Combination Chemotherapy and Inotuzumab Ozogamicin in Treating Patients With B Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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This phase II trial studies how well combination chemotherapy and inotuzumab ozogamicin work in treating patients with B acute lymphoblastic leukemia. Drugs used in chemotherapy, such as cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone, methotrexate and cytarabine, 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. Immunotherapy with monoclonal antibodies, such as inotuzumab ozogamicin, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving combination chemotherapy and inotuzumab ozogamicin may work better at treating B acute lymphoblastic leukemia.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the clinical efficacy of the sequential combination of hyper-CVAD (hyperfractionated cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone, methotrexate and cytarabine) + inotuzumab ozogamicin in patients with newly diagnosed B-cell acute lymphocytic leukemia (ALL) in terms of event-free survival (EFS). SECONDARY OBJECTIVES: I. To evaluate other efficacy endpoints such as overall survival, overall response rate, minimal residual disease (MRD) negativity rate as well as the safety of this combination. OUTLINE: INTENSIVE CHEMOTHERAPY: Patients receive cyclophosphamide intravenously (IV) over 3 hours every 12 hours on days 1-3 and dexamethasone IV or orally (PO) on days 1-4 and 11-14 of courses 1 and 3. Patients may receive ofatumumab IV over 2 hours on days 1, 2 and 11 of course 1, days 1 and 8 of courses 2 and 4, and days 1 and 11 of course 3, or rituximab IV over 2 hours on days 1 and 11 of courses 1 and 3, and days 1 and 8 of courses 2 and 4. Patients also receive methotrexate intrathecally (IT) on day 2 of courses 1 and 3, IV over 24 hours on day 1 and IT on day 8 of courses 2 and 4, doxorubicin hydrochloride IV over 24 hours on day 4 of courses 1 and 3, vincristine sulfate IV over 1 hour on days 4 and 11 of courses 1 and 3, cytarabine IT on day 7 of courses 1 and 3, and IV over 2 hours every 12 hours on days 2 and 3, and IT on day 5 of courses 2 and 4, leucovorin calcium IV 4 times a days on day 2 of courses 2 and 4. Patients then receive inotuzumab ozogamicin IV over 1 hour on days 1 and 8 of courses 5-8. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive mercaptopurine PO thrice a day, methotrexate PO once a week, vincristine sulfate IV over 1 hour on day 1 and prednisone PO on days 1-5. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and every 6 months.

Official Title
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Phase II Study of the Hyper-CVAD Regimen in Sequential Combination With Inotuzumab Ozogamicin as Frontline Therapy for Adults With B-Cell Lineage Acute Lymphocytic Leukemia

Conditions
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Acute Lymphoblastic Leukemia in Remission, B Acute Lymphoblastic Leukemia, B Acute Lymphoblastic Leukemia, Philadelphia Chromosome Negative

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Cytarabine
* Drug: Dexamethasone
* Drug: Doxorubicin Hydrochloride
* Biological: Inotuzumab Ozogamicin
* Other: Laboratory Biomarker Analysis
* Drug: Leucovorin Calcium
* Drug: Mercaptopurine
* Drug: Methotrexate
* Biological: Ofatumumab
* Drug: Prednisone
* Biological: Rituximab
* Drug: Vincristine Sulfate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with newly diagnosed, previously untreated B-lineage ALL, or having achieved complete remission (CR) with one course of induction chemotherapy Patients with extramedullary disease only are eligible Failure to one induction course of chemotherapy (these patients will be analyzed separately) Performance status of 0-3 Creatinine less than or equal to 2.0 mg/dL (unless considered tumor related) Bilirubin less than or equal to 2.0 mg/dL (unless considered tumor related) Adequate cardiac function as assessed by history and physical examination No active or co-existing malignancy with life expectancy less than 12 months Women of childbearing potential (WOCBP) or male subjects with a partner who is WOCBP must agree to use contraception during the study, if sexually active Exclusion Criteria: Pregnant or nursing women Known to be human immunodeficiency virus (HIV)-positive Philadelphia chromosome (Ph)-positive ALL Active and uncontrolled disease/infection as judged by the treating physician Unable or unwilling to sign the consent form Subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver involvement or stable chronic liver disease per investigator assessment) Chronic or current infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis and active hepatitis C

Ages Eligible for Study
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Minimum Age: 16 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (hyper-CVAD, inotuzumab ozogamicin)<br>See detailed description. | Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Cytarabine<br>* Given IT or IV<br>* Other names: WR-28453;Drug: Dexamethasone<br>* Given IV or PO<br>* Other names: Visumetazone;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Biological: Inotuzumab Ozogamicin<br>* Given IV<br>* Other names: WAY-207294;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Leucovorin Calcium<br>* Given IV<br>* Other names: Wellcovorin;Drug: Mercaptopurine<br>* Given PO<br>* Other names: WR-2785;Drug: Methotrexate<br>* Given IT, IV or PO<br>* Other names: WR-19039;Biological: Ofatumumab<br>* Given IV<br>* Other names: HuMax-CD20, 2F2;Drug: Prednisone<br>* Given PO<br>* Other names: SK-Prednisone;Biological: Rituximab<br>* Given IV<br>* Other names: RTXM83;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-Free Survival | Event-free survival defined as the time interval from date of treatment start until the date of death, disease progression or relapse. | Start of treatment up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Time from date of treatment start until date of death due to any cause or last Follow-up. | Start of treatment up to 2 years | 
| Participants to Achieve Complete Remission (CR): | Complete Remission (CR) is defined as - Normalization of the peripheral blood and bone marrow blasts </= 5% in normocellular or hypercellular marrow, granulocyte count of 1x10^9/L or above and platelets >/= 100X10^9/L and complete resolution of all sites of extramedullary disease. | Start of treatment up to 2 years | 
| Number of Participants With Minimal Residual Disease (MRD) Negativity | MRD levels continuously assessed during induction and consolidation therapy by 6-color multiparameter flow. MRD negativity defined by a value of at least 10-4 and confirmed on a second bone marrow aspiration/biopsy performed after a subsequent cycle. | Start of treatment up to 2 years | 
| Number of Participants With Adverse Events | For the purpose of toxicity monitoring, toxicities are defined as any treatment -related grade 3 or 4 non-hematologic AEs occurred any time during the trial.NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 utilized for adverse event reporting. | Start of treatment up to 30 days after last dose received. |