Brexucabtagene Autoleucel as Consolidation after Inotuzumab, Blinatumomab and Mini-HCVD or HCVAD for the Treatment of Relapsed/Refractory and Newly Diagnosed B-cell Acute Lymphocytic Leukemia

Status: active

This phase I/II trial tests the safety and effectiveness of brexucabtagene autoleucel after cytoreduction with inotuzumab, blinatumomab and either hyperfractionated cyclophosphamide, vincristine and dexamethasone (mini-HCVD) or hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high dose methotrexate and cytarabine (HCVAD) in treating patients with newly diagnosed B-cell acute lymphocytic leukemia (B-cell ALL) or B-cell ALL that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Brexucabtagene autoleucel is a type of CAR T-cell therapy that is created by collecting T-cells (another type of white blood cell) from patients. A gene for a special receptor called chimeric antigen receptor (CAR) is added to the T cells in the laboratory. These changed T cells called CAR T cells are grown in large numbers in the laboratory and given to the patient by infusion. Brexucabtagene autoleucel binds to a protein called CD19, which is found on some lymphoma cells and leukemia cells. This helps the body’s immune system kill cancer cells. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin, vincristine, methotrexate, and cytarabine work in different ways to stop the growth of cancer cells, either by killing the cells or stopping them from dividing. Giving more than one drug and giving them in different combinations may kill more tumor cells. Dexamethasone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Inotuzumab ozogamicin is a monoclonal antibody, called inotuzumab, linked to a toxic agent called ozogamicin. Inotuzumab attaches to CD22 positive cancer cells in a targeted way and delivers ozogamicin to kill them. 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. Giving brexucabtagene autoleucel after treatment with inotuzumab ozogamicin, blinatumomab, and either HCVAD or mini-HCVD to patients with relapsed/refractory or newly diagnosed B-cell ALL may help to control the disease.

Inclusion Criteria

Patients of age ≥ 18 years with documented relapsed or refractory B-cell ALL
In the newly diagnosed cohort: Patients of age ≥ 18 years with high-risk newly diagnosed B-cell ALL defined as: * KMT2A rearranged ALL * Complex cytogenetics as per National Comprehensive Cancer Network (NCCN) 2022 * Low-hypodiploidy/tetraploidy * Philadelphia-like ALL (based on CRLF2 overexpression or recurrent Ph-like genetic fusions) * Persistent or recurrent MRD by flow cytometry and/or NGS * TP53 mutation (variant allele fraction > 2%)
Performance status of 0, 1, or 2
Creatinine less than or equal to 1.6 mg/dl
Bilirubin less than or equal to 3.5 mg
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 5 times institutional upper limit of normal
Patients should be CD19 expression positive (> 50%) before enrollment
Patients with chronic viral infections like hepatitis B-virus, hepatitis C virus or human immunodeficiency virus I/II will be eligible if they are on therapy and infections are under control

Exclusion Criteria

Philadelphia chromosome positive B-cell ALL
Pregnant or lactating; women of child-bearing potential (WOCBP) must have negative pregnancy test. WOCBP defined as not post-menopausal for 12 months or no previous surgical sterilization
Prior exposure to brexu-cel or other anti-CD-19 CAR T cell therapy
Active and uncontrolled disease/infection as judged by the treating physician
Unable or unwilling to sign the consent form

PRIMARY OBJECTIVE:

I. To assess the efficacy of brexucabtagene autoleucel (anti-CD19 autologous derived chimeric antigen receptor T-cell [CAR-T]) in terms of event-free survival (EFS) in patients with relapsed/refractory (R/R) and high-risk newly diagnosed B-cell acute lymphoblastic leukemia (B-cell ALL) post cytoreduction with mini-hyper-CVD-inotuzumab-blinatumomab/hyper-CVAD-inotuzumab-blinatumomab.

SECONDARY OBJECTIVES:

I. 12 and 24-months overall survival (OS).

II. Rate of persistent measurable residual disease (MRD) negativity by flow cytometry and next-generation sequencing (NGS) at 9 and 18 months.

III. Best overall response rates (complete remission [CR] and CR with incomplete count recovery [CRi]).

IV. Achievement of MRD negativity amongst patients in CR and not MRD negative before brexucabtagene autoleucel infusion.

V. Safety.

EXPLORATORY OBJECTIVES:

I. CAR-T-cell expansion (days 1, 4, 8, 11, 14, 21, 28, monthly up to 3 months and then every 3 months up to 24 months post infusion).

II. B-cell aplasia (days 0, 7, 14, 28, monthly up to 3 months and then every 3 months up to 24 months post infusion).

III. Measurable residual disease (MRD) negativity by next-generation sequencing (NGS) (at 1 in 10^5-6 sensitivity) (peripheral blood [PB] on day 14 [D14] and PB/bone marrow [BM]: Day 28, and then every 3 months [Q3] months up to 24 months post infusion).

IV. Cytokine panel to study cytokine profile including IL6, IL1 during cytokine release syndrome (CRS) (days 0, 1, 2, 4, 7, 10, 14, 28).

V. Additional correlatives samples to address tumor samples and immune system factors will be collected at baseline, day 28 (D28) and Q3 months.

OUTLINE:

CYTOREDUCTION THERAPY: Patients may receive cytoreductive therapy with HCVAD or mini-HCVD based regimens as well as inotuzumab and/or blinatumomab as monotherapy or in combination with other chemotherapeutic agents according to established standard of care. Patients also undergo leukapheresis after 1-2 cycles of cytoreductive therapy.

CONDITIONING: Patients receive fludarabine IV over 30 minutes on days -4, -3, and -2, and cyclophosphamide IV over 60 minutes on day -2.

CAR T THERAPY: Patients receive brexucabtagene autoleucel (brexu-cel) IV on day 0.

All patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) and liver ultrasound or elastography during screening. Patients may also undergo bone marrow aspiration during screening. Patients also undergo bone marrow biopsy and aspiration and blood sample collection on study.

After completion of study treatment, patients are followed up every 3 months for up to 12 months and then every 6 months for 2 years and then annually for 12 years.

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Brexucabtagene Autoleucel as Consolidation after Inotuzumab, Blinatumomab and Mini-HCVD or HCVAD for the Treatment of Relapsed/Refractory and Newly Diagnosed B-cell Acute Lymphocytic Leukemia

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Brexucabtagene Autoleucel as Consolidation after Inotuzumab, Blinatumomab and Mini-HCVD or HCVAD for the Treatment of Relapsed/Refractory and Newly Diagnosed B-cell Acute Lymphocytic Leukemia

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