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

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ClinicalTrials.gov Identifier: NCT01564784

Recruitment Status : Completed

First Posted : March 28, 2012

Results First Posted : January 17, 2018

Last Update Posted : January 9, 2019

View this study on Beta.ClinicalTrials.gov

Sponsor:

Collaborator:

UCB Pharma

Information provided by (Responsible Party):

Pfizer

Tracking Information

First Submitted Date ^ICMJE

March 26, 2012

First Posted Date ^ICMJE

March 28, 2012

Results First Submitted Date ^ICMJE

March 2, 2017

Results First Posted Date ^ICMJE

January 17, 2018

Last Update Posted Date

January 9, 2019

Actual Study Start Date ^ICMJE

August 2, 2012

Actual Primary Completion Date

March 8, 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures ^ICMJE

Percentage of Participants With Hematologic Remission (Complete Remission [CR]/Complete Remission With Incomplete Hematologic Recovery [CRi]) as Assessed by the Endpoint Adjudication Committee (EAC) [ Time Frame: 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 ]
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.
Overall Survival (OS) [ Time Frame: Up to 5 years after randomization or 2 years from randomization of the last participant, whichever occurs first. ]
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.

Original Primary Outcome Measures ^ICMJE

Response to therapy (percentage of patients achieving a complete response and complete response with incomplete platelet and/or neutrophil recovery). [ Time Frame: 6 months ]

Change History

Current Secondary Outcome Measures ^ICMJE

Duration of Remission (DoR) for Participants Who Achieved CR/CRi (Per Investigator Assessment) [ Time Frame: Up to 2 years from randomization ]
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.
Progression-Free Survival (PFS) [ Time Frame: Up to 2 years from randomization ]
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.
Percentage of Participants Who Had a Hematopoietic Stem-Cell Transplant (HSCT) [ Time Frame: Up to 19 weeks from last dose ]
HSCT rate was defined as the percentage of participants who underwent SCT following treatment with inotuzumab ozogamicin or Investigator's choice of chemotherapy.
Percentage of Participants Achieving MRD Negativity (Based on Central Laboratory Analysis) in Participants Achieving a CR/CRi (Per EAC Assessment) [ Time Frame: Up to approximately 4 weeks (EoT) from last dose of study drug ]
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.
Cytogenetic Status (Based on Local Laboratory Analysis) of Participants With CR/CRi (Per EAC Assessment) [ Time Frame: Up to approximately 4 weeks (EoT) from last dose of study drug ]
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.
Maximum Observed Inotuzumab Ozogamicin Serum Concentration (Cmax) and Pre-Dose Inotuzumab Ozogamicin Serum Concentration (Ctrough) Following Single and Multiple Dosing [ Time Frame: Days 1, 4, 8, and 15 of Cycle 1, Days 1 and 8 of Cycle 2 and Day 1 of Cycle 4 ]
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).
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Core 30 (EORTC QLQ-C30) Score [ Time Frame: Day 1 of each cycle prior to dosing and EoT ]
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.
Change From Baseline in EuroQol 5 Dimension Health Questionnaire (EQ-5D) Index Score [ Time Frame: Day 1 of each cycle prior to dosing and EoT ]
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).
Change From Baseline in EQ-5D VAS [ Time Frame: Day 1 of each cycle prior to dosing and EoT ]
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.
Percentage of Participants With Veno-Occlusive Liver Disease (VOD)/Sinusoidal Obstruction Syndrome (SOS) Following Post Study HSCT [ Time Frame: Up to 2 years from randomization ]
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.

Original Secondary Outcome Measures ^ICMJE

Overall Survival [ Time Frame: Baseline to 24 months ]
Progression free survival [ Time Frame: Baseline to 24 months ]
Volume of distribution (Vd) for inotuzumab ozogamicin in serum [ Time Frame: Cycle 1, Days 1, 3, 8 and 15; Cycle 2 , Days 1 and 8; Cycle 4, Days 1 and 8 ]
Systemic clearance (CL) for inotuzumab ozogamicin in serum [ Time Frame: Cycle 1, Days 1, 3, 8 and 15; Cycle 2 , Days 1 and 8; Cycle 4, Days 1 and 8 ]
Duration of response [ Time Frame: Baseline to 24 months ]
Rate of stem-cell transplantation: percentage of patients having stem-cell transplant [ Time Frame: Baseline to 8 months ]
Minimal residual disease (MRD): number of leukemic cells in bone marrow after CR/CRi [ Time Frame: Baseline to 7 months ]
Cytogenetics: quantitate t(9;22), MLL, and IGH rearrangements in leukemia cells [ Time Frame: Baseline to 7 months ]
Quality of life: . EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer. Quality of Life Questionnaire, Core-30 [ Time Frame: Baseline to 6 months ]
Quality of life: EQ-5D = EuroQual -5D Health Questionnaire [ Time Frame: Baseline to 6 months ]

Current Other Pre-specified Outcome Measures

Not Provided

Original Other Pre-specified Outcome Measures

Not Provided

Descriptive Information

Brief Title ^ICMJE

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

Official Title ^ICMJE

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)

Brief Summary

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

Detailed Description

Not Provided

Study Type ^ICMJE

Interventional

Study Phase ^ICMJE

Phase 3

Study Design ^ICMJE

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment

Condition ^ICMJE

Acute Lymphoblastic Leukemia

Intervention ^ICMJE

Drug: inotuzumab ozogamicin
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
Drug: FLAG (fludarabine, cytarabine and G-CSF)
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
Drug: HIDAC (high dose cytarabine)
cytarabine 3 g/m^2 IV every 12 hours for up to 12 times
Drug: cytarabine and mitoxantrone
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

Study Arms ^ICMJE

Experimental: Arm A
Intervention: Drug: inotuzumab ozogamicin
Active Comparator: Arm B
Interventions:
- Drug: FLAG (fludarabine, cytarabine and G-CSF)
- Drug: HIDAC (high dose cytarabine)
- Drug: cytarabine and mitoxantrone

Publications *

* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.

Recruitment Information

Recruitment Status ^ICMJE

Completed

Actual Enrollment ^ICMJE

326

Original Estimated Enrollment ^ICMJE

292

Actual Study Completion Date ^ICMJE

January 4, 2017

Actual Primary Completion Date

March 8, 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria ^ICMJE

Inclusion Criteria:

CD22 expression
Adequate liver and renal functions

Exclusion Criteria:

Isolated extramedullary disease
Active Central Nervous System [CNS] disease

Sex/Gender ^ICMJE

Sexes Eligible for Study:

All

Ages ^ICMJE

18 Years and older (Adult, Older Adult)

Accepts Healthy Volunteers ^ICMJE

Contacts ^ICMJE

Contact information is only displayed when the study is recruiting subjects

Listed Location Countries ^ICMJE

Argentina, Australia, Canada, China, Czechia, Finland, France, Germany, Hungary, Italy, Japan, Korea, Republic of, Netherlands, Poland, Singapore, Spain, Sweden, Taiwan, United Kingdom, United States

Removed Location Countries

Belgium, Brazil, Croatia, Czech Republic, Serbia, Slovakia

Administrative Information

NCT Number ^ICMJE

NCT01564784

Other Study ID Numbers ^ICMJE

B1931022
2011-005491-41 ( EudraCT Number )

Has Data Monitoring Committee

Yes

U.S. FDA-regulated Product

Not Provided

IPD Sharing Statement ^ICMJE

Plan to Share IPD:	Yes
Plan Description:	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.
URL:	https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

Current Responsible Party

Pfizer

Original Responsible Party

Same as current

Current Study Sponsor ^ICMJE

Pfizer

Original Study Sponsor ^ICMJE

Same as current

Collaborators ^ICMJE

UCB Pharma

Investigators ^ICMJE

Study Director:

Pfizer CT.gov Call Center

Pfizer

PRS Account

Pfizer

Verification Date

December 2018

^ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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