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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT03677596
Registration number
NCT03677596
Ethics application status
Date submitted
27/07/2018
Date registered
19/09/2018
Date last updated
27/07/2023
Titles & IDs
Public title
A Study Of Two Inotuzumab Ozogamicin Doses in Relapsed/ Refractory Acute Lymphoblastic Leukemia Transplant Eligible Patients
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Scientific title
A PHASE 4, OPEN-LABEL, RANDOMIZED STUDY OF TWO INOTUZUMAB OZOGAMICIN DOSE LEVELS IN ADULT PATIENTS WITH RELAPSED OR REFRACTORY B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA ELIGIBLE FOR HEMATOPOIETIC STEM CELL TRANSPLANTATION AND WHO HAVE RISK FACTOR(S) FOR VENO-OCCLUSIVE DISEASE
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Secondary ID [1]
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2018-001557-27
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Secondary ID [2]
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B1931030
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Leukemia
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Precursor b-Cell Lymphoblastic Leukemia-Lymphoma
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ACUTE LYMPHOBLASTIC LEUKEMIA
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Condition category
Condition code
Cancer
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Leukaemia - Acute leukaemia
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Cancer
0
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Leukaemia - Chronic leukaemia
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Cancer
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0
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Children's - Leukaemia & Lymphoma
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Cancer
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Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
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Cancer
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Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - inotuzumab ozogamicin-dose level 2
Treatment: Drugs - Inotuzumab ozogamicin-dose level 1
Experimental: Dose Level 2 - Inotuzumab ozogamicin at starting dose 1.2 mg/m2/cycle (administered in 3 divided doses). Most patients expected to receive 2 or 3 cycles (cycle length 21 to 28 days)
Active Comparator: Dose Level 1 - Inotuzumab ozogamicin at starting dose 1.8 mg/m2/cycle (administered in 3 divided doses). Most patients expected to receive 2 or 3 cycles (cycle length 21 to 28 days)
Treatment: Drugs: inotuzumab ozogamicin-dose level 2
Inotuzumab ozogamicin (BESPONSAâ„¢) is a CD22 targeted antibody drug conjugate (ADC) approved by US FDA for treatment of adults with relapsed or refractory B cell precursor acute lymphoblastic leukemia (ALL). The approved starting dose is 1.8mg/m2/cycle. This treatment arm evaluates a lower starting dose of 1.2mg/m2/cycle.
Treatment: Drugs: Inotuzumab ozogamicin-dose level 1
Inotuzumab ozogamicin (BESPONSAâ„¢) is a CD22 targeted antibody drug conjugate (ADC) approved by US FDA for treatment of adults with relapsed or refractory B cell precursor acute lymphoblastic leukemia (ALL). The approved starting dose of 1.8mg/m2/cycle is administered in this treatment arm.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Percentage of Participants With Hematologic Remission (Complete Remission [CR]/Complete Remission With Incomplete Hematologic Recovery [CRi])
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Assessment method [1]
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CR defined 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 defined as CR except ANC <1000/µL &/or platelets <100,000/µL.
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Timepoint [1]
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At the end of treatment (within approximately 6 months from randomization)
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Primary outcome [2]
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Rate of veno-occlusive disease (VOD)
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Assessment method [2]
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Defined as the percentage of participants with VOD. VOD was defined as one of the following (a) the occurrence of bilirubin >=2mg/dL with 2 or more of the following: painful hepatomegaly, weight gain >5%, or ascites, or (b) histologically proven VOD, or (c) 2 or more of the following with hemodynamic and /or ultrasound evidence of VOD: bilirubin >=2mg/dL, painful hepatomegaly, weight gain >5%, or ascites.
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Timepoint [2]
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2 years from randomization
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Secondary outcome [1]
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Frequency of adverse events
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Assessment method [1]
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Adverse events to be reported during treatment and for at least 9 weeks after last dose. VOD reported for up to 2 years from randomization.
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Timepoint [1]
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At least 9 weeks after last dose
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Secondary outcome [2]
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Minimal residual disease (MRD) negativity
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Assessment method [2]
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MRD analysis performed at least once in participants with prior assessment of CR or CRi. Bone marrow aspirates, collected at screening and during the study to be sent to the central laboratory and analyzed using multiparametric flow cytometry. A peripheral blood sample to be provided if a participant had an inadequate bone marrow aspirate at screening. MRD negativity considered to be achieved if the lowest value of MRD from the first date of CR/CRi to EoT was <1 × 10^-4 lasts/nucleated cells.
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Timepoint [2]
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Up to approximately 4 weeks (EoT) from last dose of study drug
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Secondary outcome [3]
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Duration of remission (DoR) for Participants Who Achieved CR/CRi
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Assessment method [3]
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DoR defined as time from date of first response in responders (CR/CRi) to date of progression or death
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Timepoint [3]
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2 years from randomization
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Secondary outcome [4]
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Progression free survival (PFS)
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Assessment method [4]
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PFS defined as time from date of randomization to earliest date of the death or progressive disease
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Timepoint [4]
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2 years from randomization
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Secondary outcome [5]
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Overall survival (OS)
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Assessment method [5]
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OS defined as the time from randomization to date of death due to any cause.
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Timepoint [5]
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2 years from randomization
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Secondary outcome [6]
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Rate of hematopoietic stem cell transplantation (HSCT)
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Assessment method [6]
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HSCT rate defined as the percentage of participants who underwent HSCT following treatment with inotuzumab ozogamicin
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Timepoint [6]
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2 years from randomization
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Secondary outcome [7]
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Post HSCT relapse
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Assessment method [7]
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Post HSCT relapse defined as the time from date of HSCT to the date of first relapse post HSCT.
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Timepoint [7]
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2 years from randomization
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Secondary outcome [8]
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Post HSCT mortality
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Assessment method [8]
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Post HSCT mortality defined as the time from date of HSCT to the date of death due to any cause
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Timepoint [8]
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2 years from randomization
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Secondary outcome [9]
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Post HSCT non relapse mortality
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Assessment method [9]
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Post HSCT non relapse mortality defined as time from date of HSCT to the date of death due to any cause without prior relapse/progression post HSCT
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Timepoint [9]
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2 years from randomization
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Secondary outcome [10]
0
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Post HSCT relapse related mortality
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Assessment method [10]
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Post HSCT relapse related mortality defined as time from date of HSCT to the date of death due to any cause with prior relapse/progression post HSCT.
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Timepoint [10]
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2 years from randomization
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Secondary outcome [11]
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Pharmacokinetics, Cmax
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Assessment method [11]
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Maximum observed drug concentration (end of the infusion)
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Timepoint [11]
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Pharmacokinetic sample collections during study drug cycles (each cycle is up to 28 days): Cycle 1 days 1, 4, 8, and 15, Cycle 2 days 1 and 8, Cycle 3 days 1 and 8, and Cycle 4 days 1 and 8.
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Secondary outcome [12]
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Percentage of patients with positive anti-drug antibody response
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Assessment method [12]
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Testing for anti-drug antibodies, including neutralizing antibodies
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Timepoint [12]
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Sample collections: prior to first dose of study drug and approximately 4 weeks after the last dose of study drug
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Secondary outcome [13]
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Percentage of patients with laboratory abnormalities (NCI CTCAE grade)
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Assessment method [13]
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Magnesium, Calcium, Creatinine, Albumin, Alanine aminotransferase, Aspartate aminotransferase, Glucose, Phosphorus, Total Bilirubin, Blood urea nitrogen or urea, Uric acid or urate, Alkaline phosphatase, Lactate dehydrogenase, Gamma glutamyl transpeptidase, Total protein, Amylase and/or Lipase, Platelet Count, White Blood Cell Count (differential), hemoglobin, INR or prothrombin time, Activated partial thromboplastin time.
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Timepoint [13]
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At least 9 weeks after last dose
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Secondary outcome [14]
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Pharmacokinetics, Ctrough
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Assessment method [14]
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Drug concentration immediately prior to the next dose administration
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Timepoint [14]
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Pharmacokinetic sample collections during study drug cycles (each cycle is up to 28 days): Days 8 and 15 of Cycle 1 and day 8 of cycles 2-4)
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Secondary outcome [15]
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Pharmacokinetics, Clearance
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Assessment method [15]
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Volume of plasma cleared of drug per unit of time, calculated using non-linear mixed effects modeling
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Timepoint [15]
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Pharmacokinetic sample collections during study drug cycles (each cycle is up to 28 days): Cycle 1 days 1, 4, 8, and 15, Cycle 2 days 1 and 8, Cycle 3 days 1 and 8, and Cycle 4 days 1 and 8.
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Secondary outcome [16]
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Pharmacokinetics, Area under the curve (AUC)
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Assessment method [16]
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Calculated using non-linear mixed effects modeling
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Timepoint [16]
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Pharmacokinetic sample collections during study drug cycles (each cycle is up to 28 days): Cycle 1 days 1, 4, 8, and 15, Cycle 2 days 1 and 8, Cycle 3 days 1 and 8, and Cycle 4 days 1 and 8.
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Eligibility
Key inclusion criteria
1. Relapsed or refractory precursor CD22 positive B cell ALL with M2 or M3 marrow (=5%
blasts) and who are eligible for HSCT;
2. Have 1 or more of the following risk factors for developing VOD:
1. Due to receive Salvage 2 or greater;
2. Prior HSCT;
3. Age =55 years.
4. Ongoing or prior hepatic disease which may include a prior history of hepatitis
or drug induced liver injury, as well as hepatic steatosis, nonalcoholic
steatohepatitis, baseline elevations of bilirubin > upper limit of normal (ULN)
and =1.5 x ULN.
3. Ph+ ALL patients must have failed treatment with at least 1 second or third generation
tyrosine kinase inhibitor and standard multi agent induction chemotherapy;
4. Patients in Salvage 1 with late relapse should be deemed poor candidates for
reinduction with initial therapy;
5. Patients with lymphoblastic lymphoma and bone marrow involvement 5% lymphoblasts by
morphologic assessment;
6. Age 18 years to 75 years;
7. Eastern Cooperative Oncology Group (ECOG) performance status 0 2;
8. Adequate liver function, including total serum bilirubin =1.5 x ULN unless the patient
has documented Gilbert syndrome, and aspartate and alanine aminotransferase (AST and
ALT) =2.5 x ULN;
9. Serum creatinine =1.5 x ULN or any serum creatinine level associated with a measured
or calculated creatinine clearance of >=40 mL/min;
10. Male and female patients of childbearing potential and at risk for pregnancy must
agree to use a highly effective method of contraception throughout the study and for a
minimum of 8 months (females) and 5 months (males) after the last dose of assigned
treatment. A patient is of childbearing potential if, in the opinion of the
Investigator, he/she is biologically capable of having children and is sexually
active. Female subjects of nonchildbearing potential must meet at least 1 of the
following criteria:
1. Achieved postmenopausal status, defined as follows: cessation of regular menses
for at least 12 consecutive months with no alternative pathological or
physiological cause; and have a serum follicle stimulating hormone (FSH) level
confirming the postmenopausal state;
2. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
3. Have medically confirmed ovarian failure. All other female subjects (including
female subjects with tubal ligations) are considered to be of childbearing
potential.
11. Evidence of a personally signed and dated informed consent document indicating that
the subject has been informed of all pertinent aspects of the study; patients with
mental capacity which requires the presence of a legally authorized representative
will be excluded from the study;
12. Willing and able to comply with scheduled visits, treatment plan, laboratory tests,
and other study procedures.
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Minimum age
18
Years
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Maximum age
75
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
1. Isolated extramedullary relapse (ie, testicular or central nervous system);
2. Burkitt's or mixed phenotype acute leukemia based on the WHO 2008 criteria;
3. Active central nervous system (CNS) leukemia, as defined by unequivocal morphologic
evidence of lymphoblasts in the cerebrospinal fluid (CSF), use of CNS directed local
treatment for active disease within the prior 28 days, symptomatic CNS leukemia (ie,
cranial nerve palsies or other significant neurologic dysfunction) within 28 days.
Prophylactic intrathecal medication is not a reason for exclusion;
4. Prior chemotherapy within 2 weeks before randomization with the following exceptions:
1. To reduce the circulating lymphoblast count or palliation: ie, steroids,
hydroxyurea or vincristine;
2. For ALL maintenance: mercaptopurine, methotrexate, vincristine, thioguanine,
and/or tyrosine kinase inhibitors.
Patients must have recovered from acute non hematologic toxicity (to Grade 1 or less)
of all previous therapy prior to enrollment.
5. Prior monoclonal antibodies within 6 weeks of randomization, with the exception of
rituximab which must be discontinued at least 2 weeks prior to randomization;
6. Prior inotuzumab ozogamicin treatment or other anti CD22 immunotherapy within 6 months
before randomization;
7. Prior allogeneic hematopoietic stem cell transplant (HSCT) within 90 days before
randomization. Patients must have completed immunosuppression therapy for treatment of
graft versus host disease (GvHD) prior to enrollment. At randomization, patients must
not have Grade 2 or higher acute GvHD, or extensive chronic GvHD;
8. Peripheral absolute lymphoblast count >=10,000 /L (treatment with hydroxyurea and/or
steroids/vincristine is permitted within 2 weeks of randomization to reduce the white
blood cell [WBC] count);
9. Known systemic vasculitides (eg, Wegener's granulomatosis, polyarteritis nodosa,
systemic lupus erythematosus), primary or secondary immunodeficiency (such as human
immunodeficiency virus [HIV] infection or severe inflammatory disease);
10. Active hepatitis B infection as evidenced by hepatitis B surface antigen, active
hepatitis C infection (must be anti-hepatitis C antibody negative or hepatitis C
ribonucleic acid negative), or known seropositivity for HIV. HIV testing may need to
be performed in accordance with local regulations or local practice;
11. Major surgery within 4 weeks before randomization;
12. Unstable or severe uncontrolled medical condition (eg, unstable cardiac function or
unstable pulmonary condition);
13. Concurrent active malignancy other than non-melanoma skin cancer, carcinoma in situ of
the cervix, or localized prostate cancer that has been definitely treated with
radiation or surgery. Patients with previous malignancies are eligible provided that
they have been disease free for >=2 years;
14. Patients with active heart disease or the presence of New York Heart Association
(NYHA) stage III or IV congestive heart failure;
15. QTcF >470 msec (based on the average of 3 consecutive electrocardiogram [ECGs]);
16. Myocardial infarction within 6 months before randomization;
17. History of clinically significant ventricular arrhythmia, or unexplained syncope not
believed to be vasovagal in nature, or chronic bradycardic states such as sinoatrial
block or higher degrees of atrioventricular (AV) block unless a permanent pacemaker
has been implanted;
18. Uncontrolled electrolyte disorders that can compound the effects of a QTc prolonging
drug (eg, hypokalemia, hypocalcemia, hypomagnesemia);
19. Prior confirmed or ongoing hepatic veno occlusive disease (VOD) or sinusoidal
obstruction syndrome (SOS), or other serious or current ongoing liver disease such as
cirrhosis or nodular regenerative hyperplasia;
20. Administration of live vaccine within 6 weeks before randomization;
21. Evidence of uncontrolled current serious active infection (including sepsis,
bacteremia, fungemia) or patients with a recent history (within 4 months) of deep
tissue infections such as fascitis or osteomyelitis;
22. Patients who have had a severe allergic reaction or anaphylactic reaction to any
humanized monoclonal antibodies;
23. Pregnant female subjects; breastfeeding female subjects; fertile male subjects and
female subjects of childbearing potential who are unwilling or unable to use highly
effective contraception as outlined in this protocol for the duration of the study and
for a minimum of 8 months (females) and 5 months (males) after the last dose of
investigational product;
24. Investigative site staff members directly involved in the conduct of the study and
their family members, site staff members otherwise supervised by the Investigator, or
subjects who are Pfizer employees, including their family members, directly involved
in the conduct of the study;
25. Participation in other studies involving investigational drug(s) within 2 weeks prior
to study entry and/or during study participation (up through the end of treatment
visit);
26. Other acute or chronic medical or psychiatric condition including recent (within the
past year) or active suicidal ideation or behavior or laboratory abnormality that may
increase the risk associated with study participation or investigational product
administration or may interfere with the interpretation of study results and, in the
judgment of the Investigator, would make the subject inappropriate for entry into this
study.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 4
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
1/07/2019
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
26/05/2023
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Sample size
Target
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Accrual to date
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Final
102
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Recruitment in Australia
Recruitment state(s)
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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California
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Country [2]
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United States of America
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State/province [2]
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Illinois
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Country [3]
0
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United States of America
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State/province [3]
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Maryland
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0
0
United States of America
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State/province [4]
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Washington
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Country [5]
0
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Hungary
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State/province [5]
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Debrecen
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0
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Hungary
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State/province [6]
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Nyiregyhaza
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India
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State/province [7]
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Haryana
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India
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State/province [8]
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Maharashtra
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0
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India
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State/province [9]
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Tamil NADU
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0
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India
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State/province [10]
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Ranipet - 632517, Tamil Nadu, India
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Country [11]
0
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Poland
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State/province [11]
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Gdansk
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Poland
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State/province [12]
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Warsaw
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Poland
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Wroclaw
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0
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Singapore
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Singapore
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0
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Spain
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State/province [15]
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Asturias
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Spain
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State/province [16]
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Barcelona
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Spain
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0
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Madrid
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0
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Spain
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Sevilla
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Spain
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State/province [19]
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Valencia
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Taiwan
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Changhua
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Taiwan
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Taipei
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Turkey
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Istanbul
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Turkey
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Ankara
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Turkey
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Antalya
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Turkey
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Izmir
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Turkey
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Kayseri
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Country [27]
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Turkey
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State/province [27]
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Samsun
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Pfizer
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Address
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Country
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Ethics approval
Ethics application status
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Summary
Brief summary
This study will explore 2 different doses of inotuzumab ozogamicin including the dose that is
approved and a lower dose. The main purpose of this study is to evaluate whether a dose of
inotuzumab ozogamicin, lower than the approved dose, could be recommended for adult patient
with relapsed or refractory ALL who may be at higher risk for severe liver problems after
inotuzumab ozogamicin treatment and stem cell transplant (a potentially curative therapy that
can replace cancer cells with healthy cells). Efficacy and safety of the 2 doses will be
evaluated.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT03677596
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Trial related presentations / publications
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Public notes
This record is viewable in the ANZCTR as it had previously listed Australia and/or New Zealand as a recruitment site, however these sites have since been removed
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Contacts
Principal investigator
Name
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Pfizer CT.gov Call Center
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Address
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Pfizer
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Contact person for public queries
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Address
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Fax
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT03677596
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