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Clinical Trial Results:
A Two-Part, Open-Label, Randomized, Phase II/III Study of Dinutuximab and Irinotecan versus Irinotecan for Second Line Treatment of Subjects with Relapsed or Refractory Small Cell Lung Cancer

Summary
EudraCT number	2017-000758-20
Trial protocol	ES HU BG LT FR PL SK GB IT
Global end of trial date	26 Mar 2020

Results information
Results version number	v1(current)
This version publication date	14 Feb 2021
First version publication date	14 Feb 2021
Other versions

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

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Trial information

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Sponsor protocol code

DIV-SCLC-301

ISRCTN number

US NCT number

NCT03098030

WHO universal trial number (UTN)

Sponsor organisation name

United Therapeutics Corporation

Sponsor organisation address

55 TW Alexander Dr, P.O. Box 14186, Research Triangle Park, United States, NC 27709

Public contact

United Therapeutics Global Medical Information, United Therapeutics Corporation, 001 877-522-2950, MedicalInformation@unither.com

Scientific contact

United Therapeutics Global Medical Information, United Therapeutics Corporation, 001 877-522-2950, MedicalInformation@unither.com

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

27 Jan 2020

Is this the analysis of the primary completion data?

Yes

Primary completion date

27 Jan 2020

Global end of trial reached?

Yes

Global end of trial date

26 Mar 2020

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this study was to compare overall survival (OS) in subjects treated with dinutuximab and irinotecan versus subjects treated with irinotecan alone as a second-line treatment for relapsed or refractory small cell lung cancer (SCLC). Secondary objectives of the study included comparison of progression-free survival (PFS), objective response rate (ORR) (complete response [CR] + partial response [PR]) and clinical benefit rate (CR + PR + stable disease [SD]) in subjects treated with dinutuximab and irinotecan versus subjects treated with irinotecan alone; comparison of the safety of subjects treated with dinutuximab and irinotecan versus subjects treated with irinotecan alone; evaluation of the pharmacokinetics of subjects treated with dinutuximab; and comparison of OS, PFS, ORR and clinical benefit rate (CBR) in subjects treated with dinutuximab and irinotecan versus subjects treated with topotecan alone.

Protection of trial subjects

This study was conducted in accordance with Good Clinical Practice (GCP), International Council for Harmonisation (ICH) guidelines, all applicable regulatory requirements, and the ethical principles that have their origins in the Declaration of Helsinki. An independent Data Monitoring Committee (DMC) was established to oversee safe and ethical conduct of Part 2 of the study. Prior to each dinutuximab dose, subjects received IV hydration in addition to premedication with antihistamines and antipyretics. From Cycle 2 onwards, premedication with opioid analgesics (morphine or morphine equivalent) could be considered, if in the judgment of the investigator pain is experienced in a prior cycle necessitating use of such medications, as allowed per institutional guidelines. For subjects on opioid medications for pre-existing pain, Medical History was to be indicated as the reason for concomitant medication use on the electronic case report form (eCRF). If an opioid was also given as a premedication for possible dinutuximab-related pain, an additional use was to be included on the concomitant medication page and premedication selected as the category (i.e., two entries with distinct indications). Subjects were monitored closely for signs and symptoms of infusion reactions during and following the completion of each dinutuximab infusion in a setting where appropriate medical resources for the treatment of severe infusion reactions were available. Subjects in Part 1 were monitored for 4 hours after completion of each dinutuximab infusion. Subjects enrolled in Part 2 Group B were monitored for 4 hours after completion of each infusion for the first 2 cycles, after which the observation time decreased to 1 hour or duration deemed clinically necessary by the Investigator (if greater than 1 hour). After each dose increase, subjects were carefully monitored for tumor lysis syndrome, according to the clinical judgment of the Investigator.

Background therapy

Subjects were permitted to receive antiemetics, antidiarrheal agents, and antibiotics as necessary. Subjects receiving corticosteroids for emesis prophylaxis were to receive the lowest dose and for the shortest period of time according to clinical judgment. The use of growth factors and erythropoietin stimulating agents was permitted as per American Society of Clinical Oncology/ESMO/NCCN Guidelines. Subjects were permitted to receive red blood cell (RBC) transfusions or platelet transfusions if clinically indicated in accordance with institutional guidelines. Palliative radiation for pain management was permitted with the prior approval of the Medical Monitor.

Evidence for comparator

Irinotecan is recommended by the NCCN as one of the preferred single agents for second-line treatment of SCLC (For topotecan, irinotecan and other agents: Category 2A - Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.). Additionally, NCCN guidelines recommend irinotecan plus either cisplatin or carboplatin as a possible first-line regimen. European Society of Medical Oncology (ESMO) guidelines list irinotecan plus cisplatin as an alternative first-line regimen for those patients for whom etoposide is contraindicated. Topotecan, at the time of the study was the only drug approved in the United States for second-line treatment of SCLC. Evaluation of the effect of the combination group against the topotecan alone group was a secondary objective. Owing to the poor prognosis of patients with relapsed and refractory SCLC, OS was the primary outcome measure of interest. The study findings were intended to support registration of dinutuximab (in combination with irinotecan) if warranted.

Actual start date of recruitment

15 May 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 8

Country: Number of subjects enrolled

Slovakia: 1

Country: Number of subjects enrolled

Spain: 83

Country: Number of subjects enrolled

United Kingdom: 13

Country: Number of subjects enrolled

Bulgaria: 17

Country: Number of subjects enrolled

France: 27

Country: Number of subjects enrolled

Hungary: 21

Country: Number of subjects enrolled

Lithuania: 9

Country: Number of subjects enrolled

United States: 68

Country: Number of subjects enrolled

Korea, Republic of: 42

Country: Number of subjects enrolled

Russian Federation: 92

Country: Number of subjects enrolled

Canada: 15

Country: Number of subjects enrolled

Ukraine: 18

Country: Number of subjects enrolled

Thailand: 11

Country: Number of subjects enrolled

Italy: 5

Country: Number of subjects enrolled

Australia: 6

Country: Number of subjects enrolled

Georgia: 24

Country: Number of subjects enrolled

India: 7

Country: Number of subjects enrolled

Taiwan: 9

Country: Number of subjects enrolled

Philippines: 3

Country: Number of subjects enrolled

Malaysia: 2

Country: Number of subjects enrolled

Hong Kong: 2

Worldwide total number of subjects

483

EEA total number of subjects

184

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)

296

From 65 to 84 years

186

85 years and over

Subject disposition

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Recruitment details

A total of 483 subjects were enrolled during the study across 153 institutions in US, Spain, Korea, Russia, France, Hungary, Bulgaria, Canada, United Kingdom, Ukraine, Thailand, Italy, Australia, Georgia, India, Taiwan, Poland, Phillippines, Lithuania, Malaysia, Hong Kong and Slovakia

Screening details

Screening assessments included collection of demographic data, medical history, and ongoing medications, laboratory tests for eligibility, physical examination including ophthalmology examination, ECOG status, neurologic assessment, assessment of any pre-existing pain, 12 lead ECG, vital signs, and monitoring of AEs including SAEs.

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

Part 1 - Dinutuximab + Irinotecan

Arm description

The lead-in phase of the study (referred to as Part 1) had an enrollment target of approximately 10 subjects. In Part 1, dinutuximab was to be administered at increasing doses, as tolerated, together with irinotecan at a dose of 350 mg/m2 intravenously (IV) on Day 1 of each 21-day cycle. Subjects were to receive dinutuximab at a starting dose of 10 mg/m2 IV, with increases administered in 2 mg/m2 increments per cycle in subsequent cycles if maximal pain with the prior dose is ≤Grade 1 or Grade 2/3 that in the view of the Investigator was adequately managed and the drug was otherwise tolerated. The maximum permitted dose of dinutuximab was 17.5 mg/m2 (If this dose was reached, the last dose increment would be 1.5 mg/m2). The dinutuximab dose was to be decreased in 2 mg/m2 decrements per cycle depending on the toxicity observed to as low as 8 mg/m2. If a dose decrease from 17.5 mg/m2 was required, the initial dose reduction was to be 1.5 mg/m2 (and 2 mg/m2 for any subsequent decrements)

Arm type

Experimental

Investigational medicinal product name

Unituxin

Investigational medicinal product code

Other name

Dinutuximab

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Dinutuximab was administered at a doses of 10 mg/m2 (n=2), 14 mg/m2 (n=2), 16 mg/m2 (n=1) and 17.5 mg/m2 (n=7) together with irinotecan at a dose of 350 mg/m2 intravenously (IV) on Day 1 of each 21-day cycle.

Investigational medicinal product name

Irinotecan

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Part 2 - Irinotecan (Group A)

Arm description

Arm type

Active comparator

Investigational medicinal product name

Irinotecan

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Irinotecan was administered at a dose of 350 mg/m2 intravenously (IV) on Day 1 of each 21-day cycle.

Part 2 - Dinutuximab + Irinotecan (Group B)

Arm description

In Part 2, approximately 460 additional subjects with relapsed or refractory SCLC were to be randomized in a 2:2:1 allocation (184/irinotecan group, 184/dinutuximab + irinotecan group, and 92/topotecan group). Subjects randomized to Group B were to receive dinutuximab on Day 1 of each cycle beginning with a starting dose of 10 mg/m2 IV or a dose recommended by the SRC, and irinotecan at a dose of 350 mg/m2 on Day 1 of each cycle. Dose escalation and de-escalation for dinutuximab was to occur as in Part 1. The maximum dose of dinutuximab that may have been administered was 17.5 mg/m2 (If this dose was reached, the last dose increment would be 1.5 mg/m2. If the dose was reduced from 17.5 mg/m2, the initial dose decrement would be 1.5 mg/m2 to 16 mg/m2.)

Arm type

Experimental

Investigational medicinal product name

Unituxin

Investigational medicinal product code

Other name

Dinutuximab

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Irinotecan

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

For the first cycle dinutuximab was administered at a dose of 16 mg/m2 together with irinotecan at a dose of 350 mg/m2 intravenously (IV) on Day 1. For each subsequent 21-day cycle, dinutuximab was administered at a dose of 17.5 mg/m2 together with irinotecan at a dose of 350 mg/m2 intravenously (IV) on Day 1.Irinotecan was administered at a dose of 350 mg/m2 together with dinutuximab at a dose of 17.5 mg/m2 intravenously (IV) on Day 1 of each 21-day cycle.

Part 2 - Topotecan (Group C)

Arm description

In Part 2, approximately 460 additional subjects with relapsed or refractory SCLC were to be randomized in a 2:2:1 allocation (184/irinotecan group, 184/dinutuximab + irinotecan group, and 92/topotecan group). No crossover between groups was allowed because OS was the primary endpoint. Subjects randomized to Group C were to receive topotecan 1.5 mg/m2 IV for 5 consecutive days of each cycle.

Arm type

Active comparator

Investigational medicinal product name

Topotecan

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Topotecan was administered as a dose of 1.5 mg/m2 intravenously (IV) for 5 consecutive days of each cycle.

Number of subjects in period 1	Part 1 - Dinutuximab + Irinotecan	Part 2 - Irinotecan (Group A)	Part 2 - Dinutuximab + Irinotecan (Group B)	Part 2 - Topotecan (Group C)
Started	12	190	187	94
Completed	2	24	24	9
Not completed	10	166	163	85
Adverse event, serious fatal	10	156	156	82
Consent withdrawn by subject	-	8	7	2
Lost to follow-up	-	2	-	1

Baseline characteristics

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Reporting group title

Overall Study (overall period)

Reporting group description

Reporting group values	Overall Study (overall period)	Total
Number of subjects	483	483
Age categorical
Units: Subjects
<65 years	296	296
≥65 years	187	187
Age continuous
Units: years
arithmetic mean (standard deviation)	61.6 ± 8.7	-
Gender categorical
Units: Subjects
Female	118	118
Male	365	365
Race
Units: Subjects
White	277	277
Black or African American	6	6
American Indian or Alaska Native	0	0
Native Hawaiian or Other Pacific Islander	0	0
Asian	80	80
Multiple	1	1
Other	3	3
Unknown	116	116
Ethnicity
Units: Subjects
Hispanic or Latino	11	11
Not Hispanic or Latino	355	355
Unknown	117	117
ECOG Performance Status
Baseline was defined as the last measurement obtained prior to first dose for Part 1 subjects or randomization for Part 2 subjects. ECOG Performance Status was used as a measure of how the disease impacted the patient's daily living abilities with eligible grading levels defined as follows: 0 = Fully active, able to carry on all pre-disease performance without restriction 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature e.g. light house work, office work.
Units: Subjects
Grade 0	95	95
Grade 1	375	375
Missing	13	13
Region
North America includes United States, Canada. Western Europe includes Spain, France, United Kingdom, Italy. Central/Eastern Europe includes Bulgaria, Georgia, Hungary, Lithuania, Poland, Slovakia. Asia-Pacific includes Australia, Taiwan, Thailand, South Korea, Hong Kong, India, Philippines, Malaysia
Units: Subjects
North America	83	83
Western Europe	128	128
Central/Eastern Europe	80	80
Russia & Ukraine	110	110
Asia-Pacific	82	82
Tobacco Use
Units: Subjects
No	46	46
Yes	437	437
Tobacco Use
Number of Pack Years was defined as number of packs per day x number of years using cigarettes/chewing tobacco
Units: Years
arithmetic mean (standard deviation)	43.66 ± 28.67	-
Tobacco Use
Number of Pack Years was defined as number of packs per day x number of years using cigarettes/chewing tobacco
Units: Years
median (full range (min-max))	40.00 (0.5 to 176.0)	-
Height
Units: cm
arithmetic mean (standard deviation)	169.19 ± 8.83	-
Height
Units: cm
median (full range (min-max))	170.00 (143.0 to 191.0)	-
Weight
Units: kg
arithmetic mean (standard deviation)	74.20 ± 16.47	-
Weight
Units: kg
median (full range (min-max))	72.00 (35.8 to 139.1)	-
Body Surface Area
Units: m2
arithmetic mean (standard deviation)	1.849 ± 0.229	-
Body Surface Area
Units: m2
median (full range (min-max))	1.840 (1.23 to 2.54)	-
Body Mass Index
Units: kg/m2
arithmetic mean (standard deviation)	25.82 ± 4.94	-
Body Mass Index
Units: kg/m2
median (full range (min-max))	25.45 (14.8 to 43.9)	-

Subject analysis set title

ITT Analysis Set - Part 2 - Group A

Subject analysis set type

Intention-to-treat

Subject analysis set description

The Intent-to-Treat (ITT) Analysis Set was defined as all subjects randomized in Part 2 of the study, as assigned to treatment. The ITT population was the primary population for the analysis of OS and was also used to evaluate all secondary efficacy endpoints and subject characteristics.

Subject analysis set title

ITT Analysis Set - Part 2 - Group B

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

ITT Analysis Set - Part 2 - Group C

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Safety Analysis Set - Part 1

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Safety Analysis Set - Part 2 - Group A

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Safety Analysis Set - Part 2 - Group B

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Safety Analysis Set - Part 2 - Group C

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Efficacy Evaluable Analysis Set - Group A

Subject analysis set type

Sub-group analysis

Subject analysis set description

The Efficacy Evaluable Analysis Set was defined as all subjects randomized in Part 2 of the study who had measurable disease at Baseline, received any amount of the assigned study treatment, and had at least one evaluable post-baseline tumor assessment. Subjects with measurable disease must have had at least one measurable lesion. Measurable lesions were defined (according to RECIST criteria [version 1.1]) as those that could be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT scan, or ≥ 10 mm with calipers by clinical exam. Together with the mITT population, the Efficacy Evaluable group was used to evaluate ORR and other tumor response endpoints.

Subject analysis set title

Efficacy Evaluable Analysis Set - Group B

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Efficacy Evaluable Analysis Set - Group C

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

mITT Analysis Set - Part 2 - Group A

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

The Modified Intent-to-Treat (mITT) Analysis Set was defined as all subjects who were randomized and received at least one dose of the study drug in Part 2 of the study, as assigned to treatment. The mITT population was the primary population for the sensitivity analysis of OS and all secondary efficacy endpoints.

Subject analysis set title

mITT Analysis Set - Part 2 - Group B

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

mITT Analysis Set - Part 2 - Group C

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

Per Protocol Population Analysis Set - Group A

Subject analysis set type

Per protocol

Subject analysis set description

The Per Protocol Population was defined as all subjects randomized in Part 2 of the study who satisfied the following criteria: 1) Completed at least 2 cycles of the assigned treatment 2) Qualified for the study based on SCLC diagnosis and prior therapies (i.e., met protocol inclusion criteria 3, 4, 5 and did not meet exclusion criterion 2) 3) Received at least 80% of the prescribed study drug (i.e., their average dose during the treatment period was at least 80% of the planned dose). This population was used for sensitivity analysis of the primary efficacy endpoint.

Subject analysis set title

Per Protocol Population Analysis Set - Group B

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Per Protocol Population Analysis Set - Group C

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis sets values	ITT Analysis Set - Part 2 - Group A	ITT Analysis Set - Part 2 - Group B	ITT Analysis Set - Part 2 - Group C	Safety Analysis Set - Part 1	Safety Analysis Set - Part 2 - Group A	Safety Analysis Set - Part 2 - Group B	Safety Analysis Set - Part 2 - Group C	Efficacy Evaluable Analysis Set - Group A	Efficacy Evaluable Analysis Set - Group B	Efficacy Evaluable Analysis Set - Group C	mITT Analysis Set - Part 2 - Group A	mITT Analysis Set - Part 2 - Group B	mITT Analysis Set - Part 2 - Group C	Per Protocol Population Analysis Set - Group A	Per Protocol Population Analysis Set - Group B	Per Protocol Population Analysis Set - Group C
Number of subjects	190	187	94	12	187	183	88	157	164	80	187	183	88	153	155	80
Age categorical
Units: Subjects
<65 years	123	117	54	2	120	115	51
≥65 years	67	70	40	10	67	68	37
Age continuous
Units: years
arithmetic mean (standard deviation)	61.5 ± 9.0	61.3 ± 8.7	62.5 ± 8.4	67.9 ± 8.8	61.6 ± 8.9	61.2 ± 8.6	62.2 ± 8.3	±	±	±	±	±	±	±	±	±
Gender categorical
Units: Subjects
Female	43	45	26	4	42	44	24
Male	147	142	68	8	145	139	64
Race
Units: Subjects
White	106	113	54	4	103	110	52
Black or African American	2	1	3	0	2	1	2
American Indian or Alaska Native	0	0	0	0	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0
Asian	34	28	18	0	34	28	16
Multiple	1	0	0	0	1	0	0
Other	2	1	0	0	2	1	0
Unknown	45	44	19	8	45	43	18
Ethnicity
Units: Subjects
Hispanic or Latino	2	5	4	0	2	5	4
Not Hispanic or Latino	142	137	72	4	139	134	67
Unknown	46	45	18	8	46	44	17
ECOG Performance Status
Baseline was defined as the last measurement obtained prior to first dose for Part 1 subjects or randomization for Part 2 subjects. ECOG Performance Status was used as a measure of how the disease impacted the patient's daily living abilities with eligible grading levels defined as follows: 0 = Fully active, able to carry on all pre-disease performance without restriction 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature e.g. light house work, office work.
Units: Subjects
Grade 0	39	36	17	3	39	36	17
Grade 1	148	147	71	9	148	147	71
Missing	4	3	6	0	0	0	0
Region
North America includes United States, Canada. Western Europe includes Spain, France, United Kingdom, Italy. Central/Eastern Europe includes Bulgaria, Georgia, Hungary, Lithuania, Poland, Slovakia. Asia-Pacific includes Australia, Taiwan, Thailand, South Korea, Hong Kong, India, Philippines, Malaysia
Units: Subjects
North America	32	31	16	4	29	31	15
Western Europe	52	46	22	8	52	44	20
Central/Eastern Europe	24	34	22		24	32	21
Russia & Ukraine	43	49	18		43	49	18
Asia-Pacific	39	27	16		39	27	14
Tobacco Use
Units: Subjects
No	12	22	12	0	12	22	10
Yes	178	165	82	12	175	161	78
Tobacco Use
Number of Pack Years was defined as number of packs per day x number of years using cigarettes/chewing tobacco
Units: Years
arithmetic mean (standard deviation)	44.80 ± 31.96	43.35 ± 26.81	41.86 ± 24.77	52.75 ± 30.15	45.07 ± 32.11	43.25 ± 26.90	41.31 ± 25.04	±	±	±	±	±	±	±	±	±
Tobacco Use
Number of Pack Years was defined as number of packs per day x number of years using cigarettes/chewing tobacco
Units: Years
median (full range (min-max))	38.50 (3.6 to 176.0)	40.00 (0.5 to 150.0)	38.50 (5.0 to 141.0)	49.50 (10.0 to 122.0)	39.00 (3.6 to 176.0)	40.00 (0.5 to 150.0)	35.50 (5.0 to 141.0)
Height
Units: cm
arithmetic mean (standard deviation)	170.21 ± 8.56	168.55 ± 8.96	168.37 ± 8.97	170.59 ± 10.20	170.16 ± 8.53	168.39 ± 8.95	168.59 ± 8.72	±	±	±	±	±	±	±	±	±
Height
Units: cm
median (full range (min-max))	171.00 (150.8 to 191.0)	169.00 (143.0 to 190.0)	170.0 (145.0 to 187.0)	171.30 (153.0 to 187.0)	171.00 (150.8 to 191.0)	169.00 (143.0 to 190.0)	170.00 (149.0 to 187.0)
Weight
Units: kg
arithmetic mean (standard deviation)	75.42 ± 16.27	73.72 ± 16.58	72.70 ± 16.63	77.72 ± 18.34	75.18 ± 16.09	73.82 ± 16.62	73.10 ± 16.77	±	±	±	±	±	±	±	±	±
Weight
Units: kg
median (full range (min-max))	72.50 (38.0 to 127.0)	73.70 (35.8 to 132.9)	70.25 (43.0 to 139.1)	82.50 (50.5 to 101.0)	72.00 (38.0 to 127.0)	73.70 (35.8 to 132.9)	69.65 (43.0 to 139.1)
Body Surface Area
Units: m2
arithmetic mean (standard deviation)	1.870 ± 0.223	1.840 ± 0.233	1.826 ± 0.231	1.895 ± 0.269	1.867 ± 0.222	1.840 ± 0.233	1.833 ± 0.230	±	±	±	±	±	±	±	±	±
Body Surface Area
Units: m2
median (full range (min-max))	25.66 (14.8 to 43.4)	25.43 (16.3 to 42.0)	25.16 (16.7 to 43.9)	1.990 (1.50 to 2.21)	1.850 (1.30 to 2.54)	1.845 (1.23 to 2.48)	1.805 (1.35 to 2.51)
Body Mass Index
Units: kg/m2
arithmetic mean (standard deviation)	25.95 ± 4.91	25.84 ± 5.01	25.54 ± 4.89	26.40 ± 4.42	25.89 ± 4.89	25.92 ± 5.0	25.85 ± 4.93	±	±	±	±	±	±	±	±	±
Body Mass Index
Units: kg/m2
median (full range (min-max))	25.66 (14.8 to 43.4)	25.43 (16.3 to 42.0)	25.16 (16.7 to 43.9)	26.55 (19.1 to 32.6)	25.56 (14.8 to 43.4)	25.50 (16.3 to 42.0)	25.16 (16.7 to 43.9)

End points

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Reporting group title

Part 1 - Dinutuximab + Irinotecan

Reporting group description

Reporting group title

Part 2 - Irinotecan (Group A)

Reporting group description

Reporting group title

Part 2 - Dinutuximab + Irinotecan (Group B)

Reporting group description

Reporting group title

Part 2 - Topotecan (Group C)

Reporting group description

In Part 2, approximately 460 additional subjects with relapsed or refractory SCLC were to be randomized in a 2:2:1 allocation (184/irinotecan group, 184/dinutuximab + irinotecan group, and 92/topotecan group). No crossover between groups was allowed because OS was the primary endpoint. Subjects randomized to Group C were to receive topotecan 1.5 mg/m2 IV for 5 consecutive days of each cycle.

Subject analysis set title

ITT Analysis Set - Part 2 - Group A

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

ITT Analysis Set - Part 2 - Group B

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

ITT Analysis Set - Part 2 - Group C

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Safety Analysis Set - Part 1

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Safety Analysis Set - Part 2 - Group A

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Safety Analysis Set - Part 2 - Group B

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Safety Analysis Set - Part 2 - Group C

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Efficacy Evaluable Analysis Set - Group A

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Efficacy Evaluable Analysis Set - Group B

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Efficacy Evaluable Analysis Set - Group C

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

mITT Analysis Set - Part 2 - Group A

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

mITT Analysis Set - Part 2 - Group B

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

mITT Analysis Set - Part 2 - Group C

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

Per Protocol Population Analysis Set - Group A

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Per Protocol Population Analysis Set - Group B

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Per Protocol Population Analysis Set - Group C

Subject analysis set type

Per protocol

Subject analysis set description

Primary: Overall Survival (OS) - ITT Analysis Set

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End point title

Overall Survival (OS) - ITT Analysis Set

End point description

The primary efficacy endpoint was OS, defined as the duration of time from the date of randomization to the date of the subject’s death from any cause. The primary objective of the study was to compare OS in subjects treated with dinutuximab and irinotecan versus subjects treated with irinotecan alone as a second-line treatment for relapsed or refractory SCLC.

End point type

Primary

End point timeframe

Overall survival was calculated as (date of death – date of randomization) + 1. Subjects who were alive or permanently lost to follow-up at the cut-off date for the analysis were to be censored at the last date the subject was known to be alive.

End point values	ITT Analysis Set - Part 2 - Group A	ITT Analysis Set - Part 2 - Group B	ITT Analysis Set - Part 2 - Group C
Number of subjects analysed	190	187	94
Units: months
median (confidence interval 95%)
Kaplan-Meier Estimate of OS - 25th Quartile	3.6 (2.8 to 4.3)	3.5 (2.9 to 4.1)	3.8 (2.4 to 5.4)
Kaplan-Meier Estimate of OS - Median	7.0 (5.6 to 8.9)	6.9 (6.0 to 7.6)	7.4 (6.1 to 9.3)
Kaplan-Meier Estimate of OS - 75th Quartile	13.1 (10.8 to 16.2)	10.9 (9.7 to 13.9)	12.8 (10.0 to 14.4)
Rate (%) Surviving for at least 6 months	54.5 (47.1 to 61.3)	57.8 (50.4 to 64.6)	61.7 (51.1 to 70.7)
Rate (%) Surviving for at least 12 months	29.1 (22.8 to 35.8)	22.6 (16.8 to 28.9)	27.7 (19.1 to 36.9)
Rate (%) Surviving for at least 18 months	15.8 (10.8 to 21.7)	12.1 (7.7 to 17.6)	10.4 (5.1 to 18.1)
Rate (%) Surviving for at least 24 months	9.0 (4.4 to 15.4)	12.1 (7.7 to 17.6)	4.5 (0.8 to 13.5)

Hazard Ratio vs Irinotecan

Statistical analysis description

The treatment effect of the dinutuximab combination on OS, as compared to irinotecan, was estimated by the hazard ratio and its 95% CI; the Cox proportional hazards model was used for this analysis, stratified by the subject’s response to prior platinum therapy. Similarly, the hazard ratio and 95% CI comparing the dinutuximab + irinotecan group and the topotecan group was provided.

Comparison groups

ITT Analysis Set - Part 2 - Group B v ITT Analysis Set - Part 2 - Group A

Number of subjects included in analysis

377

Analysis specification

Pre-specified

Analysis type

other ^[1]

P-value

= 0.3132 ^[2]

Method

Logrank

Parameter type

Cox proportional hazard

Point estimate

1.12

Confidence interval

level

95%

sides

2-sided

lower limit

0.9

upper limit

1.4

Notes
[1] - Based on Cox proportional hazards model, stratified by duration of response to prior platinum therapy (<3 months, >=3 months)
[2] - Log-rank test, stratified by duration of response to prior platinum therapy (<3 months, >=3 months)

Hazard Ratio vs Topotecan

Statistical analysis description

Comparison groups

ITT Analysis Set - Part 2 - Group B v ITT Analysis Set - Part 2 - Group C

Number of subjects included in analysis

281

Analysis specification

Pre-specified

Analysis type

other ^[3]

P-value

= 0.7233 ^[4]

Method

Logrank

Parameter type

Cox proportional hazard

Point estimate

1.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.8

upper limit

1.37

Notes
[3] - Based on Cox proportional hazards model, stratified by duration of response to prior platinum therapy (<3 months, >=3 months)
[4] - Log-rank test, stratified by duration of response to prior platinum therapy (<3 months, >=3 months)

Primary: Overall Survival (OS) - mITT Analysis Set

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End point title

Overall Survival (OS) - mITT Analysis Set

End point description

End point type

Primary

End point timeframe

End point values	mITT Analysis Set - Part 2 - Group A	mITT Analysis Set - Part 2 - Group B	mITT Analysis Set - Part 2 - Group C
Number of subjects analysed	187	183	88
Units: months
number (confidence interval 95%)
Kaplan-Meier Estimate of OS - 25th Quartile	3.7 (2.8 to 4.4)	3.6 (3.1 to 4.4)	4.1 (2.4 to 5.5)
Kaplan-Meier Estimate of OS - Median	7.0 (5.6 to 8.9)	7.0 (6.1 to 7.7)	7.4 (6.1 to 9.3)
Kaplan-Meier Estimate of OS - 75th Quartile	13.1 (10.8 to 16.2)	10.9 (9.9 to 14.0)	13.2 (10.0 to 15.6)
Rate Surviving for at least 6 months	54.8 (47.4 to 61.7)	59.1 (51.6 to 65.9)	62.5 (51.5 to 71.7)
Rate Surviving for at least 12 months	29.1 (22.7 to 35.7)	23.1 (17.2 to 29.5)	29.5 (20.4 to 39.2)
Rate Surviving for at least 18 months	15.5 (10.5 to 21.4)	12.4 (7.9 to 18.0)	11.2 (5.4 to 19.2)
Rate Surviving for at least 24 months	8.5 (4.0 to 14.9)	12.4 (7.9 to 18.0)	4.8 (0.9 to 14.3)

Hazard Ratio vs Irinotecan

Statistical analysis description

Comparison groups

mITT Analysis Set - Part 2 - Group A v mITT Analysis Set - Part 2 - Group B

Number of subjects included in analysis

370

Analysis specification

Pre-specified

Analysis type

other ^[5]

P-value

= 0.4507 ^[6]

Method

Logrank

Parameter type

Cox proportional hazard

Point estimate

1.09

Confidence interval

level

95%

sides

2-sided

lower limit

0.87

upper limit

1.36

Notes
[5] - Based on Cox proportional hazards model, stratified by duration of response to prior platinum therapy (<3 months, >=3 months)
[6] - Log-rank test, stratified by duration of response to prior platinum therapy (<3 months, >=3 months)

Hazard Ratio vs Topotecan

Statistical analysis description

Comparison groups

mITT Analysis Set - Part 2 - Group B v mITT Analysis Set - Part 2 - Group C

Number of subjects included in analysis

271

Analysis specification

Pre-specified

Analysis type

other ^[7]

P-value

= 0.681 ^[8]

Method

Logrank

Parameter type

Cox proportional hazard

Point estimate

1.06

Confidence interval

level

95%

sides

2-sided

lower limit

0.81

upper limit

1.39

Notes
[7] - Based on Cox proportional hazards model, stratified by duration of response to prior platinum therapy (<3 months, >=3 months)
[8] - Log-rank test, stratified by duration of response to prior platinum therapy (<3 months, >=3 months)

Primary: Overall Survival (OS) - Sensitivity Analysis of Per-Protocol Population

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End point title

Overall Survival (OS) - Sensitivity Analysis of Per-Protocol Population

End point description

Protocol-compliant Subjects who received ≥80% Assigned Dose. The primary efficacy endpoint was OS, defined as the duration of time from the date of randomization to the date of the subject’s death from any cause. The primary objective of the study was to compare OS in subjects treated with dinutuximab and irinotecan versus subjects treated with irinotecan alone as a second-line treatment for relapsed or refractory SCLC.

End point type

Primary

End point timeframe

End point values	Per Protocol Population Analysis Set - Group A	Per Protocol Population Analysis Set - Group B	Per Protocol Population Analysis Set - Group C
Number of subjects analysed	153	155	80
Units: months
number (confidence interval 95%)
Kaplan-Meier Estimate of OS - 25th Quartile	4.4 (3.6 to 5.3)	4.1 (3.4 to 5.3)	4.7 (2.7 to 6.1)
Kaplan-Meier Estimate of OS - Median	8.3 (6.4 to 9.5)	7.6 (6.6 to 8.4)	8.4 (6.4 to 9.7)
Kaplan-Meier Estimate of OS - 75th Quartile	13.7 (11.9 to 16.6)	12.1 (10.3 to 15.5)	13.6 (11.3 to 16.0)
Rate Surviving for at least 6 months	59.5 (51.3 to 66.8)	63.5 (55.4 to 70.6)	66.3 (54.8 to 75.5)
Rate Surviving for at least 12 months	31.7 (24.5 to 39.2)	25.8 (19.1 to 33.0)	32.5 (22.6 to 42.8)
Rate Surviving for at least 18 months	16.4 (10.8 to 23.1)	14.7 (9.4 to 21.1)	12.3 (6.0 to 21.0)
Rate Surviving for at least 24 months	8.6 (3.9 to 15.7)	14.7 (9.4 to 21.1)	5.3 (0.9 to 15.6)

Hazard Ratio vs Irinotecan

Statistical analysis description

Comparison groups

Per Protocol Population Analysis Set - Group A v Per Protocol Population Analysis Set - Group B

Number of subjects included in analysis

308

Analysis specification

Pre-specified

Analysis type

other ^[9]

P-value

= 0.5514 ^[10]

Method

Logrank

Parameter type

Cox proportional hazard

Point estimate

1.08

Confidence interval

level

95%

sides

2-sided

lower limit

0.84

upper limit

1.38

Notes
[9] - Based on Cox proportional hazards model, stratified by duration of response to prior platinum therapy (<3 months, >=3 months)
[10] - Log-rank test, stratified by duration of response to prior platinum therapy (<3 months, >=3 months)

Hazard Ratio vs Topotecan

Statistical analysis description

Comparison groups

Per Protocol Population Analysis Set - Group B v Per Protocol Population Analysis Set - Group C

Number of subjects included in analysis

235

Analysis specification

Pre-specified

Analysis type

other ^[11]

P-value

= 0.8294 ^[12]

Method

Logrank

Parameter type

Cox proportional hazard

Point estimate

1.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.77

upper limit

1.38

Notes
[11] - Based on Cox proportional hazards model, stratified by duration of response to prior platinum therapy (<3 months, >=3 months)
[12] - Log-rank test, stratified by duration of response to prior platinum therapy (<3 months, >=3 months)

Primary: Overall Survival (OS) - Sensitivity Analysis Consider Subjects Lost to Follow-Up as Deaths at Last Follow-up Date

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End point title

Overall Survival (OS) - Sensitivity Analysis Consider Subjects Lost to Follow-Up as Deaths at Last Follow-up Date

End point description

Sensitivity analysis considering subjects lost to follow-up as deaths at last follow-up date inthe ITT Analysis Set. The primary efficacy endpoint was OS, defined as the duration of time from the date of randomization to the date of the subject’s death from any cause. The primary objective of the study was to compare OS in subjects treated with dinutuximab and irinotecan versus subjects treated with irinotecan alone as a second-line treatment for relapsed or refractory SCLC.

End point type

Primary

End point timeframe

End point values	ITT Analysis Set - Part 2 - Group A	ITT Analysis Set - Part 2 - Group B	ITT Analysis Set - Part 2 - Group C
Number of subjects analysed	190	187	94
Units: months
number (confidence interval 95%)
Kaplan-Meier Estimate of OS - 25th Quartile	3.6 (2.8 to 4.3)	3.5 (2.9 to 4.1)	3.8 (2.4 to 5.4)
Kaplan-Meier Estimate of OS - Median	7.0 (5.6 to 8.9)	6.9 (6.0 to 7.6)	7.4 (6.1 to 9.3)
Kaplan-Meier Estimate of OS - 75th Quartile	12.9 (10.8 to 15.7)	10.9 (9.7 to 13.9)	12.8 (10.0 to 14.4)
Rate for Survival for at least 6 months	54.5 (47.1 to 61.3)	57.8 (50.4 to 64.6)	61.7 (51.1 to 70.7)
Rate for Survival for at least 12 months	29.1 (22.8 to 35.8)	22.6 (16.8 to 28.9)	27.7 (19.1 to 36.9)
Rate for Survival for at least 18 months	14.9 (10.0 to 20.6)	12.1 (7.7 to 17.6)	9.6 (4.6 to 16.9)
Rate for Survival for at least 24 months	8.4 (4.2 to 14.6)	12.1 (7.7 to 17.6)	4.1 (0.7 to 12.6)

Hazard Ratio vs Irinotecan

Statistical analysis description

Comparison groups

ITT Analysis Set - Part 2 - Group B v ITT Analysis Set - Part 2 - Group A

Number of subjects included in analysis

377

Analysis specification

Pre-specified

Analysis type

other ^[13]

P-value

= 0.3569 ^[14]

Method

Logrank

Parameter type

Cox proportional hazard

Point estimate

1.11

Confidence interval

level

95%

sides

2-sided

lower limit

0.89

upper limit

1.38

Notes
[13] - Based on Cox proportional hazards model, stratified by duration of response to prior platinum therapy (<3 months, >=3 months)
[14] - Log-rank test, stratified by duration of response to prior platinum therapy (<3 months, >=3 months)

Hazard Ratio vs Topotecan

Statistical analysis description

Comparison groups

ITT Analysis Set - Part 2 - Group B v ITT Analysis Set - Part 2 - Group C

Number of subjects included in analysis

281

Analysis specification

Pre-specified

Analysis type

other ^[15]

P-value

= 0.7848 ^[16]

Method

Logrank

Parameter type

Cox proportional hazard

Point estimate

1.04

Confidence interval

level

95%

sides

2-sided

lower limit

0.8

upper limit

1.35

Notes
[15] - Based on Cox proportional hazards model, stratified by duration of response to prior platinum therapy (<3 months, >=3 months)
[16] - Log-rank test, stratified by duration of response to prior platinum therapy (<3 months, >=3 months)

Secondary: Progression Free Survival (PFS) - ITT Analysis Set

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End point title

Progression Free Survival (PFS) - ITT Analysis Set

End point description

PFS was evaluated using the stratified log-rank test, as described for OS, with specific conventions for censoring. PFS data were censored on the date of the last tumor assessment documenting absence of PD for subjects who 1) were given anti-tumor treatment other than the study treatment prior to observing objective tumor progression; 2) were removed from the study prior to documentation of objective tumor progression; 3) were ongoing and did not have objective tumor progression at the time of the analysis. Death or disease progression that occurred after more than one missed visit (i.e., 12 weeks) was censored on the date of the last tumor assessment prior to the first missed visit. Subjects with no post-baseline tumor assessments were censored on the date of randomization.

End point type

Secondary

End point timeframe

From the date of randomization to the date of first documentation of tumor progression or death from any cause, whichever occurred first.

End point values	ITT Analysis Set - Part 2 - Group A	ITT Analysis Set - Part 2 - Group B	ITT Analysis Set - Part 2 - Group C
Number of subjects analysed	190	187	94
Units: months
number (confidence interval 95%)
Kaplan-Meier Estimate of PFS - 25th Quartile	1.4 (1.4 to 1.7)	1.5 (1.4 to 1.8)	1.6 (1.4 to 2.5)
Kaplan-Meier Estimate of PFS - Median	3.0 (2.7 to 4.2)	3.5 (2.8 to 4.2)	3.4 (2.8 to 4.2)
Kaplan-Meier Estimate of PFS - 75th Quartile	5.7 (5.5 to 6.9)	6.2 (5.6 to 7.7)	6.1 (4.5 to 7.3)
Percentage Alive and Progression Free at 6 months	25.8 (19.7 to 32.4)	29.5 (23.0 to 36.4)	29.5 (20.4 to 39.2)
Percentage Alive and Progression Free at 12 months	5.2 (2.3 to 9.9)	9.4 (5.3 to 14.7)	5.3 (1.6 to 12.4)
Percentage Alive and Progression Free at 18 months	3.9 (1.3 to 8.7)	5.1 (2.2 to 9.8)	5.3 (1.6 to 12.4)
Percentage Alive and Progression Free at 24 months	3.9 (1.3 to 8.7)	3.1 (0.7 to 8.8)	5.3 (1.6 to 12.4)

Hazard Ratio vs Irinotecan

Statistical analysis description

Progression-Free Survival was evaluated using the stratified log-rank test, as described for OS, with specific conventions for censoring.

Comparison groups

ITT Analysis Set - Part 2 - Group B v ITT Analysis Set - Part 2 - Group A

Number of subjects included in analysis

377

Analysis specification

Pre-specified

Analysis type

other ^[17]

P-value

= 0.3482 ^[18]

Method

Logrank

Parameter type

Cox proportional hazard

Point estimate

0.9

Confidence interval

level

95%

sides

2-sided

lower limit

0.72

upper limit

1.13

Notes
[17] - Based on Cox proportional hazards model, stratified by duration of response to prior platinum therapy (<3 months, ≥3 months).
[18] - Log-rank test, stratified by duration of response to prior platinum therapy (<3 months, >=3 months)

Hazard Ratio vs Topotecan

Statistical analysis description

Progression-Free Survival was evaluated using the stratified log-rank test, as described for OS, with specific conventions for censoring.

Comparison groups

ITT Analysis Set - Part 2 - Group B v ITT Analysis Set - Part 2 - Group C

Number of subjects included in analysis

281

Analysis specification

Pre-specified

Analysis type

other ^[19]

P-value

= 0.9728 ^[20]

Method

Logrank

Parameter type

Cox proportional hazard

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.76

upper limit

1.31

Notes
[19] - Based on Cox proportional hazards model, stratified by duration of response to prior platinum therapy (<3 months, ≥3 months).
[20] - Log-rank test, stratified by duration of response to prior platinum therapy (<3 months, >=3 months)

Secondary: Best Overall Response

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End point title

Best Overall Response

End point description

The number and percentage of subjects in each BOR category (i.e., CR, PR, SD, PD, and unevaluable) were summarized by treatment group. Subjects with unconfirmed CR or PR assessments were categorized separately. The table included a category for subjects who died or discontinued the study due to disease progression prior to the first tumor assessment, as well as ongoing subjects without a tumor assessment prior to the data cut-off date for analysis. Subjects were classified as having SD if assessed as SD (or better) at least 6 weeks after first dose date.

End point type

Secondary

End point timeframe

From the start of study treatment until the last assessment of tumor response recorded during follow-up or the start of any post-treatment cancer therapy (whichever was sooner), taking into account any requirement for confirmation.

End point values	ITT Analysis Set - Part 2 - Group A	ITT Analysis Set - Part 2 - Group B	ITT Analysis Set - Part 2 - Group C	Efficacy Evaluable Analysis Set - Group A	Efficacy Evaluable Analysis Set - Group B	Efficacy Evaluable Analysis Set - Group C
Number of subjects analysed	190	187	94	157	164	80
Units: Number
Complete Response (CR)	4	1	2	4	1	2
Complete Response Unconfirmed (CRu)	1	0	0	1	0	0
Partial Response (PR)	32	31	17	32	31	17
Partial Response Unconfirmed (PRu)	10	13	4	10	13	4
Stable Disease (SD)	65	81	41	61	79	39
Progressive Disease (PD)	46	41	18	45	39	18
Not Evaluable (NE)	4	1	0	4	1	0

No statistical analyses for this end point

Secondary: Overall Response Rate (Confirmed)

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End point title

Overall Response Rate (Confirmed)

End point description

Overall Response Rate was defined as the percentage of subjects with best overall response (BOR) of either CR or PR. Subjects with no post-baseline results were considered non-responders. Overall Response Rate was calculated by treatment group for ITT and Efficacy Evaluable subjects. Both confirmed and unconfirmed CR/PR were tabulated. The rates were presented along with two-sided 95% exact CIs. The 95% CIs were derived using the Clopper-Pearson method. This method is commonly used in the literature for reporting tumor response rates and is conservative, providing no less than 95% coverage probability even for a small N.

End point type

Secondary

End point timeframe

End point values	ITT Analysis Set - Part 2 - Group A	ITT Analysis Set - Part 2 - Group B	ITT Analysis Set - Part 2 - Group C	Efficacy Evaluable Analysis Set - Group A	Efficacy Evaluable Analysis Set - Group B	Efficacy Evaluable Analysis Set - Group C
Number of subjects analysed	190	187	94	157	164	80
Units: Number
number (confidence interval 95%)
Number of Subjects with CR/PR	18.9 (13.6 to 25.3)	17.1 (12.0 to 23.3)	20.2 (12.6 to 29.8)	22.9 (16.6 to 30.3)	19.5 (13.7 to 26.4)	23.8 (14.9 to 34.6)

Odds Ratio vs Irinotecan - ITT Analysis Set

Comparison groups

ITT Analysis Set - Part 2 - Group B v ITT Analysis Set - Part 2 - Group A

Number of subjects included in analysis

377

Analysis specification

Pre-specified

Analysis type

other ^[21]

P-value

= 0.5987 ^[22]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

0.87

Confidence interval

level

95%

sides

2-sided

lower limit

0.51

upper limit

1.47

Notes
[21] - Mantel-Haenszel estimate of the odds ratio, with stratification by duration of response to prior platinum therapy (<3 months, ≥3 months). An odds ratio >1indicates an advantage for the dinutuximab combination treatment group.
[22] - p-value based on Cochran Mantel-Haenszel chi-square test, stratified by duration of response to prior platinum therapy (<3 months, ≥3 months)

Odds Ratio vs Topotecan - ITT Analysis Set

Comparison groups

ITT Analysis Set - Part 2 - Group B v ITT Analysis Set - Part 2 - Group C

Number of subjects included in analysis

281

Analysis specification

Pre-specified

Analysis type

other ^[23]

P-value

= 0.5892 ^[24]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

0.84

Confidence interval

level

95%

sides

2-sided

lower limit

0.44

upper limit

1.59

Notes
[23] - Mantel-Haenszel estimate of the odds ratio, with stratification by duration of response to prior platinum therapy (<3 months, ≥3 months). An odds ratio >1indicates an advantage for the dinutuximab combination treatment group.
[24] - p-value based on Cochran Mantel-Haenszel chi-square test, stratified by duration of response to prior platinum therapy (<3 months, ≥3 months)

Odds Ratio vs Irinotecan - Efficacy Evaluable Set

Comparison groups

Efficacy Evaluable Analysis Set - Group A v Efficacy Evaluable Analysis Set - Group B

Number of subjects included in analysis

321

Analysis specification

Pre-specified

Analysis type

other ^[25]

P-value

= 0.4375 ^[26]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

0.81

Confidence interval

level

95%

sides

2-sided

lower limit

0.47

upper limit

1.39

Notes
[25] - Mantel-Haenszel estimate of the odds ratio, with stratification by duration of response to prior platinum therapy (<3 months, ≥3 months). An odds ratio >1indicates an advantage for the dinutuximab combination treatment group.
[26] - p-value based on Cochran Mantel-Haenszel chi-square test, stratified by duration of response to prior platinum therapy (<3 months, ≥3 months)

Odds Ratio vs Topotecan - Efficacy Evaluable Set

Comparison groups

Efficacy Evaluable Analysis Set - Group B v Efficacy Evaluable Analysis Set - Group C

Number of subjects included in analysis

244

Analysis specification

Pre-specified

Analysis type

other ^[27]

P-value

= 0.477 ^[28]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

0.79

Confidence interval

level

95%

sides

2-sided

lower limit

0.41

upper limit

1.52

Notes
[27] - Mantel-Haenszel estimate of the odds ratio, with stratification by duration of response to prior platinum therapy (<3 months, ≥3 months). An odds ratio >1indicates an advantage for the dinutuximab combination treatment group.
[28] - p-value based on Cochran Mantel-Haenszel chi-square test, stratified by duration of response to prior platinum therapy (<3 months, ≥3 months)

Secondary: Overall Response Rate (Unconfirmed + Confirmed)

Top of page

End point title

Overall Response Rate (Unconfirmed + Confirmed)

End point description

End point type

Secondary

End point timeframe

End point values	ITT Analysis Set - Part 2 - Group A	ITT Analysis Set - Part 2 - Group B	ITT Analysis Set - Part 2 - Group C	Efficacy Evaluable Analysis Set - Group A	Efficacy Evaluable Analysis Set - Group B	Efficacy Evaluable Analysis Set - Group C
Number of subjects analysed	190	187	94	157	164	80
Units: Number
number (confidence interval 95%)
Number of Subjects with CR/Cru/PR/PRu	24.7 (18.8 to 31.5)	24.1 (18.1 to 30.8)	24.5 (16.2 to 34.4)	29.9 (22.9 to 37.8)	27.4 (20.8 to 34.9)	28.8 (19.2 to 40.0)

Odds Ratio vs Irinotecan - ITT Analysis Set

Comparison groups

ITT Analysis Set - Part 2 - Group B v ITT Analysis Set - Part 2 - Group A

Number of subjects included in analysis

377

Analysis specification

Pre-specified

Analysis type

other ^[29]

P-value

= 0.8043 ^[30]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

0.94

Confidence interval

level

95%

sides

2-sided

lower limit

0.58

upper limit

1.52

Notes
[29] - Mantel-Haenszel estimate of the odds ratio, with stratification by duration of response to prior platinum therapy (<3 months, ≥3 months). An odds ratio >1 indicates an advantage for the dinutuximab combination treatment group.
[30] - p-value based on Cochran Mantel-Haenszel chi-square test, stratified by duration of response to prior platinum therapy (<3 months, ≥3 months).

Odds Ratio vs Topotecan - ITT Analysis Set

Comparison groups

ITT Analysis Set - Part 2 - Group B v ITT Analysis Set - Part 2 - Group C

Number of subjects included in analysis

281

Analysis specification

Pre-specified

Analysis type

other ^[31]

P-value

= 0.9231 ^[32]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

1.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.57

upper limit

1.87

Notes
[31] - Mantel-Haenszel estimate of the odds ratio, with stratification by duration of response to prior platinum therapy (<3 months, ≥3 months). An odds ratio >1 indicates an advantage for the dinutuximab combination treatment group.
[32] - p-value based on Cochran Mantel-Haenszel chi-square test, stratified by duration of response to prior platinum therapy (<3 months, ≥3 months).

Odds Ratio vs Irinotecan - Efficacy Evaluable Set

Comparison groups

Efficacy Evaluable Analysis Set - Group A v Efficacy Evaluable Analysis Set - Group B

Number of subjects included in analysis

321

Analysis specification

Pre-specified

Analysis type

other ^[33]

P-value

= 0.5883 ^[34]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

0.87

Confidence interval

level

95%

sides

2-sided

lower limit

0.54

upper limit

1.43

Notes
[33] - Mantel-Haenszel estimate of the odds ratio, with stratification by duration of response to prior platinum therapy (<3 months, ≥3 months). An odds ratio >1 indicates an advantage for the dinutuximab combination treatment group.
[34] - p-value based on Cochran Mantel-Haenszel chi-square test, stratified by duration of response to prior platinum therapy (<3 months, ≥3 months).

Odds Ratio vs Topotecan - Efficacy Evaluable Set

Comparison groups

Efficacy Evaluable Analysis Set - Group B v Efficacy Evaluable Analysis Set - Group C

Number of subjects included in analysis

244

Analysis specification

Pre-specified

Analysis type

other ^[35]

P-value

= 0.9074 ^[36]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

0.96

Confidence interval

level

95%

sides

2-sided

lower limit

0.52

upper limit

1.79

Notes
[35] - Mantel-Haenszel estimate of the odds ratio, with stratification by duration of response to prior platinum therapy (<3 months, ≥3 months). An odds ratio >1 indicates an advantage for the dinutuximab combination treatment group.
[36] - p-value based on Cochran Mantel-Haenszel chi-square test, stratified by duration of response to prior platinum therapy (<3 months, ≥3 months).

Secondary: Clinical Benefit Rate

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End point title

Clinical Benefit Rate

End point description

The CBR was defined as the percentage of subjects with either a CR or PR, or SD (confirmed and unconfirmed). Subjects with no post-baseline tumor assessments were considered to have achieved no clinical benefit. Subjects were classified as having SD if assessed as SD (or better) at least 6 weeks after first dose date.

End point type

Secondary

End point timeframe

End point values	ITT Analysis Set - Part 2 - Group A	ITT Analysis Set - Part 2 - Group B	ITT Analysis Set - Part 2 - Group C	Efficacy Evaluable Analysis Set - Group A	Efficacy Evaluable Analysis Set - Group B	Efficacy Evaluable Analysis Set - Group C
Number of subjects analysed	190	187	94	157	164	80
Units: Number
number (confidence interval 95%)
Number of Subjects with CR/CRu/PR/PRu/SD	58.9 (51.6 to 66.0)	67.4 (60.2 to 74.0)	68.1 (57.7 to 77.3)	68.8 (60.9 to 75.9)	75.6 (68.3 to 82.0)	77.5 (66.8 to 86.1)

Odds Ratio vs Irinotecan - ITT Analysis Set

Comparison groups

ITT Analysis Set - Part 2 - Group A v ITT Analysis Set - Part 2 - Group B

Number of subjects included in analysis

377

Analysis specification

Pre-specified

Analysis type

other ^[37]

P-value

= 0.0989 ^[38]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

1.43

Confidence interval

level

95%

sides

2-sided

lower limit

0.94

upper limit

2.19

Notes
[37] - Mantel-Haenszel estimate of the odds ratio, with stratification by duration of response to prior platinum therapy (<3 months, ≥3 months). An odds ratio >1 indicates an advantage for the Dinutuximab combination treatment group.
[38] - p-value based on Cochran Mantel-Haenszel chi-square test, stratified by duration of response to prior platinum therapy (<3 months, ≥3 months).

Odds Ratio vs Topotecan - ITT Analysis Set

Comparison groups

ITT Analysis Set - Part 2 - Group B v ITT Analysis Set - Part 2 - Group C

Number of subjects included in analysis

281

Analysis specification

Pre-specified

Analysis type

other ^[39]

P-value

= 0.9605 ^[40]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

0.99

Confidence interval

level

95%

sides

2-sided

lower limit

0.58

upper limit

1.68

Notes
[39] - Mantel-Haenszel estimate of the odds ratio, with stratification by duration of response to prior platinum therapy (<3 months, ≥3 months). An odds ratio >1 indicates an advantage for the Dinutuximab combination treatment group.
[40] - p-value based on Cochran Mantel-Haenszel chi-square test, stratified by duration of response to prior platinum therapy (<3 months, ≥3 months).

Odds Ratio vs Irinotecan - Efficacy Evaluable Set

Comparison groups

Efficacy Evaluable Analysis Set - Group A v Efficacy Evaluable Analysis Set - Group B

Number of subjects included in analysis

321

Analysis specification

Pre-specified

Analysis type

other ^[41]

P-value

= 0.1768 ^[42]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

1.4

Confidence interval

level

95%

sides

2-sided

lower limit

0.86

upper limit

2.3

Notes
[41] - Mantel-Haenszel estimate of the odds ratio, with stratification by duration of response to prior platinum therapy (<3 months, ≥3 months). An odds ratio >1 indicates an advantage for the Dinutuximab combination treatment group.
[42] - p-value based on Cochran Mantel-Haenszel chi-square test, stratified by duration of response to prior platinum therapy (<3 months, ≥3 months).

Odds Ratio vs Topotecan - Efficacy Evaluable Set

Comparison groups

Efficacy Evaluable Analysis Set - Group B v Efficacy Evaluable Analysis Set - Group C

Number of subjects included in analysis

244

Analysis specification

Pre-specified

Analysis type

other ^[43]

P-value

= 0.7719 ^[44]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

0.91

Confidence interval

level

95%

sides

2-sided

lower limit

0.48

upper limit

1.72

Notes
[43] - Mantel-Haenszel estimate of the odds ratio, with stratification by duration of response to prior platinum therapy (<3 months, ≥3 months). An odds ratio >1 indicates an advantage for the Dinutuximab combination treatment group.
[44] - p-value based on Cochran Mantel-Haenszel chi-square test, stratified by duration of response to prior platinum therapy (<3 months, ≥3 months).

Other pre-specified: Time to Response

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End point title

Time to Response

End point description

The TTR was defined as the time interval between the date of randomization and the date of first documented CR or PR. Complete Response or PR required confirmation at least 4 weeks apart. Once confirmed, the first documented CR or PR was considered as the start of the response. Time to Response was descriptively summarized for subjects who responded.

End point type

Other pre-specified

End point timeframe

From the date of randomization and the date of first documented CR or PR.

End point values	ITT Analysis Set - Part 2 - Group A	ITT Analysis Set - Part 2 - Group B	ITT Analysis Set - Part 2 - Group C
Number of subjects analysed	190	187	94
Units: weeks
arithmetic mean (standard deviation)
Mean	8.08 ± 4.63	11.58 ± 10.28	10.92 ± 8.78

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events were collected for all enrolled subjects beginning with first dose of study medication.

Adverse event reporting additional description

For AE reporting, the Investigator was to report the highest NCI-CTCAE version 4.03 grade if there was a difference in the reported value between contemporaneous local laboratory and central laboratory results. Serious adverse events (and AEs based on local regulations) were to be collected starting on the day of written informed consent.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.1

Reporting group title

Safety Analysis Set - Part 1

Reporting group description

The Safety Analysis Set was defined as all subjects who received at least one dose of any study medication (even a partial dose), grouped by actual treatment received. This set served as the basis for the evaluation of all safety data, as well as demographic and baseline disease characteristics, prior cancer therapy, study drug exposure, and dose modifications. Unless noted otherwise, safety data were summarized or listed separately for Part 1 and Part 2 (even when included within the same table or listing). The lead-in phase of the study (referred to as Part 1) had an enrollment target of approximately 10 subjects. In Part 1, dinutuximab was to be administered at increasing doses, as tolerated, together with irinotecan at a dose of 350 mg/m2 intravenously (IV) on Day 1 of each 21-day cycle.

Reporting group title

Safety Analysis Set - Part 2 - Group A

Reporting group description

The Safety Analysis Set was defined as all subjects who received at least one dose of any study medication (even a partial dose), grouped by actual treatment received. This set served as the basis for the evaluation of all safety data, as well as demographic and baseline disease characteristics, prior cancer therapy, study drug exposure, and dose modifications. Unless noted otherwise, safety data were summarized or listed separately for Part 1 and Part 2 (even when included within the same table or listing). In Part 2, approximately 460 additional subjects with relapsed or refractory SCLC were to be randomized in a 2:2:1 allocation (184/irinotecan group, 184/dinutuximab + irinotecan group, and 92/topotecan group). Subjects randomized to Group A were to receive irinotecan at a dose of 350 mg/m2 on Day 1 of each cycle.

Reporting group title

Safety Analysis Set - Part 2 - Group B

Reporting group description

The Safety Analysis Set was defined as all subjects who received at least one dose of any study medication (even a partial dose), grouped by actual treatment received. This set served as the basis for the evaluation of all safety data, as well as demographic and baseline disease characteristics, prior cancer therapy, study drug exposure, and dose modifications. Unless noted otherwise, safety data were summarized or listed separately for Part 1 and Part 2 (even when included within the same table or listing). In Part 2, approximately 460 additional subjects with relapsed or refractory SCLC were to be randomized in a 2:2:1 allocation (184/irinotecan group, 184/dinutuximab + irinotecan group, and 92/topotecan group). Subjects randomized to Group B were to receive dinutuximab on Day 1 of each cycle beginning with a starting dose of 10 mg/m2 IV or a dose recommended by the SRC, and irinotecan at a dose of 350 mg/m2 on Day 1 of each cycle.

Reporting group title

Safety Analysis Set - Part 2 - Group C

Reporting group description

The Safety Analysis Set was defined as all subjects who received at least one dose of any study medication (even a partial dose), grouped by actual treatment received. This set served as the basis for the evaluation of all safety data, as well as demographic and baseline disease characteristics, prior cancer therapy, study drug exposure, and dose modifications. Unless noted otherwise, safety data were summarized or listed separately for Part 1 and Part 2 (even when included within the same table or listing). In Part 2, approximately 460 additional subjects with relapsed or refractory SCLC were to be randomized in a 2:2:1 allocation (184/irinotecan group, 184/dinutuximab + irinotecan group, and 92/topotecan group). No crossover between groups was allowed because OS was the primary endpoint. Subjects randomized to Group C were to receive topotecan 1.5 mg/m2 IV for 5 consecutive days of each cycle.

Serious adverse events	Safety Analysis Set - Part 1	Safety Analysis Set - Part 2 - Group A	Safety Analysis Set - Part 2 - Group B	Safety Analysis Set - Part 2 - Group C
Total subjects affected by serious adverse events
subjects affected / exposed	5 / 12 (41.67%)	76 / 187 (40.64%)	74 / 183 (40.44%)	39 / 88 (44.32%)
number of deaths (all causes)	1	15	20	6
number of deaths resulting from adverse events	1	15	20	6
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Small cell lung cancer
subjects affected / exposed	0 / 12 (0.00%)	1 / 187 (0.53%)	1 / 183 (0.55%)	2 / 88 (2.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	1 / 1	1 / 1	2 / 2
Vascular disorders
Hypovolaemic shock
subjects affected / exposed	0 / 12 (0.00%)	0 / 187 (0.00%)	1 / 183 (0.55%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
Shock haemorrhagic
subjects affected / exposed	0 / 12 (0.00%)	0 / 187 (0.00%)	1 / 183 (0.55%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	1 / 12 (8.33%)	0 / 187 (0.00%)	0 / 183 (0.00%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Death
subjects affected / exposed	0 / 12 (0.00%)	0 / 187 (0.00%)	1 / 183 (0.55%)	1 / 88 (1.14%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
General physical health deterioration
subjects affected / exposed	0 / 12 (0.00%)	2 / 187 (1.07%)	0 / 183 (0.00%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0
Sudden death
subjects affected / exposed	0 / 12 (0.00%)	1 / 187 (0.53%)	0 / 183 (0.00%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary haemorrhage
subjects affected / exposed	0 / 12 (0.00%)	0 / 187 (0.00%)	1 / 183 (0.55%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
Respiratory failure
subjects affected / exposed	0 / 12 (0.00%)	0 / 187 (0.00%)	1 / 183 (0.55%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
Acute respiratory distress syndrome
subjects affected / exposed	0 / 12 (0.00%)	1 / 187 (0.53%)	0 / 183 (0.00%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	1 / 12 (8.33%)	2 / 187 (1.07%)	0 / 183 (0.00%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	1 / 1	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 12 (0.00%)	1 / 187 (0.53%)	0 / 183 (0.00%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 12 (0.00%)	1 / 187 (0.53%)	0 / 183 (0.00%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 12 (0.00%)	1 / 187 (0.53%)	0 / 183 (0.00%)	2 / 88 (2.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	2 / 2
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 12 (8.33%)	0 / 187 (0.00%)	0 / 183 (0.00%)	2 / 88 (2.27%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 12 (0.00%)	0 / 187 (0.00%)	1 / 183 (0.55%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
Investigations
Blood creatine increased
subjects affected / exposed	1 / 12 (8.33%)	1 / 187 (0.53%)	0 / 183 (0.00%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardio-respiratory arrest
subjects affected / exposed	0 / 12 (0.00%)	0 / 187 (0.00%)	2 / 183 (1.09%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 12 (0.00%)	0 / 187 (0.00%)	1 / 183 (0.55%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
Acute coronary syndrome
subjects affected / exposed	0 / 12 (0.00%)	0 / 187 (0.00%)	0 / 183 (0.00%)	1 / 88 (1.14%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
Atrial fibrillation
Additional description: Acute fibrillation
subjects affected / exposed	1 / 12 (8.33%)	0 / 187 (0.00%)	0 / 183 (0.00%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Haemorrhagic stroke
subjects affected / exposed	0 / 12 (0.00%)	1 / 187 (0.53%)	1 / 183 (0.55%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	0 / 12 (0.00%)	17 / 187 (9.09%)	8 / 183 (4.37%)	3 / 88 (3.41%)
occurrences causally related to treatment / all	0 / 0	17 / 17	2 / 8	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0
Neutropenia
subjects affected / exposed	1 / 12 (8.33%)	7 / 187 (3.74%)	7 / 183 (3.83%)	4 / 88 (4.55%)
occurrences causally related to treatment / all	1 / 1	7 / 7	7 / 7	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
Anaemia
subjects affected / exposed	0 / 12 (0.00%)	2 / 187 (1.07%)	4 / 183 (2.19%)	6 / 88 (6.82%)
occurrences causally related to treatment / all	0 / 0	2 / 2	4 / 4	6 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	2 / 12 (16.67%)	17 / 187 (9.09%)	8 / 183 (4.37%)	1 / 88 (1.14%)
occurrences causally related to treatment / all	2 / 2	17 / 17	8 / 8	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Acute hepatic failure
subjects affected / exposed	0 / 12 (0.00%)	1 / 187 (0.53%)	0 / 183 (0.00%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 12 (8.33%)	3 / 187 (1.60%)	0 / 183 (0.00%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	1 / 1	3 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	1 / 12 (8.33%)	9 / 187 (4.81%)	6 / 183 (3.28%)	1 / 88 (1.14%)
occurrences causally related to treatment / all	1 / 1	9 / 9	6 / 6	1 / 1
deaths causally related to treatment / all	0 / 0	2 / 2	3 / 3	0 / 0
Sepsis
subjects affected / exposed	0 / 12 (0.00%)	1 / 187 (0.53%)	2 / 183 (1.09%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	2 / 2	0 / 0
Neutropenic sepsis
subjects affected / exposed	0 / 12 (0.00%)	0 / 187 (0.00%)	1 / 183 (0.55%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
Septic shock
subjects affected / exposed	1 / 12 (8.33%)	3 / 187 (1.60%)	1 / 183 (0.55%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	1 / 1	3 / 3	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 12 (8.33%)	0 / 187 (0.00%)	0 / 183 (0.00%)	2 / 88 (2.27%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	1 / 12 (8.33%)	4 / 187 (2.14%)	0 / 183 (0.00%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	1 / 1	4 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Tumour lysis syndrome
subjects affected / exposed	0 / 12 (0.00%)	1 / 187 (0.53%)	0 / 183 (0.00%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	1 / 12 (8.33%)	0 / 187 (0.00%)	1 / 183 (0.55%)	0 / 88 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Safety Analysis Set - Part 1	Safety Analysis Set - Part 2 - Group A	Safety Analysis Set - Part 2 - Group B	Safety Analysis Set - Part 2 - Group C
Total subjects affected by non serious adverse events
subjects affected / exposed	12 / 12 (100.00%)	183 / 187 (97.86%)	183 / 183 (100.00%)	86 / 88 (97.73%)
Investigations
Weight decreased
subjects affected / exposed	1 / 12 (8.33%)	25 / 187 (13.37%)	24 / 183 (13.11%)	8 / 88 (9.09%)
occurrences all number	1	25	24	8
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 12 (0.00%)	6 / 187 (3.21%)	19 / 183 (10.38%)	5 / 88 (5.68%)
occurrences all number	0	6	19	5
Neutrophil count decreased
subjects affected / exposed	1 / 12 (8.33%)	28 / 187 (14.97%)	18 / 183 (9.84%)	23 / 88 (26.14%)
occurrences all number	1	28	18	23
Alanine aminotransferase increased
subjects affected / exposed	0 / 12 (0.00%)	13 / 187 (6.95%)	12 / 183 (6.56%)	8 / 88 (9.09%)
occurrences all number	0	13	12	8
Aspartate aminotransferase increased
subjects affected / exposed	0 / 12 (0.00%)	11 / 187 (5.88%)	10 / 183 (5.46%)	8 / 88 (9.09%)
occurrences all number	0	11	10	8
Platelet count decreased
subjects affected / exposed	1 / 12 (8.33%)	6 / 187 (3.21%)	10 / 183 (5.46%)	18 / 88 (20.45%)
occurrences all number	1	6	10	18
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 12 (0.00%)	6 / 187 (3.21%)	7 / 183 (3.83%)	5 / 88 (5.68%)
occurrences all number	0	6	7	5
White blood cell count decreased
subjects affected / exposed	0 / 12 (0.00%)	12 / 187 (6.42%)	6 / 183 (3.28%)	14 / 88 (15.91%)
occurrences all number	0	12	6	14
Lymphocyte count decreased
subjects affected / exposed	0 / 12 (0.00%)	4 / 187 (2.14%)	5 / 183 (2.73%)	5 / 88 (5.68%)
occurrences all number	0	4	5	5
Vascular disorders
Hypotension
subjects affected / exposed	1 / 12 (8.33%)	9 / 187 (4.81%)	15 / 183 (8.20%)	5 / 88 (5.68%)
occurrences all number	1	9	15	5
Hypertension
subjects affected / exposed	1 / 12 (8.33%)	4 / 187 (2.14%)	14 / 183 (7.65%)	3 / 88 (3.41%)
occurrences all number	1	4	14	3
Nervous system disorders
Headache
subjects affected / exposed	2 / 12 (16.67%)	12 / 187 (6.42%)	21 / 183 (11.48%)	4 / 88 (4.55%)
occurrences all number	2	12	21	4
Dizziness
subjects affected / exposed	0 / 12 (0.00%)	15 / 187 (8.02%)	12 / 183 (6.56%)	6 / 88 (6.82%)
occurrences all number	0	15	12	6
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	3 / 12 (25.00%)	55 / 187 (29.41%)	67 / 183 (36.61%)	58 / 88 (65.91%)
occurrences all number	3	55	67	58
Neutropenia
subjects affected / exposed	4 / 12 (33.33%)	47 / 187 (25.13%)	59 / 183 (32.24%)	45 / 88 (51.14%)
occurrences all number	4	47	59	45
Leukopenia
subjects affected / exposed	0 / 12 (0.00%)	22 / 187 (11.76%)	30 / 183 (16.39%)	12 / 88 (13.64%)
occurrences all number	0	22	30	12
Thrombocytopenia
subjects affected / exposed	0 / 12 (0.00%)	13 / 187 (6.95%)	18 / 183 (9.84%)	22 / 88 (25.00%)
occurrences all number	0	13	18	22
Febrile neutropenia
subjects affected / exposed	0 / 12 (0.00%)	18 / 187 (9.63%)	11 / 183 (6.01%)	4 / 88 (4.55%)
occurrences all number	0	18	11	4
General disorders and administration site conditions
Asthenia
subjects affected / exposed	4 / 12 (33.33%)	39 / 187 (20.86%)	44 / 183 (24.04%)	25 / 88 (28.41%)
occurrences all number	4	39	44	25
Fatigue
subjects affected / exposed	3 / 12 (25.00%)	48 / 187 (25.67%)	36 / 183 (19.67%)	16 / 88 (18.18%)
occurrences all number	3	48	36	16
Non-cardiac chest pain
subjects affected / exposed	1 / 12 (8.33%)	8 / 187 (4.28%)	24 / 183 (13.11%)	5 / 88 (5.68%)
occurrences all number	1	8	24	5
Pyrexia
subjects affected / exposed	2 / 12 (16.67%)	10 / 187 (5.35%)	19 / 183 (10.38%)	13 / 88 (14.77%)
occurrences all number	2	10	19	13
Pain
subjects affected / exposed	0 / 12 (0.00%)	5 / 187 (2.67%)	13 / 183 (7.10%)	1 / 88 (1.14%)
occurrences all number	0	5	13	1
Chest pain
subjects affected / exposed	1 / 12 (8.33%)	5 / 187 (2.67%)	11 / 183 (6.01%)	1 / 88 (1.14%)
occurrences all number	1	5	11	1
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	10 / 12 (83.33%)	116 / 187 (62.03%)	118 / 183 (64.48%)	13 / 88 (14.77%)
occurrences all number	10	116	118	13
Abdominal pain
subjects affected / exposed	5 / 12 (41.67%)	24 / 187 (12.83%)	82 / 183 (44.81%)	9 / 88 (10.23%)
occurrences all number	5	24	82	9
Nausea
subjects affected / exposed	7 / 12 (58.33%)	88 / 187 (47.06%)	81 / 183 (44.26%)	22 / 88 (25.00%)
occurrences all number	7	88	81	22
Vomiting
subjects affected / exposed	5 / 12 (41.67%)	57 / 187 (30.48%)	65 / 183 (35.52%)	6 / 88 (6.82%)
occurrences all number	5	57	65	6
Abdominal pain upper
subjects affected / exposed	2 / 12 (16.67%)	11 / 187 (5.88%)	30 / 183 (16.39%)	5 / 88 (5.68%)
occurrences all number	2	11	30	5
Constipation
subjects affected / exposed	4 / 12 (33.33%)	16 / 187 (8.56%)	16 / 183 (8.74%)	13 / 88 (14.77%)
occurrences all number	4	16	16	13
Dysphagia
subjects affected / exposed	1 / 12 (8.33%)	3 / 187 (1.60%)	6 / 183 (3.28%)	0 / 88 (0.00%)
occurrences all number	1	3	6	0
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 12 (8.33%)	4 / 187 (2.14%)	4 / 183 (2.19%)	1 / 88 (1.14%)
occurrences all number	1	4	4	1
Stomatitis
subjects affected / exposed	1 / 12 (8.33%)	9 / 187 (4.81%)	4 / 183 (2.19%)	6 / 88 (6.82%)
occurrences all number	1	9	4	6
Abdominal pain lower
subjects affected / exposed	1 / 12 (8.33%)	2 / 187 (1.07%)	3 / 183 (1.64%)	0 / 88 (0.00%)
occurrences all number	1	2	3	0
Dry mouth
subjects affected / exposed	1 / 12 (8.33%)	4 / 187 (2.14%)	3 / 183 (1.64%)	1 / 88 (1.14%)
occurrences all number	1	4	3	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	4 / 12 (33.33%)	16 / 187 (8.56%)	28 / 183 (15.30%)	9 / 88 (10.23%)
occurrences all number	4	16	28	9
Dyspnoea
subjects affected / exposed	0 / 12 (0.00%)	18 / 187 (9.63%)	27 / 183 (14.75%)	13 / 88 (14.77%)
occurrences all number	0	18	27	13
Productive cough
subjects affected / exposed	1 / 12 (8.33%)	6 / 187 (3.21%)	11 / 183 (6.01%)	3 / 88 (3.41%)
occurrences all number	1	6	11	3
Dysphonia
subjects affected / exposed	1 / 12 (8.33%)	4 / 187 (2.14%)	8 / 183 (4.37%)	1 / 88 (1.14%)
occurrences all number	1	4	8	1
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	1 / 12 (8.33%)	33 / 187 (17.65%)	49 / 183 (26.78%)	10 / 88 (11.36%)
occurrences all number	1	33	49	10
Psychiatric disorders
Insomnia
subjects affected / exposed	0 / 12 (0.00%)	6 / 187 (3.21%)	9 / 183 (4.92%)	4 / 88 (4.55%)
occurrences all number	0	6	9	4
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	6 / 12 (50.00%)	11 / 187 (5.88%)	47 / 183 (25.68%)	6 / 88 (6.82%)
occurrences all number	6	11	47	6
Pain in extremity
subjects affected / exposed	3 / 12 (25.00%)	5 / 187 (2.67%)	31 / 183 (16.94%)	3 / 88 (3.41%)
occurrences all number	3	5	31	3
Musculoskeletal pain
subjects affected / exposed	1 / 12 (8.33%)	8 / 187 (4.28%)	16 / 183 (8.74%)	2 / 88 (2.27%)
occurrences all number	1	8	16	2
Myalgia
subjects affected / exposed	0 / 12 (0.00%)	3 / 187 (1.60%)	13 / 183 (7.10%)	2 / 88 (2.27%)
occurrences all number	0	3	13	2
Musculoskeletal chest pain
subjects affected / exposed	2 / 12 (16.67%)	3 / 187 (1.60%)	12 / 183 (6.56%)	3 / 88 (3.41%)
occurrences all number	2	3	12	3
Arthralgia
subjects affected / exposed	2 / 12 (16.67%)	2 / 187 (1.07%)	11 / 183 (6.01%)	4 / 88 (4.55%)
occurrences all number	2	2	11	4
Muscular weakness
subjects affected / exposed	1 / 12 (8.33%)	10 / 187 (5.35%)	2 / 183 (1.09%)	3 / 88 (3.41%)
occurrences all number	1	10	2	3
Infections and infestations
Pneumonia
subjects affected / exposed	1 / 12 (8.33%)	11 / 187 (5.88%)	12 / 183 (6.56%)	9 / 88 (10.23%)
occurrences all number	1	11	12	9
Upper respiratory tract infection
subjects affected / exposed	1 / 12 (8.33%)	10 / 187 (5.35%)	5 / 183 (2.73%)	2 / 88 (2.27%)
occurrences all number	1	10	5	2
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	5 / 12 (41.67%)	58 / 187 (31.02%)	60 / 183 (32.79%)	23 / 88 (26.14%)
occurrences all number	5	58	60	23
Hypokalaemia
subjects affected / exposed	1 / 12 (8.33%)	16 / 187 (8.56%)	18 / 183 (9.84%)	4 / 88 (4.55%)
occurrences all number	1	16	18	4
Hyponatraemia
subjects affected / exposed	0 / 12 (0.00%)	17 / 187 (9.09%)	14 / 183 (7.65%)	2 / 88 (2.27%)
occurrences all number	0	17	14	2
Dehydration
subjects affected / exposed	2 / 12 (16.67%)	14 / 187 (7.49%)	10 / 183 (5.46%)	1 / 88 (1.14%)
occurrences all number	2	14	10	1
Hyperglycaemia
subjects affected / exposed	0 / 12 (0.00%)	4 / 187 (2.14%)	8 / 183 (4.37%)	9 / 88 (10.23%)
occurrences all number	0	4	8	9
Hypomagnesaemia
subjects affected / exposed	3 / 12 (25.00%)	9 / 187 (4.81%)	7 / 183 (3.83%)	4 / 88 (4.55%)
occurrences all number	3	9	7	4
Hypoalbuminaemia
subjects affected / exposed	0 / 12 (0.00%)	11 / 187 (5.88%)	6 / 183 (3.28%)	0 / 88 (0.00%)
occurrences all number	0	11	6	0

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Were there any global substantial amendments to the protocol? Yes

10 Apr 2017

Amendment 1 Additions to protect safety of trial participants, including addition of exclusion criteria for subjects with a history of atypical thrombotic thrombocytopenic purpura or hemolytic uremic syndrome Added prompt for Investigators to consider discontinuing dinutuximab if Grade 3 pain recurred after reducing the dose of dinutuximab once. Added statement to inform Investigators of potential for immunogenic interaction between rasburicase and dinutuximab. Added ophthalmology examination to determine whether any clinically significant deterioration in vision was observed during the study. Updated collection time points for sparse PK sample collection in Part 2, Group B. Added text regarding a detailed pain medication log to allow for a more thorough analysis of pain and pain management associated with dinutuximab. Details regarding safety monitoring and data analyses, including when the DMC will be alerted to the potential for excess risk and grounds for stopping the study due to elevated mortality risk associated with dinutuximab. Added details on when the DMC will meet and the review and consideration of safety data including AEs of particular concern for dinutuximab. Added a reference to support approach for safety data monitoring.

19 Dec 2017

Amendment 2 Added summary of Part 1 data in adults from the current study in Section 1.15 of the protocol and made edits throughout protocol resulting from availability of Part 1 data, including updates to dinutuximab dosing. Clarified the intended patient population to be enrolled through additional or clearer language and updated contraception requirements to be consistent with international guidelines. Modified prior treatment/trauma exclusion criteria to be consistent with recovery based criteria, removed hypersensitivity exclusion given prior therapy with study drugs is prohibited and based on Part 1 experience, and added exclusion criterion based on prescribing information for irinotecan. Updated Estimated Study Duration section to focus on Part 2 only and define study end. Updated text to allow for locally approved prescribing information and maximize potential for dinutuximab treatment effect. Clarified potential reasons for treatment discontinuation and main reasons subjects may withdraw or be withdrawn from the study. Clarified how treatment delays should be handled for subjects randomized to Group B. Updated pain management guidelines and management guidelines for peripheral neuropathy based on Part 1 study experience. Post-screening assessments specific to pain were removed in order to avoid biasing the results. Pain was still reported as an AE, as appropriate, but the subjects were not specifically asked about pain every 15 minutes throughout the infusion. Clarified source of irinotecan and topotecan prescribing information and included additional information from topotecan US prescribing information. Clarified collection of concomitant medication information for enrolled/randomized subjects, expanded the list of permitted concomitant medications, and addressed the use of steroids.

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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Clinical Trial Results:
A Two-Part, Open-Label, Randomized, Phase II/III Study of Dinutuximab and Irinotecan versus Irinotecan for Second Line Treatment of Subjects with Relapsed or Refractory Small Cell Lung Cancer

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Clinical trials

Clinical Trial Results: A Two-Part, Open-Label, Randomized, Phase II/III Study of Dinutuximab and Irinotecan versus Irinotecan for Second Line Treatment of Subjects with Relapsed or Refractory Small Cell Lung Cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Overall Survival (OS) - ITT Analysis Set

Primary: Overall Survival (OS) - ITT Analysis Set

Primary: Overall Survival (OS) - mITT Analysis Set

Primary: Overall Survival (OS) - mITT Analysis Set

Primary: Overall Survival (OS) - Sensitivity Analysis of Per-Protocol Population

Primary: Overall Survival (OS) - Sensitivity Analysis of Per-Protocol Population

Primary: Overall Survival (OS) - Sensitivity Analysis Consider Subjects Lost to Follow-Up as Deaths at Last Follow-up Date

Primary: Overall Survival (OS) - Sensitivity Analysis Consider Subjects Lost to Follow-Up as Deaths at Last Follow-up Date

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Substantial protocol amendments (globally)

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Clinical Trial Results:
A Two-Part, Open-Label, Randomized, Phase II/III Study of Dinutuximab and Irinotecan versus Irinotecan for Second Line Treatment of Subjects with Relapsed or Refractory Small Cell Lung Cancer