points. - Changes in the staticital analysis: Transformation of the original group sequential design into the corresponding inverse normal design.

06 Jul 2018

- Update if trial conduct: R1 and R3 accrual was discontinued on April 1st 2018 - Statistical design has been adapted for final analysis: Adaption of the statistical analysis strategy for the final analysis of the primary endpoint, because the required number of events for the upcoming interim/final analyses cannot be reached. Due to the statistical design change, no further interim analyses will be performed. In the R1 and R3 trial the final analysis will be performed at the end of the trial. - Changes in drug supply: Zoledronic acid is no longer supplied by Novartis - Prophylaxis of ifosfamide-induced encephalopathy was changed: Methylene blue (50mg) should be given 4 times daily

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

http://www.ncbi.nlm.nih.gov/pubmed/30188789
http://www.ncbi.nlm.nih.gov/pubmed/31553693

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Clinical trials

Clinical Trial Results:
EWING 2008

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: R1: Event-free survival (EFS)

Primary: R1: Event-free survival (EFS)

Primary: R3 trial: Event-free survival (EFS)

Primary: R3 trial: Event-free survival (EFS)

Secondary: R1 trial: Overall survival (OS)

Secondary: R1 trial: Overall survival (OS)

Secondary: R3 trial: Overall survival (OS)

Secondary: R3 trial: Overall survival (OS)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: EWING 2008

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: R1: Event-free survival (EFS)

Primary: R1: Event-free survival (EFS)

Primary: R3 trial: Event-free survival (EFS)

Primary: R3 trial: Event-free survival (EFS)

Secondary: R1 trial: Overall survival (OS)

Secondary: R1 trial: Overall survival (OS)

Secondary: R3 trial: Overall survival (OS)

Secondary: R3 trial: Overall survival (OS)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
EWING 2008