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Clinical Trial Results:
An Open-Label, Randomized Phase 3 Study of Inotuzumab Ozogamicin Compared to a Defined Investigator’s Choice in Adult Patients with Relapsed or Refractory CD22-Positive Acute Lymphoblastic Leukemia (ALL)

Summary
EudraCT number	2011-005491-41
Trial protocol	HU CZ SK SE ES GB DE FI IT NL BE
Global end of trial date

Results information
Results version number	v1
This version publication date	23 Mar 2017
First version publication date	23 Mar 2017
Other versions	v2

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

B1931022

ISRCTN number

US NCT number

NCT01564784

WHO universal trial number (UTN)

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., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com

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

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

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

Analysis stage

Interim

Date of interim/final analysis

08 Mar 2016

Is this the analysis of the primary completion data?

Yes

Primary completion date

08 Mar 2016

Global end of trial reached?

Main objective of the trial

The primary objectives of the study were to compare hematological remission rate (complete remission and complete remission with incomplete hematologic recovery), as assessed by the independent external Endpoint Adjudication Committee (EAC), and overall survival in patients with relapsed or refractory cluster of differentiation (CD) 22 positive B-cell ALL randomized to receive inotuzumab ozogamicin or Investigator’s choice of chemotherapy.

Protection of trial subjects

This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonisation Good Clinical Practice Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial participants. The final protocol, any amendments and informed consent documentation were reviewed and approved by the Institutional Review Board(s) and/or Independent Ethics Committee(s) at each of the investigational centres participating in the study.

Background therapy

Evidence for comparator

The choice of a comparator was complicated by the small patient population, the heterogeneity of the population, and the lack of an appropriate universal comparator. In the salvage setting, multiple miscellaneous regimens are used ranging from single agents to combination therapies such as combinations with cytarabine (conventional or high-dose), hyper-cyclophosphamide, vincristine, doxorubicin and dexamethasone, combinations with methotrexate and/or asparaginase, etc. Patients with Philadelphia chromosome positive (Ph+) ALL are treated with combinations including tyrosine kinase inhibitors (TKIs) such as imatinib and dasatinib. In the second and later salvage settings, treatments used will depend on responses to the treatments used in the frontline and first salvage settings further complicating the choice of comparator in these multiply-treated patients. In the patient population eligible for this study, it was expected that most patients would have been treated with intensive combination chemotherapy including anthracyclines and that physicians would select therapies, such as those shown above, or experimental therapies based on the patient’s condition, prior therapies, as well as standard practice. Therefore, the comparator arm included a defined list of 3 induction chemotherapy regimens commonly used in relapsed and refractory ALL, from which the investigator chose the optimal regimen for the patient: fludarabine, cytarabine, granulocyte colony-stimulating factor (G-CSF) (FLAG); mitoxantrone and cytarabine (MXN/Ara-C); or, high dose cytarabine (HIDAC). To avoid potential bias the investigator must have chosen the treatment of choice before patient randomization.

Actual start date of recruitment

02 Aug 2012

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy

Long term follow-up duration

2 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 2

Country: Number of subjects enrolled

China: 12

Country: Number of subjects enrolled

Czech Republic: 7

Country: Number of subjects enrolled

Germany: 19

Country: Number of subjects enrolled

Spain: 18

Country: Number of subjects enrolled

Finland: 2

Country: Number of subjects enrolled

France: 12

Country: Number of subjects enrolled

United Kingdom: 9

Country: Number of subjects enrolled

Hungary: 2

Country: Number of subjects enrolled

Italy: 26

Country: Number of subjects enrolled

Japan: 19

Country: Number of subjects enrolled

Netherlands: 4

Country: Number of subjects enrolled

Poland: 12

Country: Number of subjects enrolled

Korea, Republic of: 5

Country: Number of subjects enrolled

Singapore: 3

Country: Number of subjects enrolled

Sweden: 4

Country: Number of subjects enrolled

Taiwan: 2

Country: Number of subjects enrolled

United States: 149

Worldwide total number of subjects

307

EEA total number of subjects

115

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)

261

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

Participants were screened locally for characterization of leukemia, including CD22 immunophenotyping (flow cytometry) from peripheral blood or bone marrow aspirate obtained within 28 days of randomization. If CD22 immunophenotyping was negative per local laboratory results, central results may have been used for determining eligibility.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Inotuzumab Ozogamicin

Arm description

Participants were treated with inotuzumab ozogamicin at a starting dose of 1.8 mg/m^2 (according to body surface area) per cycle with a divided-dose regimen using 3 weekly administrations. Participants received 0.8 mg/m^2/cycle on Week 1 (Day 1), followed by 0.5 mg/m^2 on Week 2 (Day 8) and Week 3 (Day 15) of a 21-day cycle, and administered as an intravenous infusion over 60 minutes. For participants who achieved a CR or CRi, or to allow recovery from toxicity, the length of Cycle 1 could be extended up to 28 days (ie, 1 week treatment-free interval starting on Day 21). For participants who achieved CR or CRi, the inotuzumab ozogamicin dose administered on Week 1 was reduced to 0.5 mg/m^2 (for a total cycle dose of 1.5 mg/m^2/cycle) for Cycles 2 through 6 (maximum number of cycles permitted). For Cycles 2 through 6, the cycle length was 28 days for all patients (regardless of remission status).

Arm type

Experimental

Investigational medicinal product name

Inotuzumab ozogamicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Inotuzumab ozogamicin was administered intravenously at a starting dose of 1.8 mg/m^2 (according to body surface area) per cycle with a divided-dose regimen using 3 weekly administrations. Participants received 0.8 mg/m^2/cycle on Week 1 (Day 1), followed by 0.5 mg/m^2 on Week 2 (Day 8) and Week 3 (Day 15) of a 21-day cycle, and administered as an intravenous infusion over 60 minutes. For participants who achieved a CR or CRi, or to allow recovery from toxicity, the length of Cycle 1 could be extended up to 28 days (ie, 1 week treatment-free interval starting on Day 21). For participants who achieved CR or CRi, the inotuzumab ozogamicin dose administered on Week 1 was reduced to 0.5 mg/m^2 (for a total cycle dose of 1.5 mg/m^2/cycle) for Cycles 2 through 6 (maximum number of cycles permitted). For Cycles 2 through 6, the cycle length was 28 days for all patients (regardless of remission status).

Defined Investigator’s Choice of Chemotherapy

Arm description

Patients received fludarabine, cytarabine, granulocyte-colony stimulating factor (FLAG), mitoxantrone + cytarabine (MXN/Ara-C), or high-dose cytarabine (HIDAC), according to the Investigator’s choice.

Arm type

Active comparator

Investigational medicinal product name

Participants were treated with FLAG, MXN/Ara-C, or HIDAC, according to the Investigator’s choice.

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants treated with FLAG received cytarabine 2 g/m^2/day intravenous (IV) infusion over 4 hours on Day 1 (could be omitted per local standard of care), fludarabine 30 mg/m^2/day 30-minute IV infusion followed 4 hours later with cytarabine 2 g/m^2/day IV infusion over 4 hours on Days 2 to 6, and G-CSF 5 µg/kg/day or per local standard of care. Participants treated with MXN/Ara-C received mitoxantrone 12 mg/m^2 (dose could be reduced to 8 mg/m^2 based on patient age, comorbidities and prior anthracycline use) IV over 20 minutes on Day 1, cytarabine 200 mg/m^2/day continuous IV infusion over 7 days from Day 1 and mitoxantrone 12 mg/m^2 IV over 20 minutes on Days 2 to 3. Participants treated with HIDAC received cytarabine 3 g/m^2 IV over 1 to 3 hours every 12 hours for up to 12 doses starting on Day 1 of up to 6. For participants ≥55 years of age, the dose of cytarabine could be reduced up to 1.5 g/m^2. For participants over 60 years of age, the dose was reduced to 1.5 g/m^2.

Number of subjects in period 1	Inotuzumab Ozogamicin	Defined Investigator’s Choice of Chemotherapy
Started	164	143
Completed	0	0
Not completed	164	143
Adverse event, serious fatal	122	120
Ongoing in study	39	15
Unspecified	1	-
Subject refused further follow-up	1	7
Lost to follow-up	1	1

Baseline characteristics

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Reporting group title

Inotuzumab Ozogamicin

Reporting group description

Reporting group title

Defined Investigator’s Choice of Chemotherapy

Reporting group description

Reporting group values	Inotuzumab Ozogamicin	Defined Investigator’s Choice of Chemotherapy	Total
Number of subjects	164	143	307
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	134	127	261
From 65-84 years	30	16	46
85 years and over	0	0	0
Age Continuous
Units: Years
arithmetic mean (standard deviation)	45.9 ± 17.07	45.6 ± 16.32	-
Gender, Male/Female
Units: Subjects
Female	73	51	124
Male	91	92	183

End points

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Reporting group title

Inotuzumab Ozogamicin

Reporting group description

Reporting group title

Defined Investigator’s Choice of Chemotherapy

Reporting group description

Subject analysis set title

Inotuzumab Ozogamicin

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Defined Investigator’s Choice of Chemotherapy

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Defined Investigator’s Choice of Chemotherapy

Subject analysis set type

Intention-to-treat

Subject analysis set description

Primary: Percentage of Participants with Hematologic Remission (complete remission [CR]/complete remission with incomplete hematologic recovery [CRi]) as Assessed by the EAC

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End point title

Percentage of Participants with Hematologic Remission (complete remission [CR]/complete remission with incomplete hematologic recovery [CRi]) as Assessed by the EAC

End point description

CR was disappearance of leukemia indicated by <5 % marrow blasts & absence of peripheral blood leukemic blasts, with recovery of hematopoiesis defined by absolute neutrophil count (ANC) ≥1000/μL & platelets ≥100,000/μL. C1 extramedullary disease status (i.e. complete disappearance of measurable/non-measurable extramedullary disease with the following exceptions: for participants with at least 1 measurable lesion, all nodal masses >1.5 cm in greatest transverse diameter (GTD) at baseline must have regressed to ≤1.5 cm in GTD; all nodal masses ≥1 cm & ≤1.5 cm in GTD at baseline must have regressed to <1 cm GTD or reduced by 75% in sum of products of greatest diameters, no new lesions, spleen/other previously enlarged organs must have regressed in size & not be palpable) was required. CRi was defined as CR except ANC <1000/μL &/or platelets <100,000/μL. ITT218 population - included the intention-to-treat (ITT) population (all participants randomized) for the initial 218 participants.

End point type

Primary

End point timeframe

Screening, Day 16 to 28 of Cycles 1, 2 and 3, then every 1 to 2 cycles (or as clinically indicated) up to approximately 4 weeks (end of treatment [EoT]) from the last dose

End point values	Inotuzumab Ozogamicin	Defined Investigator’s Choice of Chemotherapy
Number of subjects analysed	109	109
Units: Percentage of Participants
number (confidence interval 95%)	80.7 (72.1 to 87.7)	29.4 (21 to 38.8)

Statistical Analysis of CR/CRi

Comparison groups

Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy

Number of subjects included in analysis

218

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

1-sided p-value based on Chi-square test

Parameter type

Rate difference

Point estimate

51.4

Confidence interval

level

97.5%

sides

2-sided

lower limit

38.4

upper limit

64.3

Primary: Overall Survival (OS)

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End point title

Overall Survival (OS) ^[1]

End point description

OS was defined as the time from randomization to date of death due to any cause. Participants last known to be alive were censored at date of last contact.

End point type

Primary

End point timeframe

Up to 5 years after randomization or 2 years from randomization of the last patient, whichever occurs first. Analysis population = ITT population - included all participants randomized.

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The baseline period arm for Defined Investigator’s Choice of Chemotherapy includes only those participants treated (i.e. the safety population). This outcome measure was analyzed for all participants randomized (i.e. the intention-to-treat [ITT] population).

End point values	Inotuzumab Ozogamicin	Defined Investigator’s Choice of Chemotherapy
Number of subjects analysed	164	162
Units: Months
median (confidence interval 95%)	7.7 (6 to 9.2)	6.7 (4.9 to 8.3)

Statistical Analysis of OS

Comparison groups

Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy

Number of subjects included in analysis

326

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0203

Method

1-sided stratified log-rank p-value

Parameter type

Hazard ratio (HR)

Point estimate

0.77

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.578

upper limit

1.026

Secondary: Duration of Remission (DoR) for Patients Who Achieved CR/CRi (per Investigator Assessment)

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End point title

Duration of Remission (DoR) for Patients Who Achieved CR/CRi (per Investigator Assessment)

End point description

DoR was defined as time from date of first response in responders (CR/CRi per Investigator assessment) to date of PFS event (i.e. death, progressive disease [objective progression, relapse from CR/CRi or treatment discontinuation due to global deterioration of health status] or starting new induction therapy or post-therapy stem cell transplant [SCT] without achieving CR/CRi). Responders without PFS events were censored at the last valid disease assessment including follow-up. Analysis population = ITT218 population

End point type

Secondary

End point timeframe

Up to 2 years from randomization

End point values	Inotuzumab Ozogamicin	Defined Investigator’s Choice of Chemotherapy
Number of subjects analysed	84	32
Units: Months
median (confidence interval 95%)	5.4 (4.2 to 8)	3.5 (2.9 to 6.6)

Statistical Analysis of DoR

Comparison groups

Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy

Number of subjects included in analysis

116

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0031

Method

1-sided stratified log-rank p-value

Parameter type

Hazard ratio (HR)

Point estimate

0.502

Confidence interval

level

95%

sides

2-sided

lower limit

0.303

upper limit

0.832

Secondary: Progression-Free Survival (PFS)

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End point title

Progression-Free Survival (PFS) ^[2]

End point description

PFS was defined as time from date of randomization to earliest date of the following events: death, progressive disease (objective progression, relapse from CR/CRi or treatment discontinuation due to global deterioration of health status) and starting new induction therapy or post-therapy SCT without achieving CR/CRi. Participants without a PFS event at time of analysis were censored at the last valid disease assessment. In addition, participants with documentation of an event after an unacceptably long interval (>28 weeks if there was post-baseline disease assessment, or >12 weeks if there was no post-baseline assessment) since the previous disease assessment were censored at the time of the previous assessment (date of randomization if no post-baseline assessment). Post-study treatment follow-up disease assessments was included. 2-sided 95% confidence interval (CI) calculated based on the Brookmeyer and Crowley method. Analysis population = ITT population.

End point type

Secondary

End point timeframe

Up to 2 years from randomization

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The baseline period arm for Defined Investigator’s Choice of Chemotherapy includes only those participants treated (i.e. the safety population). This outcome measure was analysed for all participants randomised (i.e. the intention-to-treat [ITT] population).

End point values	Inotuzumab Ozogamicin	Defined Investigator’s Choice of Chemotherapy
Number of subjects analysed	164	162
Units: Months
median (confidence interval 95%)	5 (3.7 to 5.6)	1.8 (1.5 to 2.2)

Statistical Analysis of PFS

Comparison groups

Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy

Number of subjects included in analysis

326

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

1-sided stratified log-rank p-value

Parameter type

Hazard ratio (HR)

Point estimate

0.452

Confidence interval

level

97.5%

sides

2-sided

lower limit

0.336

upper limit

0.609

Secondary: Percentage of Participants who had a Hematopoietic Stem-Cell Transplant (HSCT)

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End point title

Percentage of Participants who had a Hematopoietic Stem-Cell Transplant (HSCT) ^[3]

End point description

HSCT rate was defined as the percentage of participants who underwent SCT following treatment with inotuzumab ozogamicin or Investigator's choice of chemotherapy. Analysis population = ITT population.

End point type

Secondary

End point timeframe

From first dose date to start of post induction therapy

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The baseline period arm for Defined Investigator’s Choice of Chemotherapy includes only those participants treated (i.e. the safety population). This outcome measure was analyzed for all participants randomized (i.e. the intention-to-treat [ITT] population).

End point values	Inotuzumab Ozogamicin	Defined Investigator’s Choice of Chemotherapy
Number of subjects analysed	164	162
Units: Percentage of Participants
number (confidence interval 95%)	43.3 (35.6 to 51.2)	11.1 (6.7 to 17)

Statistical Analysis of HSCT

Comparison groups

Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy

Number of subjects included in analysis

326

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

1-sided p-value based on Chi-square test

Parameter type

Rate difference

Point estimate

32.2

Confidence interval

level

95%

sides

2-sided

lower limit

23.2

upper limit

41.2

Secondary: Percentage of Participants Achieving MRD Negativity (Based on Central Laboratory Analysis) in Patients Achieving a CR/CRi (per EAC Assessment)

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End point title

Percentage of Participants Achieving MRD Negativity (Based on Central Laboratory Analysis) in Patients Achieving a CR/CRi (per EAC Assessment)

End point description

MRD analysis was performed at least once in participants with prior assessment of CR or CRi. Bone marrow aspirates, collected at screening and during the study, were sent to the central laboratory and analyzed using multiparametric flow cytometry. The antibody combinations were designed to maximize discrimination between normal and abnormal cells of B-cell lineage and similar maturational stage and included antibodies detecting cluster of differentiation (CD) 9, CD10, CD13, CD19, CD20, CD33, CD34, CD38, CD45, CD58, CD66c, and CD123. A peripheral blood sample was provided if a participant had an inadequate bone marrow aspirate at screening. MRD negativity was considered to have been achieved if the lowest value of MRD from the first date of CR/CRi to EoT was <1 × 10^-4 blasts/nucleated cells. Analysis population = ITT218 population.

End point type

Secondary

End point timeframe

Up to approximately 4 weeks (EoT) from last dose of study drug

End point values	Inotuzumab Ozogamicin	Defined Investigator’s Choice of Chemotherapy
Number of subjects analysed	88	32
Units: Percentage of Participants
number (confidence interval 95%)	78.4 (68.4 to 86.5)	28.1 (13.7 to 46.7)

Statistical Analysis of MRD Negativity

Comparison groups

Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy

Number of subjects included in analysis

120

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

1-sided p-value based on Chi-Square test

Confidence interval

Secondary: Cytogenetic Status (Based on Local Laboratory Analysis) of Participants with CR/CRi (per EAC Assessment)

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End point title

Cytogenetic Status (Based on Local Laboratory Analysis) of Participants with CR/CRi (per EAC Assessment)

End point description

Karyotyping was required locally, at screening and at least once during the study in participants who had abnormal cytogenetics at baseline and who achieved CR/CRi. Data presented below are for participants who achieved CR/CRi per EAC and had abnormal karyotype at screening. Analysis population = ITT218 population.

End point type

Secondary

End point timeframe

Up to approximately 4 weeks (EoT) from last dose of study drug

End point values	Inotuzumab Ozogamicin	Defined Investigator’s Choice of Chemotherapy
Number of subjects analysed	88 ^[4]	32 ^[5]
Units: Percentage of Participants
number (confidence interval 95%)
Abnormal at screening in CR/CRi subjects (Group 1)	61.4 (50.4 to 71.6)	68.8 (50 to 83.9)
Abnormal after remission in Group 1 subjects	3.7 (0.5 to 12.7)	18.2 (5.2 to 40.3)

Notes
[4] - n = 54 for participants who achieved CR/CRi per EAC and had abnormal karyotype at screening.
[5] - n = 22 for participants who achieved CR/CRi per EAC and had abnormal karyotype at screening.

Statistical Analysis of Cytogenetics

Statistical analysis description

Abnormal after remission

Comparison groups

Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy

Number of subjects included in analysis

120

Analysis specification

Pre-specified

Analysis type

P-value

= 0.216

Method

1-sided p-value based on Chi-Square test

Confidence interval

Statistical Analysis of Cytogenetics

Statistical analysis description

Abnormal at Screening

Comparison groups

Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy

Number of subjects included in analysis

120

Analysis specification

Pre-specified

Analysis type

P-value

= 0.3168

Method

1-sided p-value based on Chi-Square test

Confidence interval

Secondary: Maximum Observed Inotuzumab Ozogamicin Serum Concentration (Cmax) and Pre-Dose Inotuzumab Ozogamicin Serum Concentration (Ctrough) Following Single (Cycle 1 Day 1) and Multiple (Cycle 4 Day 1) Dosing

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End point title

Maximum Observed Inotuzumab Ozogamicin Serum Concentration (Cmax) and Pre-Dose Inotuzumab Ozogamicin Serum Concentration (Ctrough) Following Single (Cycle 1 Day 1) and Multiple (Cycle 4 Day 1) Dosing ^[6]

End point description

Blood samples were collected and analyzed for inotuzumab ozogamicin serum concentrations using a validated high performance liquid chromatography with tandem mass spectrometry (HPLC/MS/MS) method with a lower limit of quantification of 1.0 nanograms per milliliter (ng/mL). Cmax was the maximum observed concentration occurring between 0-8 hours post-dose. Ctrough was the concentration prior to subsequent dose (pre-dose) occurring after 8 hours. n = number of observations (non-missing concentrations). Analysis population = Pharmacokinetic (PK) evaluable population - included all participants with available PK data.

End point type

Secondary

End point timeframe

Days 1, 4, 8, and 15 of Cycle 1, Days 1 and 8 of Cycle 2 and Day 1 of Cycle 4

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only participants from the Inotuzumab Ozogamicin treatment arm were planned to be analyzed for this end point.

End point values	Inotuzumab Ozogamicin
Number of subjects analysed	163
Units: ng/mL
arithmetic mean (standard deviation)
Cmax (Cycle 1 Day 1, 1 hour post-dose) (n=128)	211 ± 232
Ctrough (Cycle 4 Day 1, pre-dose) (n=46)	57.9 ± 29.8
Cmax (Cycle 4 Day 1, 1 hour post-dose) (n=37)	308 ± 362

No statistical analyses for this end point

Secondary: Between Treatment Comparison of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Core 30 (EORTC QLQ-C30) Score

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End point title

Between Treatment Comparison of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Core 30 (EORTC QLQ-C30) Score ^[7]

End point description

This questionnaire is comprised of 30 questions in total. Within the 30 questions are 9 multi-item scales and 6 single-item measures. There are 5 functional scales; physical, role, cognitive, emotional and social, 3 symptom scales; fatigue, pain and nausea and vomiting, and also a global health status/quality of life (QOL) scale. There are 5 single item measures assessing additional symptoms commonly reported by cancer patients (loss of appetite, insomnia, constipation, diarrhea, and dyspnea) and a single item concerning perceived financial impact of the disease. Analysis population = ITT population.

End point type

Secondary

End point timeframe

Day 1 of each cycle prior to dosing and EoT

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The baseline period arm for Defined Investigator’s Choice of Chemotherapy includes only those participants treated (i.e. the safety population). This outcome measure was analyzed for all participants randomized (i.e. the intention-to-treat [ITT] population).

End point values	Inotuzumab Ozogamicin	Defined Investigator’s Choice of Chemotherapy
Number of subjects analysed	164	162
Units: Score on a scale
arithmetic mean (confidence interval 95%)
Physical Functioning	75 (72.1 to 77.8)	68.1 (63.4 to 72.7)
Role Functioning	64.7 (60.8 to 68.7)	53.4 (46.3 to 60.4)
Emotional Functioning	77.4 (75 to 79.7)	79.6 (75.7 to 83.6)
Cognitive Functioning	85.3 (83.1 to 87.4)	82.5 (78.9 to 86.1)
Social Functioning	68.1 (64.3 to 72)	59.8 (53.1 to 66.5)
Global Health Status	62.1 (59.1 to 65.1)	57.8 (52.6 to 63)
Dyspnoea	14.7 (11.8 to 17.7)	19.4 (14.1 to 24.8)
Insomnia	25.4 (21.9 to 28.8)	27.1 (21.1 to 33.1)
Appetite Loss	17.6 (14.4 to 21.1)	26.3 (19.9 to 32.7)
Constipation	12.1 (9.2 to 15)	10.7 (5.6 to 15.7)
Diarrhoea	5.9 (3.9 to 7.8)	8.9 (5.2 to 12.6)
Financial Difficulties	29.5 (25.9 to 33)	32 (25.7 to 38.2)
Fatigue	35 (31.7 to 38.3)	39.4 (33.9 to 44.9)
Nausea and Vomiting	8.7 (6.6 to 10.8)	10.4 (6.6 to 14.2)
Pain	21.3 (18 to 24.6)	22 (16.2 to 27.7)

Statistical Analysis of EORTC QLQ-C30

Statistical analysis description

Physical Functioning

Comparison groups

Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy

Number of subjects included in analysis

326

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0139

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

6.9

Confidence interval

level

95%

sides

2-sided

lower limit

1.4

upper limit

12.3

Statistical Analysis of EORTC QLQ-C30

Statistical analysis description

Role Functioning

Comparison groups

Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy

Number of subjects included in analysis

326

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0065

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

11.4

Confidence interval

level

95%

sides

2-sided

lower limit

3.2

upper limit

19.5

Statistical Analysis of EORTC QLQ-C30

Statistical analysis description

Emotional Functioning

Comparison groups

Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy

Number of subjects included in analysis

326

Analysis specification

Pre-specified

Analysis type

P-value

= 0.3307

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-2.3

Confidence interval

level

95%

sides

2-sided

lower limit

-6.9

upper limit

2.3

Statistical Analysis of EORTC QLQ-C30

Statistical analysis description

Cognitive Functioning

Comparison groups

Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy

Number of subjects included in analysis

326

Analysis specification

Pre-specified

Analysis type

P-value

= 0.1904

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

2.8

Confidence interval

level

95%

sides

2-sided

lower limit

-1.4

upper limit

Statistical Analysis of EORTC QLQ-C30

Statistical analysis description

Social Functioning

Comparison groups

Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy

Number of subjects included in analysis

326

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0336

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

8.4

Confidence interval

level

95%

sides

2-sided

lower limit

0.7

upper limit

16.1

Statistical Analysis of EORTC QLQ-C30

Statistical analysis description

Global Health Status

Comparison groups

Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy

Number of subjects included in analysis

326

Analysis specification

Pre-specified

Analysis type

P-value

= 0.1572

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

4.3

Confidence interval

level

95%

sides

2-sided

lower limit

-1.7

upper limit

10.3

Statistical Analysis of EORTC QLQ-C30

Statistical analysis description

Dyspnoea

Comparison groups

Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy

Number of subjects included in analysis

326

Analysis specification

Pre-specified

Analysis type

P-value

= 0.1281

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-4.7

Confidence interval

level

95%

sides

2-sided

lower limit

-10.8

upper limit

1.4

Statistical Analysis of EORTC QLQ-C30

Statistical analysis description

Insomnia

Comparison groups

Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy

Number of subjects included in analysis

326

Analysis specification

Pre-specified

Analysis type

P-value

= 0.6207

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-1.7

Confidence interval

level

95%

sides

2-sided

lower limit

-8.7

upper limit

5.2

Statistical Analysis of EORTC QLQ-C30

Statistical analysis description

Appetite Loss

Comparison groups

Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy

Number of subjects included in analysis

326

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0193

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-8.7

Confidence interval

level

95%

sides

2-sided

lower limit

-16

upper limit

-1.4

Statistical Analysis of EORTC QLQ-C30

Statistical analysis description

Constipation

Comparison groups

Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy

Number of subjects included in analysis

326

Analysis specification

Pre-specified

Analysis type

P-value

= 0.6249

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

1.4

Confidence interval

level

95%

sides

2-sided

lower limit

-4.4

upper limit

7.3

Statistical Analysis of EORTC QLQ-C30

Statistical analysis description

Diarrhoea

Comparison groups

Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy

Number of subjects included in analysis

326

Analysis specification

Pre-specified

Analysis type

P-value

= 0.1534

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-3

Confidence interval

level

95%

sides

2-sided

lower limit

-7.2

upper limit

1.1

Statistical Analysis of EORTC QLQ-C30

Statistical analysis description

Financial Difficulties

Comparison groups

Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy

Number of subjects included in analysis

326

Analysis specification

Pre-specified

Analysis type

P-value

= 0.4915

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-2.5

Confidence interval

level

95%

sides

2-sided

lower limit

-9.7

upper limit

4.7

Statistical Analysis of EORTC QLQ-C30

Statistical analysis description

Fatigue

Comparison groups

Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy

Number of subjects included in analysis

326

Analysis specification

Pre-specified

Analysis type

P-value

= 0.1789

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-4.4

Confidence interval

level

95%

sides

2-sided

lower limit

-10.8

upper limit

Statistical Analysis of EORTC QLQ-C30

Statistical analysis description

Nausea and Vomiting

Comparison groups

Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy

Number of subjects included in analysis

326

Analysis specification

Pre-specified

Analysis type

P-value

= 0.4578

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-1.6

Confidence interval

level

95%

sides

2-sided

lower limit

-6

upper limit

2.7

Statistical Analysis of EORTC QLQ-C30

Statistical analysis description

Pain

Comparison groups

Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy

Number of subjects included in analysis

326

Analysis specification

Pre-specified

Analysis type

P-value

= 0.8428

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-7.3

upper limit

Secondary: Between Treatment Comparison of EuroQol Five Dimension Health Questionnaire (EQ-5D) Index Score

Top of page

End point title

Between Treatment Comparison of EuroQol Five Dimension Health Questionnaire (EQ-5D) Index Score ^[8]

End point description

The EQ-5D self-report questionnaire is a standardized measure of health status developed by the EuroQoL Group. It consists of the EQ-5D descriptive system and a visual analogue scale (VAS), EQ-VAS. The EQ-5D descriptive system measures a participants’ health state on 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 levels, reflecting “no problems”, “some problems”, and “extreme problems”. The EQ-VAS records the respondent’s self-rated health on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health state. Analysis population = ITT population.

End point type

Secondary

End point timeframe

Day 1 of each cycle prior to dosing and EoT

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The baseline period arm for Defined Investigator’s Choice of Chemotherapy includes only those participants treated (i.e. the safety population). This outcome measure was analyzed for all participants randomized (i.e. the intention-to-treat [ITT] population).

End point values	Inotuzumab Ozogamicin	Defined Investigator’s Choice of Chemotherapy
Number of subjects analysed	164	162
Units: Score on a scale
arithmetic mean (confidence interval 95%)	0.8 (0.77 to 0.82)	0.76 (0.73 to 0.8)

Statistical Analysis of EQ-5D

Comparison groups

Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy

Number of subjects included in analysis

326

Analysis specification

Pre-specified

Analysis type

P-value

= 0.171

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-0.01

upper limit

0.07

Secondary: Between Treatment Comparison of EQ-5D VAS

Top of page

End point title

Between Treatment Comparison of EQ-5D VAS ^[9]

End point description

End point type

Secondary

End point timeframe

Day 1 of each cycle prior to dosing and EoT

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The baseline period arm for Defined Investigator’s Choice of Chemotherapy includes only those participants treated (i.e. the safety population). This outcome measure was analyzed for all participants randomized (i.e. the intention-to-treat [ITT] population).

End point values	Inotuzumab Ozogamicin	Defined Investigator’s Choice of Chemotherapy
Number of subjects analysed	164	162
Units: Score on a scale
arithmetic mean (confidence interval 95%)	67.1 (64 to 70.2)	62.5 (57.6 to 67.4)

Statistical Analysis of EQ-5D VAS

Comparison groups

Inotuzumab Ozogamicin v Defined Investigator’s Choice of Chemotherapy

Number of subjects included in analysis

326

Analysis specification

Pre-specified

Analysis type

P-value

= 0.1172

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

4.6

Confidence interval

level

95%

sides

2-sided

lower limit

-1.2

upper limit

10.4

Secondary: Percentage of Participants with Veno-Occlusive Liver Disease (VOD)/Sinusoidal Obstruction Syndrome (SOS) Following Post Study HSCT

Top of page

End point title

Percentage of Participants with Veno-Occlusive Liver Disease (VOD)/Sinusoidal Obstruction Syndrome (SOS) Following Post Study HSCT

End point description

VOD/SOS was defined as the occurrence of 2 out of the following 3 clinical criteria: 1) total serum bilirubin level >34 micromoles per liter (μmol/L) (>2.0 milligrams per deciliter [mg/dL]), 2) an increase in liver size from baseline or development of right upper quadrant pain of liver origin and 3) sudden weight gain >2.5% (eg, within a 72 hour period) because of fluid accumulation in the weeks following infusion of study drug or chemotherapy, or HSCT conditioning/preparative therapy, or development of ascites not present at baseline following such exposures AND the absence of other explanations for these signs and symptoms, OR development of bilirubin elevation, weight gain, or hepatomegaly plus histologic abnormalities on liver biopsy demonstrating hepatocyte necrosis in zone 3 of the liver acinus, sinusoidal fibrosis, and centrilobular hemorrhage, with or without fibrosis of the terminal hepatic venules. Analysis population = Safety population.

End point type

Secondary

End point timeframe

Up to 2 years from randomization

End point values	Inotuzumab Ozogamicin	Defined Investigator’s Choice of Chemotherapy
Number of subjects analysed	77	32
Units: Percentage of Participants
number (not applicable)	22.1	3.1

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

SAEs were assessed from informed consent up to at least 28 calendar days after last dose of investigational product. AEs were recorded on or after Cycle 1 Day 1 but within 42 days of last dose (all-causality) and all treatment-related AEs thereafter.

Adverse event reporting additional description

An event may appear as both an AE & SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant & non-serious in another participant, or 1 participant may have experienced both a serious & non-serious event.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.1

Reporting group title

Defined Investigator’s Choice of Chemotherapy

Reporting group description

Reporting group title

Inotuzumab Ozogamicin

Reporting group description

Serious adverse events	Defined Investigator’s Choice of Chemotherapy	Inotuzumab Ozogamicin
Total subjects affected by serious adverse events
subjects affected / exposed	71 / 143 (49.65%)	84 / 164 (51.22%)
number of deaths (all causes)	16	24
number of deaths resulting from adverse events	4	4
Vascular disorders
Hypertension
subjects affected / exposed	1 / 143 (0.70%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypotension
subjects affected / exposed	3 / 143 (2.10%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Shock haemorrhagic
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Thrombophlebitis
subjects affected / exposed	1 / 143 (0.70%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 143 (0.00%)	3 / 164 (1.83%)
occurrences causally related to treatment / all	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Chest pain
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Disease progression
subjects affected / exposed	5 / 143 (3.50%)	8 / 164 (4.88%)
occurrences causally related to treatment / all	0 / 5	0 / 8
deaths causally related to treatment / all	0 / 5	1 / 11
Fatigue
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mucosal inflammation
subjects affected / exposed	1 / 143 (0.70%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Multi-organ failure
Additional description: In the 'Investigator Choice' treatment arm 'Multiple organ dysfunction syndrome' appears as a fatal event for 2 participants in the Safety Data Warehouse, but as fatal SAEs of 'Multi-organ failure' in the clinical database.
subjects affected / exposed	2 / 143 (1.40%)	2 / 164 (1.22%)
occurrences causally related to treatment / all	1 / 3	2 / 3
deaths causally related to treatment / all	1 / 2	0 / 0
Pain
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	3 / 143 (2.10%)	5 / 164 (3.05%)
occurrences causally related to treatment / all	1 / 3	2 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Epistaxis
subjects affected / exposed	1 / 143 (0.70%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pharyngeal stenosis
subjects affected / exposed	1 / 143 (0.70%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	6 / 143 (4.20%)	2 / 164 (1.22%)
occurrences causally related to treatment / all	3 / 7	1 / 2
deaths causally related to treatment / all	1 / 3	1 / 2
Respiratory tract oedema
subjects affected / exposed	1 / 143 (0.70%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	3 / 143 (2.10%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 143 (0.70%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Cardiac failure congestive
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Left ventricular dysfunction
subjects affected / exposed	0 / 143 (0.00%)	2 / 164 (1.22%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	1 / 143 (0.70%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	1 / 143 (0.70%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	2 / 2	0 / 1
deaths causally related to treatment / all	1 / 1	0 / 1
Headache
subjects affected / exposed	0 / 143 (0.00%)	2 / 164 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorder
subjects affected / exposed	1 / 143 (0.70%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	2 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	27 / 143 (18.88%)	19 / 164 (11.59%)
occurrences causally related to treatment / all	27 / 31	14 / 23
deaths causally related to treatment / all	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 143 (0.00%)	2 / 164 (1.22%)
occurrences causally related to treatment / all	0 / 0	8 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	2 / 143 (1.40%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	1 / 143 (0.70%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Blindness unilateral
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 143 (0.70%)	3 / 164 (1.83%)
occurrences causally related to treatment / all	1 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain lower
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis ischaemic
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Diarrhoea
subjects affected / exposed	1 / 143 (0.70%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	1 / 143 (0.70%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis haemorrhagic
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Ileal perforation
subjects affected / exposed	1 / 143 (0.70%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal ischaemia
subjects affected / exposed	1 / 143 (0.70%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	1 / 1
Intra-abdominal haemorrhage
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Large intestinal ulcer
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mesenteric haemorrhage
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 143 (0.00%)	2 / 164 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal stenosis
subjects affected / exposed	1 / 143 (0.70%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Proctalgia
subjects affected / exposed	1 / 143 (0.70%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	1 / 143 (0.70%)	2 / 164 (1.22%)
occurrences causally related to treatment / all	1 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic vein thrombosis
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	3 / 143 (2.10%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	1 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Venoocclusive liver disease
subjects affected / exposed	1 / 143 (0.70%)	22 / 164 (13.41%)
occurrences causally related to treatment / all	0 / 1	26 / 28
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Dermatitis allergic
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 143 (0.00%)	2 / 164 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Haematuria
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 143 (0.00%)	2 / 164 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Bone infarction
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neck pain
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Adenoviral upper respiratory infection
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	1 / 143 (0.70%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	1 / 143 (0.70%)	3 / 164 (1.83%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 0
Bacterial infection
subjects affected / exposed	1 / 143 (0.70%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Brain abscess
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchopulmonary aspergillosis
subjects affected / exposed	1 / 143 (0.70%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Candida infection
subjects affected / exposed	1 / 143 (0.70%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 143 (0.70%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	1 / 143 (0.70%)	2 / 164 (1.22%)
occurrences causally related to treatment / all	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Corona virus infection
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cytomegalovirus chorioretinitis
subjects affected / exposed	1 / 143 (0.70%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enteritis necroticans
subjects affected / exposed	1 / 143 (0.70%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Enterococcal bacteraemia
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enterococcal sepsis
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia bacteraemia
subjects affected / exposed	2 / 143 (1.40%)	2 / 164 (1.22%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	2 / 143 (1.40%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	2 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile infection
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fungaemia
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fungal infection
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 143 (0.00%)	2 / 164 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Klebsiella bacteraemia
subjects affected / exposed	1 / 143 (0.70%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Klebsiella infection
subjects affected / exposed	1 / 143 (0.70%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Liver abscess
subjects affected / exposed	1 / 143 (0.70%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung infection
subjects affected / exposed	2 / 143 (1.40%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	2 / 2	0 / 1
deaths causally related to treatment / all	1 / 1	0 / 0
Necrotising fasciitis fungal
subjects affected / exposed	1 / 143 (0.70%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed	4 / 143 (2.80%)	3 / 164 (1.83%)
occurrences causally related to treatment / all	4 / 4	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 1
Parainfluenzae virus infection
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 143 (0.00%)	10 / 164 (6.10%)
occurrences causally related to treatment / all	0 / 0	5 / 13
deaths causally related to treatment / all	0 / 0	1 / 3
Pneumonia fungal
subjects affected / exposed	3 / 143 (2.10%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia pseudomonal
subjects affected / exposed	1 / 143 (0.70%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Pseudomonal bacteraemia
subjects affected / exposed	2 / 143 (1.40%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	1 / 2	0 / 1
deaths causally related to treatment / all	1 / 1	0 / 1
Pseudomonal sepsis
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	10 / 143 (6.99%)	4 / 164 (2.44%)
occurrences causally related to treatment / all	4 / 12	0 / 5
deaths causally related to treatment / all	0 / 2	0 / 3
Septic embolus
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Septic shock
subjects affected / exposed	3 / 143 (2.10%)	3 / 164 (1.83%)
occurrences causally related to treatment / all	1 / 3	3 / 4
deaths causally related to treatment / all	0 / 1	1 / 1
Serratia bacteraemia
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sinusitis fungal
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal bacteraemia
subjects affected / exposed	1 / 143 (0.70%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal sepsis
subjects affected / exposed	1 / 143 (0.70%)	2 / 164 (1.22%)
occurrences causally related to treatment / all	2 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Systemic candida
subjects affected / exposed	1 / 143 (0.70%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Systemic mycosis
subjects affected / exposed	1 / 143 (0.70%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 143 (0.70%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection fungal
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Fluid overload
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 143 (0.00%)	2 / 164 (1.22%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Lactic acidosis
subjects affected / exposed	0 / 143 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour lysis syndrome
subjects affected / exposed	0 / 143 (0.00%)	2 / 164 (1.22%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Defined Investigator’s Choice of Chemotherapy	Inotuzumab Ozogamicin
Total subjects affected by non serious adverse events
subjects affected / exposed	143 / 143 (100.00%)	159 / 164 (96.95%)
Vascular disorders
Hypertension
subjects affected / exposed	8 / 143 (5.59%)	9 / 164 (5.49%)
occurrences all number	8	12
Hypotension
subjects affected / exposed	22 / 143 (15.38%)	12 / 164 (7.32%)
occurrences all number	27	13
General disorders and administration site conditions
Asthenia
subjects affected / exposed	14 / 143 (9.79%)	14 / 164 (8.54%)
occurrences all number	16	20
Chest pain
subjects affected / exposed	9 / 143 (6.29%)	3 / 164 (1.83%)
occurrences all number	9	3
Chills
subjects affected / exposed	17 / 143 (11.89%)	18 / 164 (10.98%)
occurrences all number	22	21
Fatigue
subjects affected / exposed	24 / 143 (16.78%)	41 / 164 (25.00%)
occurrences all number	28	76
Mucosal inflammation
subjects affected / exposed	19 / 143 (13.29%)	6 / 164 (3.66%)
occurrences all number	21	7
Oedema peripheral
subjects affected / exposed	13 / 143 (9.09%)	13 / 164 (7.93%)
occurrences all number	16	19
Pain
subjects affected / exposed	8 / 143 (5.59%)	12 / 164 (7.32%)
occurrences all number	10	12
Pyrexia
subjects affected / exposed	57 / 143 (39.86%)	49 / 164 (29.88%)
occurrences all number	90	76
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	23 / 143 (16.08%)	22 / 164 (13.41%)
occurrences all number	28	25
Dyspnoea
subjects affected / exposed	18 / 143 (12.59%)	10 / 164 (6.10%)
occurrences all number	20	13
Epistaxis
subjects affected / exposed	11 / 143 (7.69%)	24 / 164 (14.63%)
occurrences all number	11	27
Oropharyngeal pain
subjects affected / exposed	10 / 143 (6.99%)	6 / 164 (3.66%)
occurrences all number	10	6
Pleural effusion
subjects affected / exposed	8 / 143 (5.59%)	3 / 164 (1.83%)
occurrences all number	8	4
Psychiatric disorders
Anxiety
subjects affected / exposed	11 / 143 (7.69%)	8 / 164 (4.88%)
occurrences all number	14	8
Depression
subjects affected / exposed	9 / 143 (6.29%)	4 / 164 (2.44%)
occurrences all number	9	4
Insomnia
subjects affected / exposed	22 / 143 (15.38%)	24 / 164 (14.63%)
occurrences all number	25	24
Investigations
Alanine aminotransferase increased
subjects affected / exposed	18 / 143 (12.59%)	25 / 164 (15.24%)
occurrences all number	26	35
Aspartate aminotransferase increased
subjects affected / exposed	16 / 143 (11.19%)	37 / 164 (22.56%)
occurrences all number	23	61
Blood alkaline phosphatase increased
subjects affected / exposed	10 / 143 (6.99%)	22 / 164 (13.41%)
occurrences all number	10	29
Gamma-glutamyltransferase increased
subjects affected / exposed	12 / 143 (8.39%)	35 / 164 (21.34%)
occurrences all number	12	48
Lipase increased
subjects affected / exposed	1 / 143 (0.70%)	15 / 164 (9.15%)
occurrences all number	1	31
White blood cell count decreased
subjects affected / exposed	9 / 143 (6.29%)	10 / 164 (6.10%)
occurrences all number	13	18
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	3 / 143 (2.10%)	10 / 164 (6.10%)
occurrences all number	3	11
Fall
subjects affected / exposed	4 / 143 (2.80%)	11 / 164 (6.71%)
occurrences all number	5	13
Cardiac disorders
Tachycardia
subjects affected / exposed	16 / 143 (11.19%)	6 / 164 (3.66%)
occurrences all number	21	6
Nervous system disorders
Dizziness
subjects affected / exposed	16 / 143 (11.19%)	12 / 164 (7.32%)
occurrences all number	17	14
Headache
subjects affected / exposed	38 / 143 (26.57%)	45 / 164 (27.44%)
occurrences all number	45	58
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	79 / 143 (55.24%)	54 / 164 (32.93%)
occurrences all number	191	160
Febrile neutropenia
subjects affected / exposed	52 / 143 (36.36%)	27 / 164 (16.46%)
occurrences all number	66	33
Leukopenia
subjects affected / exposed	54 / 143 (37.76%)	47 / 164 (28.66%)
occurrences all number	119	174
Lymphopenia
subjects affected / exposed	35 / 143 (24.48%)	31 / 164 (18.90%)
occurrences all number	76	116
Neutropenia
subjects affected / exposed	66 / 143 (46.15%)	79 / 164 (48.17%)
occurrences all number	126	246
Thrombocytopenia
subjects affected / exposed	86 / 143 (60.14%)	80 / 164 (48.78%)
occurrences all number	297	286
Eye disorders
Dry eye
subjects affected / exposed	8 / 143 (5.59%)	1 / 164 (0.61%)
occurrences all number	8	1
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	2 / 143 (1.40%)	10 / 164 (6.10%)
occurrences all number	3	14
Abdominal pain
subjects affected / exposed	26 / 143 (18.18%)	19 / 164 (11.59%)
occurrences all number	29	23
Abdominal pain upper
subjects affected / exposed	12 / 143 (8.39%)	11 / 164 (6.71%)
occurrences all number	12	12
Constipation
subjects affected / exposed	34 / 143 (23.78%)	28 / 164 (17.07%)
occurrences all number	39	31
Diarrhoea
subjects affected / exposed	54 / 143 (37.76%)	30 / 164 (18.29%)
occurrences all number	66	34
Dyspepsia
subjects affected / exposed	9 / 143 (6.29%)	3 / 164 (1.83%)
occurrences all number	11	3
Nausea
subjects affected / exposed	68 / 143 (47.55%)	52 / 164 (31.71%)
occurrences all number	89	72
Stomatitis
subjects affected / exposed	9 / 143 (6.29%)	5 / 164 (3.05%)
occurrences all number	12	6
Vomiting
subjects affected / exposed	35 / 143 (24.48%)	25 / 164 (15.24%)
occurrences all number	39	41
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	23 / 143 (16.08%)	35 / 164 (21.34%)
occurrences all number	41	66
Skin and subcutaneous tissue disorders
Erythema
subjects affected / exposed	9 / 143 (6.29%)	7 / 164 (4.27%)
occurrences all number	10	9
Pruritus
subjects affected / exposed	10 / 143 (6.99%)	8 / 164 (4.88%)
occurrences all number	11	9
Rash
subjects affected / exposed	27 / 143 (18.88%)	14 / 164 (8.54%)
occurrences all number	32	15
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	7 / 143 (4.90%)	9 / 164 (5.49%)
occurrences all number	7	10
Back pain
subjects affected / exposed	10 / 143 (6.99%)	16 / 164 (9.76%)
occurrences all number	10	20
Bone pain
subjects affected / exposed	10 / 143 (6.99%)	3 / 164 (1.83%)
occurrences all number	10	3
Pain in extremity
subjects affected / exposed	16 / 143 (11.19%)	13 / 164 (7.93%)
occurrences all number	19	14
Infections and infestations
Bacteraemia
subjects affected / exposed	13 / 143 (9.09%)	4 / 164 (2.44%)
occurrences all number	14	4
Pneumonia
subjects affected / exposed	12 / 143 (8.39%)	4 / 164 (2.44%)
occurrences all number	13	5
Sinusitis
subjects affected / exposed	8 / 143 (5.59%)	4 / 164 (2.44%)
occurrences all number	9	5
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	18 / 143 (12.59%)	19 / 164 (11.59%)
occurrences all number	25	23
Fluid overload
subjects affected / exposed	8 / 143 (5.59%)	2 / 164 (1.22%)
occurrences all number	8	2
Hyperglycaemia
subjects affected / exposed	12 / 143 (8.39%)	11 / 164 (6.71%)
occurrences all number	19	19
Hypoalbuminaemia
subjects affected / exposed	7 / 143 (4.90%)	10 / 164 (6.10%)
occurrences all number	14	13
Hypocalcaemia
subjects affected / exposed	15 / 143 (10.49%)	11 / 164 (6.71%)
occurrences all number	29	19
Hypokalaemia
subjects affected / exposed	33 / 143 (23.08%)	25 / 164 (15.24%)
occurrences all number	49	37
Hypomagnesaemia
subjects affected / exposed	12 / 143 (8.39%)	10 / 164 (6.10%)
occurrences all number	14	13
Hyponatraemia
subjects affected / exposed	9 / 143 (6.29%)	5 / 164 (3.05%)
occurrences all number	13	8
Hypophosphataemia
subjects affected / exposed	10 / 143 (6.99%)	9 / 164 (5.49%)
occurrences all number	19	10

More information

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Were there any global substantial amendments to the protocol? Yes

09 Apr 2012

Inclusion and exclusion criteria were added or modified. The assessment of bone marrow biopsies was only required for patients with inadequate hematologic recovery. Patient follow-up time for survival was extended. Requirement for effective contraception was extended to 90 days post therapy. Redundant/unnecessary laboratory tests were removed. Administrative corrections and clarifications were made throughout the protocol.

24 Jun 2013

Removed time to progression as a secondary endpoint. Dose of inotuzumab ozogamicin was reduced to 0.5 mg/m^2 at Day 1 of Cycle 2 and beyond in patients achieving either CR or CRi. Revised sites required for study completion from 100 to 190. Changed the statistical power for testing CR/CRi from 88 to 89%. Allowed immunohistochemistry for the determination of CD22 expression at screening in patients with inadequate bone marrow aspirate and no circulating blasts. Added collection of an additional bone marrow sample for analysis of leukemic blast phenotype/genotype by other test methods. Changed the timing of disease assessment to allow bone marrow recovery for patients in the control arm. Updated background information with clinical data for inotuzumab ozogamicin from prior/ongoing studies in patients with relapsed or refractory ALL. Revised and clarified some inclusion/exclusion criteria. Updated study drug administration tables. Modified dose reduction schema to allow for drug related toxicities in the inotuzumab ozogamicin arm. Updated section on destruction of partially used or empty drug vials. Clarified disease assessment including time of radiographic assessment and bone marrow biopsy. Updated SAE reporting section. Added additional details on the sample size calculation. Implemented administrative corrections and clarifications throughout the protocol.

28 Mar 2014

Updated the inotuzumab ozogamicin clinical background section. Increased the total sample size from 292 to 325 patients due to higher number of patients in the control arm withdrawing from treatment before start of chemotherapy than initially anticipated and loss of follow-up data in the control arm. Capped the percentage of patients with Ph+ ALL that had failed TKI-based therapies at approximately 20% of the study patient population to reflect the relapsed and refractory ALL adult population. Clarified recommendations to reduce the risk of VOD/SOS for patients proceeding to HSCT; these recommendations included avoidance of hepatotoxic myeloablative regimens for subsequent HSCT and limiting the number of cycles of inotuzumab ozogamicin treatment in patients proceeding to HSCT. Modified CD22 immunophenotyping performed at screening such that patients were eligible for the study if they were considered to be CD22-positive based on assessment by the central laboratory even if they were considered to be CD22-negative based on assessment by the local laboratory. Added requirement for medications used as prophylaxis for hepatotoxicities or for the treatment of VOD/SOS to be reported for up to 2 years from randomization. Implemented administrative corrections and clarifications throughout the protocol.

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: An Open-Label, Randomized Phase 3 Study of Inotuzumab Ozogamicin Compared to a Defined Investigator’s Choice in Adult Patients with Relapsed or Refractory CD22-Positive Acute Lymphoblastic Leukemia (ALL)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants with Hematologic Remission (complete remission [CR]/complete remission with incomplete hematologic recovery [CRi]) as Assessed by the EAC

Primary: Percentage of Participants with Hematologic Remission (complete remission [CR]/complete remission with incomplete hematologic recovery [CRi]) as Assessed by the EAC

Primary: Overall Survival (OS)

Primary: Overall Survival (OS)

Secondary: Duration of Remission (DoR) for Patients Who Achieved CR/CRi (per Investigator Assessment)

Secondary: Duration of Remission (DoR) for Patients Who Achieved CR/CRi (per Investigator Assessment)

Secondary: Progression-Free Survival (PFS)

Secondary: Progression-Free Survival (PFS)

Secondary: Percentage of Participants who had a Hematopoietic Stem-Cell Transplant (HSCT)

Secondary: Percentage of Participants who had a Hematopoietic Stem-Cell Transplant (HSCT)

Secondary: Percentage of Participants Achieving MRD Negativity (Based on Central Laboratory Analysis) in Patients Achieving a CR/CRi (per EAC Assessment)

Secondary: Percentage of Participants Achieving MRD Negativity (Based on Central Laboratory Analysis) in Patients Achieving a CR/CRi (per EAC Assessment)

Secondary: Cytogenetic Status (Based on Local Laboratory Analysis) of Participants with CR/CRi (per EAC Assessment)

Secondary: Cytogenetic Status (Based on Local Laboratory Analysis) of Participants with CR/CRi (per EAC Assessment)

Secondary: Maximum Observed Inotuzumab Ozogamicin Serum Concentration (Cmax) and Pre-Dose Inotuzumab Ozogamicin Serum Concentration (Ctrough) Following Single (Cycle 1 Day 1) and Multiple (Cycle 4 Day 1) Dosing

Secondary: Maximum Observed Inotuzumab Ozogamicin Serum Concentration (Cmax) and Pre-Dose Inotuzumab Ozogamicin Serum Concentration (Ctrough) Following Single (Cycle 1 Day 1) and Multiple (Cycle 4 Day 1) Dosing

Secondary: Between Treatment Comparison of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Core 30 (EORTC QLQ-C30) Score

Secondary: Between Treatment Comparison of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Core 30 (EORTC QLQ-C30) Score

Secondary: Between Treatment Comparison of EuroQol Five Dimension Health Questionnaire (EQ-5D) Index Score

Secondary: Between Treatment Comparison of EuroQol Five Dimension Health Questionnaire (EQ-5D) Index Score

Secondary: Between Treatment Comparison of EQ-5D VAS

Secondary: Between Treatment Comparison of EQ-5D VAS

Secondary: Percentage of Participants with Veno-Occlusive Liver Disease (VOD)/Sinusoidal Obstruction Syndrome (SOS) Following Post Study HSCT

Secondary: Percentage of Participants with Veno-Occlusive Liver Disease (VOD)/Sinusoidal Obstruction Syndrome (SOS) Following Post Study HSCT

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
An Open-Label, Randomized Phase 3 Study of Inotuzumab Ozogamicin Compared to a Defined Investigator’s Choice in Adult Patients with Relapsed or Refractory CD22-Positive Acute Lymphoblastic Leukemia (ALL)