Inotuzumab Ozogamicin and Frontline Chemotherapy in Treating Young Adults With Newly Diagnosed B Acute Lymphoblastic Leukemia

PRIMARY OBJECTIVES:

I. To confirm tolerability of the combination regimen with the addition of inotuzumab ozogamicin to the pediatric-inspired regimen of cancer and leukemia group B (CALGB) 10403.

II. To determine whether the addition of inotuzumab ozogamicin significantly improves the event-free survival (EFS) in patients who achieve an induction response achieved with the pediatric-inspired regimen of CALGB 10403, without censoring for transplant. (Phase III) III. To determine the safety and tolerability of a reduced dose of inotuzumab ozogamicin and two cycles of blinatumomab added to the pediatric-inspired regimen of CALGB 10403 (Pilor cohort).

SECONDARY OBJECTIVES:

I. To determine the impact of inotuzumab ozogamicin on disease-free (DFS) and overall survival (OS) in patients who achieve an induction response.

II. To determine whether the addition of inotuzumab ozogamicin significantly improves the event-free survival (EFS) in patients who achieve an induction response achieved with the pediatric-inspired regimen of CALGB 10403, with censoring for transplant.

III. To determine the impact of inotuzumab ozogamicin on minimal residual disease (MRD) and correlate this with the EFS, DFS and OS.

IV. To determine the prognosis based on patients' low-density array (LDA) gene signature in terms of EFS, DFS, and OS after treatment with or without inotuzumab ozogamicin when added to the C10403 backbone regimen.

V. To evaluate the toxicity and tolerability of the addition of inotuzumab ozogamicin to the pediatric-inspired regimen of CALGB 10403.

CORRELATIVE SCIENCE OBJECTIVES:

I. To assess both the correlation of MRD post-induction and at sequential timepoints with LDA signature.

II. To evaluate the influence of MRD status (detectable vs. not and as a continuous measure) in relation to EFS both in the univariate setting as well as adjusting for other clinical features including initial white blood cell (WBC), ethnicity, sex and age at diagnosis.

III. To evaluate the impact of inotuzumab ozogamicin (inotuzumab) on the kinetics of MRD during treatment with inotuzumab in patients randomized to the experimental treatment arm.

IV. To perform genomic analyses to identify and evaluate the incidence and clinical significance of recurring novel fusion genes including those associated with the BCR-ABL1-like signature and to correlate with MRD status, CR rate, EFS and OS.

V. To assess whether rs4958351 is correlated with L-asp allergic reaction in the adolescent and young adult (AYA) population.

VI. To assess the incidence of inherited genetic variants in the GR1A1, CEP72, CPA2, TPMT, NUDT15, GRIN3A, GRIK1, and other genes (which can be found using a whole genome association study \[GWAS\]), are correlated with increased rates of target toxicities including peripheral neuropathy, hepatotoxicity, pancreatitis, myelosuppression, neurotoxicity, thrombosis, and osteonecrosis, and correlate with treatment discontinuation and other clinical response parameters including complete response (CR) rate, EFS, and OS.

VII. To evaluate asparaginase pharmacokinetics in adolescents and young adults, and investigate its correlation with toxicities and treatment outcomes.

VIII. To investigate the effect of anti-polyethylene glycol (PEG) and anti-agouti signaling protein (ASP) antibodies (PEG-ASP) on ASP enzyme activity.

IX. To measure adherence to oral 6 mercaptopurine (MP) and methotrexate in AYAs with acute lymphoblastic leukemia (ALL) and to examine sociodemographic and behavioral determinants of adherence.

X. To determine the impact of adherence on risk of relapse among AYAs with ALL. XI. To correlate specific karyotype groups (normal or various primary and secondary chromosomal abnormalities) with clinical and laboratory parameters.

XII. To correlate specific karyotype groups with response rates, response duration, survival, and cure in patients treated on this protocol.

XIII. To correlate specific karyotype groups with MRD. XIV. To determine karyotype changes at relapse and the influence of the type of change (or no change) in karyotype at relapse.

XV. To define the rate, analytical performance, and diagnostic yield of ChromoSeq vs. conventional G-banded karyotyping and fluorescence in situ hybridization (FISH) for B ALL patients in a multicenter setting.

OUTLINE:

COURSE I (REMISSION INDUCTION THERAPY): All patients receive allopurinol orally (PO) once daily until peripheral blasts and extramedullary disease are reduced and cytarabine intrathecally (IT) over 1 minute on day 1. Patients also receive daunorubicin hydrochloride intravenously, over 1 to 30 minutes (IV) and vincristine sulfate IV on days 1, 8, 15 and 22, dexamethasone PO or IV twice daily (BID) on days 1-7 and 15-21, pegaspargase for patients \>21.5 years IV, over 1 to 2 hours on day 4, 5, or 6, or calaspargase pegol IV, over 1 hour, on days 4, 5 or 6 and methotrexate IT over 1 minute on days 8 and 29. Patients with central nervous system (CNS) 3 disease receive methotrexate IT over 1 minute also on days 15 and 22. All patients then undergo bone marrow aspirate and biopsy on day 29.

Patients enrolled prior to Update 8 with response to remission induction therapy are randomized to 1 of 2 arms. Patients enrolled after amendment 8 are assigned to the pilot cohort. Patients with no response are omitted from the study.

ARM I (CLOSED 7/23/2025):

COURSE II (REMISSION CONSOLIDATION CHEMOTHERAPY): Patients receive cyclophosphamide IV on days 1 and 29, cytarabine IV or SC on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO on days 1-14 and 29-42, and vincristine sulfate IV, over 1 to 10 minutes on days 15, 22, 43, and 50. Patients \>21.5 years also receive pegaspargase IV, over 1 to 2 hours, on days 15 and 43 and patients \<21.5 years old receive calaspargase pegol IV, over 1 hour, on days 2 and 22, and methotrexate IT on days 1, 8, 15, and 22. Patients with CNS3 receive methotrexate IT only on days 1 and 8. CD20 positive (+) patients receive rituximab IV on days 1, 8, 29, and 36. Patients with evidence of testicular disease at diagnosis also receive radiation therapy (RT). Patients who are MRD+ and CD19+ after completion of this course receive dexamethasone IV or PO on day 1 and blinatumomab IV via continuous infusion on days 1-28, followed by a 14 day break. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Patients then undergo bone marrow aspirate and biopsy on day 56.

COURSE III (INTERIM MAINTENANCE CHEMOTHERAPY): Patients receive vincristine sulfate IV, over 1 to 10 minutes, on days 1, 11, 21, 31, and 41, methotrexate IV, over 24 hours, and IT on days 1, 11, 21, 31, and 41, patients \>21.5 years old receive pegaspargase IV, over 1 to 2 hours, and patients \< 21.5 years old receive calaspargase pegol IV, over 1 hour on days 2 and 22. CD20+ patients receive rituximab IV on days 1 and 11.

COURSE IV (DELAYED INTENSIFICATION): Patients receive vincristine sulfate IV, over 1 to 10 minutes, on days 1, 8, 15, 43, and 50, dexamethasone PO or IV BID on days 1-7 and 15-21, doxorubicin IV, over 3 to 60 minutes, on days 1, 8, and 15, patients \>21.5 years old receive pegaspargase IV, over 1 to 2 hours, on day 4, 5, or 6 and day 43, patients \<21.5 years old receive calaspargase pegol IV, over 1 hour, on days 2 and 22. Patients also receive cyclophosphamide IV on day 29, cytarabine IV or SC on days 29-32 and 36-39, thioguanine PO on days 29-42 and methotrexate IT on days 1, 29, and 36. CD20+ patients receive rituximab IV on days 1 and 8. Patients then undergo bone marrow aspirate and biopsy one week after completion of course IV.

COURSE V (MAINTENANCE THERAPY): Patients receive vincristine sulfate IV, over 1 to 10 minutes, on days 1, 29, and 57, dexamethasone PO or IV BID on days 1-5, 29-33, and 57-61, and mercaptopurine PO on days 1-84. Patients also receive methotrexate IT or PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Treatment repeats every 12 weeks for up to 3 years in the absence of disease progression or unacceptable toxicity.

Patients undergo multigated acquisition scan (MUGA) or echocardiography and x ray imaging during screening, bone marrow aspiration and biopsy and lumbar puncture and blood sample collection throughout the study.

ARM II (CLOSED 7/23/2025): Patients receive inotuzumab ozogamicin IV, over 1 hour, on days 1, 8, and 15 and undergo bone marrow aspirate and biopsy on day 28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients who are MRD+ and CD19+ after completion of 2 cycles of inotuzumab ozogamicin receive dexamethasone IV or PO on day 1 and blinatumomab IV via continuous infusion on days 1-28, followed by a 14 day break. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive remission consolidated chemotherapy, interim maintenance chemotherapy, delayed intensification, and maintenance therapy as in Arm I.

Patients undergo MUGA or echocardiography and x ray imaging during screening, bone marrow aspiration and biopsy and lumbar puncture and blood sample collection throughout the study.

PILOT COHORT: Patients receive inotuzumab ozogamicin IV, over 1 hour, on days 1, 8, and 15 and undergo bone marrow aspirate and biopsy on day 28.

COURSE II (REMISSION CONSOLIDATION CHEMOTHERAPY): Patients receive cyclophosphamide IV on days 1 and 29, cytarabine IV or SC on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO on days 1-14 and 29-42, and vincristine sulfate IV, over 1 to 10 minutes, on days 15, 22, 43, and 50. Patients \> 21.5 years old also receive pegaspargase IV, over 1 to 2 hours, on days 15 and 43 and patients \< 21.5 years old receive calaspargase pegol IV, over 1 hour, on days 15 and 43, and methotrexate IT on days 1, 8, 15, and 22. Patients with CNS3 receive methotrexate IT only on days 1 and 8. CD20+ patients receive rituximab IV on days 1, 8, 29, and 36. Patients with evidence of testicular disease at diagnosis also receive RT. Patients then undergo bone marrow aspirate and biopsy on day 56.

BLINATUMOMAB: Patients receive blinatumomab IV, continuously, on days 1-28 of one 42-day cycle in the absence of disease progression or unacceptable toxicity. Patients also receive dexamethasone PO or IV prior to starting the blinatumomab cycle, and a single dose of methotrexate IT between cycle days 29 and 42.

COURSE III (INTERIM MAINTENANCE CHEMOTHERAPY): Patients receive vincristine sulfate IV, over 1 to 10 minutes, on days 1, 11, 21, 31, and 41, methotrexate IV, over 24 hours, and IT on days 1, 11, 21, 31, and 41, patients \>21.5 years old receive pegaspargase IV, over 1 to 2 hours, and patients \< 21.5 years old receive calaspargase pegol IV, over 1 hour on days 2 and 22. CD20+ patients receive rituximab IV on days 1 and 11.

BLINATUMOMAB: Patients receive blinatumomab IV, continuously, on days 1-28 of one 42-day cycle in the absence of disease progression or unacceptable toxicity. Patients also receive dexamethasone PO or IV prior to starting the blinatumomab cycle, and a single dose of methotrexate IT between cycle days 29 and 42. Patients who are MRD positive and CD19+ after Course II may continue to receive blinatumomab IV, continuously on days 1-28 of each cycle. Cycles repeat every 42 days for an additional 2 cycles in the absence of disease progression or unacceptable toxicity, per investigator discretion.

COURSE IV (DELAYED INTENSIFICATION): Patients receive vincristine sulfate IV, over 1 to 10 minutes on days 1, 8, 15, 43, and 50, dexamethasone PO or IV BID on days 1-7 and 15-21, doxorubicin IV, over 3 to 60 minutes, on days 1, 8, and 15, patients \> 21.5 years old receive pegaspargase IV, over 1 to 2 hours, on day 4, 5, or 6 and day 43, patients \< 21.5 years old receive calaspargase pegol IV, over 1 hour, on day 4, 5, or 6 and 43. Patients also receive cyclophosphamide IV on day 29, cytarabine IV or

• Disease-free survival (DFS) [Срок оценки: Time from achievement of complete response (CR) to the time of relapse and/or death, assessed up to 10 years]
• Overall Survival (OS) [Срок оценки: Time from randomization to the time of death due to any cause, assessed up to 10 years]
• Proportion of patients who achieve CR or any response to induction therapy [Срок оценки: Up to 10 years]
• Overall induction response rates [Срок оценки: Up to 10 years]
• Incidence of adverse events as assessed by Common Terminology Criteria for Adverse Events version 5.0 [Срок оценки: Up to 10 years]
• Proportion of patients who go off treatment due to adverse reactions [Срок оценки: Up to 10 years]
• Proportion of patients who refuse further treatment for lesser toxicities that inhibit their willingness to continue participation on the trial [Срок оценки: Up to 10 years]