University of Kansas Medical Center

Conditions

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

Eligibility

Eligible Ages

Over 18 Years

Eligible Genders

All

Accepts Healthy Volunteers

No

Criteria

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)

Recruiting Locations

Study Contact

Detailed Description

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.