Inotuzumab Ozogamicin and Blinatumomab in Treating Patients with Newly Diagnosed, Recurrent, or Refractory CD22-Positive B-Lineage Acute Lymphoblastic Leukemia

Summary

Objectives

PRIMARY OBJECTIVES:
I. To confirm tolerability of the combination regimen of inotuzumab ozogamicin followed by blinatumomab.
II. To estimate the 1-year event-free survival of older, transplant-ineligible patients with newly diagnosed, Philadelphia (Ph)-negative, CD22-positive, B-cell acute lymphoblastic leukemia (ALL) treated with inotuzumab ozogamicin induction followed by blinatumomab consolidation. (Cohort 1)
III. To estimate the 1-year event-free survival of patients with relapsed or refractory Ph-negative, CD22-positive, B-cell ALL treated with inotuzumab ozogamicin induction followed by blinatumomab consolidation. (Cohort 2)

SECONDARY OBJECTIVES:
I. To estimate the median, 1-year, and 3-year overall survival (OS) in all eligible patients. (Cohort 1)
II. To estimate the median, 1-year, and 3-year relapse-free survival (RFS) in all eligible patients. (Cohort 1)
III. To estimate the median and 3-year event-free survival (EFS) in all eligible patients. (Cohort 1)
IV. To estimate the complete response (CR) rate and overall response rate (ORR, defined as complete response [CR] + complete response with incomplete count recovery [CRi]) to inotuzumab ozogamicin followed by blinatumomab (regimen CR rate and ORR). (Cohort 1)
V. To estimate the CR rate and ORR (CR + CRi) to inotuzumab ozogamicin induction alone (induction CR and ORR). (Cohort 1)
VI. To estimate the minimal residual disease (MRD) negativity rate in subjects achieving a CR or CRi. (Cohort 1)
VII. To estimate the treatment-related mortality with this regimen. (Cohort 1)
VIII. To describe the safety and tolerability of this regimen. (Cohort 1)
IX. To estimate the median, 1-year, and 3-year OS in all eligible patients. (Cohort 2)
X. To estimate the median, 1-year, and 3-year RFS in all eligible patients. (Cohort 2)
XI. To estimate the median and 3-year EFS in all eligible patients. (Cohort 2)
XII. To estimate ORR (CR/CRi and CR/complete response with partial hematologic recovery [CRh]) to blinatumomab in patients with ALL refractory to inotuzumab ozogamicin. (Cohort 2)
XIII. To estimate the CR, CRi, and CRh rates at defined time points and cumulatively for the entire regimen. (Cohort 2)
XIV. To determine the MRD negativity (< 10^-4) rate at defined time points including prior to allogeneic HCT and cumulatively in patients achieving a CR, CRh, or CRi. (Cohort 2)
XV. To determine the allogeneic hematopoietic cell transplantation (HCT) rate in eligible subjects. (Cohort 2)
XVI. To estimate the treatment-related mortality with this regimen. (Cohort 2)
XVII. To describe the safety and tolerability of this regimen. (Cohort 2)

OTHER OBJECTIVES:
I. Results of the primary analysis will be examined for consistency, while accounting for the stratification factors and/or covariates of baseline quality of life (QOL) and fatigue.

CORRELATIVE SCIENCE OBJECTIVES:
I. To correlate specific karyotype groups (normal or various primary and secondary chromosomal abnormalities) with clinical and laboratory parameters.
II. To correlate specific karyotype groups with response rates, response duration, survival, and cure in patients treated with inotuzumab ozogamicin followed by blinatumomab.
III. To correlate specific karyotype groups with MRD.
IV. To determine karyotype changes at relapse and the influence of the type of change (or no change) in karyotype at relapse.
V. To assess the correlation of quantitative MRD post-induction with inotuzumab ozogamicin and at sequential consolidation time points with blinatumomab with RFS, EFS, and OS.
VI. To correlate the influence of MRD status (detectable versus [vs.] not and as a continuous measure) in relation to EFS, RFS, and OS with other clinical and biological factors (e.g. previously untreated vs. relapsed disease cohorts; age, initial white blood cell [WBC] count, cytogenetics).
VII. To identify genetic variants and predictors of ex vivo resistance.
VIII. To identify genetic variants and predictors of MRD.
IX. To identify genetic variants and predictors of relapse.
X. To determine inter-patient variability in drug sensitivity of adult ALL.
XI. To examine the associations of drug sensitivity with host and leukemia molecular features.

EXPLORATORY OBJECTIVES:
I. To estimate the median, 1-year, and 3-year RFS, EFS, and OS in patients achieving a CR/CRi to inotuzumab ozogamicin. (Cohort 1)
II. To compare the median, 1-year, and 3-year RFS, EFS, and OS among patients achieving MRD-negative vs. MRD-positive CR/CRi to inotuzumab ozogamicin. (Cohort 1)
III. To compare the median, 1-year, and 3-year RFS, EFS, and OS among patients achieving MRD-negative vs. MRD-positive CR/CRi at any time. (Cohort 1)
IV. To describe the rate, severity, and timing of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) of the liver after limited inotuzumab ozogamicin exposure and identify risk factors for SOS/VOD. (Cohort 1)
V. To estimate the rate of cytokine release syndrome in this population. (Cohort 1)
VI. To estimate the median, 1-year, and 3-year RFS from time of CR/CRi to inotuzumab ozogamicin in patients receiving inotuzumab ozogamicin followed by blinatumomab and not undergoing allogeneic hematopoietic cell transplantation (HCT). (Cohort 2)
VII. To estimate median, 1-year, and 3-year OS after CR/CRi to inotuzumab ozogamicin in patients not undergoing allogeneic HCT. (Cohort 2)
VIII. To compare in a non-randomized fashion median, 1-year, and 3-year OS, median, 1-year, and 3-year RFS, cumulative incidence of relapse (CIR), and non-relapse mortality (NRM) between patients achieving CR/CRi and receiving consolidation with or without allogeneic HCT. (Cohort 2)
IX. To describe the rate, severity, and timing of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) of the liver after limited inotuzumab ozogamicin exposure and identify risk factors for SOS/VOD. (Cohort 2)
X. To estimate the rate of cytokine release syndrome in this population. (Cohort 2)

OUTLINE: Patients are assigned to 1 of 2 cohorts.

COHORT 1: Patients receive inotuzumab ozogamicin intravenously (IV) over 1 hour on day 1, 8, and 15 (Course IA). By the end of Course IA (day 21), patients with adequate ALL cytoreduction continue to Course IB/IC, and patients who fail to achieve ALL cytoreduction continue to Course II. By the end of Course II, patients with CR-CRi to Course IB/IC and Course II continue to Course IIIA, patients without adequate ALL cytoreduction to Course IA or refractory to Course IB/IC but CR/CRi to Course II continue to Course IIIB.

COHORT 2: Patients receive inotuzumab ozogamicin IV over 1 hour on day 1, 8, and 15 (Course IA). By the end of Course IA (day 21), patients with adequate ALL cytoreduction continue to Course IB/IC, and patients who fail to achieve ALL cytoreduction continue to Course II. Patients with CR/CRi at the end of Course II continue to Course IIIB.

COURSE IB/IC: Patients receive inotuzumab ozogamicin IV over 1 hour on days 1, 8, and 15. Treatment continues for 1 course (28 days) in the absence of disease progression or unacceptable toxicity.

COURSE II: Patients receive blinatumomab IV continuously on days 1-28 and 43-70. Treatment continues for 1 course (84 days) in the absence of disease progression or unacceptable toxicity.

COURSE IIIA: Patients receive blinatumomab IV continuously on days 1-28 and 43-70. Treatment continues for 1 course (84 days) in the absence of disease progression or unacceptable toxicity.

COURSE IIIB: Patients receive blinatumomab IV continuously on days 1-28, 43-70, and 85-112. Treatment continues for 1 course (126 days) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 3 years, and then every 6 months for up to 10 years.