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Blinatumomab in Combination with Tyrosine Kinase Inhibitor Therapy for the Treatment of Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Trial Status: Active

This phase II trial studies the activity and side effects of blinatumomab in combination with tyrosine kinase inhibitor (TKI) therapy and corticosteroids in treating patients with Philadelphia chromosome positive acute lymphoblastic leukemia. Blinatumomab is a bispecific antibody that binds to two different proteins—one on the surface of cancer cells and one on the surface of cells in the immune system. An antibody is a protein made by the immune system to help fight infections and other harmful processes / cells / molecules. Blinatumomab may bind to the cancer cell and a T cell (which plays a key role in the immune system's fighting response) at the same time. Blinatumomab may strengthen the immune system's ability to fight cancer cells by activating the body's own immune cells to destroy the tumor. TKI therapy may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Corticosteroids are naturally occurring hormones that have immune suppressive effect and are used to treat some side effects of cancer and its treatment. Giving blinatumomab in combination with corticosteroid and TKI therapy may work better in treating patients with acute lymphoblastic leukemia compared to corticosteroid and TKI therapy alone.

Inclusion Criteria

  • Able to give informed consent
  • Direct bilirubin =< 2 x upper limit of normal (ULN). Higher bilirubin levels are acceptable if thought related to Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =<10 x upper limit of normal (ULN). Higher AST/ALT levels are acceptable if thought related to Ph+ ALL
  • Confirmed diagnosis of acute lymphoblastic leukemia (ALL) by morphology, immunohistochemistry, and/or multiparameter flow cytometry, with confirmation of Philadelphia chromosome positivity (Ph+) by cytogenetic studies (karyotype/fluorescence in situ hybridization [FISH]), molecular studies (BCR-ABL1 fusion transcripts), or targeted ribonucleic acid (RNA) sequencing
  • No prior therapy for ALL beyond corticosteroids, hydroxyurea, or prophylactic intrathecal/intra-Ommaya chemotherapy
  • Acceptable end-organ function (i.e. not meeting exclusion criteria below)
  • Amenable to practicing an effective method of birth control during treatment and for at least 3 months following treatment on study
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2

Exclusion Criteria

  • Philadelphia chromosome-negative ALL
  • Mature B-cell ALL (e.g. Burkitt leukemia/lymphoma)
  • Active extramedullary disease at time of study entry, including known central nervous system (CNS)-3 disease (>= 5 white blood cell [WBC]/microliter and positive cytology or flow cytometry). Note: Lumbar puncture (LP) and/or CNS imaging prior to treatment initiation is not required, but if the patient is found to have active CNS-3 disease (by LP) or evidence of CNS involvement on imaging in the course of evaluation of clinical findings, enrollment is not permissible
  • Presence of known ABL kinase mutations conferring resistance to dasatinib at time of study entry, including T315I mutation. Note: ABL mutation testing prior to treatment initiation is neither recommended nor required, but if results of such mutation testing are known, enrollment of a patient with known ABL kinase mutations conferring dasatinib resistance is not permissible
  • Unable to tolerate initial therapy with dasatinib in the determination of the investigator, or unable to tolerate oral medication
  • Creatinine > 1.5 x upper limit of normal and estimated glomerular filtration rate (GFR) < 30 mL/min (based on 24-hour urine collection to determine creatine clearance or Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation)
  • Heart disease meeting one or more of the following criteria: * New York Heart Association (NYHA) stage III or IV congestive heart failure * Myocardial infarction < 6 months prior to enrollment * History of clinically significant ventricular arrhythmia * History of cardiomyopathy with left ventricular ejection fraction =< 20% * Pre-treatment Fridericia-adjusted QTc (QTcF) of > 500 msec, unless the patient is thought to be an acceptable candidate for dasatinib after consultation with a cardiologist (including, but not limited to situations in which QTcF is thought not representative of true length of repolarization due to pre-existing bundle branch block or ventricular pacing)
  • Patients with active hepatitis B infection (as manifest by either detectable hepatitis B virus deoxyribonucleic acid [DNA] by PCR and/or positivity for hepatitis B surface antigen) are ineligible
  • Patients with active hepatitis C infection (as manifest by detectable hepatitis C virus RNA by PCR) are ineligible. Patients with detectable antibodies to hepatitis C virus will be screened by PCR for evidence of active infection
  • Patients with human immunodeficiency virus (HIV) infection are ineligible, unless on antiretroviral therapy with undetectable HIV RNA by PCR (using an assay with sensitivity to detect levels of >= 50 copies/mL) and otherwise eligible in the determination of the investigator
  • Ongoing need for systemic T-cell suppressive therapy (e.g. corticosteroids, tacrolimus, cyclosporine for active autoimmune disease or prior solid organ transplantation)
  • Concurrent active malignancies as defined by malignancies requiring any therapy other than expectant observation or hormonal therapy, with the exception of squamous and basal cell carcinoma of skin
  • Uncontrolled systemic fungal, bacterial, viral or other infection
  • History or presence of uncontrolled or clinically significant neurological disorders such as generalized seizure disorder or severe brain injury
  • Any other issue which, in the opinion of the treating physician, would make the patient ineligible for the study

New York

New York
Memorial Sloan Kettering Cancer Center
Status: ACTIVE
Contact: Mark Blaine Geyer
Phone: 212-639-3290

PRIMARY OBJECTIVE:

I. To determine the proportion of evaluable patients achieving minimal residual disease (MRD) negativity by multiparameter flow cytometry and quantitative polymerase chain reaction (PCR) of BCR-ABL transcripts (complete molecular response [CMR]) at any time during Part 1 (TKI + corticosteroid induction) or Part 2 of the study (up to 3 cycles of blinatumomab in combination with an oral TKI).

SECONDARY OBJECTIVES:

I. To characterize the safety and toxicity profile of blinatumomab in combination with dasatinib, in those proceeding to Part 2 of the study who remain on dasatinib.

II. To estimate the proportion of patients with CMR or molecular MRD positivity with flow MRD negativity.

III. To describe duration of complete molecular response among patients achieving MRD negativity after dasatinib + corticosteroid induction, followed by 1-3 cycles of blinatumomab in combination with an oral TKI.

IV. To estimate the cumulative incidence of relapse following consolidative therapy with blinatumomab in combination with an oral TKI.

V. To assess event-free survival and overall survival following consolidative therapy with blinatumomab in combination with an oral TKI.

VI. To estimate the proportions of patients first achieving CMR during Part 1 (induction) versus (vs.) Part 2 (consolidation).

EXPLORATORY OBJECTIVES:

I. To characterize the safety and toxicity profile of blinatumomab in combination with TKIs other than dasatinib, in patients who receive a TKI other than dasatinib at any point during Part 2 or Part 3 of the study.

II. To characterize patterns of resistance among patients experiencing progression of ALL following consolidative therapy with blinatumomab in combination with an oral TKI.

III. To describe the above outcomes among patients not undergoing allogeneic hematopoietic cell transplantation in first complete remission (CR1) following consolidative therapy with blinatumomab in combination with an oral TKI.

OUTLINE:

PRE-PHASE: Patients receive dexamethasone orally (PO) once daily (QD) or prednisone PO QD on days -6 to 0.

INDUCTION: Patients receive dasatinib orally PO QD on days 1-42 and dexamethasone PO QD on days 1-24 with a taper on days 25-32 in the absence of disease progression or unacceptable toxicity. Patients who are intolerant to dasatinib may receive nilotinib PO twice daily (BID), bosutinib PO QD, or imatinib PO QD on days 1-42. Patients who do not achieve a complete response (CR) or complete response with incomplete hematologic recovery (CRi) may receive dasatinib PO QD for an additional 21 days. Patients achieving CR or CRi continue to consolidation therapy.

CONSOLIDATION THERAPY: Patients receive blinatumomab via continuous intravenous (IV) infusion on days 1-28. Treatment repeats every 28 days, followed by 2 weeks off, for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive dasatinib PO QD, nilotinib PO BID, bosutinib PO QD, or imatinib PO QD as in Induction on days 1-28. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients achieving CMR may undergo allogeneic hematopoietic stem cell transplantation (alloHSCT) or continue to maintenance therapy.

MAINTENANCE THERAPY: Patients receive blinatumomab via continuous IV on days 1-28. Treatment repeats every 28 days, followed by 4 weeks off, for up to 4 additional cycles in the absence of disease progression or unacceptable toxicity. Patients also receive dasatinib PO QD, nilotinib PO BID, bosutinib PO QD, or imatinib PO QD as in Induction on days 1-28. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Mark Blaine Geyer

  • Primary ID 19-343
  • Secondary IDs NCI-2020-02348
  • Clinicaltrials.gov ID NCT04329325