Inotuzumab Ozogamicin and Blinatumomab with Standard Chemotherapy in Treating Newly Diagnosed Patients with B-Cell Precursor Acute Lymphoblastic Leukemia and Lymphoma
This phase II trial studies how well adding inotuzumab ozogamicin and blinatumomab to standard chemotherapy works in treating patients with B-cell precursor acute lymphoblastic leukemia and lymphoma. Inotuzumab ozogamicin is a monoclonal antibody called inotuzumab linked to a drug called ozogamicin. It is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of cancer cells, known as CD22, and delivers ozogamicin to kill them. Bispecific antibodies such as blinatumomab connect a part of the patient's immune system called T-cells to cancer cells and help the immune system kill the cancer cell. Blinatumomab targets cancer cells through a specific molecule called CD19. Standard chemotherapy drugs 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. Adding inotuzumab ozogamicin and blinatumomab to standard chemotherapy may be better at getting rid of leukemia in the blood and bone marrow than giving standard chemotherapy alone.
Inclusion Criteria
- Enrollment on INITIALL.
- Age 1-18.99 years at the time of enrollment on INITIALL.
- B-Acute lymphoblastic leukemia or lymphoblastic lymphoma.
- No prior chemotherapy excluding therapy given on or allowed by INITIALL.
- NCI high-risk (age 10 years or greater or presenting white blood cell [WBC] count ≥ 50,000 cells/microL) or NCI standard-risk and a high-risk (HR) clinical feature as listed below: * Central nervous system (CNS)3 disease (≥ 5 WBC/microL cerebrospinal fluid [CSF] with blasts present) * Testicular involvement of leukemia * Steroid pretreatment defined as > 24 hours of therapy in the 14 days prior to enrollment on INITIALL if a preceding WBC to define NCI risk is unavailable
- For lymphoblastic lymphoma, stage 3-4 disease OR stage 1-2 disease in patient ages ≥ 10 years OR HR clinical feature as defined above.
- Total bilirubin ≤ 1.5 x the upper limit of normal for age and alanine aminotransferase (ALT) ≤ 5 x the upper limit of normal for age. Patients with an elevated total bilirubin due to hemolysis are eligible if they have a direct bilirubin < 1.5 x the upper limit of normal
- Calculated glomerular filtration rate (GFR) ≥ 50 mL/min/1.73m^2 using the Bedside Schwartz equation OR creatinine below or equal to the maximum defined below: * 1 to < 2 years: Maximum serum creatinine (Male 0.6mg/dL) (Female 0.6mg/dL) * 2 to < 6 years: Maximum serum creatinine (Male 0.8mg/dL) (Female 0.8 mg/dL) * 6 to < 10 years: Maximum serum creatinine (Male 1mg/dL) (Female 1mg/dL) * 10 to < 13 years: Maximum serum creatinine (Male 1.2mg/dL) (Female 1.2mg/dL) * 13 to < 16 years: Maximum serum creatinine (Male 1.5mg/dL) (Female 1.4mg/dL) * ≥ 16 years: Maximum serum creatinine (Male 1.7mg/dL) (Female 1.4mg/dL)
- Eligibility for inclusion post-Induction requires meeting the first 4 criteria as above AND: * Treatment on SJALL23H for Induction OR * Lymphoblastic lymphoma, initially treated on an SJALL protocol OR standard (non-protocol) therapy, without a complete response at the end of Induction OR * NCI-standard risk (SR) ALL at diagnosis and treated with an SJALL protocol OR standard (non-protocol) therapy who have ** Slow response to therapy (≥ 0.1% MRD at end of Induction for patients with hyperdiploid ALL or ≥ 0.01% MRD at end of Induction for others with ALL) OR ** HR genetics ** These patients may receive no more than 2 weeks of post-induction therapy and should be transitioned to SJALL23H post-induction as soon as the qualifying genetic or MRD result is available
Exclusion Criteria
- Presence of ETV6::RUNX1 fusion unless also having a HR clinical feature OR slow response to Induction.
- History or presence of clinically relevant CNS pathology or event such as epilepsy, childhood or adult non-febrile seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome, or psychosis. History of simple febrile seizure during childhood and presence of CNS leukemia at diagnosis are not exclusions to participation.
- Active uncontrolled infection.
- Current active autoimmune disease or history of autoimmune disease with the potential for CNS involvement.
- History of venoocclusive disease/ sinusoidal obstructive syndrome.
- Unstable cardiac disease including corrected QT interval (QTc) > 500msec.
- Inability or unwillingness to give informed consent/ assent as applicable.
- Pregnant or lactating.
- For patients of reproductive potential, unwillingness to use effective contraception for the duration of protocol therapy.
Additional locations may be listed on ClinicalTrials.gov for NCT06533748.
Locations matching your search criteria
United States
Oklahoma
Tulsa
Tennessee
Memphis
PRIMARY OBJECTIVE:
I. To assess if the flow-cytometry assessed minimal residual disease (MRD)-negative remission rate following an immunotherapy-based Induction in National Cancer Institute (NCI)-high risk patients without favorable genetic features is higher than the results of similar patients treated on AALL1131.
SECONDARY OBJECTIVES:
I. To compare flow-cytometry assessed MRD-negative rates at the end of Induction for patients treated with this therapy compared to similar patients treated on TOT17.
II. To compare the rate of significant toxicities in patients treated with this therapy to those treated with standard-risk therapy on TOT17.
III. To assess the event free and overall survival of patients treated with this therapy.
EXPLORATORY OBJECTIVES:
I. To describe response to this therapy in patients with Murphy stage 3/4 B-acute lymphoblastic lymphoma (B-LLy) regardless of age and in patients with Murphy stage 1/2 B-LLy who are ≥ 10 years old at diagnosis.
II. To assess the association between the pharmacokinetics of inotuzumab and both efficacy and toxicity.
III. To estimate the proportion of patients who achieve negative MRD by flow cytometry and remained free of non-hematological grade 4-5 toxicities during Induction.
IV. To compare outcomes including survival, need for intensified therapy, and high- grade toxicities as a composite endpoint to the comparable cohort in Total 17, using a win-ratio statistic.
V. To compare the clinical significance and kinetics of high-throughput sequencing (HTS)-based MRD response during therapy to that of MRD assessed by flow cytometry using bulk tumor, single cell and cell free genomic approaches.
VI. To identify germline and somatic genomic variants associated with disease resistance/ treatment failure and/or treatment toxicity.
VII. To examine tumor intrinsic and extrinsic determinants of response to therapy, including immunotherapy.
VIII. To describe the event free and overall survival of patients with NCI-standard risk therapy during Induction who receive high-risk therapy post-Induction for either elevated MRD levels or high-risk genomic features.
IX. To assess the impact of this therapy on patient reported outcomes, neurocognitive outcomes, and clinically measured toxicities.
OUTLINE:
INDUCTION: Patients receive dexamethasone orally (PO) or intravenously (IV) twice daily (BID) on days 1-8, vincristine IV on days 1 and 8, and inotuzumab ozogamicin IV on days 2 and 8. Patients with ABL-class gene fusions receive dasatinib PO daily on days 12-37. Patients with M2/M3 marrow disease or MRD ≥ 5% on day 8, or patients with unknown marrow status by day 12 receive lower-dose blinatumomab IV on days 9-15 and higher-dose blinatumomab IV on days 16-36. Patients with M1 marrow disease or MRD < 5% receive lower-dose blinatumomab IV on days 9-11 and higher-dose blinatumomab IV on days 12-36. Treatment continues for 36 days in the absence of disease progression or unacceptable toxicity. Patients with CD19-negative disease stop blinatumomab early and don't receive additional blinatumomab on the study. Patients with CD22-negative disease on day 22 or 36 do not receive inotuzumab ozogamicin in Consolidation treatment. Patients unable to receive inotuzumab ozogamicin by day 3 receive cyclophosphamide IV every 12 hours on days 3-4.
CONSOLIDATION: Patients receive cyclophosphamide IV on day 1, cytarabine IV on days 1-4 and 8-11, and inotuzumab ozogamicin IV on days 3 and 9 (NOTE: Day 9 omitted for patients with end of Induction MRD < 1x10^-5 and/or Down syndrome). Patients also receive methotrexate intrathecally (IT), hydrocortisone IT, and cytarabine IT on days 1, 8, 15 (NOTE: Day 8 omitted for patients with CNS1 disease and without high-risk features). Patients with ABL-class gene fusions receive dasatinib PO daily on days 13-21. Treatment continues for 21 days in the absence of disease progression or unacceptable toxicity.
BLINATUMOMAB 1: Patients receive blinatumomab IV on days 1-28. Patients also receive methotrexate IT, hydrocortisone IT, and cytarabine IT once between days -1 to 15. Patients with ABL-class gene fusions receive dasatinib PO daily on days 1-28. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity.
HIGH-DOSE METHOTREXATE: Patients receive methotrexate IV over 24 hours on days 1, 15, 29, and 43 and 6-mercaptopurine PO daily on days 1-56. Patients also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on days 1, 15, 29, and 43. Patients with ABL-class gene fusions receive dasatinib PO daily on days 1-56. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
RE-INDUCTION: Patients receive dexamethasone PO BID on days 1-7 and 15-21, vincristine IV on days 1, 8, and 15, calaspargase IV on day 1, and daunorubicin IV on day 1. Patients also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 1. Patients with ABL-class gene fusions receive dasatinib PO daily on days 1-21. Treatment continues for 21 days in the absence of disease progression or unacceptable toxicity.
INTERIM: Patients receive dexamethasone PO BID on days 1-5 of week 5, vincristine IV on day 1 of weeks 2 and 5, daunorubicin IV on day 1 of weeks 2 and 5, calaspargase IV on day 1 of weeks 1 and 4, and 6-mercaptopurine PO daily on days 1-7 of weeks 1-6. Patients also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 1 of week 4. Patients with ABL-class gene fusions receive dasatinib PO daily on days 1-7 of weeks 1-7. Treatment continues for 7 weeks in the absence of disease progression or unacceptable toxicity.
RECONSOLIDATION: Patients receive cyclophosphamide IV on day 1, cytarabine IV on days 1-4 and 8-11, 6-mercaptopurine PO daily on days 1-14. Patients also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 1. Patients with ABL-class gene fusions receive dasatinib PO daily on days 1-21. Treatment continues for 21 days in the absence of disease progression or unacceptable toxicity.
BLINATUMOMAB 2: Patients without clonal IgH rearrangements, those with end of Induction MRD ≥1x10^-5, those in whom next-generation based sequencing MRD is unavailable, patients who did not receive blinatumomab during induction, or patients with Down syndrome receive blinatumomab IV on days 1-28. Patients also receive methotrexate IT, hydrocortisone IT, and cytarabine IT once between days -1 to 15. Patients with ABL-class gene fusions receive dasatinib PO daily on days 1-28. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity.
EARLY MAINTENANCE: Patients receive dexamethasone PO BID on days 1-5 of weeks 1, 5, 9, 13, 17, 21, 25, and 29, vincristine IV on day 1 of weeks 1, 5, 9, 13, 17, 21, 25, and 29, methotrexate IV, PO, or intramuscularly (IM) on day 1 of weeks 2-4, 6-8, 10-12, 14-16, 18-20, 22-24, and 26-28, and 6-mercaptopurine PO on days 1-7 of weeks 1-29. Patients also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 1 of weeks 1, 5, 9, 13, 17, 21, 25, and 29. Patients with ABL-class gene fusions receive dasatinib PO daily on days 1-7 of weeks 1-29. Treatment continues for 29 weeks in the absence of disease progression or unacceptable toxicity.
LATE MAINTENANCE: Patients receive methotrexate IV, PO, or IM on day 1 of weeks 30-80 and 6-mercaptopurine PO daily on days 1-7 of weeks 30-80. Patients also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 1 of weeks 37, 45, 53, 61, 69 and 77. Patients with ABL-class gene fusions receive dasatinib PO daily on days 1-7 of weeks 30-80. Treatment continues for 51 weeks in the absence of disease progression or unacceptable toxicity.
Patients with leukemia or lymphoma outside of the bone marrow will undergo X-ray, computed tomography (CT), magnetic resonance imaging (MRI), and/or positron emission tomography (PET) throughout the trial. Patients also undergo blood sample collection on study and bone marrow aspiration throughout the trial.
After completion of study treatment, patients are followed every 4 months for 1 year, every 6 months for 1 year and then yearly until the patient is in remission for 10 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationSaint Jude Children's Research Hospital
Principal InvestigatorSeth Evan Karol
- Primary IDSJALL23H
- Secondary IDsNCI-2024-06013
- ClinicalTrials.gov IDNCT06533748