Testing the Use of Steroids and Tyrosine Kinase Inhibitors With Blinatumomab or Chemotherapy for Newly Diagnosed BCR-ABL-Positive Acute Lymphoblastic Leukemia in Adults
Purpose
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.
Condition
- B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1
Eligibility
- Eligible Ages
- Between 18 Years and 75 Years
- Eligible Genders
- All
- Accepts Healthy Volunteers
- No
Criteria
Inclusion Criteria:
- ELIGIBILITY CRITERIA FOR PRE-REGISTRATION (TO STEP 0)
- Patient must be >= 18 and =< 75 years of age
- Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status
between 0-3
- Patient must be newly diagnosed with B acute lymphoblastic leukemia (B-ALL) or is
suspected to have acute lymphoblastic leukemia (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 aspirate and/or peripheral blood specimen must be
submitted to the ECOG-American College of Radiology Imaging Network
(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
aspirate 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, with recommendation 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
- Patient must not have a diagnosis of BCR/ABL T-ALL
- Patient must not have received chemotherapy for B-ALL. Patients who received up to
five days of therapy (hydroxyurea and/or steroids of any kind) with the aim to
reduce disease burden prior to study registration to Step 1 are eligible
- Patient must not have unstable epilepsy that requires treatment
- Patients with lymphoid blast crisis chronic myeloid leukemia (CML) are not eligible
- ELIGIBILITY CRITERIA FOR REGISTRATION TO STEP 1
- Patient must have a diagnosis of Philadelphia chromosome positive (Ph+) ALL that has
been determined locally and bone marrow and/or peripheral blood was sent and receipt
confirmed for central confirmation or determined centrally by the ECOG-ACRIN
Leukemia Laboratory at MD Anderson Cancer Center
- Patient 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 patients of childbearing potential must have a
blood test or urine study within 14 days prior to registration to rule out
pregnancy. A patient 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)
- Patients 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 step 1 registration, while on study treatment, and until at least six
months after the last dose of study treatment
- Total bilirubin =< 3 mg/dL (patients with Gilbert's syndrome must have a total
bilirubin =< 5 mg/dL) (obtained =< 28 days prior to step 1 registration)
- 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) (obtained =< 28 days
prior to step 1 registration)
- Estimated creatinine clearance > 45 mL/min (based on Cockcroft-Gault equation)
(obtained =< 28 days prior to step 1 registration)
- Patients with acute organ dysfunction at step 1 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
- Patients who presented with no evidence of acute organ dysfunction but during step 0
experienced a rise in liver enzymes which investigator suspects to be a side effect
of any of prescribed drugs, are allowed to be registered regardless of the level of
liver enzymes. Step 2 randomization must be withheld until the eligibility criteria
outline is met but no more than 14 days after concluding Arm A therapy
- 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
- 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
are eligible
- Patient 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
- 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
- ELIGIBILITY CRITERIA FOR RANDOMIZATION TO STEP 2
- Patient must have completed at least 7 and no more than 21 days of
protocol-treatment on Arm A prior to step 2 randomization. (Days in which arm A
therapy was withheld for any reason are not counted)
- NOTE: First day of steroids prescription after registration will be considered
as the first day of study therapy. The selected TKI must be initiated prior to
randomization
- Patients who presented with acute organ dysfunction within 2 weeks of registration
to step 1 must have total bilirubin =< 2 X institutional upper limit of normal (ULN)
- AST(SGOT)/ ALT(SGPT) =< 2 X the institutional upper limit of normal (ULN)
- Estimated creatinine clearance > 45 mL/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
- 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
- Patients must have resolved any serious infectious complications related to therapy
- Any significant medical complications related to therapy must have resolved
- ELIGIBILITY CRITERIA FOR REGISTRATION TO STEP 3 (RE-INDUCTION)
- Institution has received centralized MRD results confirming positive status
- Patients who presented with acute organ dysfunction within 2 weeks of registration
to step 1 must have total bilirubin =< 2 X institutional ULN
- Patients who presented with acute organ dysfunction must have AST (SGOT)/ALT (SGPT)
=< 2 X institutional upper limit of normal (ULN)
- Patients who presented with acute organ dysfunction must have an estimated
creatinine clearance > 45 mL/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
- Step 3 (Re-Induction): Patients must have resolved any serious infectious
complications related to therapy
- Step 3 (Re-Induction): Any significant medical complications related to therapy must
have resolved
Study Design
- Phase
- Phase 3
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover Assignment
- Primary Purpose
- Treatment
- Masking
- None (Open Label)
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
|
Active Comparator Arm A (steroid, TKI), Single Arm Pre-Induction |
Patients receive prednisone PO QD on days 1-21 and ponatinib PO QD or dasatinib PO QD on days 1-21 based on investigator's choice. |
|
|
Experimental Arm B (steroid, TKI, chemotherapy) |
See Detailed Description. |
|
|
Experimental Arm C (steroid, TKI, chemotherapy, immunotherapy) |
CYCLE 1: Patients receive ponatinib PO QD or dasatinib PO QD on days 1-28. Patients also receive dexamethasone PO or IV on day 1 and blinatumomab IV continuously on days 1-28, followed by methotrexate IT on day 29 or 30. CYCLE 2: Patients receive ponatinib PO QD or dasatinib PO QD on days 1-28. 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. |
|
|
Experimental Arm D (steroid, TKI, chemotherapy, immunotherapy) |
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. 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. |
|
|
Experimental Arm E (steroid, TKI, chemotherapy) |
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. |
|
Recruiting Locations
Nashville, Tennessee 37232
Site Public Contact
800-811-8480
More Details
- Status
- Recruiting
- Sponsor
- National Cancer Institute (NCI)
Study Contact
Detailed Description
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 vs. 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 (PRE-INDUCTION): 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). Patients undergo bone marrow aspiration with biopsy, lumbar punctures, echocardiogram (ECHO), and multigated acquisition (MUGA) scans as indicated by investigator. 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 QD or ponatinib 30mg/day PO QD on days 1-21, methotrexate IV over 24 hours and IT on day 1, and cytarabine IV over 2 hours BID on days 2-3 of each cycle. 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 of each cycle. Patients also receive methotrexate IV over 24 hours and IT on day 1, and cytarabine IV over 2 hours BID on days 2-3 of each cycle. 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 1-28. Patients also receive dexamethasone PO or IV on day 1 and blinatumomab IV continuously on days 1-28, followed by methotrexate IT on day 29 or 30. CYCLE 2: Patients receive ponatinib PO QD or dasatinib PO QD on days 1-28. 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 every 3 months for first 2 years (from study registration), every 6 months for years 3-5, and then every 12 months for years 6-10.