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

Study Overview
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Brief Summary
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This partially randomized phase III trial studies the side effects of inotuzumab ozogamicin and how well it works when given with frontline chemotherapy in treating patients with newly diagnosed B acute lymphoblastic leukemia. Monoclonal antibodies, such as inotuzumab ozogamicin, may block cancer growth in different ways by targeting certain cells. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving inotuzumab ozogamicin with chemotherapy may work better in treating young adults with B acute lymphoblastic leukemia.

Detailed Description
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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) 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. TERTIARY 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, gender 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. 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 (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, pegylated L-aspiraginase IV on day 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 with response to remission induction therapy are randomized to 1 of 2 arms. Patients with no response are omitted from the study. ARM I: 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 on days 15, 22, 43, and 50. Patients also receive pegylated L-aspiraginase IV 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 positive (+) patients receive rituximab IV on days 1, 8, 29, and 36. Patients then undergo bone marrow aspirate and biopsy on day 56. COURSE III (INTERIM MAINTENANCE CHEMOTHERAPY): Patients receive vincristine sulfate IV on days 1, 11, 21, 31, and 41, methotrexate IV and IT on days 1, 11, 21, 31, and 41, and pegylated L-aspiraginase IV on days 2 and 22. CD20+ patients receive rituximab IV on days 1 and 11. COURSE IV (DELAYED INTENSIFICATION): Patients receive vincristine sulfate IV on days 1, 8, 15, 43, and 50, dexamethasone PO or IV BID on days 1-7 and 15-21, doxorubicin IV on days 1, 8, and 15, and pegylated L-aspiraginase IV on day 4, 5, or 6 and day 43. 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 on day 50. COURSE V (MAINTENANCE THERAPY): Patients receive vincristine sulfate IV 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. ARM II: Patients receive inotuzumab ozogamicin IV 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 courses 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. After completion of study treatment, patients are followed up every month for the first year, every 2 months for the second year, every 3 months for the third year, and every 6 months for the fourth through tenth year.

Official Title
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A Phase III Trial to Evaluate the Efficacy of the Addition of Inotuzumab Ozogamicin (a Conjugated Anti-CD22 Monoclonal Antibody) to Frontline Therapy in Young Adults (Ages 18-39 Years) With Newly Diagnosed Precursor B-Cell ALL

Conditions
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B Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: Allopurinol
* Drug: Cytarabine
* Drug: Daunorubicin Hydrochloride
* Drug: Vincristine Sulfate
* Drug: Dexamethasone
* Drug: Pegylated L-Asparaginase
* Drug: Methotrexate
* Procedure: Bone Marrow Aspiration and Biopsy
* Drug: Cyclophosphamide
* Drug: Mercaptopurine
* Biological: Rituximab
* Drug: Doxorubicin
* Drug: Thioguanine
* Biological: Inotuzumab Ozogamicin
* Other: Laboratory Biomarker Analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: REGISTRATION ELIGIBILITY CRITERIA (STEP 1) Newly diagnosed patients with CD-22 positive B-cell acute lymphoblastic leukemia (WHO criteria) are eligible. Patients with Burkitt type ALL are NOT eligible Patients who have BCR-ABL fusion transcript determined by fluorescence in situ hybridization (FISH) or real time-polymerase chain reaction (RT-PCR) or t(9;22)(q34;q11) by cytogenetics are not eligible and should be considered for enrollment on studies that incorporate imatinib during induction; please note: flow cytometry is to be performed at the local reference lab and must include assessment of CD20 and CD22 positivity, as well as CD29 and CD22 anti-positivity No prior therapy except for limited treatment (< 7 days) with corticosteroids or hydroxyurea and a single dose of intrathecal cytarabine No prior therapy for acute leukemia except emergency therapy (corticosteroids or hydroxyurea) for blast cell crisis, superior vena cava syndrome, or renal failure due to leukemic infiltration of the kidneys; when indicated, leukapheresis or exchange transfusion is recommended to reduce the WBC Single-dose intrathecal cytarabine is allowed prior to registration or prior to initiation of systematic therapy for patient convenience; systemic chemotherapy must begin within 72 hours of this intrathecal therapy Patients receiving prior steroid therapy are eligible for study; the dose and duration of previous steroid therapy should be carefully documented on case report forms Not pregnant and not nursing; for women of childbearing potential only, a negative urine or serum pregnancy test done =< 7 days prior to registration is required Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Patients with down syndrome are excluded from this study Aspartate aminotransferase (AST), alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN), unless suspected leukemic involvement of the liver Direct bilirubin =< 3 x upper limit of normal (ULN), unless suspected leukemic involvement of the liver Calculated (calc.) creatinine clearance >= 50 mL/min by Cockcroft-Gault RANDOMIZATION ELIGIBILITY CRITERIA (STEP 2) Completion of remission induction therapy Patients with M2 marrow or better are eligible; patients with M3 or M4 marrow (greater than 25% lymphoblasts) will not be eligible to be randomized Rating: M0, M1; Blast Cells (%): 0-5.0 Rating: M2; Blast Cells (%): 5.1-25.0 Rating: M3; Blast Cells (%): > 25-50 Rating: M4; Blast Cells (%): > 50.0 The term blast cell includes any cell that cannot be classified as a more mature normal element, and includes leukemic cells, pathologic lymphocytes, and stem cells No ascites, effusions or significant edema Absolute neutrophil count (ANC) >= 1,000/mm^3 Platelet count >= 100,000/mm^3 Total bilirubin =< 1.5 x upper limit of normal (ULN), except for patients with known Gilbert's syndrome Aspartate aminotransferase (AST) =< 8 x upper limit of normal (ULN) Completion of first 12 weeks (12+ weeks) of maintenance therapy (Course V) Patient has at least 24 weeks (24+ weeks) remaining before end of maintenance therapy (Course V) Patient is in complete continuous first remission at entry into A041501-HO1 Patient is receiving oral anti-metabolite chemotherapy during the maintenance phase of therapy; treatment plan must call for the following doses of antimetabolites: 6MP 75 mg/m2/day orally; methotrexate (MTX) 20 mg/m2/week orally (modification of 6 MP or MTX dosing based on laboratory or clinical parameters is acceptable) Patient is able and willing to use the Medication Event Monitoring System (MEMS) TrackCap (e.g. not using a pillbox)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 39 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I (frontline chemotherapy)<br>See detailed description. | Drug: Allopurinol<br>* Given PO<br>Drug: Cytarabine<br>* Given IT, IV, SC<br>Drug: Daunorubicin Hydrochloride<br>* Given IV<br>Drug: Vincristine Sulfate<br>* Given IV<br>Drug: Dexamethasone<br>* Given PO or IV<br>Drug: Pegylated L-Asparaginase<br>* Given IV<br>Drug: Methotrexate<br>* Given IT, IV, PO<br>Procedure: Bone Marrow Aspiration and Biopsy<br>* Undergo bone marrow aspiration and biopsy<br>Drug: Cyclophosphamide<br>* Given IV<br>Drug: Mercaptopurine<br>* Given PO<br>Biological: Rituximab<br>* Given IV<br>Drug: Thioguanine<br>* Given PO<br>Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|
| Experimental: Arm II (frontline chemotherapy, inotuzumab ozogamicin)<br>Patients receive inotuzumab ozogamicin IV 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 courses 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. | Drug: Allopurinol<br>* Given PO<br>Drug: Cytarabine<br>* Given IT, IV, SC<br>Drug: Daunorubicin Hydrochloride<br>* Given IV<br>Drug: Vincristine Sulfate<br>* Given IV<br>Drug: Dexamethasone<br>* Given PO or IV<br>Drug: Pegylated L-Asparaginase<br>* Given IV<br>Drug: Methotrexate<br>* Given IT, IV, PO<br>Procedure: Bone Marrow Aspiration and Biopsy<br>* Undergo bone marrow aspiration and biopsy<br>Drug: Cyclophosphamide<br>* Given IV<br>Drug: Mercaptopurine<br>* Given PO<br>Biological: Rituximab<br>* Given IV<br>Drug: Doxorubicin<br>* Given IV<br>Drug: Thioguanine<br>* Given PO<br>Biological: Inotuzumab Ozogamicin<br>* Given IV<br>Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EFS | Will be compared using log-rank tests. EFS curves will be constructed using the Kaplan-Meier product limit method, and additional analyses will be done using the Cox proportional hazards model. The corresponding hazard ratio, 2- and 3-year EFS estimates will be assessed, and EFS medians along with their 95% confidence intervals for the two treatment arms. | Time from induction response to the time of progressive-disease, secondary malignancy, or death, assessed up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DFS |  | Time from achievement of CR to the time of relapse and/or death, assessed up to 10 years | 
| OS | Will be evaluated using Kaplan-Meier as well as Cox regression models. | 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 | Will be summarized as the proportion of patients who achieve any type of response to induction therapy divided by the number of all evaluable patients registered to this trial and who received at least one dose of induction therapy. Corresponding 95% binomial confidence intervals will also be calculated. | Up to 10 years | 
| Overall induction response rates | Will be summarized as the proportion of patients who achieve any type of response to induction therapy divided by the number of all evaluable patients registered to this trial and who received at least one dose of induction therapy. Corresponding 95% binomial confidence intervals will also be calculated. | Up to 10 years | 
| Incidence of adverse events as assessed by Common Terminology Criteria for Adverse Events version 4.0 | The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. In addition, all adverse event data that is graded as 3, 4, or 5 will be reviewed and classified as either unrelated or unlikely to be related to study treatment in the event of an actual relationship developing. The incidence of severe (grade 3+) adverse events or toxicities will be described for each treatment arm, but will also be compared between the arms. Fisher's exact tests will be used to quantitatively compare the incidence of severe as well as specific toxicities of interest between the treatment arms and we will graphically assess differences in maximum grades observed for toxicities between the arms. Tolerability of the treatment arms will be assessed through assessing the number of patients who required dose modifications and/or dose delays. | Up to 10 years | 
| Proportion of patients who go off treatment due to adverse reactions | Will be assessed within each of the treatment arms and differences explores in these measures between the arms. | Up to 10 years | 
| Proportion of patients who refuse further treatment for lesser toxicities that inhibit their willingness to continue participation on the trial | Will be assessed within each of the treatment arms and differences explores in these measures between the arms. | Up to 10 years |