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Dose: inotuzumab ozogamicin 0.8-0.5 mg/m\^2 IV, weekly, 3 times per cycle Cycle length: 21-28 days Total number of cycles: 6

inotuzumab ozogamicin

Dose: cytarabine 2.0 g/m\^2/day IV days 1-6 fludarabine30 mg/m\^2/day IV days 2-6 Cycle length: 28 days Total number of cycles: 4

FLAG (fludarabine, cytarabine and G-CSF)

cytarabine 3 g/m\^2 IV every 12 hours for up to 12 times

HIDAC (high dose cytarabine)

mitoxantrone 12 mg/m\^2 IV days 1-3 cytarabine 200 mg/m\^2/day IV over 7 days cycle length: 15-20 days Total number of cycles: 4

cytarabine and mitoxantrone

Pfizer CT.gov Call Center

This study will compare the efficacy, in terms of complete responses and overall survival, of inotuzumab ozogamicin versus investigator's choice of chemotherapy.

A Study Of Inotuzumab Ozogamicin Versus Investigator's Choice Of Chemotherapy In Patients With Relapsed Or Refractory Acute Lymphoblastic Leukemia

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)

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

CR was the disappearance of leukemia indicated by less than (\<) 5 percent (%) marrow blasts \& absence of peripheral blood leukemic blasts, with recovery of hematopoiesis defined by absolute neutrophil count (ANC) greater than or equal to (≥)1000 per microliter (/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 greater than (\>) 1.5 centimeters (cm) in greatest transverse diameter (GTD) at baseline must have regressed to less than or equal 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 \& must not be palpable) was required. CRi was defined as CR except ANC \<1000/μL \&/or platelets \<100,000/μL.

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.

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.

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. Kaplan-Meier method used and 2-sided 95% confidence interval (CI) calculated based on the Brookmeyer and Crowley method.

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

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.

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.

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).

This questionnaire comprised 30 questions within which are 9 multi-item scales \& 6 single-item measures. There are 5 functional scales; physical, role, cognitive, emotional \& social, 3 symptom scales; fatigue, pain, \& nausea \& vomiting, \& 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, \& dyspnea) \& a single item concerning perceived financial impact of the disease. Most questions used a 4 point scale (1='not at all' to 4='very much'); 2 questions used a 7-point scale (1='very poor' to 7='excellent'). Scores were averaged \& transformed to a scale ranging from 0 to 100; a higher score indicates a better level of functioning or greater degree of symptoms.

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. EQ-5D summary index is obtained with a formula that weights each level of the dimensions. The index-based score is interpreted along a continuum of 0 (death) to 1 (perfect health).

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.

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.

UCB Pharma

Pfizer

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. Events were reported up to at least 28 days after last dose.

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 participants (regardless of remission status).

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

Defined Investigator's Choice of Chemotherapy

Total

Age, Continuous

Sex: Female, Male

Pfizer ClinicalTrials.gov Call Center

ITT218 population - included the ITT population (all participants randomized) for the initial 218 participants.

Percentage of Participants With Hematologic Remission (Complete Remission [CR]/Complete Remission With Incomplete Hematologic Recovery [CRi]) as Assessed by the Endpoint Adjudication Committee (EAC)

ITT population - included all participants randomized. Although only 143 participants were treated in the Defined Investigator's Choice of Chemotherapy arm, all 162 randomized participants were included in the ITT population.

Overall Survival (OS)

Participants in the ITT218 population who achieved CR/CRi

Duration of Remission (DoR) for Participants Who Achieved CR/CRi (Per Investigator Assessment)

ITT population. Although only 143 participants were treated in the Defined Investigator's Choice of Chemotherapy arm, all 162 randomized participants were included in the ITT population.

Progression-Free Survival (PFS)

Percentage of Participants Who Had a Hematopoietic Stem-Cell Transplant (HSCT)

Participants in the ITT218 population achieving CR/CRi (per EAC Assessment)

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

Participants in the ITT218 population who had abnormal cytogenetics at baseline and who achieved CR/CRi

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

Cmax (Cycle 1 Day 1, 1 hour post-dose) (n=128)

Ctrough (Cycle 4 Day 1, pre-dose) (n=46)

Cmax (Cycle 4 Day 1, 1 hour post-dose) (n=37)

Pharmacokinetic (PK) evaluable population - included all participants with available PK data.

Maximum Observed Inotuzumab Ozogamicin Serum Concentration (Cmax) and Pre-Dose Inotuzumab Ozogamicin Serum Concentration (Ctrough) Following Single and Multiple Dosing

Physical Functioning C2D1

Physical Functioning C3D1

Physical Functioning C4D1

Physical Functioning C5D1

Physical Functioning C6D1

Physical Functioning EoT

Role Functioning C2D1

Role Functioning C3D1

Role Functioning C4D1

Role Functioning C5D1

Role Functioning C6D1

Role Functioning EoT

Emotional Functioning C2D1

Emotional Functioning C3D1

Emotional Functioning C4D1

Emotional Functioning C5D1

Emotional Functioning C6D1

Emotional Functioning EoT

Cognitive Functioning C2D1

Cognitive Functioning C3D1

Cognitive Functioning C4D1

Cognitive Functioning C5D1

Cognitive Functioning C6D1

Cognitive Functioning EoT

Social Functioning C2D1

Social Functioning C3D1

Social Functioning C4D1

Social Functioning C5D1

Social Functioning C6D1

Social Functioning EoT

Global Health Status C2D1

Global Health Status C3D1

Global Health Status C4D1

Global Health Status C5D1

Global Health Status C6D1

Global Health Status EoT

Dyspnoea C2D1

Dyspnoea C3D1

Dyspnoea C4D1

Dyspnoea C5D1

Dyspnoea C6D1

Dyspnoea EoT

Insomnia C2D1

Insomnia C3D1

Insomnia C4D1

Insomnia C5D1

Insomnia C6D1

Insomnia EoT

Appetite Loss C2D1

Appetite Loss C3D1

Appetite Loss C4D1

Appetite Loss C5D1

Appetite Loss C6D1

Appetite Loss EoT

Constipation C2D1

Constipation C3D1

Constipation C4D1

Constipation C5D1

Constipation C6D1

Constipation EoT

Diarrhoea C2D1

Diarrhoea C3D1

Diarrhoea C4D1

Diarrhoea C5D1

Diarrhoea C6D1

Diarrhoea EoT

Financial Difficulties C2D1

Financial Difficulties C3D1

Financial Difficulties C4D1

Financial Difficulties C5D1

Financial Difficulties C6D1

Financial Difficulties EoT

Fatigue C2D1

Fatigue C3D1

Fatigue C4D1

Fatigue C5D1

Fatigue C6D1

Fatigue Eot

Nausea and Vomiting C2D1

Nausea and Vomiting C3D1

Nausea and Vomiting C4D1

Nausea and Vomiting C5D1

Nausea and Vomiting C6D1

Nausea and Vomiting EoT

Pain C2D1

Pain C3D1

Pain C4D1

Pain C5D1

Pain C6D1

Pain EoT

ITT population. Although only 143 participants were treated in the Defined Investigator's Choice of Chemotherapy arm, all 162 randomized participants were included in the ITT population

Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Core 30 (EORTC QLQ-C30) Score

Cycle 2, Day 1

Cycle 3, Day 1

Cycle 4, Day 1

Cycle 5, Day 1

Cycle 6, Day 1

Change From Baseline in EuroQol 5 Dimension Health Questionnaire (EQ-5D) Index Score

Change From Baseline in EQ-5D VAS

Participants in the Safety population with post-study HSCT. A site visit in July 2017 (after clinical database lock), confirmed a fourth case of VOD/SOS occurred in the Defined Investigators Choice of Chemotherapy arm in March 2013 (approximately 3 months after the last dose).This was not entered on the CRF and therefore, is not included below.

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

Overall Study

Spots Global Cancer Trial Database for hidac (high dose cytarabine)