Testing the Use of Steroids and Tyrosine Kinase Inhibitors With Blinatumomab or Chemotherapy for Newly Diagnosed BCR-ABL-Positive Acute Lymphoblastic Leukemia in Adults
Testing the Use of Steroids and Tyrosine Kinase Inhibitors With Blinatumomab or Chemotherapy for Newly Diagnosed BCR-ABL-Positive Acute Lymphoblastic Leukemia in Adults
This phase III trial compares the effect of usual treatment of chemotherapy and steroids and
 a tyrosine kinase inhibitor (TKI) to the same treatment plus blinatumomab. Blinatumomab is a
 Bi-specific T-Cell Engager ('BiTE') that may interfere with the ability of cancer cells to
 grow and spread. The information gained from this study may help researchers determine if
 combination therapy with steroids, TKIs, and blinatumomab work better than the standard of
 care.
PRIMARY OBJECTIVE:

 I. To compare the overall survival (OS) following induction with steroids + TKI +
 blinatumomab versus induction with steroids + TKI + chemotherapy.

 SECONDARY OBJECTIVES:

 I. To compare the rate of minimal residual disease (MRD) negativity for patients treated with
 chemotherapy versus (vs) blinatumomab at the end of first induction (week 15).

 II. To evaluate the rate of the MRD negativity by treatment arm for those patients MRD
 positive after the first induction and administered of second induction.

 III. To compare event free survival (EFS) for patients initially randomized for chemotherapy
 vs blinatumomab.

 IV. To assess the toxicities of blinatumomab + TKI and steroids + TKI + chemotherapy in this
 patient population.

 V. To assess the toxicities of the chemotherapy regimen in this patient population.

 VI. To describe the outcome of patients who proceed to allogeneic stem cell transplant after
 treatment with blinatumomab + TKI only.

 OUTLINE:

 ARM A (RUN-IN): Patients receive prednisone orally (PO) once daily (QD) on days 1-21 and
 ponatinib hydrochloride (ponatinib) PO QD or dasatinib PO QD on days 1-21 based on
 investigator's choice.

 Patients are randomized to 1 of 2 arms (Arm B or C).

 ARM B (INDUCTION THERAPY):

 CYCLE 1: Patients receive cyclophosphamide intravenously (IV) twice daily (BID) on days 1-3,
 dexamethasone PO or IV on days 1-4 and 11-14, cytarabine intrathecally (IT) on day 1,
 doxorubicin hydrochloride (doxorubicin) IV on day 4, vincristine sulfate (vincristine) IV on
 days 4 and 11, and methotrexate IT on day 8. Patients also receive Mesna 600mg/m^2 IV as a
 'chemoprotectant' via continuous infusion on days 1-3, (beginning 1 hour prior to
 cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide).

 CYCLE 2 (AGE 18-70): Starting in cycle 2, fit patients aged 18-70 receive dasatinib 70mg/day
 PO or ponatinib 30mg/day PO on days 1-21, methotrexate IV over 24 hours and IT on day 1, and
 cytarabine IV over 2 hours on days 2-3. On day 22 of cycle 2 or later, as soon as the
 absolute neutrophil count (ANC) is greater than 1000 cells/ul and platelets are greater than
 50,000 cells/ul, patients receive hyper cyclophosphamide, vincristine, doxorubicin, and
 dexamethasone (CVAD) for 2 additional cycles.

 CYCLE 2 (AGE > 70 or unfit < 70): Starting in cycle 2, patients age > 70 or younger unfit
 patients for Hyper-CVAD receive ponatinib PO QD or dasatinib PO QD on days 1-21. Patients
 also receive methotrexate IV over 24 hours and IT on day 1, and cytarabine IV over 2 hours on
 days 2-3. Cycle 1 and 2 regimens are each repeated once starting on day 22 of cycle 2, or
 later, but as soon as the ANC is greater than 1000 cells/ul and platelets are greater than
 50,000 cells/ul.

 Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or
 unacceptable toxicity. Patients who achieve remission (significant reduction in the amount of
 leukemia in bone marrow and blood/MRD negative) after 4 cycles may receive alternative
 treatment, either consolidation with two cycles of Hyper-CVAD followed by TKI maintenance
 therapy or undergo allogeneic stem cell transplantation followed by maintenance therapy.
 Patients who do not achieve a remission (MRD positive) are assigned to Arm D. Patients who
 experience un-resolving renal failure or life-threatening infection which may require a
 treatment delay of 21 days cross-over to Arm C to receive the prescribed course of
 blinatumomab.

 ARM C (INDUCTION THERAPY):

 CYCLE 1: Patients receive ponatinib PO QD or dasatinib PO QD on days 1-21. Patients also
 receive dexamethasone PO or IV on day 1 and blinatumomab IV continuously on days 1-28,
 followed by methotrexate IT on day 28 or 29.

 CYCLE 2: Patients receive ponatinib PO QD or dasatinib PO QD on days 1-21. Patients also
 receive dexamethasone PO or IV on day 1 and blinatumomab IV continuously on days 1-28.

 Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or
 unacceptable toxicity.

 ARM D (RE-INDUCTION): Patients treated on Arm B who remain MRD positive at the end of
 induction therapy receive blinatumomab based re-induction identical to the regimen described
 for Arm C.

 ARM E (RE-INDUCTION): Patients treated on Arm C who remain MRD positive at the end of
 induction therapy receive chemotherapy based re-induction which is identical to regimen
 described for Arm B according to patient's age and the pre-specified chemotherapy arm.

 Patients whose molecular test remains MRD positive after re-induction proceed to follow-up at
 the discretion of the investigator or receive anti CD-19 CAR- T cell therapy, inotuzumab
 ozogamicin, intensive chemotherapy, or palliative care.

 Patients are followed up for 10 years from the date of registration.
Inclusion Criteria:

 -  PREREGISTRATION (STEP 0) ELIGIBILITY CRITERIA - INCLUSION

 -  Patient must be newly diagnosed with B-ALL or is suspected to have ALL

 -  Patient must have BCR-ABL1 positive disease. The diagnosis of ALL and the
 presence of BCR-ABL translocation must be confirmed centrally. Patients can be
 registered and begin Step 1 therapy while awaiting central laboratory eligibility
 confirmation

 -  NOTE: Bone marrow and/or peripheral blood specimen must be submitted to the
 Eastern Cooperative Oncology Group-American College of Radiology Imaging
 Network (ECOG-ACRIN) Leukemia Laboratory at MD Anderson Cancer Center to
 determine patient's eligibility for registration to Step 1 or confirm
 patient evaluability. Centrally fluorescence-activated cell sorting (FACS)
 analysis will be performed to determine B-ALL and to exclude acute myeloid
 leukemia (AML) or acute bi-phenotypic leukemia and baseline BCR-ABL status
 will be determined by fluorescent in situ hybridization (FISH). The
 ECOG-ACRIN Leukemia Laboratory will forward results within 48 hours of
 receipt of the specimen to the submitting institution. Bone marrow is to be
 from first pull (initial or re-direct). Specimens must contain sufficient
 blast cells. In cases where the bone marrow aspiration may be inadequate, or
 the bone marrow examination has already been performed prior to study
 consent and enrollment on Step 0, peripheral blood may be submitted, given
 that adequate circulating blasts are present (> 10%). If a diagnosis of
 BCR-ABL positive B-ALL has already been established by local Clinical
 Laboratory Improvement Act (CLIA) certified laboratories, the patient may be
 registered to Step 1 without waiting for central confirmation

 -  Patients who started any kind of TKI prior to study registration are allowed to
 proceed on the study if they received no more than 14 days of TKI

 -  STEP 1 REGISTRATION ELIGIBILITY CRITERIA - INCLUSION

 -  The diagnosis of Philadelphia chromosome positive (Ph+) ALL has been determined
 locally, and bone marrow and/or peripheral blood was sent for central confirmation or
 determined centrally by the ECOG-ACRIN Leukemia Laboratory at MD Anderson Cancer
 Center

 -  Total bilirubin =< 3 mg/dL (unless related to Gilbert's syndrome in which case total
 bilirubin must be =< 5 mg/dL)

 -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
 [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
 =< 2.5 X the institutional upper limit of normal (ULN)

 -  Estimated creatinine clearance > 45 mg/min (based on Cockcroft-Gault equation)

 -  Patients with acute organ dysfunction at registration, which may be attributed to
 leukemia can be registered regardless of lab results at presentation. Such patients
 will be allowed to register and can start Arm A steroid + TKI therapy but will only be
 allowed to proceed to Step 2 randomization if the eligibility criteria outlined is met

 -  Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
 therapy with undetectable viral load within 6 months are eligible for this trial

 -  For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
 load must be undetectable or on suppressive therapy, if indicated

 -  Patients with a history of hepatitis C virus (HCV) infection must have an undetectable
 HCV viral load and if indicated, on treatment

 -  Patients with a prior malignancy whose natural history or treatment does not have the
 potential to interfere with the safety or efficacy assessment of the investigational
 regimen are eligible for this trial

 -  Patients with known history or current symptoms of cardiac disease, or history of
 treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
 function using the New York Heart Association Functional Classification. To be
 eligible for this trial, patients must be class 2B or better

 -  Investigators must confirm which TKI patient is to receive

 -  NOTE: Patients with known T315I mutation status should receive ponatinib
 treatment

 -  NOTE: In situations due to insurance coverage issues and the pre-selected TKI is
 not immediately available, patients can receive dasatinib or imatinib during Step
 1. The investigator must re-specify dasatinib or ponatinib prior to Step 2
 randomization and from then on patients must receive the pre-selected TKI only

 -  STEP 2: RANDOMIZATION - ELIGIBILITY CRITERIA - INCLUSION

 -  Patient must have completed at least 7 of 21 days of protocol-treatment on Arm A prior
 to randomization

 -  NOTE: First day of steroids prescription after registration will be considered as
 the first day of study therapy. The selected TKI should be initiated prior to
 randomization

 -  Patients who presented with acute organ dysfunction at Step 1 must have their total
 bilirubin and AST (SGOT)/ALT (SGPT) reduce to < 2 X institutional ULN and have an
 estimated creatinine clearance > 45 mg/min (based on Cockcroft-Gault equation)

 -  Investigators must confirm which TKI patient is to receive.

 -  NOTE: Patients with known T315I mutation status should receive ponatinib
 treatment

 -  For patients under age 70, intended chemotherapy regimen must have been determined
 prior to randomization

 -  STEP 3: REGISTRATION (RE-INDUCTION) - ELIGIBILITY CRITERIA - INCLUSION

 -  Institution has received centralized MRD results confirming positive status

 -  Patients who presented with acute organ dysfunction must have their total bilirubin
 and AST (SGOT)/ALT (SGPT) reduce to < 2 X institutional ULN

 -  Patients who presented with acute organ dysfunction must have an estimated creatinine
 clearance > 45 mg/min (based on Cockcroft-Gault equation)

 -  Investigators must confirm which TKI patient is to receive

 -  NOTE: Patients with known T315I mutation status should receive ponatinib
 treatment

 -  For patients under age 70 and previously assigned to Arm C, intended chemotherapy
 regimen must have been determined

 Exclusion Criteria:

 -  PREREGISTRATION (STEP 0) ELIGIBILITY CRITERIA - EXCLUSION

 -  Patient must not have received chemotherapy for B-ALL. Patients who received up to
 five days of hydroxyurea or steroids of any kind with the aim to reduce disease burden
 prior to study registration are eligible

 -  Patient must not have unstable epilepsy that requires treatment

 -  STEP 1 REGISTRATION ELIGIBILITY CRITERIA - EXCLUSION

 -  Women must not be pregnant or breast-feeding due to the potential harm to an unborn
 fetus and possible risk for adverse events in nursing infants with the treatment
 regimens being used. All females of childbearing potential must have a blood test or
 urine study within 14 days prior to registration to rule out pregnancy. A female of
 childbearing potential is defined as any woman, regardless of sexual orientation or
 whether they have undergone tubal ligation, who meets the following criteria: 1) has
 achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral
 oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer
 therapy does not rule out childbearing potential) for at least 24 consecutive months
 (i.e., has had menses at any time in the preceding 24 consecutive months)

 -  Women of childbearing potential and sexually active males must not expect to conceive
 or father children by using accepted and effective method(s) of contraception or by
 abstaining from sexual intercourse from the time of registration, while on study
 treatment, and until at least six months after the last dose of study treatment

 -  Patient must not have active concomitant malignancy. Patients on chronic hormonal
 therapy for breast or prostate cancer or patients treated with maintenance with
 targeted agents but are in remission with no evidence for the primary malignancies can
 be included

 -  Patients must not have complaints of symptoms and/or have clinical and/or radiological
 signs that indicate an uncontrolled infection or any other concurrent medical
 condition that could be exacerbated by the treatment or would seriously complicate
 compliance with the protocol

 -  STEP 2: RANDOMIZATION - ELIGIBILITY CRITERIA - EXCLUSION

 -  Patient must not have active central nervous system (CNS) involvement by leukemic
 blasts. Patients with signs of CNS involvement at presentation are eligible for
 randomization if clearance of blasts from the cerebrospinal fluid (CSF) is
 demonstrated