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 Sex

All

Accepts Healthy Volunteers

No

Criteria

Inclusion 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.

- 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.

- STEP 1: CD22-positive disease defined as CD22 expression by >= 20% of lymphoblasts
by local hematopathology evaluation.

- STEP 1: Philadelphia chromosome/BCR-ABL1-negative or Philadelphia
chromosome/BCR-ABL1-positive B-cell ALL by cytogenetics, fluorescence in situ
hybridization (FISH), and/or polymerase chain reaction (PCR).

- STEP 1: 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)

- STEP 1: 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.

- STEP 1: 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.

- STEP 1: Eastern Cooperative Oncology Group (ECOG) performance status: 0-2

- STEP 1: No unstable cardiac disease such as myocardial infarction, angina pectoris,
uncontrolled heart failure, or uncontrolled cardiac arrhythmia within 6 months of
registration.

- STEP 1: 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).

- STEP 1: 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.

- STEP 1: 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.

- STEP 1: 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.

- STEP 1: 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.

- STEP 1: 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.

- STEP 1: 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.

- STEP 1: No history of chronic liver disease, including cirrhosis.

- STEP 1: No history of sinusoidal occlusion syndrome/veno-occlusive disease of the
liver.

- STEP 1: No uncontrolled infection or recent history (within 4 months prior to
registration) of deep tissue infections such as fasciitis or osteomyelitis.

- STEP 1: 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.

- STEP 1: Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN

- STEP 1: Creatinine, serum =< 1.5 ULN OR creatinine clearance >= 40 mL/min

- STEP 1: QT interval by Fridericia's correction formula (QTcF) =< 470 msec

- COHORT 1: Age >= 60 years.

- COHORT 1: Diagnosis of Philadelphia chromosome/BCR-ABL1-negative B-cell ALL.

- COHORT 1: 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.

- COHORT 1: No plan for allogeneic or autologous hematopoietic cell transplantation
(HCT).

- COHORT 2: Age >= 18 years.

- COHORT 2: Diagnosis of Philadelphia chromosome/BCR-ABL1-negative B-cell ALL.

- COHORT 2: Relapsed or refractory disease in salvage 1 or 2.

- COHORT 2: No isolated extramedullary relapse.

- COHORT 2: Prior allogeneic HCT permitted.

- COHORT 2: Patients with prior allogeneic HCT must have completed transplantation >=
4 months prior to registration.

- COHORT 2: 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.

- COHORT 2: Prior treatment with inotuzumab ozogamicin, blinatumomab, other
CD22-directed therapy, or other CD19-directed therapy is not allowed.

- COHORT 2: Prior treatment with rituximab must be completed >= 7 days prior to
registration.

- COHORT 2: Prior treatment with other monoclonal antibodies must be completed >= 6
weeks prior to registration.

- COHORT 2: 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.

- COHORT 2: 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.

- COHORT 2: Peripheral blood absolute lymphoblast count =< 10,000/uL (treatment
allowed as above to reduce blast count to =< 10,000/uL)

- COHORT 3: Age ≥ 75 years OR age ≥ 18 years AND ineligible for hyperfractionated
cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HyperCVAD) regimens

- COHORT 3: Diagnosis of Philadelphia chromosome/BCR-ABL1-positive B-cell ALL

- COHORT 3: No prior treatment for ALL except a single dose of intrathecal
chemotherapy, corticosteroids, hydroxyurea, BCR-ABL1-targeted tyrosine kinase
inhibitor, and/or leukapheresis to reduce peripheral blast count and prevent ALL
complications. Allowed non-protocol therapy may be administered for no more than 14
days and must be completed ≥ 24 hours prior to the initiation of protocol therapy.

- COHORT 3: No chronic, strong CYP3A4 inducers

Recruiting Locations

Study Contact

Detailed Description

PRIMARY OBJECTIVES: Ia. For Philadelphia (Ph)-negative B-cell acute lymphoblastic leukemia (ALL), to confirm tolerability of the combination regimen of inotuzumab ozogamicin followed by blinatumomab. Ib. For Ph-positive B-cell ALL, to confirm tolerability of ponatinib in combination with inotuzumab ozogamicin and blinatumomab. II. To estimate the 1-year event-free survival of older, transplant-ineligible patients with newly diagnosed, 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) IV. To determine the feasibility of the regimen in adult patients with CD22-positive, Ph/BCR-ABL1-positive B-cell ALL. (Cohort 3) 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) XVIII. To estimate the 24-week complete molecular response rate. (Cohort 3) XIX. To estimate the median, 1-year, and 3-year OS in all eligible patients. (Cohort 3) XX. To estimate the median, 1-year, and 3-year RFS in all eligible patients. (Cohort 3) XXI. To estimate the median and 3-year EFS in all eligible patients. (Cohort 3) XXII. 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 3) XXIII. To estimate the CR, CRi, and CRh rates at defined time points and cumulatively for the entire regimen. (Cohort 3) XXIV. To determine the complete molecular response rate at defined time points and cumulatively in patients achieving a CR, CRh, or CRi. (Cohort 3) XXV. To estimate the treatment-related mortality with this regimen. (Cohort 3) XXVI. To describe the safety and tolerability of this regimen. (Cohort 3) 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. XII. To evaluate T-cell populations and T-cell function during therapy using T-cell markers which include the T-cell subset defining markers CD45, CD3, CD4, CD8, CD45RA, CD45RO, CCR7, CD25, CD127, FOXP3, CD 27, CD28, among others, and markers of T cell exhaustion and senescence including CD57, PD-1, Tim-3, LAG-3, TIGIT, CTLA4, CD160, and ICOS among others. XIII. To evaluate cytokine levels, and compare between patients who attain a CR vs. those with stable or progressive disease. 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) XI. To estimate the median, 1-year, and 3-year RFS, EFS, and OS in patients achieving a CR/CRi to inotuzumab ozogamicin. (Cohort 3) XII. To compare the median, 1-year, and 3-year RFS, EFS, and OS among patients with CR/CRi achieving complete molecular response vs. not to inotuzumab ozogamicin. (Cohort 3) XIII. To compare the median, 1-year, and 3-year RFS, EFS, and OS among patients achieving CR/CRi achieving complete molecular response vs. not at any time. (Cohort 3) XIV. 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 3) XV. To estimate the rate of cytokine release syndrome in this population. (Cohort 3) XVI. To assess ABL1 mutational patterns at relapse. (Cohort 3) 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. Patients undergo bone marrow aspiration and biopsy and blood sample collection throughout the study. Patients undergo lumbar puncture with cerebrospinal fluid sample collection at baseline and may undergo additionally throughout the study. 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. Patients undergo bone marrow aspiration and biopsy and blood sample collection throughout the study. Patients undergo lumbar puncture with cerebrospinal fluid sample collection at baseline and may undergo additionally throughout the study. COHORT 3: INDUCTION: COURSE I: Patients receive ponatinib orally (PO) daily (QD) on day 1-35, dexamethasone PO QD on days 1-7 and 15-21 and methotrexate intrathecally (IT) on day 1, 15 and 29 for 1 course (35 days) in the absence of disease progression or unacceptable toxicity. Patients with CR or CRi continue to consolidation course IIA or end the study treatment to receive allogenic HCT per the treating physician. Patients without CR or CRi with but adequate ALL cytoreduction (defined as ≥ 50% reduction in bone marrow lymphoblasts from the pre-registration bone marrow aspirate/biopsy and/or ≤ 20% marrow cellularity at the end of Course I bone marrow aspirate/biopsy) also proceed to consolidation course IIA. Patients with progression or failure to achieve adequate ALL cytoreduction are removed from study treatment. CONSOLIDATION: COURSE IIA: Patients receive ponatinib PO QD on days 1-21, inotuzumab ozogamicin IV over 1 hour on days 1, 8 and 15 and methotrexate IT on day 1 for 1 course (21 days) in the absence of disease progression or unacceptable toxicity. Patients with CR or CRi continue to consolidation course IIB or or end the study treatment to receive allogenic HCT per the treating physician. Patients without CR or CRi and without progressive disease proceed to course IIC. Patients with progression are removed from study treatment. COURSE IIB/C: Patients receive ponatinib PO QD on days 1-28, inotuzumab ozogamicin IV over 1 hour on days 1, 8 and 15 and methotrexate IT on day 1 for 1 course (28 days) in the absence of disease progression or unacceptable toxicity. Patients with CR or CRi end the study treatment to receive allogenic HCT per the treating physician. Patients with progression are removed from study treatment. All other patients proceed to course III. COURSE III: Patients receive ponatinib PO QD on days 1-84 and 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. Patients in CR/CRi proceed to course IV. Patients not in CR/CRi are removed from study treatment. COURSE IV: Patients receive ponatinib PO QD on days 1-84 and 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. Patients in CR/CRi proceed to maintenance. Patients not in CR/CRi are removed from study treatment. MAINTENANCE: Patients receive ponatinib PO QD for 24 months in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow aspiration and biopsy and blood sample collection throughout the study. Patients undergo lumbar puncture with cerebrospinal fluid sample collection at baseline and may undergo additionally throughout the study. 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.