Testing the Use of Steroids and Tyrosine Kinase Inhibitors With Blinatumomab or Chemotherapy for Newly Diagnosed BCR-ABL-Positive Acute Lymphoblastic Leukemia in Adults
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| ClinicalTrials.gov Identifier: NCT04530565 |
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Recruitment Status :
Recruiting
First Posted : August 28, 2020
Last Update Posted : March 30, 2023
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Sponsor:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
National Cancer Institute (NCI)
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Brief Summary:
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 or disease | Intervention/treatment | Phase |
|---|---|---|
| B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1 | Procedure: Biospecimen Collection Biological: Blinatumomab Procedure: Bone Marrow Aspiration and Biopsy Drug: Cyclophosphamide Drug: Cytarabine Drug: Dasatinib Drug: Dexamethasone Drug: Doxorubicin Hydrochloride Procedure: Echocardiography Procedure: Electrocardiography Procedure: Lumbar Puncture Drug: Mesna Drug: Methotrexate Procedure: Multigated Acquisition Scan Drug: Ponatinib Hydrochloride Drug: Prednisone Drug: Vincristine Sulfate | Phase 3 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 348 participants |
| Allocation: | Randomized |
| Intervention Model: | Crossover Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | A Phase III Randomized Trial of Steroids + Tyrosine Kinase Inhibitor (TKI) Induction With Chemotherapy or Blinatumomab for Newly Diagnosed BCR-ABL-Positive Acute Lymphoblastic Leukemia (ALL) in Adults |
| Actual Study Start Date : | October 14, 2020 |
| Estimated Primary Completion Date : | July 1, 2028 |
| Estimated Study Completion Date : | July 1, 2028 |
Resource links provided by the National Library of Medicine
Drug Information available for:
Blinatumomab
| Arm | Intervention/treatment |
|---|---|
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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.
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Procedure: Biospecimen Collection
Correlative studies
Other Names:
Procedure: Bone Marrow Aspiration and Biopsy Undergo bone marrow aspiration and biopsy Drug: Dasatinib Given PO
Other Names:
Procedure: Echocardiography Undergo ECHO
Other Name: EC Procedure: Electrocardiography Undergo ECG
Other Names:
Procedure: Lumbar Puncture Undergo lumbar puncture
Other Names:
Procedure: Multigated Acquisition Scan Undergo MUGA
Other Names:
Drug: Ponatinib Hydrochloride Given PO
Other Names:
Drug: Prednisone Given PO
Other Names:
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Experimental: Arm B (steroid, TKI, chemotherapy)
See Detailed Description.
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Procedure: Biospecimen Collection
Correlative studies
Other Names:
Procedure: Bone Marrow Aspiration and Biopsy Undergo bone marrow aspiration and biopsy Drug: Cyclophosphamide Given IV
Other Names:
Drug: Cytarabine Given IV or IT
Other Names:
Drug: Dasatinib Given PO
Other Names:
Drug: Dexamethasone Given PO or IV
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
Other Names:
Procedure: Echocardiography Undergo ECHO
Other Name: EC Procedure: Electrocardiography Undergo ECG
Other Names:
Procedure: Lumbar Puncture Undergo lumbar puncture
Other Names:
Drug: Mesna Given IV
Other Names:
Drug: Methotrexate Given IV or IT
Other Names:
Procedure: Multigated Acquisition Scan Undergo MUGA
Other Names:
Drug: Ponatinib Hydrochloride Given PO
Other Names:
Drug: Vincristine Sulfate Given IV
Other Names:
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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 28 or 29. 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. |
Procedure: Biospecimen Collection
Correlative studies
Other Names:
Biological: Blinatumomab Given IV
Other Names:
Procedure: Bone Marrow Aspiration and Biopsy Undergo bone marrow aspiration and biopsy Drug: Dasatinib Given PO
Other Names:
Drug: Dexamethasone Given PO or IV
Other Names:
Procedure: Echocardiography Undergo ECHO
Other Name: EC Procedure: Electrocardiography Undergo ECG
Other Names:
Procedure: Lumbar Puncture Undergo lumbar puncture
Other Names:
Drug: Mesna Given IV
Other Names:
Drug: Methotrexate Given IV or IT
Other Names:
Procedure: Multigated Acquisition Scan Undergo MUGA
Other Names:
Drug: Ponatinib Hydrochloride Given PO
Other Names:
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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. |
Procedure: Biospecimen Collection
Correlative studies
Other Names:
Biological: Blinatumomab Given IV
Other Names:
Procedure: Bone Marrow Aspiration and Biopsy Undergo bone marrow aspiration and biopsy Drug: Cyclophosphamide Given IV
Other Names:
Drug: Dasatinib Given PO
Other Names:
Drug: Dexamethasone Given PO or IV
Other Names:
Procedure: Echocardiography Undergo ECHO
Other Name: EC Procedure: Electrocardiography Undergo ECG
Other Names:
Procedure: Lumbar Puncture Undergo lumbar puncture
Other Names:
Drug: Methotrexate Given IV or IT
Other Names:
Procedure: Multigated Acquisition Scan Undergo MUGA
Other Names:
Drug: Ponatinib Hydrochloride Given PO
Other Names:
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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. |
Procedure: Biospecimen Collection
Correlative studies
Other Names:
Procedure: Bone Marrow Aspiration and Biopsy Undergo bone marrow aspiration and biopsy Drug: Cyclophosphamide Given IV
Other Names:
Drug: Cytarabine Given IV or IT
Other Names:
Drug: Dasatinib Given PO
Other Names:
Drug: Dexamethasone Given PO or IV
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
Other Names:
Procedure: Echocardiography Undergo ECHO
Other Name: EC Procedure: Electrocardiography Undergo ECG
Other Names:
Procedure: Lumbar Puncture Undergo lumbar puncture
Other Names:
Drug: Methotrexate Given IV or IT
Other Names:
Procedure: Multigated Acquisition Scan Undergo MUGA
Other Names:
Drug: Ponatinib Hydrochloride Given PO
Other Names:
Drug: Vincristine Sulfate Given IV
Other Names:
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Primary Outcome Measures :
- Overall survival (OS) [ Time Frame: Time between randomization and death from any cause, assessed up to 10 years from the date of registration ]Will compare OS following induction with steroids + tyrosine kinase inhibitor (TKI) + blinatumomab and induction with steroids + TKI + chemotherapy. Will be based on an intent-to-treat analysis. Estimates of OS including medians and confidence intervals, will be calculated using the Kaplan-Meier method. Comparisons of OS between treatment arms will be conducted using the one-sided stratified log-rank test with steroid responsiveness, type of TKI intended to receive and age at diagnosis, the same factors used in randomization, as stratification factors. Cox proportional hazards models of OS, stratified on the same factors used in the randomization, will be used to assess the effect of treatment by adjusting other possible clinical and biological risk factors, including cytogenetic abnormalities.
Secondary Outcome Measures :
- Rate of minimal residual disease (MRD) negativity [ Time Frame: At week 15 ]Will be centrally evaluated. Will be compared between two arms using Fisher's exact test with a one-sided type I error rate of 2.5%. Multivariable logistic regression modeling will be used to adjust for other possible clinical and biological risk factors. For patients registered to Step 3 (re-induction), the rates of MRD negativity and their corresponding 95% confidence intervals after re-induction will be given by treatment arm.
- Event free survival (EFS) [ Time Frame: Time from randomization to failure to achieve induction molecular remission by week 15, confirmed molecular relapse after molecular remission or to death in remission, assessed up to 10 years from the date of registration ]Will be based on an intent-to-treat analysis. Estimates of EFS including medians and confidence intervals, will be calculated using the Kaplan-Meier method. Comparisons of EFS between treatment arms will be conducted using the one-sided stratified log-rank test with steroid responsiveness, type of TKI intended to receive and age at diagnosis, the same factors used in randomization, as stratification factors. Cox proportional hazards models of EFS, stratified on the same factors used in the randomization, will be used to assess the effect of treatment by adjusting other possible clinical and biological risk factors, including cytogenetic abnormalities
- Rate of MRD negativity [ Time Frame: After re-induction and safety ]Will be centrally evaluated. Will be compared between two arms using Fisher's exact test with a one-sided type I error rate of 2.5%. Multivariable logistic regression modeling will be used to adjust for other possible clinical and biological risk factors. For patients registered to Step 3 (re-induction), the rates of MRD negativity and their corresponding 95% confidence intervals after re-induction will be given by treatment arm.
- Incidence of adverse events [ Time Frame: Up to 10 years from the date of registration ]All toxicity grades and reportable adverse events will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
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| Ages Eligible for Study: | 18 Years to 75 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- ELIGIBILITY CRITERIA FOR PREREGISTRATION (TO STEP 0) - INCLUSION
- Patient must be >= 18 and =< 75 years of age
- Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status between 0-3
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Patient must be newly diagnosed with B-ALL or is suspected to have ALL
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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 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 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, 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
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- Patients who started any kind of TKI prior to study registration to Step 1 are allowed to proceed on the study if they received no more than 14 days of TKI
- ELIGIBILITY CRITERIA FOR REGISTRATION TO STEP 1 - INCLUSION
- 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
- 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
- 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 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
- 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. An ECHO/MUGA is required.
- 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
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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- INCLUSION
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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 mLg/min (based on Cockcroft-Gault equation)
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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
- 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) - INCLUSION
- 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)
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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 a diagnosis of BCR/ABL T-ALL
- 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 to Step 1 are eligible
- Patient must not have unstable epilepsy that requires treatment
- Patients with lymphoid blast crisis CML are not eligible
- STEP 1 REGISTRATION ELIGIBILITY CRITERIA - EXCLUSION
- 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
- 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
- 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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04530565
Locations
Show 157 study locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
| Principal Investigator: | Yishai Ofran | ECOG-ACRIN Cancer Research Group |
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT04530565 |
| Other Study ID Numbers: |
NCI-2020-06381 NCI-2020-06381 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) EA9181 ( Other Identifier: ECOG-ACRIN Cancer Research Group ) EA9181 ( Other Identifier: CTEP ) U10CA180820 ( U.S. NIH Grant/Contract ) |
| First Posted: | August 28, 2020 Key Record Dates |
| Last Update Posted: | March 30, 2023 |
| Last Verified: | March 2023 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page |
| URL: | https://grants.nih.gov/policy/sharing.htm |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Additional relevant MeSH terms:
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Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Cytarabine Dexamethasone Dexamethasone acetate Prednisone Cortisone Cyclophosphamide |
Doxorubicin Liposomal doxorubicin Methotrexate Vincristine Dasatinib Blinatumomab Ponatinib Antineoplastic Agents, Immunological Muromonab-CD3 Antibodies Immunoglobulins Antibodies, Monoclonal Antibodies, Bispecific BB 1101 Mesna |