Inotuzumab Ozogamicin and Post-Induction Chemotherapy in Treating Patients With High-Risk B-ALL, Mixed Phenotype Acute Leukemia, and B-LLy

ConditionsB Acute Lymphoblastic Leukemia B Lymphoblastic Lymphoma Central Nervous System Leukemia Mixed Phenotype Acute Leukemia Testicular Leukemia

Trial statusRecruiting

Trial phasePhase 3

Trial typeInterventional

Biological sexAll

Age365-25

SponsorChildren's Oncology Group

About this trial

This phase III trial studies whether inotuzumab ozogamicin added to post-induction chemotherapy and immunotherapy (chemo-immunotherapy) for patients with High-Risk B-cell Acute Lymphoblastic Leukemia (B-ALL) improves outcomes. Inotuzumab ozogamicin is a monoclonal antibody, which is a type of protein that can bind to certain targets on the surface of cells. Inotuzumab ozogamicin is a monoclonal antibody that is linked to a type of chemotherapy called calicheamicin. Inotuzumab attaches to cancer cells by binding to the CD22 protein on the surface of the cancer cell and delivering calicheamicin inside the cells to kill them. Other drugs used in the chemotherapy regimen, such as cyclophosphamide, cytarabine, dexamethasone, doxorubicin, daunorubicin, methotrexate, leucovorin, mercaptopurine, prednisone, thioguanine, vincristine, and pegaspargase or calaspargase pegol work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Blinatumomab is a specialized type of monoclonal antibody known as a bispecific T-cell engager (BiTE). It works by simultaneously binding to CD19 on cancer cells and CD3 on normal immune cells, bringing them together to destroy leukemia cells. Blinatumomab is a standard part of chemo-immunotherapy treatment for B-ALL. This trial also studies the outcomes of patients with mixed phenotype acute leukemia (MPAL), and B-lymphoblastic lymphoma (B-LLy) when treated with ALL therapy without inotuzumab ozogamicin or blinatumomab.

The overall goal of this study is to understand if adding inotuzumab ozogamicin to standard of care chemo-immunotherapy maintains or improves outcomes in High Risk B-cell Acute Lymphoblastic Leukemia (HR B-ALL). The first part of the study includes the first phase of therapy: Induction. This part will collect information on the leukemia, as well as the effects of the initial treatment, to classify patients into post-induction treatment groups. On the second part of this study, patients with HR B-ALL will receive the remainder of the chemotherapy cycles (consolidation, blinatumomab block 1, interim maintenance 1, blinatumomab block 2, delayed intensification, interim maintenance 2, maintenance), with some patients randomized to receive inotuzumab. The patients that receive inotuzumab will not receive part of consolidation or part of delayed intensification. Other aims of this study include evaluating 1) side effects of treatment using patient-reported outcomes and health-related quality of life, 2) the best ways to help patients adhere to oral chemotherapy regimens, 3) the relationship between levels of inotuzumab ozogamicin in the blood and side effects, 4) the impact of chemo-immunotherapy on the immune system and risk of infection, and 5) the impact of social determinants of health on outcomes. Finally, this study will be the first to track the outcomes of subjects with disseminated B-cell Lymphoblastic Leukemia (B-LLy) or Mixed Phenotype Acute Leukemia (MPAL) when treated with B-ALL chemotherapy.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

B-ALL and MPAL patients must be enrolled on APEC14B1 and consented to eligibility studies (Part A) prior to treatment and enrollment on AALL1732. Note that central confirmation of MPAL diagnosis must occur within 22 days of enrollment for suspected MPAL patients. If not performed within this time frame, patients will be taken off protocol.

APEC14B1 is not a requirement for B-LLy patients but for institutional compliance every patient should be offered participation in APEC14B1. B-LLy patients may directly enroll on AALL1732.

Patients must be > 365 days and < 25 years of age

Age 1-9.99 years: WBC >= 50,000/uL

Disqualifiers

Patients with Down syndrome are not eligible

With the exception of steroid pretreatment and steroid cytoreduction or the administration of intrathecal cytarabine, patients must not have received any prior cytotoxic chemotherapy for the current diagnosis of B-ALL, MPAL, or B-LLy or for any cancer diagnosed prior to initiation of protocol therapy on AALL1732.

Patients who have received > 72 hours of hydroxyurea within one week prior to start of systemic protocol therapy.

Patients with B-ALL or MPAL who do not have sufficient diagnostic bone marrow submitted for APEC14B1 testing and who do not have a peripheral blood sample submitted containing > 1,000/uL circulating leukemia cells.

Trial design

Design model

Parallel

Treatments tested in this trial

Biospecimen Collection
Procedure/Surgery
Undergo blood sample collection
Blinatumomab
Biological/Vaccine
Given IV
Bone Marrow Aspiration
Procedure/Surgery
Undergo bone marrow aspiration
Bone Marrow Biopsy
Procedure/Surgery
Undergo bone marrow biopsy
Bone Scan
Procedure/Surgery
Undergo bone scan
Calaspargase Pegol
Drug
Given IV
Computed Tomography
Procedure/Surgery
Undergo CT
Cyclophosphamide
Drug
Given IV
Cytarabine
Drug
Given IV, IT, or SC
Daunorubicin Hydrochloride
Drug
Given IV
Dexamethasone
Drug
Given PO or IV
Doxorubicin Hydrochloride
Drug
Given IV
Inotuzumab Ozogamicin
Biological/Vaccine
Given IV
Leucovorin Calcium
Drug
Given PO or IV
Magnetic Resonance Imaging
Procedure/Surgery
Undergo MRI
Mercaptopurine
Drug
Given PO
Methotrexate
Drug
Given IT or IV
Pegaspargase
Drug
Given IV or IM
Positron Emission Tomography
Procedure/Surgery
Undergo PET
Prednisolone
Drug
Given PO or IV
Prednisone
Drug
Given PO or IV
Questionnaire Administration
Other intervention
Ancillary studies
Radiation Therapy
Radiation
Undergo testicular radiation therapy
Radiation Therapy
Radiation
Undergo cranial radiation therapy
Thioguanine
Drug
Given PO
Vincristine Sulfate
Drug
Given IV

Treatment groups

5,951 Participants

are divided into 4 treatment groups

Group A: Arm D (CD 22 positive HR B-ALL)Active comparator 20 interventions

Group B: Arm E (CD22 positive HR B-ALL)Experimental treatment 20 interventions

Group C: Arm I (MPAL)Experimental treatment 18 interventions

Group D: Arm II (B-LLy)Experimental treatment 23 interventions

Trial outcomes

Primary outcomes

Post-induction 5-year event-free survival (EFS)

Will compare in a randomized manner the post-induction 5-year EFS for children and young adults with High Risk (HR) B-cell acute lymphoblastic leukemia (B-ALL) treated with a modified Berlin-Frankfurt-Münster (mBFM) chemo-immunotherapy backbone that includes blinatumomab and replaces Consolidation Part 2 and Delayed Intensification (DI) Part 2 with two blocks of inotuzumab ozogamicin, versus those treated with a full mBFM chemo-immunotherapy backbone that includes blinatumomab and retains Consolidation Part 2 and DI Part 2 without the addition of inotuzumab ozogamicin.

Time frame

From study entry to first event (induction failure, induction death, end of induction [EOI] minimal residual disease [MRD] ≥ 5%,EO consolidation [C] MRD ≥ 0.01%, relapse, second malignancy, remission death) or date of last contact, assessed up to 5 years

Secondary outcomes

5-year DFS for favorable risk subset of NCI HR B-ALL (HR favorable) when treated with mBFM chemotherapy with a single high-dose methotrexate (HD MTX) Interim Maintenance (IM) phase and treatment duration of 2 years from the start of IM regardless of sex

Will be estimated using the Kaplan-Meier method and standard errors and confidence intervals estimated by the method of Peto. Estimation of treatment effect will be done using ITT analysis based on randomized group.

Time frame

From EOC to first event (relapse, second malignant neoplasm, remission death) or date of last contact, assessed up to 5 years

Incidence of adverse events for the integration of inotuzumab ozogamicin into the mBFM chemotherapy backbone in HR B-ALL

Graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Will be monitored and reported.

Time frame

Up to 5 years

5-year event-free survival (EFS) for patients with mixed phenotype acute leukemia (MPAL) receiving mBFM HR B-ALL therapy that includes a second IM phase with Capizzi escalating intravenous MTX without leucovorin rescue+pegaspargase or calaspargase pegol

Time frame

From study entry to first event (induction failure, Induction death, end of induction (EOI) minimal residual disease (MRD) >= 5%, EOC MRD >= 0.01%, relapse, second malignancy, remission death) or date of last contact, assessed up to 5 years

5-year EFS for patients with disseminated (Murphy stage III-IV) B-cell lymphoblastic lymphoma (B-LLy) receiving mBFM HR B-ALL therapy that includes a second IM phase with C-MTX

Time frame

From study entry to first event (progressive disease, induction death, relapse, second malignancy, remission death) or date of last contact, assessed up to 5 years

Other outcomes

Overall survival (OS)

OS rates will be estimated using the Kaplan-Meier method and standard errors and confidence intervals estimated by the method of Peto.

Time frame

Time from study entry to death or date of last contact for those alive at last contact, assessed up to 5 years

Therapy administered to patients with MPAL who come off protocol therapy due to poor disease response to ALL therapy

Will be described.

Time frame

Up to 5 years

Disease response in patients with MPAL who come off protocol therapy due to poor disease response to ALL therapy

Will be described.

Time frame

Up to 5 years

Survival outcomes of patients with MPAL who come off protocol therapy due to poor disease response to ALL therapy

Will be described.

Time frame

Up to 5 years

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

Children's Oncology Group

Lead sponsor

National Cancer Institute (NCI)

Collaborator

Source ClinicalTrials.gov

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