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Clinical Trial Results:
A Phase 1/2 Study of PF-02341066, an Oral Small Molecule Inhibitor of Anaplastic Lymphoma Kinase (ALK) and C-Met, in Children With Relapsed/Refractory Solid Tumors and Anaplastic Large Cell Lymphoma

Summary
EudraCT number	2020-003468-19
Trial protocol	Outside EU/EEA
Global end of trial date	19 Jan 2018

Results information
Results version number	v1(current)
This version publication date	11 Nov 2020
First version publication date	11 Nov 2020
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

ADVL0912

ISRCTN number

US NCT number

NCT00939770

WHO universal trial number (UTN)

Other trial identifiers

Clinical Trial Reporting Program: NCI-2011-01937

Sponsor organisation name

Pfizer Inc.

Sponsor organisation address

235 E 42nd Street, New York, United States, NY 10017

Public contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

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

Yes

EMA paediatric investigation plan number(s)

EMEA-001493-PIP03-18

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

21 May 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

19 Jan 2018

Was the trial ended prematurely?

Main objective of the trial

•To estimate the maximum tolerated dose (MTD) and recommend a Phase 2 dose of Crizotinib administered orally twice daily to children with relapsed/refractory solid tumors and anaplastic large cell lymphoma (ALCL). •To define and describe the toxicities of Crizotinib administered on this schedule. •To characterise the pharmacokinetics of Crizotinib in children with refractory cancer.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

29 Sep 2009

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 118

Country: Number of subjects enrolled

Canada: 4

Worldwide total number of subjects

122

EEA total number of subjects

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)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Study was conducted in the United States and Canada from 29 September 2009 to 19 January 2018. A total of 122 subjects were enrolled, out of which only 121 received treatment.

Screening details

Study was conducted in 2 phases. Phase 1 was the dose finding part and Phase 2 was the dose expansion conducted on the maximum tolerated dose (MTD) identified in Phase 1.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase 1 and 2: Anaplastic Large Cell Lymphoma (ALCL) Group

Arm description

Subjects with anaplastic lymphoma kinase (ALK)-positive ALCL, received Crizotinib, orally, twice daily (BID) in each cycle of 28 days until progressive disease or drug-related dose-limiting toxicity that required removal from therapy (up to 88.8 months). Subjects received 165 milligram per meter square (mg/m^2) (Phase 1) and 280 mg/m^2 (Phase 1 and 2) doses of crizotinib.

Arm type

Experimental

Investigational medicinal product name

Crizotinib

Investigational medicinal product code

PF-02341066

Other name

Xalkori

Pharmaceutical forms

Oral solution, Powder for oral solution, Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects with ALK-positive ALCL, received Crizotinib, orally, BID in each cycle of 28 days until progressive disease or drug-related dose-limiting toxicity that required removal from therapy. Subjects received 165 mg/m^2 (Phase 1) and 280 mg/m^2 (Phase 1 and 2) doses of crizotinib.

Phase 1 and 2: Inflammatory Myofibroblastic Tumors (IMT) Group

Arm description

Subjects with ALK-positive IMT, received Crizotinib, orally, BID in each cycle of 28 days until progressive disease or drug-related dose-limiting toxicity that required removal from therapy (up to 88.8 months). Starting dose of crizotinib was 100 mg/m^2 in Phase 1 which was escalated as 165 mg/m^2 (Phase 1) and 280 mg/m^2 (Phase 2).

Arm type

Experimental

Investigational medicinal product name

Crizotinib

Investigational medicinal product code

PF-02341066

Other name

Xalkori

Pharmaceutical forms

Oral solution, Powder for oral solution, Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects with ALK-positive IMT, received Crizotinib, orally, BID in each cycle of 28 days until progressive disease or drug-related dose-limiting toxicity that required removal from therapy. Starting dose of crizotinib was 100 mg/m^2 in Phase 1 which was escalated as 165 mg/m^2 (Phase 1) and 280 mg/m^2 (Phase 2).

Phase 1 and 2: Other Tumors Group

Arm description

Subjects with ALK-positive neuroblastoma (NB), received Crizotinib, orally, BID in each cycle of 28 days until progressive disease or drug-related dose-limiting toxicity that required removal from therapy (up to 88.8 months). Starting dose of crizotinib was 100 mg/m^2 in Phase 1 which was escalated as 130, 165, 215, 280 and up to 365 mg/m^2 (Phase 1 and 2).

Arm type

Experimental

Investigational medicinal product name

Crizotinib

Investigational medicinal product code

PF-02341066

Other name

Xalkori

Pharmaceutical forms

Oral solution, Powder for oral solution, Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects with ALK-positive neuroblastoma (NB), received Crizotinib, orally, BID in each cycle of 28 days until progressive disease or drug-related dose-limiting toxicity that required removal from therapy. Starting dose of crizotinib was 100 mg/m^2 in Phase 1 which was escalated as 130, 165, 215, 280 and up to 365 mg/m^2 (Phase 1 and 2).

Number of subjects in period 1	Phase 1 and 2: Anaplastic Large Cell Lymphoma (ALCL) Group	Phase 1 and 2: Inflammatory Myofibroblastic Tumors (IMT) Group	Phase 1 and 2: Other Tumors Group
Started	26	14	82
Treated	26	14	81
Completed	2	3	1
Not completed	24	11	81
Therapy refusal by Patient/Parent/Guardian	7	1	8
Consent withdrawn by subject	1	-	-
Physician decision	8	4	1
Adverse Event	2	4	6
Progressive Disease	3	-	65
Enrolled but not Treated	-	-	1
Non-Compliance With Study Drug	1	2	-
Lost to follow-up	1	-	-
No Longer Meets Eligibility Criteria	1	-	-

Baseline characteristics

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Reporting group title

Phase 1 and 2: Anaplastic Large Cell Lymphoma (ALCL) Group

Reporting group description

Reporting group title

Phase 1 and 2: Inflammatory Myofibroblastic Tumors (IMT) Group

Reporting group description

Reporting group title

Phase 1 and 2: Other Tumors Group

Reporting group description

Reporting group values	Phase 1 and 2: Anaplastic Large Cell Lymphoma (ALCL) Group	Phase 1 and 2: Inflammatory Myofibroblastic Tumors (IMT) Group	Phase 1 and 2: Other Tumors Group	Total
Number of subjects	26	14	82	122
Age Categorical
Units: Subjects
<2 years	0	0	1	1
2-<6 years	4	4	18	26
6-<12 years	11	8	32	51
12-<18 years	7	2	19	28
18-21 years	4	0	12	16
Age Continuous
Data reported for 121 subjects.
Units: years
arithmetic mean (standard deviation)	11.2 ± 5.02	7.1 ± 3.53	10.0 ± 5.35	-
Gender Categorical
Units: Subjects
Female	8	9	43	60
Male	18	5	39	62
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	3	3	7	13
Not Hispanic or Latino	22	8	68	98
Unknown or Not Reported	1	3	7	11
Race (NIH/OMB)
Units: Subjects
Asian	2	0	4	6
Black or African American	5	1	5	11
White	14	10	63	87
Unknown or Not Reported	5	3	10	18

End points

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Reporting group title

Phase 1 and 2: Anaplastic Large Cell Lymphoma (ALCL) Group

Reporting group description

Reporting group title

Phase 1 and 2: Inflammatory Myofibroblastic Tumors (IMT) Group

Reporting group description

Reporting group title

Phase 1 and 2: Other Tumors Group

Reporting group description

Subject analysis set title

Phase 1: Crizotinib 100 mg/m^2 BID

Subject analysis set type

Per protocol

Subject analysis set description

In Phase 1, subjects received Crizotinib at a dose of 100 mg/m^2, orally twice daily until progressive disease or drug-related dose-limiting toxicity that required removal from therapy (up to 88.8 months).

Subject analysis set title

Phase 1: Crizotinib 130 mg/m^2 BID

Subject analysis set type

Per protocol

Subject analysis set description

In Phase 1, subjects received Crizotinib at a dose of 130 mg/m^2, orally twice daily until progressive disease or drug-related dose-limiting toxicity that required removal from therapy (up to 88.8 months).

Subject analysis set title

Phase 1: Crizotinib 165 mg/m^2 BID

Subject analysis set type

Per protocol

Subject analysis set description

In Phase 1, subjects received Crizotinib at a dose of 165 mg/m^2, orally twice daily until progressive disease or drug-related dose-limiting toxicity that required removal from therapy (up to 88.8 months).

Subject analysis set title

Phase 1: Crizotinib 215 mg/m^2 BID

Subject analysis set type

Per protocol

Subject analysis set description

In Phase 1, subjects received Crizotinib at a dose of 215 mg/m^2, orally twice daily until progressive disease or drug-related dose-limiting toxicity that required removal from therapy (up to 88.8 months).

Subject analysis set title

Phase 1: Crizotinib 280 mg/m^2 BID

Subject analysis set type

Per protocol

Subject analysis set description

In Phase 1, subjects received Crizotinib at a dose of 280 mg/m^2, orally twice daily until progressive disease or drug-related dose-limiting toxicity that required removal from therapy (up to 88.8 months).

Subject analysis set title

Phase 1: Crizotinib 365 mg/m^2 BID

Subject analysis set type

Per protocol

Subject analysis set description

In Phase 1, subjects received Crizotinib at a dose of 365 mg/m^2, orally twice daily until progressive disease or drug-related dose-limiting toxicity that required removal from therapy (up to 88.8 months).

Subject analysis set title

ALCL: Crizotinib 165 mg/m^2 BID

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects with relapsed/refractory solid tumors or ALCL received Crizotinib at a dose of 165 mg/m^2, orally twice daily until progressive disease or drug-related dose-limiting toxicity that required removal from therapy (up to 88.8 months).

Subject analysis set title

ALCL: Crizotinib 280 mg/m^2 BID

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects with relapsed/refractory solid tumors or ALCL received Crizotinib at a dose of 280 mg/m^2, orally twice daily until progressive disease or drug-related dose-limiting toxicity that required removal from therapy (up to 88.8 months).

Subject analysis set title

IMT: Crizotinib 100 mg/m^2 BID

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects with relapsed/refractory solid tumors or IMT received Crizotinib at a dose of 100 mg/m^2, orally twice daily until progressive disease or drug-related dose-limiting toxicity that required removal from therapy (up to 88.8 months).

Subject analysis set title

IMT: Crizotinib 165 mg/m^2 BID

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects with relapsed/refractory solid tumors or IMT received Crizotinib at a dose of 165 mg/m^2, orally twice daily until progressive disease or drug-related dose-limiting toxicity that required removal from therapy (up to 88.8 months).

Subject analysis set title

IMT: Crizotinib 280 mg/m^2 BID

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects with relapsed/refractory solid tumors or IMT received Crizotinib at a dose of 280 mg/m^2, orally twice daily until progressive disease or drug-related dose-limiting toxicity that required removal from therapy (up to 88.8 months).

Subject analysis set title

ALCL and IMT: Crizotinib 100 mg/m^2 BID

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects with relapsed/refractory solid tumors or ALCL and IMT received Crizotinib at a dose of 100 mg/m^2, orally twice daily until progressive disease or drug-related dose-limiting toxicity that required removal from therapy (up to 88.8 months).

Subject analysis set title

ALCL and IMT: Crizotinib 165 mg/m^2 BID

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects with relapsed/refractory solid tumors or ALCL and IMT received Crizotinib at a dose of 165 mg/m^2, orally twice daily until progressive disease or drug-related dose-limiting toxicity that required removal from therapy (up to 88.8 months).

Subject analysis set title

ALCL and IMT: Crizotinib 280 mg/m^2 BID

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects with relapsed/refractory solid tumors or ALCL and IMT received Crizotinib at a dose of 280 mg/m^2, orally twice daily until progressive disease or drug-related dose-limiting toxicity that required removal from therapy (up to 88.8 months).

Subject analysis set title

Total (ALCL): 165 mg/m^2 BID and 280 mg/m^2 BID

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects with relapsed/refractory solid tumors or ALCL received Crizotinib at a dose of 165 mg/m^2 and 280 mg/m^2, orally twice daily until progressive disease or drug-related dose-limiting toxicity that required removal from therapy (up to 88.8 months).

Subject analysis set title

Total (IMT): 165 mg/m^2 BID and 280 mg/m^2 BID

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects with relapsed/refractory solid tumors or IMT received Crizotinib at a dose of 165 mg/m^2 and 280 mg/m^2, orally twice daily until progressive disease or drug-related dose-limiting toxicity that required removal from therapy (up to 88.8 months).

Subject analysis set title

Phase 1: Crizotinib 280 mg/m^2 BID for DLT

Subject analysis set type

Per protocol

Subject analysis set description

Primary: Phase 1: Number of Subjects Reporting Dose Limiting Toxicities (DLTs) With Crizotinib

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End point title

Phase 1: Number of Subjects Reporting Dose Limiting Toxicities (DLTs) With Crizotinib ^[1]

End point description

DLT: protocol-specified events possibly, probably or definitely attributable to crizotinib. Non-hematological DLT: Any Grade(G)4 non-hematological toxicity; Any G3 non-hematological toxicity:G3 nausea, vomiting <3 days,G3 ALT/AST return to levels that met initial eligibility criteria in 7 days of study drug interruption,G3 fever or infection <5 days, G3 hypophosphatemia, hypokalemia, hypocalcemia or hypomagnesemia responsive to oral supplementation; G2 allergic reactions necessitated discontinuation of study drug were not considered DLT; Any G2 non-hematological toxicity persisted for >=7 days,was medically significant or intolerable;Any adverse event with interruption of study drug for >=7 days. Hematological DLT:G4 thrombocytopenia or G4 neutropenia. Grades based on NCI-CTCAE version 4. Only hematological toxicities reported in this endpoint. Per-protocol analysis set included subjects with DLT or without DLT. Number of subjects analysed=subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

Cycle 1 (28 days)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics was planned to be summarized for this endpoint.

End point values	Phase 1: Crizotinib 100 mg/m^2 BID	Phase 1: Crizotinib 130 mg/m^2 BID	Phase 1: Crizotinib 165 mg/m^2 BID	Phase 1: Crizotinib 215 mg/m^2 BID	Phase 1: Crizotinib 365 mg/m^2 BID	Phase 1: Crizotinib 280 mg/m^2 BID for DLT
Number of subjects analysed	5	6	21	10	7	26
Units: subjects
number (not applicable)	0	0	1	0	1	1

No statistical analyses for this end point

Secondary: Phase 1: PK Parameter- Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crizotinib After Single Dose Administration

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End point title

Phase 1: PK Parameter- Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crizotinib After Single Dose Administration

End point description

PK parameter analysis set included all enrolled subjects who received at least one dose of crizotinib and had sufficient information to estimate at least one of the PK parameters of interest. Here, ‘Number of subjects analysed’ signifies subjects evaluable for this endpoint. None of the subjects were evaluated for 280 mg/m^2 BID and 365 mg/m^2 BID dose and were not reported.

End point type

Secondary

End point timeframe

Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8-10 and 22-26 hours post morning dose for subjects >=10 kg; Pre-dose, 1, 2, 4, 6, 8-10 and 22-26 hours post morning dose for subjects <10 kg

End point values	Phase 1: Crizotinib 100 mg/m^2 BID	Phase 1: Crizotinib 130 mg/m^2 BID	Phase 1: Crizotinib 165 mg/m^2 BID	Phase 1: Crizotinib 215 mg/m^2 BID
Number of subjects analysed	5	5	14	2
Units: hours
median (full range (min-max))	2 (1 to 4)	4 (2 to 6)	4 (2 to 8)	4 (4 to 4)

No statistical analyses for this end point

Secondary: Phase 1: PK Parameter- Maximum Observed Plasma Concentration (Cmax) of Crizotinib After Single Dose Administration

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End point title

Phase 1: PK Parameter- Maximum Observed Plasma Concentration (Cmax) of Crizotinib After Single Dose Administration

End point description

PK parameter analysis set included all enrolled subjects who received at least one dose of crizotinib and had sufficient information to estimate at least one of the PK parameters of interest. Here, 99999 in data field signifies that data cannot be estimated for parameters with less than 3 evaluable measurements. Here, ‘Number of subjects analysed’ signifies subjects evaluable for this endpoint. None of the subjects were evaluated for 280 mg/m^2 BID and 365 mg/m^2 BID dose and were not reported.

End point type

Secondary

End point timeframe

Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8-10 and 22-26 hours post morning dose for subjects >=10 kg; Pre-dose, 1, 2, 4, 6, 8-10 and 22-26 hours post morning dose for subjects <10 kg

End point values	Phase 1: Crizotinib 100 mg/m^2 BID	Phase 1: Crizotinib 130 mg/m^2 BID	Phase 1: Crizotinib 165 mg/m^2 BID	Phase 1: Crizotinib 215 mg/m^2 BID
Number of subjects analysed	5	5	14	2
Units: nanograms per millilitre (ng/mL)
geometric mean (geometric coefficient of variation)	111.8 ± 55	169.6 ± 75	111.2 ± 63	99999 ± 99999

No statistical analyses for this end point

Secondary: Phase 1: PK Parameter- Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of Crizotinib After Single Dose Administration

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End point title

Phase 1: PK Parameter- Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of Crizotinib After Single Dose Administration

End point description

PK parameter analysis set included all enrolled subjects who received at least one dose of crizotinib and had sufficient information to estimate at least one of the PK parameters of interest. Here, 99999 in data field signifies that data cannot be estimated for parameters with less than 3 evaluable measurements. Here, ‘Number of subjects analysed’ signifies subjects evaluable for this endpoint. None of the subjects were evaluated for 280 mg/m^2 BID and 365 mg/m^2 BID dose and were not reported.

End point type

Secondary

End point timeframe

Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8-10 and 22-26 hours post morning dose for subjects >=10 kg; Pre-dose, 1, 2, 4, 6, 8-10 and 22-26 hours post morning dose for subjects <10 kg

End point values	Phase 1: Crizotinib 100 mg/m^2 BID	Phase 1: Crizotinib 130 mg/m^2 BID	Phase 1: Crizotinib 165 mg/m^2 BID	Phase 1: Crizotinib 215 mg/m^2 BID
Number of subjects analysed	5	4	14	2
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)	921.7 ± 74	1547 ± 151	867.8 ± 100	99999 ± 99999

No statistical analyses for this end point

Secondary: Phase 1: PK Parameter- Steady State Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crizotinib

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End point title

Phase 1: PK Parameter- Steady State Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crizotinib

End point description

PK parameter analysis set included all enrolled subjects who received at least one dose of crizotinib and had sufficient information to estimate at least one of the PK parameters of interest. Here ‘Number of subjects analysed’ signifies subjects evaluable for this endpoint. None of the subjects were evaluated for 100 mg/m^2 BID and 130 mg/m^2 BID dose and were not reported.

End point type

Secondary

End point timeframe

Between Days 15 and 28 in Cycle 1: pre-dose (12 hours after the last dose), 1 hour, 2 hour, 4 hours, and 6-8 hours post morning dose

End point values	Phase 1: Crizotinib 165 mg/m^2 BID	Phase 1: Crizotinib 215 mg/m^2 BID	Phase 1: Crizotinib 280 mg/m^2 BID	Phase 1: Crizotinib 365 mg/m^2 BID
Number of subjects analysed	1	4	45	3
Units: hours
median (full range (min-max))	5.98 (5.98 to 5.98)	4.08 (2.00 to 6.08)	4.00 (0 to 6.38)	4.00 (1.25 to 6.00)

No statistical analyses for this end point

Secondary: Phase 1: PK Parameter- Steady State Maximum Observed Plasma Concentration (Cmax) of Crizotinib

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End point title

Phase 1: PK Parameter- Steady State Maximum Observed Plasma Concentration (Cmax) of Crizotinib

End point description

PK parameter analysis set included all enrolled subjects who received at least one dose of crizotinib and had sufficient information to estimate at least one of the PK parameters of interest. Here, 99999 in data field signifies that data cannot be estimated for parameters with less than 3 evaluable measurements. Here ‘Number of subjects analysed’ signifies subjects evaluable for this endpoint. None of the subjects were evaluated for 100 mg/m^2 BID and 130 mg/m^2 BID dose and were not reported.

End point type

Secondary

End point timeframe

Between Days 15 and 28 in Cycle 1: pre-dose (12 hours after the last dose), 1 hour, 2 hour, 4 hours, and 6-8 hours post morning dose

End point values	Phase 1: Crizotinib 165 mg/m^2 BID	Phase 1: Crizotinib 215 mg/m^2 BID	Phase 1: Crizotinib 280 mg/m^2 BID	Phase 1: Crizotinib 365 mg/m^2 BID
Number of subjects analysed	1	4	45	3
Units: ng/mL
geometric mean (geometric coefficient of variation)	99999 ± 99999	627.5 ± 17	631.6 ± 69	713.7 ± 26

No statistical analyses for this end point

Secondary: Phase 1: PK Parameter- Steady State Trough Plasma Concentration (Ctrough) of Crizotinib

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End point title

Phase 1: PK Parameter- Steady State Trough Plasma Concentration (Ctrough) of Crizotinib

End point description

Ctrough is the predose plasma concentration. PK parameter analysis set included all enrolled subjects who received at least one dose of crizotinib and had sufficient information to estimate at least one of the PK parameters of interest. Here, 99999 in data field signifies that data cannot be estimated for parameters with less than 3 evaluable measurements. Here ‘Number of subjects analysed’ signifies subjects evaluable for this endpoint. None of the subjects were evaluated for 100 mg/m^2 BID and 130 mg/m^2 BID dose and were not reported.

End point type

Secondary

End point timeframe

Between Days 15 and 28 in Cycle 1: pre-dose (12 hours after the last dose), 1 hour, 2 hour, 4 hours, and 6-8 hours post morning dose

End point values	Phase 1: Crizotinib 165 mg/m^2 BID	Phase 1: Crizotinib 215 mg/m^2 BID	Phase 1: Crizotinib 280 mg/m^2 BID	Phase 1: Crizotinib 365 mg/m^2 BID
Number of subjects analysed	1	3	44	3
Units: ng/mL
geometric mean (geometric coefficient of variation)	99999 ± 99999	306.0 ± 32	459.3 ± 39	546.4 ± 16

No statistical analyses for this end point

Secondary: Phase 1: PK Parameter- Steady State Area Under the Curve from Time Zero to end of dosing interval (AUCtau) of Crizotinib

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End point title

Phase 1: PK Parameter- Steady State Area Under the Curve from Time Zero to end of dosing interval (AUCtau) of Crizotinib

End point description

PK parameter analysis set included all enrolled subjects who received at least one dose of crizotinib and had sufficient information to estimate at least one of the PK parameters of interest. Here, 99999 in data field signifies that data cannot be estimated for parameters with less than 3 evaluable measurements. Here ‘Number of subjects analysed’ signifies subjects evaluable for this endpoint. None of the subjects were evaluated for 100 mg/m^2 BID and 130 mg/m^2 BID dose and were not reported.

End point type

Secondary

End point timeframe

Between Days 15 and 28 in Cycle 1: pre-dose (12 hours after the last dose), 1 hour, 2 hour, 4 hours, and 6-8 hours post morning dose

End point values	Phase 1: Crizotinib 165 mg/m^2 BID	Phase 1: Crizotinib 215 mg/m^2 BID	Phase 1: Crizotinib 280 mg/m^2 BID	Phase 1: Crizotinib 365 mg/m^2 BID
Number of subjects analysed	1	3	44	3
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)	99999 ± 99999	5286 ± 14	6621 ± 34	6794 ± 10

No statistical analyses for this end point

Secondary: Phase 1: PK Parameter- Steady State Apparent Clearance (CL/F) of Crizotinib

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End point title

Phase 1: PK Parameter- Steady State Apparent Clearance (CL/F) of Crizotinib

End point description

Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Clearance obtained after oral dose is influenced by the fraction of the dose absorbed. PK parameter analysis set included all enrolled subjects who received at least one dose of crizotinib and had sufficient information to estimate at least one of the PK parameters of interest. Here, 99999 in data field signifies that data cannot be estimated for parameters with less than 3 evaluable measurements. Here ‘Number of subjects analysed’ signifies subjects evaluable for this endpoint. None of the subjects were evaluated for 100 mg/m^2 BID and 130 mg/m^2 BID dose and were not reported.

End point type

Secondary

End point timeframe

Between Days 15 and 28 of BID dosing in Cycle 1, pre-dose (12 hours after the last dose), 1 hour, 2 hour, 4 hours, and 6-8 hours post morning dose

End point values	Phase 1: Crizotinib 165 mg/m^2 BID	Phase 1: Crizotinib 215 mg/m^2 BID	Phase 1: Crizotinib 280 mg/m^2 BID	Phase 1: Crizotinib 365 mg/m^2 BID
Number of subjects analysed	1	3	44	3
Units: litres/hour
geometric mean (geometric coefficient of variation)	99999 ± 99999	41.78 ± 66	46.61 ± 54	64.22 ± 40

No statistical analyses for this end point

Secondary: Percentage of Subjects With Objective Response (OR)

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End point title

Percentage of Subjects With Objective Response (OR)

End point description

OR defined as subjects with complete response (CR), CR unconfirmed (CRu) or partial response (PR). Per Cheson criteria, (for ALCL), CR= disappearance of all evidence of disease from all sites for >=4 weeks. CRu= >=75% shrinkage in sums of the perpendicular diameters (SPD) of lesions and no residual FDG PET activity; PR= >=50% decrease in the SPD of the lesions. As per RECIST v1.0, (for IMT), CR= disappearance of all target and non-target lesions; PR= >=30% decrease in sum of longest diameters (LD) of target lesions taking as a reference the baseline sum LD. Response evaluable (RE) analysis set included all randomised subjects who received study drug, had measurable or evaluable disease at baseline by investigator assessment, or had baseline disease assessment per central review. Here ‘Number of subjects analysed’ signifies subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

From randomisation to progression of disease, start of new anti-cancer therapy or discontinuation from study or death, whichever occurred first (up to 88.8 months)

End point values	ALCL: Crizotinib 165 mg/m^2 BID	ALCL: Crizotinib 280 mg/m^2 BID	IMT: Crizotinib 100 mg/m^2 BID	IMT: Crizotinib 165 mg/m^2 BID	IMT: Crizotinib 280 mg/m^2 BID
Number of subjects analysed	6	20	1	1	12
Units: percentage of subjects
median (confidence interval 95%)	83.3 (43.6 to 97.0)	90.0 (69.9 to 97.2)	0 (0.0 to 79.3)	100 (20.7 to 100.0)	91.7 (64.6 to 98.5)

No statistical analyses for this end point

Secondary: Duration of Objective Tumor Response (DR)

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End point title

Duration of Objective Tumor Response (DR)

End point description

DR: time from first documentation of OR (CR/CRu or PR) to first documentation of objective tumor progression or death due to any cause based on central review. Per Cheson criteria, (for ALCL), CR= disappearance of all evidence of disease from all sites for >=4 weeks. CRu= >=75% shrinkage in the SPD of the lesions and no residual FDG PET activity; PR= >=50% decrease in SPD lesions. As per RECIST v1.0, (for IMT), CR= disappearance of all target and non-target lesions; PR= >=30% decrease in sum of LD of target lesions taking as reference baseline sum LD. RE analysis set included all randomised subjects who received study drug, had measurable or evaluable disease at baseline by investigator assessment, or had baseline disease assessment per central review. Here ‘Number of subjects analysed’ signifies subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline until disease progression or death due to any cause (up to 88.8 months)

End point values	ALCL: Crizotinib 165 mg/m^2 BID	ALCL: Crizotinib 280 mg/m^2 BID	IMT: Crizotinib 165 mg/m^2 BID	IMT: Crizotinib 280 mg/m^2 BID	Total (ALCL): 165 mg/m^2 BID and 280 mg/m^2 BID	Total (IMT): 165 mg/m^2 BID and 280 mg/m^2 BID
Number of subjects analysed	5	18	1	11	23	12
Units: months
median (full range (min-max))	6.9 (2.5 to 10.2)	3.0 (0.0 to 18.6)	48.9 (48.9 to 48.9)	12.7 (2.8 to 39.9)	3.9 (0.0 to 18.6)	14.8 (2.8 to 48.9)

No statistical analyses for this end point

Secondary: Time to Objective Tumor Response (TTR)

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End point title

Time to Objective Tumor Response (TTR)

End point description

TTR: time from first dose Cycle 1 Day 1 (C1D1) to first documentation of objective tumor response (CR/CRu or PR). Per Cheson criteria, (for ALCL), CR= disappearance of all evidence of disease from all sites for >=4 weeks. CRu= >=75% shrinkage in the SPD of the lesions and no residual FDG PET activity; PR= >=50% decrease in SPD lesions. As per RECIST v1.0, (for IMT), CR= disappearance of all target and non-target lesions; PR= >=30% decrease in sum of LD of target lesions taking as reference baseline sum LD. RE analysis set included all randomised subjects who received study drug, had measurable or evaluable disease at baseline by investigator assessment, or had baseline disease assessment per central review. Here ‘Number of subjects analysed’ signifies subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

From the date of randomisation to the first documentation of objective response (CR or PR) (up to 88.8 months)

End point values	ALCL: Crizotinib 165 mg/m^2 BID	ALCL: Crizotinib 280 mg/m^2 BID	IMT: Crizotinib 165 mg/m^2 BID	IMT: Crizotinib 280 mg/m^2 BID	Total (ALCL): 165 mg/m^2 BID and 280 mg/m^2 BID	Total (IMT): 165 mg/m^2 BID and 280 mg/m^2 BID
Number of subjects analysed	5	18	1	11	23	12
Units: months
median (full range (min-max))	0.9 (0.8 to 1.0)	0.9 (0.8 to 2.1)	0.8 (0.8 to 0.8)	1.0 (0.9 to 4.6)	0.9 (0.8 to 2.1)	1.0 (0.8 to 4.6)

No statistical analyses for this end point

Secondary: Anaplastic Lymphoma Kinase (ALK)-Positive Status in Pediatric Subjects with IMT or ALCL

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End point title

Anaplastic Lymphoma Kinase (ALK)-Positive Status in Pediatric Subjects with IMT or ALCL

End point description

Subjects were considered ALK-positive based on indication of ALK abnormality and/or proven ALK-positive disease. Data was presented on the safety analysis set which included all enrolled subjects who received at least one dose of crizotinib and accounted for all IMT and ALCL pediatric subjects.

End point type

Secondary

End point timeframe

From baseline up to 88.8 months

End point values	ALCL: Crizotinib 165 mg/m^2 BID	ALCL: Crizotinib 280 mg/m^2 BID	IMT: Crizotinib 100 mg/m^2 BID	IMT: Crizotinib 165 mg/m^2 BID	IMT: Crizotinib 280 mg/m^2 BID
Number of subjects analysed	6	20	1	1	12
Units: subjects
number (not applicable)	6	16	1	1	12

No statistical analyses for this end point

Secondary: Levels of Nucleophosmin-Anaplastic Lymphoma Kinase (NPM-ALK) in Peripheral Blood by Visit, Dose Level in ALK-positive ALCL Subjects

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End point title

Levels of Nucleophosmin-Anaplastic Lymphoma Kinase (NPM-ALK) in Peripheral Blood by Visit, Dose Level in ALK-positive ALCL Subjects

End point description

In subjects with ALCL, peripheral blood samples were collected at baseline and following treatment at protocol specified time-points. Biomarker analysis set included all randomised subjects who had at least 1 dose of study drug and had at least one measure of minimal residual disease (MRD) based on peripheral blood using quantitative reverse transcription polymerase chain reaction (qRT-PCR) with a baseline measurement. Here, 99999 in data field signifies that data cannot be estimated. Here ‘Number of subjects analysed’ signifies subjects evaluable for this endpoint. Here 'n' signifies number of subjects evaluable at specified time points for 165 mg/m^2 and 280 mg/m^2 BID dose group, respectively.

End point type

Secondary

End point timeframe

Baseline, Cycle 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 42, 45, 48, 54

End point values	ALCL: Crizotinib 165 mg/m^2 BID	ALCL: Crizotinib 280 mg/m^2 BID
Number of subjects analysed	4	19
Units: number of copies/10,000 ABL copies
median (full range (min-max))
Baseline (n= 4, 19)	19.00 (0 to 4126.0)	58.00 (0 to 501.0)
Cycle 1 (n= 4, 13)	29.50 (0 to 77.0)	0 (0 to 1692.0)
Cycle 2 (n= 3, 16)	0 (0 to 23.0)	0 (0 to 15038.0)
Cycle 3 (n= 3, 11)	0 (0 to 8.0)	0 (0 to 5.0)
Cycle 4 (n= 2, 9)	0 (0 to 0)	0 (0 to 5.0)
Cycle 5 (n= 3, 7)	0 (0 to 3.0)	0 (0 to 3.0)
Cycle 6 (n= 4, 7)	0 (0 to 3.0)	0 (0 to 33.0)
Cycle 7 (n= 3, 4)	0 (0 to 0)	0 (0 to 0)
Cycle 8 (n= 3, 3)	0 (0 to 0)	0 (0 to 0)
Cycle 9 (n= 2, 5)	0 (0 to 0)	3.00 (0 to 12.0)
Cycle 10 (n= 2, 5)	4.50 (0 to 9.0)	0 (0 to 399.0)
Cycle 11 (n= 2, 5)	11.50 (10.0 to 13.0)	0 (0 to 12.0)
Cycle 12 (n= 2, 4)	4.75 (0 to 9.5)	2.00 (0 to 11.0)
Cycle 13 (n= 2, 3)	3.50 (0 to 7.0)	0 (0 to 513.0)
Cycle 14 (n= 1, 5)	0 (0 to 0)	0 (0 to 4.0)
Cycle 15 (n= 2, 2)	0.50 (0 to 1.0)	7.00 (0 to 14.0)
Cycle 16 (n= 2, 3)	7.00 (3.0 to 11.0)	0 (0 to 0)
Cycle 17 (n= 2, 3)	1.50 (0 to 3.0)	0 (0 to 6.0)
Cycle 18 (n= 2, 3)	0.25 (0 to 0.5)	0 (0 to 0)
Cycle 19 (n= 1, 2)	35.00 (35.00 to 35.00)	9.50 (0 to 19.0)
Cycle 20 (n= 2, 2)	2 (0 to 4.0)	21.50 (0 to 43.0)
Cycle 21 (n= 2, 1)	4.00 (0 to 8.0)	0 (0 to 0)
Cycle 22 (n= 2, 1)	9.00 (0 to 18.0)	0 (0 to 0)
Cycle 23 (n= 1, 2)	0 (0 to 0)	6.00 (0 to 12.0)
Cycle 24 (n= 2, 0)	2.50 (0 to 5.0)	99999 (99999 to 99999)
Cycle 25 (n= 1, 0)	202.50 (202.5 to 202.5)	99999 (99999 to 99999)
Cycle 26 (n= 1, 0)	3.50 (3.5 to 3.5)	99999 (99999 to 99999)
Cycle 27 (n= 1, 0)	0 (0 to 0)	99999 (99999 to 99999)
Cycle 28 (n= 2, 0)	0 (0 to 0)	99999 (99999 to 99999)
Cycle 29 (n= 2, 0)	0.50 (0 to 1.0)	99999 (99999 to 99999)
Cycle 30 (n= 1, 0)	12.00 (12.00 to 12.00)	99999 (99999 to 99999)
Cycle 31 (n= 2, 0)	0 (0 to 0)	99999 (99999 to 99999)
Cycle 32 (n= 2, 0)	0 (0 to 0)	99999 (99999 to 99999)
Cycle 33 (n= 2, 0)	0 (0 to 0)	99999 (99999 to 99999)
Cycle 34 (n= 2, 0)	11.00 (0 to 22.0)	99999 (99999 to 99999)
Cycle 35 (n= 2, 0)	0 (0 to 0)	99999 (99999 to 99999)
Cycle 36 (n= 1, 0)	0 (0 to 0)	99999 (99999 to 99999)
Cycle 37 (n= 2, 0)	0 (0 to 0)	99999 (99999 to 99999)
Cycle 38 (n= 1, 0)	9.00 (9.0 to 9.0)	99999 (99999 to 99999)
Cycle 39 (n= 1, 0)	0 (0 to 0)	99999 (99999 to 99999)
Cycle 40 (n= 1, 0)	0 (0 to 0)	99999 (99999 to 99999)
Cycle 42 (n= 1, 0)	0 (0 to 0)	99999 (99999 to 99999)
Cycle 45 (n= 2, 0)	0 (0 to 0)	99999 (99999 to 99999)
Cycle 48 (n= 1, 0)	0 (0 to 0)	99999 (99999 to 99999)
Cycle 54 (n= 1, 0)	4.00 (4.00 to 4.00)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Taste Assessment of Crizotinib Oral Solution Using Taste Feedback Questionnaire

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End point title

Taste Assessment of Crizotinib Oral Solution Using Taste Feedback Questionnaire

End point description

Only very few taste questionnaire were completed, and the information in there is mainly in the form of open text fields, therefore no formal analysis was performed.

End point type

Secondary

End point timeframe

Weekly during Cycle 1

End point values	Phase 1 and 2: Anaplastic Large Cell Lymphoma (ALCL) Group	Phase 1 and 2: Inflammatory Myofibroblastic Tumors (IMT) Group	Phase 1 and 2: Other Tumors Group
Number of subjects analysed	0 ^[2]	0 ^[3]	0 ^[4]
Units: subjects
number (not applicable)

Notes
[2] - Few questionnaires were completed, and no formal analysis was completed
[3] - Few questionnaires were completed, and no formal analysis was completed
[4] - Few questionnaires were completed, and no formal analysis was completed

No statistical analyses for this end point

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) All Causalities

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End point title

Number of Subjects With Treatment-Emergent Adverse Events (AEs) All Causalities

End point description

An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. Treatment-emergent were defined as events that occurred between first dose of study drug up to the end of study (88.8 months). Safety analysis set included all randomised subjects who received the study drug. Here ‘Number of subjects analysed’ signifies subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

From baseline up to 88.8 months

End point values	Phase 1 and 2: Anaplastic Large Cell Lymphoma (ALCL) Group	Phase 1 and 2: Inflammatory Myofibroblastic Tumors (IMT) Group	Phase 1 and 2: Other Tumors Group
Number of subjects analysed	26	14	81
Units: subjects
number (not applicable)	26	14	81

No statistical analyses for this end point

Secondary: Number of Subjects With Laboratory Test Abnormalities

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End point title

Number of Subjects With Laboratory Test Abnormalities

End point description

Data for this endpoint was not reported because laboratory test abnormality have been captured under adverse event.

End point type

Secondary

End point timeframe

From baseline up to 88.8 months

End point values	Phase 1 and 2: Anaplastic Large Cell Lymphoma (ALCL) Group	Phase 1 and 2: Inflammatory Myofibroblastic Tumors (IMT) Group	Phase 1 and 2: Other Tumors Group
Number of subjects analysed	0 ^[5]	0 ^[6]	0 ^[7]
Units: subjects
number (not applicable)

Notes
[5] - Data for this endpoint is reported under adverse events
[6] - Data for this endpoint is reported under adverse events
[7] - Data for this endpoint is reported under adverse events

No statistical analyses for this end point

Secondary: Number of Subjects With Vital Signs Abnormalities

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End point title

Number of Subjects With Vital Signs Abnormalities

End point description

Vital signs included assessment of body weight. Abnormality criteria included: increase from Baseline >=7% or decrease from Baseline >=3.5%. Safety analysis set included all randomised subjects who received the study drug. Here ‘Number of subjects analysed’ signifies subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

From baseline up to 88.8. months

End point values	ALCL and IMT: Crizotinib 100 mg/m^2 BID	ALCL and IMT: Crizotinib 165 mg/m^2 BID	ALCL and IMT: Crizotinib 280 mg/m^2 BID
Number of subjects analysed	1	7	32
Units: kilograms (Kg)
number (not applicable)
Maximum Increase from baseline >=7%	1	6	18
Maximum Decrease from baseline >=3.5%	0	3	6

No statistical analyses for this end point

Secondary: Number of Subjects Reporting Growth Plate Toxicity

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End point title

Number of Subjects Reporting Growth Plate Toxicity

End point description

Number of subjects with evidence of growth plate toxicity (assessed by thickening in growth plate [a response of ‘Yes’]) was reported. Safety analysis set included all randomised subjects who received the study drug. Here ‘Number of subjects analysed’ signifies subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Cycle 1, 3, 4, 5, 7, 9, 10, 15, 16, 18, 19, 21, 22, 23, 25, 29

End point values	Phase 1 and 2: Anaplastic Large Cell Lymphoma (ALCL) Group	Phase 1 and 2: Inflammatory Myofibroblastic Tumors (IMT) Group	Phase 1 and 2: Other Tumors Group
Number of subjects analysed	10	6	16
Units: subjects
number (not applicable)
Baseline	0	0	0
Cycle 1	0	0	0
Cycle 3	0	0	0
Cycle 4	0	0	0
Cycle 5	0	0	0
Cycle 7	0	0	0
Cycle 9	0	0	0
Cycle 10	0	0	0
Cycle 15	0	0	0
Cycle 16	0	1	0
Cycle 18	0	1	0
Cycle 19	0	1	0
Cycle 21	0	0	0
Cycle 22	0	0	0
Cycle 23	0	0	0
Cycle 25	0	0	0
Cycle 29	0	0	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse Event data was collected from Baseline up to 88.8 months

Adverse event reporting additional description

Same event may appear as AE, Serious Adverse Events (SAE), what is presented are distinct events. Event may be serious in 1 and as non-serious in another or 1 subject may have experienced both. Due to limitation in COG AE CRF page, non-SAEs were not assessed separately and therefore overall AE’s are reported under “other Adverse Events” section.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

22.1

Reporting group title

Phase 1: Crizotinib 100 mg/m^2 BID

Reporting group description

Reporting group title

Phase 1: Crizotinib 130 mg/m^2 BID

Reporting group description

Reporting group title

Phase 1: Crizotinib 165 mg/m^2 BID

Reporting group description

Reporting group title

Phase 1: Crizotinib 215 mg/m^2 BID

Reporting group description

Reporting group title

Phase 1: Crizotinib 280 mg/m^2 BID

Reporting group description

Reporting group title

Phase 1: Crizotinib 365 mg/m^2 BID

Reporting group description

Serious adverse events	Phase 1: Crizotinib 100 mg/m^2 BID	Phase 1: Crizotinib 130 mg/m^2 BID	Phase 1: Crizotinib 165 mg/m^2 BID	Phase 1: Crizotinib 215 mg/m^2 BID	Phase 1: Crizotinib 280 mg/m^2 BID	Phase 1: Crizotinib 365 mg/m^2 BID
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 6 (50.00%)	3 / 8 (37.50%)	14 / 23 (60.87%)	8 / 11 (72.73%)	18 / 62 (29.03%)	4 / 11 (36.36%)
number of deaths (all causes)	0	0	2	2	2	2
number of deaths resulting from adverse events	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Central nervous system neoplasm
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Neoplasm progression
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	2 / 62 (3.23%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
Nephroblastoma
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Neuroblastoma
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Osteosarcoma
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rhabdomyosarcoma
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 62 (0.00%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Second primary malignancy
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tumour pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	3 / 62 (4.84%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Disease progression
alternative assessment type: Systematic
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 23 (8.70%)	1 / 11 (9.09%)	0 / 62 (0.00%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 1	0 / 0	0 / 1
Fatigue
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 23 (8.70%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Bronchospasm
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	2 / 62 (3.23%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 62 (0.00%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wheezing
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 62 (0.00%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 62 (0.00%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood creatinine abnormal
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 23 (8.70%)	1 / 11 (9.09%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gamma-glutamyltransferase abnormal
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	2 / 62 (3.23%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemoglobin
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemoglobin decreased
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lymphocyte count decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	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
Neutrophil count abnormal
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutrophil count decreased
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	5 / 23 (21.74%)	3 / 11 (27.27%)	2 / 62 (3.23%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	11 / 13	6 / 6	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
White blood cell count decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 23 (8.70%)	2 / 11 (18.18%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	3 / 3	3 / 3	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femur fracture
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Sinus bradycardia
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	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
Myocarditis
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebral haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral sensory neuropathy
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	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
Seizure
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anemia
alternative assessment type: Systematic
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	2 / 62 (3.23%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
alternative assessment type: Systematic
subjects affected / exposed	2 / 6 (33.33%)	0 / 8 (0.00%)	1 / 23 (4.35%)	1 / 11 (9.09%)	2 / 62 (3.23%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	1 / 1	0 / 1	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lymphopenia
alternative assessment type: Systematic
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 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
Neutropenia
alternative assessment type: Systematic
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	2 / 23 (8.70%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Cyanopsia
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 23 (0.00%)	1 / 11 (9.09%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Flatulence
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Large intestinal obstruction
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	1 / 23 (4.35%)	1 / 11 (9.09%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric fistula
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Erythema nodosum
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	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
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	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
Kidney enlargement
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Bone pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myositis
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 62 (0.00%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Cellulitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	2 / 11 (18.18%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chest wall abscess
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 23 (8.70%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infective myositis
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	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
Lymph gland infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	3 / 62 (4.84%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	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
Varicella
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Varicella zoster virus infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	1 / 23 (4.35%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoalbuminaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 23 (8.70%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	2 / 23 (8.70%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypophosphataemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Obesity
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tumour lysis syndrome
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	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

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

Non-serious adverse events	Phase 1: Crizotinib 100 mg/m^2 BID	Phase 1: Crizotinib 130 mg/m^2 BID	Phase 1: Crizotinib 165 mg/m^2 BID	Phase 1: Crizotinib 215 mg/m^2 BID	Phase 1: Crizotinib 280 mg/m^2 BID	Phase 1: Crizotinib 365 mg/m^2 BID
Total subjects affected by non serious adverse events
subjects affected / exposed	6 / 6 (100.00%)	8 / 8 (100.00%)	23 / 23 (100.00%)	11 / 11 (100.00%)	62 / 62 (100.00%)	11 / 11 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lipoma
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0
Skin papilloma
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 23 (8.70%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	3	0	1	0
Tumour pain
subjects affected / exposed	1 / 6 (16.67%)	1 / 8 (12.50%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	1	1	0	0	2	0
Vascular disorders
Flushing
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	4 / 23 (17.39%)	0 / 11 (0.00%)	5 / 62 (8.06%)	0 / 11 (0.00%)
occurrences all number	0	0	4	0	5	0
Hypertension
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	9 / 23 (39.13%)	0 / 11 (0.00%)	10 / 62 (16.13%)	0 / 11 (0.00%)
occurrences all number	0	0	18	0	15	0
Hypotension
subjects affected / exposed	2 / 6 (33.33%)	1 / 8 (12.50%)	5 / 23 (21.74%)	2 / 11 (18.18%)	9 / 62 (14.52%)	0 / 11 (0.00%)
occurrences all number	4	1	22	3	10	0
General disorders and administration site conditions
Catheter site pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0
Chills
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	5 / 23 (21.74%)	1 / 11 (9.09%)	4 / 62 (6.45%)	0 / 11 (0.00%)
occurrences all number	0	0	6	1	4	0
Face oedema
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	1 / 11 (9.09%)	4 / 62 (6.45%)	1 / 11 (9.09%)
occurrences all number	0	0	1	1	9	1
Fatigue
subjects affected / exposed	2 / 6 (33.33%)	1 / 8 (12.50%)	12 / 23 (52.17%)	8 / 11 (72.73%)	32 / 62 (51.61%)	8 / 11 (72.73%)
occurrences all number	2	3	33	9	50	9
Gait disturbance
subjects affected / exposed	1 / 6 (16.67%)	1 / 8 (12.50%)	2 / 23 (8.70%)	0 / 11 (0.00%)	7 / 62 (11.29%)	1 / 11 (9.09%)
occurrences all number	1	1	2	0	8	1
Influenza like illness
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 23 (8.70%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	2	0	1	0
Localised oedema
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	4 / 23 (17.39%)	0 / 11 (0.00%)	4 / 62 (6.45%)	0 / 11 (0.00%)
occurrences all number	0	0	7	0	4	0
Malaise
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 23 (8.70%)	0 / 11 (0.00%)	2 / 62 (3.23%)	1 / 11 (9.09%)
occurrences all number	0	0	12	0	2	1
Non-cardiac chest pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	8 / 23 (34.78%)	1 / 11 (9.09%)	5 / 62 (8.06%)	2 / 11 (18.18%)
occurrences all number	0	1	11	1	7	2
Oedema peripheral
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	4 / 23 (17.39%)	1 / 11 (9.09%)	9 / 62 (14.52%)	0 / 11 (0.00%)
occurrences all number	0	1	11	1	23	0
Pain
subjects affected / exposed	2 / 6 (33.33%)	0 / 8 (0.00%)	7 / 23 (30.43%)	1 / 11 (9.09%)	16 / 62 (25.81%)	2 / 11 (18.18%)
occurrences all number	2	0	16	2	19	2
Pyrexia
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	9 / 23 (39.13%)	4 / 11 (36.36%)	30 / 62 (48.39%)	1 / 11 (9.09%)
occurrences all number	0	2	54	8	60	1
Respiratory, thoracic and mediastinal disorders
Atelectasis
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	2 / 62 (3.23%)	0 / 11 (0.00%)
occurrences all number	0	0	1	0	3	0
Bronchospasm
subjects affected / exposed	2 / 6 (33.33%)	1 / 8 (12.50%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	1	0	0	0	0
Cough
subjects affected / exposed	5 / 6 (83.33%)	2 / 8 (25.00%)	12 / 23 (52.17%)	3 / 11 (27.27%)	28 / 62 (45.16%)	2 / 11 (18.18%)
occurrences all number	5	2	62	4	49	2
Dysphonia
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	0	0	0
Dyspnoea
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	5 / 23 (21.74%)	0 / 11 (0.00%)	5 / 62 (8.06%)	2 / 11 (18.18%)
occurrences all number	0	0	7	0	5	2
Epistaxis
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	1 / 62 (1.61%)	1 / 11 (9.09%)
occurrences all number	1	0	1	0	2	1
Hypoxia
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	2 / 23 (8.70%)	0 / 11 (0.00%)	4 / 62 (6.45%)	1 / 11 (9.09%)
occurrences all number	0	1	3	0	4	1
Laryngeal inflammation
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	1 / 11 (9.09%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	1	1	1	0
Laryngeal pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	6 / 23 (26.09%)	0 / 11 (0.00%)	2 / 62 (3.23%)	0 / 11 (0.00%)
occurrences all number	0	0	10	0	4	0
Nasal congestion
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	5 / 23 (21.74%)	1 / 11 (9.09%)	9 / 62 (14.52%)	0 / 11 (0.00%)
occurrences all number	0	0	24	4	13	0
Oropharyngeal pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	6 / 23 (26.09%)	2 / 11 (18.18%)	13 / 62 (20.97%)	1 / 11 (9.09%)
occurrences all number	0	0	15	5	13	1
Pleural effusion
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 23 (8.70%)	0 / 11 (0.00%)	5 / 62 (8.06%)	0 / 11 (0.00%)
occurrences all number	0	0	2	0	5	0
Productive cough
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	5 / 62 (8.06%)	2 / 11 (18.18%)
occurrences all number	0	0	3	0	5	3
Rhinitis allergic
subjects affected / exposed	3 / 6 (50.00%)	0 / 8 (0.00%)	8 / 23 (34.78%)	0 / 11 (0.00%)	8 / 62 (12.90%)	0 / 11 (0.00%)
occurrences all number	3	0	11	0	9	0
Rhinorrhoea
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	3 / 23 (13.04%)	0 / 11 (0.00%)	6 / 62 (9.68%)	0 / 11 (0.00%)
occurrences all number	0	0	16	0	8	0
Tachypnoea
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	1	0	1	0
Upper-airway cough syndrome
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	1 / 11 (9.09%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	2	0	0
Wheezing
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	2 / 62 (3.23%)	0 / 11 (0.00%)
occurrences all number	0	0	7	0	2	0
Psychiatric disorders
Agitation
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	5 / 23 (21.74%)	0 / 11 (0.00%)	6 / 62 (9.68%)	1 / 11 (9.09%)
occurrences all number	0	1	8	0	6	1
Anxiety
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	4 / 23 (17.39%)	1 / 11 (9.09%)	4 / 62 (6.45%)	2 / 11 (18.18%)
occurrences all number	0	1	4	1	5	2
Depression
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 23 (8.70%)	1 / 11 (9.09%)	2 / 62 (3.23%)	1 / 11 (9.09%)
occurrences all number	0	0	2	1	2	1
Insomnia
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	1 / 23 (4.35%)	2 / 11 (18.18%)	3 / 62 (4.84%)	1 / 11 (9.09%)
occurrences all number	0	1	2	2	10	2
Irritability
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	3 / 62 (4.84%)	2 / 11 (18.18%)
occurrences all number	0	0	1	0	3	2
Suicidal ideation
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	5 / 6 (83.33%)	2 / 8 (25.00%)	16 / 23 (69.57%)	9 / 11 (81.82%)	50 / 62 (80.65%)	8 / 11 (72.73%)
occurrences all number	7	3	65	14	94	15
Anion gap decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	2	0
Aspartate aminotransferase increased
subjects affected / exposed	4 / 6 (66.67%)	2 / 8 (25.00%)	16 / 23 (69.57%)	10 / 11 (90.91%)	45 / 62 (72.58%)	9 / 11 (81.82%)
occurrences all number	5	3	85	21	94	17
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	10 / 23 (43.48%)	3 / 11 (27.27%)	11 / 62 (17.74%)	3 / 11 (27.27%)
occurrences all number	0	3	24	12	35	4
Blood bilirubin decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	2 / 62 (3.23%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	5	0
Blood bilirubin increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	3 / 23 (13.04%)	0 / 11 (0.00%)	2 / 62 (3.23%)	0 / 11 (0.00%)
occurrences all number	1	0	6	0	2	0
Blood chloride increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	4 / 62 (6.45%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	7	0
Blood cholesterol increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 23 (0.00%)	2 / 11 (18.18%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	1	0	0	2	3	0
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 23 (8.70%)	1 / 11 (9.09%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	4	1	1	0
Blood creatinine increased
subjects affected / exposed	3 / 6 (50.00%)	1 / 8 (12.50%)	14 / 23 (60.87%)	4 / 11 (36.36%)	27 / 62 (43.55%)	6 / 11 (54.55%)
occurrences all number	6	1	73	17	81	8
Blood urea decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	2 / 62 (3.23%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	2	0
C-reactive protein increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	2 / 62 (3.23%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	8	0
Carbon dioxide increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0
Ejection fraction decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 23 (8.70%)	0 / 11 (0.00%)	3 / 62 (4.84%)	0 / 11 (0.00%)
occurrences all number	0	0	2	0	3	0
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 6 (16.67%)	1 / 8 (12.50%)	4 / 23 (17.39%)	0 / 11 (0.00%)	6 / 62 (9.68%)	3 / 11 (27.27%)
occurrences all number	1	1	33	0	9	4
Haemoglobin increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	4	0	1	0
Lipase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	3 / 62 (4.84%)	1 / 11 (9.09%)
occurrences all number	0	0	0	1	3	1
Lymphocyte count decreased
subjects affected / exposed	3 / 6 (50.00%)	4 / 8 (50.00%)	16 / 23 (69.57%)	6 / 11 (54.55%)	33 / 62 (53.23%)	5 / 11 (45.45%)
occurrences all number	5	9	31	11	77	7
Lymphocyte count increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	3 / 62 (4.84%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	13	0
Neutrophil count decreased
subjects affected / exposed	2 / 6 (33.33%)	2 / 8 (25.00%)	15 / 23 (65.22%)	7 / 11 (63.64%)	51 / 62 (82.26%)	8 / 11 (72.73%)
occurrences all number	4	5	136	19	189	17
Neutrophil count increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	2 / 62 (3.23%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	8	0
Platelet count decreased
subjects affected / exposed	3 / 6 (50.00%)	3 / 8 (37.50%)	8 / 23 (34.78%)	3 / 11 (27.27%)	12 / 62 (19.35%)	0 / 11 (0.00%)
occurrences all number	3	4	10	3	16	0
Protein total decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	4 / 62 (6.45%)	0 / 11 (0.00%)
occurrences all number	0	0	0	1	12	0
Weight decreased
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	5 / 23 (21.74%)	3 / 11 (27.27%)	6 / 62 (9.68%)	1 / 11 (9.09%)
occurrences all number	1	0	10	4	7	1
Weight increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	5 / 23 (21.74%)	0 / 11 (0.00%)	9 / 62 (14.52%)	0 / 11 (0.00%)
occurrences all number	0	0	12	0	13	0
White blood cell count decreased
subjects affected / exposed	2 / 6 (33.33%)	1 / 8 (12.50%)	14 / 23 (60.87%)	6 / 11 (54.55%)	42 / 62 (67.74%)	8 / 11 (72.73%)
occurrences all number	3	4	95	19	126	17
White blood cell count increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	6	0
Injury, poisoning and procedural complications
Ankle fracture
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0
Contusion
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	1 / 23 (4.35%)	1 / 11 (9.09%)	1 / 62 (1.61%)	2 / 11 (18.18%)
occurrences all number	1	0	1	1	1	2
Fall
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	4 / 62 (6.45%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	4	0
Fracture
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	6 / 62 (9.68%)	0 / 11 (0.00%)
occurrences all number	0	0	1	0	6	0
Infusion related reaction
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	2 / 62 (3.23%)	0 / 11 (0.00%)
occurrences all number	0	0	2	0	3	0
Joint injury
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0
Limb injury
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	1	0	1	0
Wound complication
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0
Cardiac disorders
Myocarditis
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0
Sinus bradycardia
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	5 / 23 (21.74%)	1 / 11 (9.09%)	8 / 62 (12.90%)	1 / 11 (9.09%)
occurrences all number	0	1	12	2	10	1
Sinus tachycardia
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	6 / 23 (26.09%)	0 / 11 (0.00%)	4 / 62 (6.45%)	1 / 11 (9.09%)
occurrences all number	1	0	11	0	4	1
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	7 / 23 (30.43%)	2 / 11 (18.18%)	11 / 62 (17.74%)	2 / 11 (18.18%)
occurrences all number	0	0	11	3	12	3
Dysgeusia
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 23 (0.00%)	2 / 11 (18.18%)	10 / 62 (16.13%)	2 / 11 (18.18%)
occurrences all number	1	0	0	3	10	2
Dyskinesia
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0
Headache
subjects affected / exposed	1 / 6 (16.67%)	1 / 8 (12.50%)	13 / 23 (56.52%)	5 / 11 (45.45%)	19 / 62 (30.65%)	3 / 11 (27.27%)
occurrences all number	1	3	53	5	30	4
Paraesthesia
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	3 / 23 (13.04%)	0 / 11 (0.00%)	3 / 62 (4.84%)	0 / 11 (0.00%)
occurrences all number	0	0	3	0	3	0
Peripheral sensory neuropathy
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	1 / 23 (4.35%)	1 / 11 (9.09%)	4 / 62 (6.45%)	0 / 11 (0.00%)
occurrences all number	0	1	2	1	5	0
Seizure
subjects affected / exposed	0 / 6 (0.00%)	2 / 8 (25.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	2	1	0	1	0
Lethargy
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 23 (8.70%)	0 / 11 (0.00%)	1 / 62 (1.61%)	1 / 11 (9.09%)
occurrences all number	0	0	2	0	1	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 6 (33.33%)	2 / 8 (25.00%)	13 / 23 (56.52%)	7 / 11 (63.64%)	33 / 62 (53.23%)	9 / 11 (81.82%)
occurrences all number	4	6	46	18	73	11
Bone marrow failure
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0
Febrile neutropenia
subjects affected / exposed	1 / 6 (16.67%)	1 / 8 (12.50%)	1 / 23 (4.35%)	0 / 11 (0.00%)	3 / 62 (4.84%)	0 / 11 (0.00%)
occurrences all number	1	1	1	0	3	0
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	3 / 23 (13.04%)	0 / 11 (0.00%)	2 / 62 (3.23%)	0 / 11 (0.00%)
occurrences all number	0	0	3	0	2	0
Eye disorders
Chalazion
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0
Dry eye
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0
Dyschromatopsia
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0
Eye pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 23 (8.70%)	0 / 11 (0.00%)	4 / 62 (6.45%)	2 / 11 (18.18%)
occurrences all number	0	0	2	0	4	2
Lacrimation increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	1 / 23 (4.35%)	1 / 11 (9.09%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	1	0	1	1	1	0
Optic nerve disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	5	0
Periorbital oedema
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	2 / 62 (3.23%)	0 / 11 (0.00%)
occurrences all number	0	0	1	0	2	0
Photophobia
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	4 / 23 (17.39%)	0 / 11 (0.00%)	4 / 62 (6.45%)	1 / 11 (9.09%)
occurrences all number	0	0	4	0	4	1
Photopsia
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	1 / 23 (4.35%)	2 / 11 (18.18%)	7 / 62 (11.29%)	0 / 11 (0.00%)
occurrences all number	0	5	1	2	8	0
Vision blurred
subjects affected / exposed	0 / 6 (0.00%)	2 / 8 (25.00%)	4 / 23 (17.39%)	3 / 11 (27.27%)	18 / 62 (29.03%)	2 / 11 (18.18%)
occurrences all number	0	3	4	3	21	2
Visual impairment
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	3 / 23 (13.04%)	1 / 11 (9.09%)	9 / 62 (14.52%)	2 / 11 (18.18%)
occurrences all number	0	0	3	1	10	2
Vitreous floaters
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	6 / 62 (9.68%)	3 / 11 (27.27%)
occurrences all number	0	0	1	0	11	3
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	3 / 23 (13.04%)	0 / 11 (0.00%)	7 / 62 (11.29%)	2 / 11 (18.18%)
occurrences all number	0	2	4	0	10	2
Abdominal pain
subjects affected / exposed	2 / 6 (33.33%)	1 / 8 (12.50%)	11 / 23 (47.83%)	2 / 11 (18.18%)	24 / 62 (38.71%)	2 / 11 (18.18%)
occurrences all number	2	3	19	2	34	4
Abdominal pain upper
subjects affected / exposed	2 / 6 (33.33%)	0 / 8 (0.00%)	4 / 23 (17.39%)	0 / 11 (0.00%)	7 / 62 (11.29%)	3 / 11 (27.27%)
occurrences all number	3	0	5	0	7	3
Anal incontinence
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	2 / 62 (3.23%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	2	0
Colitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	2 / 62 (3.23%)	0 / 11 (0.00%)
occurrences all number	0	0	1	0	2	0
Constipation
subjects affected / exposed	0 / 6 (0.00%)	2 / 8 (25.00%)	9 / 23 (39.13%)	5 / 11 (45.45%)	20 / 62 (32.26%)	3 / 11 (27.27%)
occurrences all number	0	3	24	5	27	3
Dental caries
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	2 / 62 (3.23%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	2	0
Diarrhoea
subjects affected / exposed	3 / 6 (50.00%)	3 / 8 (37.50%)	15 / 23 (65.22%)	6 / 11 (54.55%)	46 / 62 (74.19%)	9 / 11 (81.82%)
occurrences all number	4	3	80	20	80	13
Dyspepsia
subjects affected / exposed	1 / 6 (16.67%)	1 / 8 (12.50%)	6 / 23 (26.09%)	1 / 11 (9.09%)	3 / 62 (4.84%)	0 / 11 (0.00%)
occurrences all number	5	1	8	1	3	0
Dysphagia
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	1 / 23 (4.35%)	0 / 11 (0.00%)	5 / 62 (8.06%)	0 / 11 (0.00%)
occurrences all number	0	1	3	0	5	0
Flatulence
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 23 (8.70%)	2 / 11 (18.18%)	4 / 62 (6.45%)	0 / 11 (0.00%)
occurrences all number	0	0	2	3	4	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	2 / 62 (3.23%)	0 / 11 (0.00%)
occurrences all number	0	0	1	0	4	0
Nausea
subjects affected / exposed	4 / 6 (66.67%)	5 / 8 (62.50%)	19 / 23 (82.61%)	9 / 11 (81.82%)	41 / 62 (66.13%)	9 / 11 (81.82%)
occurrences all number	6	6	51	15	87	12
Oesophagitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	4 / 62 (6.45%)	1 / 11 (9.09%)
occurrences all number	0	0	0	1	4	1
Oral pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	4 / 62 (6.45%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	4	1
Stomatitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	5 / 23 (21.74%)	1 / 11 (9.09%)	5 / 62 (8.06%)	0 / 11 (0.00%)
occurrences all number	0	0	5	1	5	0
Tooth discolouration
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0
Toothache
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	3 / 62 (4.84%)	0 / 11 (0.00%)
occurrences all number	0	0	1	0	3	0
Vomiting
subjects affected / exposed	3 / 6 (50.00%)	3 / 8 (37.50%)	19 / 23 (82.61%)	8 / 11 (72.73%)	48 / 62 (77.42%)	11 / 11 (100.00%)
occurrences all number	3	3	77	17	144	16
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	2 / 6 (33.33%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	1 / 62 (1.61%)	2 / 11 (18.18%)
occurrences all number	2	0	1	0	1	2
Dermatitis acneiform
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	3 / 62 (4.84%)	1 / 11 (9.09%)
occurrences all number	0	0	2	0	3	1
Dry skin
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	5 / 23 (21.74%)	1 / 11 (9.09%)	5 / 62 (8.06%)	1 / 11 (9.09%)
occurrences all number	0	0	9	3	6	2
Erythema
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	1 / 62 (1.61%)	1 / 11 (9.09%)
occurrences all number	0	0	1	0	2	1
Onychoclasis
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0
Onychomadesis
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	0	1	1	0
Pruritus
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	5 / 23 (21.74%)	1 / 11 (9.09%)	10 / 62 (16.13%)	1 / 11 (9.09%)
occurrences all number	0	0	6	1	11	1
Rash
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0
Rash maculo-papular
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	11 / 23 (47.83%)	0 / 11 (0.00%)	6 / 62 (9.68%)	0 / 11 (0.00%)
occurrences all number	1	0	22	0	12	0
Scab
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	0	0	0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	3 / 62 (4.84%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	3	0
Haematuria
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	3 / 62 (4.84%)	0 / 11 (0.00%)
occurrences all number	0	0	0	1	3	0
Proteinuria
subjects affected / exposed	0 / 6 (0.00%)	2 / 8 (25.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	2 / 62 (3.23%)	1 / 11 (9.09%)
occurrences all number	0	2	2	0	2	1
Urinary incontinence
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	2 / 23 (8.70%)	0 / 11 (0.00%)	4 / 62 (6.45%)	0 / 11 (0.00%)
occurrences all number	0	1	2	0	5	0
Urinary retention
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	2 / 23 (8.70%)	0 / 11 (0.00%)	1 / 62 (1.61%)	1 / 11 (9.09%)
occurrences all number	0	1	2	0	1	1
Urinary tract pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 23 (8.70%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	2	0	1	0
Endocrine disorders
Hypothyroidism
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	3 / 23 (13.04%)	1 / 11 (9.09%)	2 / 62 (3.23%)	0 / 11 (0.00%)
occurrences all number	1	0	4	1	2	0
Back pain
subjects affected / exposed	2 / 6 (33.33%)	1 / 8 (12.50%)	2 / 23 (8.70%)	2 / 11 (18.18%)	6 / 62 (9.68%)	3 / 11 (27.27%)
occurrences all number	2	1	2	2	9	3
Bone pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	1 / 11 (9.09%)	3 / 62 (4.84%)	0 / 11 (0.00%)
occurrences all number	0	0	2	1	3	0
Exostosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	0	0	0
Muscular weakness
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	3 / 23 (13.04%)	0 / 11 (0.00%)	4 / 62 (6.45%)	0 / 11 (0.00%)
occurrences all number	0	0	4	0	4	0
Myalgia
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	2 / 23 (8.70%)	0 / 11 (0.00%)	4 / 62 (6.45%)	0 / 11 (0.00%)
occurrences all number	1	0	2	0	5	0
Myositis
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	1	2
Pain in extremity
subjects affected / exposed	2 / 6 (33.33%)	0 / 8 (0.00%)	5 / 23 (21.74%)	2 / 11 (18.18%)	22 / 62 (35.48%)	3 / 11 (27.27%)
occurrences all number	2	0	12	6	31	3
Infections and infestations
Conjunctivitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	3 / 23 (13.04%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	3	0	1	0
Enterocolitis infectious
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	1	0	1	0	3	0
Gastroenteritis
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0
Gastroenteritis viral
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	2 / 62 (3.23%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	3	0
Influenza
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	1	0
Lice infestation
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0
Lymphangitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	1	0	1	0
Otitis media
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	4 / 62 (6.45%)	1 / 11 (9.09%)
occurrences all number	0	0	1	0	6	1
Paronychia
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	2 / 62 (3.23%)	0 / 11 (0.00%)
occurrences all number	0	0	2	0	4	0
Pharyngitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	3 / 23 (13.04%)	0 / 11 (0.00%)	2 / 62 (3.23%)	0 / 11 (0.00%)
occurrences all number	0	0	3	0	2	0
Pneumonia
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	2 / 23 (8.70%)	0 / 11 (0.00%)	3 / 62 (4.84%)	0 / 11 (0.00%)
occurrences all number	0	1	4	0	3	0
Rash pustular
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 23 (8.70%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	2	0	1	0
Rhinitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 23 (8.70%)	0 / 11 (0.00%)	2 / 62 (3.23%)	0 / 11 (0.00%)
occurrences all number	0	0	3	0	2	0
Sinusitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	1 / 11 (9.09%)	2 / 62 (3.23%)	0 / 11 (0.00%)
occurrences all number	0	0	1	1	3	0
Skin infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	4 / 23 (17.39%)	2 / 11 (18.18%)	6 / 62 (9.68%)	0 / 11 (0.00%)
occurrences all number	0	0	7	2	14	0
Upper respiratory tract infection
subjects affected / exposed	1 / 6 (16.67%)	1 / 8 (12.50%)	10 / 23 (43.48%)	1 / 11 (9.09%)	13 / 62 (20.97%)	1 / 11 (9.09%)
occurrences all number	2	1	22	1	14	1
Urinary tract infection
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 23 (0.00%)	0 / 11 (0.00%)	3 / 62 (4.84%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	3	0
Viral infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 23 (8.70%)	0 / 11 (0.00%)	2 / 62 (3.23%)	0 / 11 (0.00%)
occurrences all number	0	0	3	0	2	0
Metabolism and nutrition disorders
Acidosis
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	4 / 23 (17.39%)	1 / 11 (9.09%)	0 / 62 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	5	1	0	0
Decreased appetite
subjects affected / exposed	0 / 6 (0.00%)	2 / 8 (25.00%)	9 / 23 (39.13%)	5 / 11 (45.45%)	26 / 62 (41.94%)	7 / 11 (63.64%)
occurrences all number	0	2	24	6	33	7
Dehydration
subjects affected / exposed	1 / 6 (16.67%)	2 / 8 (25.00%)	4 / 23 (17.39%)	1 / 11 (9.09%)	4 / 62 (6.45%)	2 / 11 (18.18%)
occurrences all number	1	3	5	1	4	2
Hypercalcaemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	2 / 23 (8.70%)	0 / 11 (0.00%)	3 / 62 (4.84%)	1 / 11 (9.09%)
occurrences all number	0	1	2	0	15	1
Hyperglycaemia
subjects affected / exposed	2 / 6 (33.33%)	1 / 8 (12.50%)	14 / 23 (60.87%)	4 / 11 (36.36%)	30 / 62 (48.39%)	5 / 11 (45.45%)
occurrences all number	3	1	50	10	42	9
Hyperkalaemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 8 (12.50%)	7 / 23 (30.43%)	3 / 11 (27.27%)	14 / 62 (22.58%)	0 / 11 (0.00%)
occurrences all number	0	1	8	5	20	0
Hypermagnesaemia
subjects affected / exposed	0 / 6 (0.00%)	2 / 8 (25.00%)	5 / 23 (21.74%)	4 / 11 (36.36%)	19 / 62 (30.65%)	3 / 11 (27.27%)
occurrences all number	0	2	8	5	30	4
Hypernatraemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 8 (0.00%)	3 / 23 (13.04%)	1 / 11 (9.09%)	10 / 62 (16.13%)	1 / 11 (9.09%)
occurrences all number	1	0	6	1	16	1
Hyperphosphataemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 62 (1.61%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	9	0
Hyperuricaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 23 (8.70%)	0 / 11 (0.00%)	4 / 62 (6.45%)	1 / 11 (9.09%)
occurrences all number	0	0	4	0	6	2
Hypoalbuminaemia
subjects affected / exposed	5 / 6 (83.33%)	2 / 8 (25.00%)	15 / 23 (65.22%)	5 / 11 (45.45%)	36 / 62 (58.06%)	5 / 11 (45.45%)
occurrences all number	10	4	82	21	86	6
Hypocalcaemia
subjects affected / exposed	3 / 6 (50.00%)	3 / 8 (37.50%)	17 / 23 (73.91%)	8 / 11 (72.73%)	32 / 62 (51.61%)	5 / 11 (45.45%)
occurrences all number	8	6	57	21	73	5
Hypoglycaemia
subjects affected / exposed	2 / 6 (33.33%)	0 / 8 (0.00%)	4 / 23 (17.39%)	1 / 11 (9.09%)	21 / 62 (33.87%)	4 / 11 (36.36%)
occurrences all number	3	0	12	13	32	6
Hypokalaemia
subjects affected / exposed	3 / 6 (50.00%)	2 / 8 (25.00%)	9 / 23 (39.13%)	4 / 11 (36.36%)	12 / 62 (19.35%)	4 / 11 (36.36%)
occurrences all number	4	4	20	10	15	4
Hypomagnesaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 8 (0.00%)	8 / 23 (34.78%)	0 / 11 (0.00%)	9 / 62 (14.52%)	1 / 11 (9.09%)
occurrences all number	0	0	10	0	11	1
Hyponatraemia
subjects affected / exposed	3 / 6 (50.00%)	2 / 8 (25.00%)	9 / 23 (39.13%)	0 / 11 (0.00%)	13 / 62 (20.97%)	1 / 11 (9.09%)
occurrences all number	3	3	12	0	16	1
Hypophosphataemia
subjects affected / exposed	3 / 6 (50.00%)	0 / 8 (0.00%)	7 / 23 (30.43%)	6 / 11 (54.55%)	14 / 62 (22.58%)	5 / 11 (45.45%)
occurrences all number	3	0	12	17	20	7

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Were there any global substantial amendments to the protocol? Yes

27 Jul 2017

Pfizer is not the Sponsor and cannot provide details of substantial changes. The final protocol amendment is available here https://clinicaltrials.gov/ProvidedDocs/70/NCT00939770/Prot_SAP_ICF_001.pdf

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 trials

Clinical Trial Results: A Phase 1/2 Study of PF-02341066, an Oral Small Molecule Inhibitor of Anaplastic Lymphoma Kinase (ALK) and C-Met, in Children With Relapsed/Refractory Solid Tumors and Anaplastic Large Cell Lymphoma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase 1: Number of Subjects Reporting Dose Limiting Toxicities (DLTs) With Crizotinib

Primary: Phase 1: Number of Subjects Reporting Dose Limiting Toxicities (DLTs) With Crizotinib

Secondary: Phase 1: PK Parameter- Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crizotinib After Single Dose Administration

Secondary: Phase 1: PK Parameter- Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crizotinib After Single Dose Administration

Secondary: Phase 1: PK Parameter- Maximum Observed Plasma Concentration (Cmax) of Crizotinib After Single Dose Administration

Secondary: Phase 1: PK Parameter- Maximum Observed Plasma Concentration (Cmax) of Crizotinib After Single Dose Administration

Secondary: Phase 1: PK Parameter- Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of Crizotinib After Single Dose Administration

Secondary: Phase 1: PK Parameter- Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of Crizotinib After Single Dose Administration

Secondary: Phase 1: PK Parameter- Steady State Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crizotinib

Secondary: Phase 1: PK Parameter- Steady State Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crizotinib

Secondary: Phase 1: PK Parameter- Steady State Maximum Observed Plasma Concentration (Cmax) of Crizotinib

Secondary: Phase 1: PK Parameter- Steady State Maximum Observed Plasma Concentration (Cmax) of Crizotinib

Secondary: Phase 1: PK Parameter- Steady State Trough Plasma Concentration (Ctrough) of Crizotinib

Secondary: Phase 1: PK Parameter- Steady State Trough Plasma Concentration (Ctrough) of Crizotinib

Secondary: Phase 1: PK Parameter- Steady State Area Under the Curve from Time Zero to end of dosing interval (AUCtau) of Crizotinib

Secondary: Phase 1: PK Parameter- Steady State Area Under the Curve from Time Zero to end of dosing interval (AUCtau) of Crizotinib

Secondary: Phase 1: PK Parameter- Steady State Apparent Clearance (CL/F) of Crizotinib

Secondary: Phase 1: PK Parameter- Steady State Apparent Clearance (CL/F) of Crizotinib

Secondary: Percentage of Subjects With Objective Response (OR)

Secondary: Percentage of Subjects With Objective Response (OR)

Secondary: Duration of Objective Tumor Response (DR)

Secondary: Duration of Objective Tumor Response (DR)

Secondary: Time to Objective Tumor Response (TTR)

Secondary: Time to Objective Tumor Response (TTR)

Secondary: Anaplastic Lymphoma Kinase (ALK)-Positive Status in Pediatric Subjects with IMT or ALCL

Secondary: Anaplastic Lymphoma Kinase (ALK)-Positive Status in Pediatric Subjects with IMT or ALCL

Secondary: Levels of Nucleophosmin-Anaplastic Lymphoma Kinase (NPM-ALK) in Peripheral Blood by Visit, Dose Level in ALK-positive ALCL Subjects

Secondary: Levels of Nucleophosmin-Anaplastic Lymphoma Kinase (NPM-ALK) in Peripheral Blood by Visit, Dose Level in ALK-positive ALCL Subjects

Secondary: Taste Assessment of Crizotinib Oral Solution Using Taste Feedback Questionnaire

Secondary: Taste Assessment of Crizotinib Oral Solution Using Taste Feedback Questionnaire

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) All Causalities

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) All Causalities

Secondary: Number of Subjects With Laboratory Test Abnormalities

Secondary: Number of Subjects With Laboratory Test Abnormalities

Secondary: Number of Subjects With Vital Signs Abnormalities

Secondary: Number of Subjects With Vital Signs Abnormalities

Secondary: Number of Subjects Reporting Growth Plate Toxicity

Secondary: Number of Subjects Reporting Growth Plate Toxicity

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Phase 1/2 Study of PF-02341066, an Oral Small Molecule Inhibitor of Anaplastic Lymphoma Kinase (ALK) and C-Met, in Children With Relapsed/Refractory Solid Tumors and Anaplastic Large Cell Lymphoma