Study Evaluating Inotuzumab Ozogamicin In Acute Lymphocytic Leukemia

DLT was any of the following in the first cycle & attributable to inotuzumab ozogamicin: any greater than or equal to (≥) Grade 4 non-hematologic toxicity except nausea/vomiting (if manageable with supportive care), alopecia, & toxicities secondary to neutropenia & sepsis; prolonged myelosuppression (absolute neutrophil count \[ANC\] less than \[\<\] 500 per microliter \[/µL\] or platelet count \<25,000/µL in bone marrow with \<5 percent (%) blasts & no evidence of leukemia more than 45 days beyond the most recent dose of test article); any Grade 3 non-hematologic toxicity (excluding toxicities such as alopecia or those secondary to neutropenia & sepsis) not resolving to ≥ Grade 2 within 7 days of the most recent dose of test article or was clinically significant irrespective of duration; any ≥ Grade 3 elevation of alanine aminotransferase, aspartate aminotransferase or bilirubin lasting ≥7 days; any test article related toxicity resulting in permanent discontinuation of test article.

Time frame: Cycle 1

Population: Safety analysis set

CR was defined as a disappearance of leukemia as indicated by \<5% marrow blasts and the absence of peripheral blood leukemic blasts, with recovery of hematopoiesis defined by ANC ≥1000/µL and platelets ≥100,000/µL. C1 extramedullary disease status was required. CRi was defined as CR except with ANC \<1000/µL and/or platelets \<100,000/µL. PR was defined as an improved or no worsening of acute lymphocytic leukemia as indicated by no peripheral blood blasts, and either or both of the following: at least a 50% decrease in the marrow blast percentage, compared to the pre-treatment value, and marrow blast percentage ≥5% and ≤25% and/or C2 extramedullary disease status.

Time frame: From screening to progressive disease or another induction therapy started, up to approximately 2 years

Population: Safety analysis set

CR was defined as a disappearance of leukemia as indicated by \<5% marrow blasts and the absence of peripheral blood leukemic blasts, with recovery of hematopoiesis defined by ANC ≥1000/µL and platelets ≥100,000/µL. C1 extramedullary disease status was required. CRi was defined as CR except with ANC \<1000/µL and/or platelets \<100,000/µL.

Time frame: From screening to progressive disease or another induction therapy started, up to approximately 2 years

Population: Safety analysis set

CR was the disappearance of leukemia indicated by \<5% marrow blasts and absence of peripheral blood leukemic blasts, with recovery of hematopoiesis defined by ANC ≥1000/µL and platelets ≥100,000/µL. C1 extramedullary disease status was required. CRi was as for CR except with ANC \<1000/µL and/or platelets \<100,000/µL. PR was an improved or no worsening of acute lymphocytic leukemia indicated by no peripheral blood blasts, and/or at least a 50% decrease in the marrow blast percentage, compared to pre-treatment value, and marrow blast percentage ≥5% and less than or equal to (≤)25% and/or C2 extramedullary disease status. RD occurred if a participant survived ≥7 days following completion of initial treatment course and had persistent leukemia in the most recent peripheral blood smear or bone marrow and/or persistent disease involvement at any extramedullary site after completion of therapy.

Time frame: From screening to progressive disease or another induction therapy started, up to approximately 2 years

Population: Safety analysis set

Duration of follow-up was defined as the time from the date of first dose of study drug to the date of last contact for participants known to be alive.

Time frame: From first dose up to approximately 2 years

Population: Participants who were alive

DoR1 was defined for participants who responded as the time from the date of first documentation of Complete Hematologic Response (CR or CRi) to the date of the first documentation of relapse after CR or CRi, treatment discontinuation due to global deterioration of health status) or to death due to any cause. Participants last known to be 1) alive and 2) without a DoR1 event, were censored at the date of the last disease assessment that verified lack of event.

Time frame: Up to approximately 2 years from first dose

Population: All participants who achieved CR or CRi

DoR was defined for participants who respond as the time from the date of first documentation of Hematologic Response (CR, CRi, or PR) to the date of the first documentation of DoR event (earliest date of PD, treatment discontinuation due to global deterioration of health status, first induction therapy or transplant after PR, relapse after CR or CRi or death due to any cause). Participants last known to be 1) alive and 2) without a DoR event, were censored at the date of the last disease assessment that verified lack of event.

Time frame: Up to approximately 2 years from first dose

Population: All participants who achieved CR, CRi or PR.

Optional blood samples for pharmacogenomic parameters were collected during Cycle 1 prior to the start of the inotuzumab ozogamicin infusion (0 hours) and 1 hour post-dose (original Final Protocol and Protocol Amendments 1 and 2) or 3 hours post-dose (Protocol Amendments 3 and 4) on Day 1 and Day 15 from those participants who provided consent. Gene expression analysis of samples collected pre- and post-dosing was performed using 96-gene TaqMan® low density array cards to examine the concordance between clinical outcome and expression of genes such as those involved in DNA damage response, apoptosis, B-cell antigen expression, glutathione metabolism, drug transport and the phosphoinositide 3-kinase/mammalian target of rapamycin pathway. Expression for each gene was reported as a normalized value, 2\^-change in (∆) threshold cycle (Ct), where ∆Ct is Ct\^target gene minus Ct\^reference genes, averaged.

Time frame: Predose and postdose on Days 1 and 15 of Cycle 1

Population: Pharmacogenomics population - included all enrolled participants who received at least 1 dose of any study drug, and had at least 1 biomarker parameter from the corresponding assay sample with both a baseline and post-treatment assessment.

MRD negativity was defined as \<0.01% mononuclear cells.

Time frame: From screening to progressive disease or another induction therapy started, up to approximately 2 years

Population: Number of participants who achieved CR and CRi

OS was defined as the time from Cycle 1 Day 1 to date of death due to any cause. If death was not documented, censoring occurred at the date at which the participant was last known to be alive.

Time frame: Up to approximately 2 years from first dose

Population: Safety analysis set

CD22+ leukemic blasts assessed in abnormal B cells from bone marrow (data from central laboratories only).

Time frame: Pre-dose on Days 1 and 15 of Cycles 1 and 2, and Day 1 of Cycle 4

Population: Safety analysis set

CD22+ leukemic blasts assessed in abnormal B cells from blood (data from central laboratories only).

Time frame: Pre-dose on Days 1 and 15 of Cycles 1 and 2, and Day 1 of Cycle 4

Population: Safety analysis set

Post-treatment SCT rate was defined as the percentage of participants who underwent SCT following treatment with inotuzumab ozogamicin.

Time frame: Up to approximately 2 years from first dose

Population: Safety analysis set

CR was defined as a disappearance of leukemia as indicated by \<5% marrow blasts and the absence of peripheral blood leukemic blasts, with recovery of hematopoiesis defined by ANC ≥1000/µL and platelets ≥100,000/µL. C1 extramedullary disease status was required. CRi was defined as CR except with ANC \<1000/µL and/or platelets \<100,000/µL. PR was defined as an improved or no worsening of acute lymphocytic leukemia as indicated by no peripheral blood blasts, and either or both of the following: at least a 50% decrease in the marrow blast percentage, compared to the pre-treatment value, and marrow blast percentage ≥5% and ≤25% and/or C2 extramedullary disease status.

Time frame: From screening to progressive disease or another induction therapy started, up to approximately 2 years

Population: Safety analysis set

CR was defined as a disappearance of leukemia as indicated by \<5% marrow blasts and the absence of peripheral blood leukemic blasts, with recovery of hematopoiesis defined by ANC ≥1000/µL and platelets ≥100,000/µL. C1 extramedullary disease status was required. CRi was defined as CR except with ANC \<1000/µL and/or platelets \<100,000/µL.

Time frame: From screening to progressive disease or another induction therapy started, up to approximately 2 years

Population: Safety analysis set (n refers to number of participants evaluated)

PFS was defined as the time from Cycle 1 Day 1 to first documentation of PFS event (earliest date of objective progression \[PD\], treatment discontinuation due to global deterioration of health status, subsequent induction or transplant after best response of PR or resistant disease, relapse after CR or CRi, or death due to any cause). Participants last known to be 1) alive and 2) without a PFS event, were censored at the date of the last disease assessment that verified lack of event.

Time frame: Up to approximately 2 years from first dose

Population: Safety analysis set

Time to MRD negativity was defined as the time from the date of first dose of study drug to the date of first documentation of MRD negativity.

Time frame: Screening, Day 21 of Cycles 1 to 6 and up to 4 to 6 weeks after the last dose (up to 34 weeks)

Population: All participants who achieved CR/CRi and MRD negativity.

Time to remission was defined as the time from the date of first dose of study drug to the date of first documentation of hematologic remission (CR or CRi) in participants achieving remission during study therapy.

Time frame: Up to approximately 2 years from first dose

Population: All participants who achieved CR or CRi

Time to response was defined as the time from the date of first dose of study drug to the date of first documentation of hematologic response (CR, CRi, or PR).

Time frame: Up to approximately 2 years from first dose

Population: All participants who achieved CR, CRi or PR.