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

Study Overview
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Brief Summary
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This phase II trial studies how well inotuzumab ozogamicin and blinatumomab work in treating patients with CD22-positive B-lineage acute lymphoblastic leukemia that is newly diagnosed, has come back, or does not respond to treatment. Immunotherapy with monoclonal antibodies, such as inotuzumab ozogamicin and blinatumomab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Detailed Description
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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.

Official Title
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A Phase II Study of Inotuzumab Ozogamicin Followed by Blinatumomab for Ph-Negative CD22-Positive B-Lineage Acute Lymphoblastic Leukemia in Newly Diagnosed Older Adults or Adults With Relapsed or Refractory Disease

Conditions
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B Acute Lymphoblastic Leukemia, Philadelphia Chromosome Negative, Recurrent B Acute Lymphoblastic Leukemia, Refractory B Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Biological: Blinatumomab
* Biological: Inotuzumab Ozogamicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pre-registration Eligibility Criteria (Step 0) Submission of bone marrow aspirate and peripheral blood for MRD analysis is mandatory prior to registration; the bone marrow sample should be from the first aspiration (i.e. first pull). Aspirate needle should be redirected if needed to get first pull bone marrow aspirate. It should be initiated as soon as possible after pre-registration. The specimens should be sent to the HEME Biobank. Lumbar Puncture (Spinal Tap) and Intrathecal Methotrexate: Patients may receive the day 1 of course IA dose of intrathecal (IT) methotrexate during the prior-to-registration lumbar puncture (or the venous line placement) to avoid a second lumbar puncture. If the dose is administered prior to registration, then systemic chemotherapy must begin within 7 days of this IT chemotherapy. Registration Eligibility Criteria (Step 1) Morphologic diagnosis of precursor B-cell acute lymphoblastic leukemia (ALL) based on World Health Organization (WHO) criteria. Patients with Burkitt lymphoma/leukemia are not eligible. CD22-positive disease defined as CD22 expression by >= 20% of lymphoblasts by local hematopathology evaluation. Philadelphia chromosome/BCR-ABL1-negative ALL by cytogenetics, fluorescence in situ hybridization (FISH), and/or polymerase chain reaction (PCR). If any test is positive for Philadelphia chromosome/BCR-ABL1, then the patient is ineligible. No active central nervous system (CNS) leukemia (i.e. only CNS-1 disease allowed). Active CNS leukemia is defined as morphologic evidence of lymphoblasts in the cerebrospinal fluid (CSF), use of CNS-directed local treatment for active disease within 28 days prior to registration, symptomatic CNS leukemia (i.e. cranial nerve palsies or other significant neurological dysfunction) within the 28 days prior to registration, and/or known asymptomatic parenchymal CNS mass lesions; see below for additional guidance. Prophylactic intrathecal medication alone is not an exclusion. Categories of CNS Involvement for CNS Evaluation Prior to Registration: CNS 1: CSF has < 5 WBC/uL with cytospin negative for blasts; or >= 10 red blood cell (RBC)/uL with cytospin negative for blasts. CNS 2: CSF has < 5 WBC/uL with cytospin positive for blasts; or >= 10 RBC/uL with cytospin positive for blasts; or >= 10 RBC/uL, WBC/uL >= 5 but less than Steinherz/Bleyer algorithm with cytospin positive for blasts (see below). CNS 3: CSF has >= 5 WBC/uL with cytospin positive for blasts; or >= 10 RBC/uL, >= 5 WBC/uL and positive by Steinherz/Bleyer algorithm (see below); or clinical signs of CNS leukemia (such as facial nerve palsy, brain/eye involvement or hypothalamic syndrome). Steinherz/Bleyer Method of Evaluating Initial Traumatic Lumbar Punctures: If the patient has leukemia cells in the peripheral blood and the lumbar puncture is traumatic and contains >= 5 WBC/uL with blasts, the following algorithm should be used to define CNS disease: CSF WBC/CSF RBC > 2 x (Blood WBC/Blood RBC count) Patients with known or suspected testicular involvement by leukemia are allowed provided that the patient receives concomitant scrotal/testicular radiotherapy. Unilateral or bilateral testicular enlargement should be assessed by ultrasound or other imaging technique. Biopsy is recommended if clinical findings are equivocal or suggestive of hydrocele or a non-leukemic mass, but further assessments are per treating physician discretion. Not pregnant and not nursing. This study involves agents that have known genotoxic, mutagenic, and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required. Eastern Cooperative Oncology Group (ECOG) performance status: 0-2 No unstable cardiac disease such as myocardial infarction, angina pectoris, uncontrolled heart failure, or uncontrolled cardiac arrhythmia within 6 months of registration. No impaired cardiac function, defined as left ventricular ejection fraction (LVEF) < 45% or New York Heart Association (NYHA) stage III or IV congestive heart failure (CHF). Patients with known human immunodeficiency virus (HIV) infection are eligible if they have been on effective antiretroviral therapy with an undetectable viral load tested within 6 months of registration. Patients with hepatitis B virus (HBV) are eligible only if they meet all the following: On HBV-suppressive therapy. No evidence of active virus. No evidence of HBV-related liver damage. Patients with hepatitis C virus (HCV) are eligible only if they meet all the following: Successfully completed complete-eradication therapy with undetectable viral load. No evidence of HCV-related liver damage. No history of clinically relevant neurologic disorder such as epilepsy, seizure, aphasia, stroke, severe brain injury, structural brain abnormality, benign brain tumor, dementia, Parkinson's disease, movement disorder, cerebellar disease, or other significant CNS abnormalities. No prior additional malignancy (i.e. in addition to ALL) except adequately treated basal- or squamous-cell skin cancer, in situ cervical cancer, stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for >= 2 years. No history of clinically significant ventricular arrhythmia, unexplained non-vasovagal syncope, or chronic bradycardic states such as sinoatrial block or higher degree of atrioventricular block unless a permanent pacemaker has been implanted. No history of chronic liver disease, including cirrhosis. No history of sinusoidal occlusion syndrome/veno-occlusive disease of the liver. No uncontrolled infection or recent history (within 4 months prior to registration) of deep tissue infections such as fasciitis or osteomyelitis. Total bilirubin, serum =< 1.5 x upper limit of normal (ULN)* Except in the event of: 1) Gilbert disease, in which case total bilirubin must be =< 2 x ULN, or 2) elevated bilirubin believed by investigator to be due to leukemic infiltration, in which case total bilirubin must be =< 2 x ULN. Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN Creatinine, serum =< 1.5 ULN OR creatinine clearance >= 40 mL/min QT interval by Fridericia's correction formula (QTcF) =< 470 msec Cohort 1 Patients Only Age >= 60 years. No prior treatment for ALL except a single dose of intrathecal chemotherapy, corticosteroids, hydroxyurea, and/or leukapheresis to reduce peripheral blast count and prevent ALL complications. Allowed therapy may be administered for no more than 14 days and must be completed >= 24 hours prior to the initiation of protocol therapy. No plan for allogeneic or autologous hematopoietic cell transplantation (HCT). Cohort 2 Patients Only: Age >= 18 years. Relapsed or refractory disease in salvage 1 or 2. No isolated extramedullary relapse. Prior allogeneic HCT permitted. Patients with prior allogeneic HCT must have completed transplantation >= 4 months prior to registration. Patients with prior allogeneic HCT must have no evidence of graft-versus-host disease and must have completed immunosuppressive therapy >= 30 days prior to registration. Prior treatment with inotuzumab ozogamicin, blinatumomab, other CD22-directed therapy, or other CD19-directed therapy is not allowed. Prior treatment with rituximab must be completed >= 7 days prior to registration. Prior treatment with other monoclonal antibodies must be completed >= 6 weeks prior to registration. Prior treatment for ALL must be completed >= 14 days prior to registration with the following exceptions: intrathecal chemotherapy, hydroxyurea, corticosteroids, 6-mercaptopurine, methotrexate, vincristine, and/or leukapheresis to reduce circulating absolute lymphoblast count to =< 10,000/uL or prevent complications related to ALL are allowed but must be completed >= 24 hours prior to the initiation of protocol therapy. Patients should have resolution of any acute non-hematologic toxicities of prior therapy to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0 grade =< 1. Peripheral blood absolute lymphoblast count =< 10,000/uL (treatment allowed as above to reduce blast count to =< 10,000/uL)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 (inotuzumab ozogamicin, blinatumomab)<br>See Detailed Description | Biological: Blinatumomab<br>* Given IV<br>* Other names: MT103;Biological: Inotuzumab Ozogamicin<br>* Given IV<br>* Other names: WAY-207294;|
| Experimental: Cohort 2 (inotuzumab ozogamicin, blinatumomab)<br>See Detailed Description. | Biological: Blinatumomab<br>* Given IV<br>* Other names: MT103;Biological: Inotuzumab Ozogamicin<br>* Given IV<br>* Other names: WAY-207294;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival | Will be defined as time from start of treatment to failure to achieve complete response (CR)/complete response with incomplete count recovery (CRi) after completing Course II of blinatumomab, relapse after CR/CRi, progression on study requiring withdrawal from study therapy, or death from any cause | At 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Will be evaluated using the Kaplan-Meier method. A 95% confidence interval for the 1- and 3-year rates will be constructed using a point-wise confidence interval for the survival function based on a log-minus-log transformation. Will also calculate a 95% confidence interval by using a point-wise confidence interval for the survival function based on a log-minus-log transformation. | Time from start of study therapy to death from any cause censored at the last known alive date, assessed up to 10 years | 
| Relapse-free survival (RFS) | Will be evaluated using the Kaplan-Meier method. A 95% confidence interval for the 1- and 3-year rates will be constructed using a point-wise confidence interval for the survival function based on a log-minus-log transformation. Will also calculate a 95% confidence interval by using a point-wise confidence interval for the survival function based on a log-minus-log transformation. | Time from first CR/CRi to progressive disease (relapse, treatment discontinuation due to health deterioration) or death, assessed up to 10 years | 
| Event-free survival (EFS) | Will be evaluated using the Kaplan-Meier method. A 95% confidence interval for the 1- and 3-year rates will be constructed using a point-wise confidence interval for the survival function based on a log-minus-log transformation. Will also calculate a 95% confidence interval by using a point-wise confidence interval for the survival function based on a log-minus-log transformation. | Time from start of treatment to failure to achieve CR/CRi after completing Course II of blinatumomab, relapse after CR/CRi, progression on study requiring withdrawal from study therapy, or death from any cause, assessed up to 10 years | 
| Complete and overall response rate | Point and interval estimates of the rates will be shown using a 95% binomial confidence interval. | Up to 10 years | 
| Minimal residual disease negativity |  | Up to 10 years | 
| Allogeneic hematopoietic cell transplantation rate (Cohort 2) | Point and interval estimates of the rate will be shown using a 95% binomial confidence interval. | Up to 10 years |