Combination Chemotherapy and Nelarabine in Treating Patients With T-cell Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma

Study Overview
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Brief Summary
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This phase II trial studies the side effects and how well combination chemotherapy and nelarabine work in treating patients with T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma. Drugs used in chemotherapy, such as cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine, mercaptopurine, prednisone, pegaspargase, nelarabine, and venetoclax 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.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the complete remission (CR) rate and progression-free survival following treatment with hyperfractionated cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone (hyper-CVAD) in combination with nelarabine in previously untreated patients with T-cell acute lymphoblastic leukemia (ALL) and T-cell lymphoblastic lymphoma. II. To determine the safety and overall survival of previously untreated patients with T-cell ALL and T-cell lymphoblastic lymphoma. III. To determine the safety and efficacy of adding pegaspargase to the regimen. IV. To determine the safety and efficacy of adding venetoclax to the regimen. OUTLINE: COURSES 1, 3, 5, and 7 (hyper-CVAD): Patients receive cyclophosphamide intravenously (IV) over 3 hours twice daily (BID) on day 1-3, doxorubicin IV over 24 hours on day 4, vincristine IV over 15-30 minutes on days 4 and 11, and dexamethasone IV or orally (PO) once daily (QD) on days 1-4 and 11-14. COURSES 2, 4, 6, and 8 (methotrexate/cytarabine): Patients receive methotrexate IV over 24 hours on day 1 and cytarabine IV over 2 hours BID on days 2 and 3. Patients also receive venetoclax PO QD on days 1-14 of each course. Courses of hyper-CVAD and methotrexate/cytarabine repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also receive nelarabine IV over 2 hours once daily (QD) for 5 days and pegaspargase IV over 2 hours on day 5 after completion of course 4 and after the completion of course 5 in the absence of disease progression or unacceptable toxicity. MAINTENANCE COURSES 1-5, 8-17, and 20-30 (mercaptopurine, vincristine, methotrexate, and prednisone [POMP]): Patients receive mercaptopurine PO thrice daily (TID), methotrexate PO once weekly, vincristine sulfate IV on day 1, prednisone PO QD on days 1-5, and venetoclax PO QD on days 1-7. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. INTENSIFICATION COURSES 6 and 7: Patients receive nelarabine IV QD over 2 hours on days 1-5 and pegaspargase IV over 2 hours on day 5. Patients also receive venetoclax PO QD on days 1-14. Courses repeat every 21-35 days in the absence of disease progression or unacceptable toxicity. INTENSIFICATION COURSES 18 and 19: Patients receive methotrexate IV over 2 hours on day 1, pegaspargase IV over 2 hours on day 2, and venetoclax PO QD on days 1-14 in the absence of disease progression or unacceptable toxicity. POMP maintenance therapy continues for 30 months in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3-6 months.

Official Title
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Phase II Study of Hyper-CVAD Plus Nelarabine in Previously Untreated T-ALL and Lymphoblastic Lymphoma

Conditions
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T Acute Lymphoblastic Leukemia, T Lymphoblastic Lymphoma

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Cytarabine
* Drug: Dexamethasone
* Drug: Doxorubicin Hydrochloride
* Drug: Mercaptopurine
* Drug: Methotrexate
* Drug: Nelarabine
* Drug: Pegaspargase
* Drug: Prednisone
* Drug: Venetoclax
* Drug: Vincristine Sulfate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Previously untreated T cell ALL including T cell lymphoblastic lymphoma; failure to one induction course of chemotherapy are eligible; patients in CR after =< 2 courses are also eligible Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 3 Serum bilirubin less than or equal to 2.0 mg/dL unless considered due to involvement by tumor when an upper limit of 5.0 mg/dL is acceptable Serum glutamic oxaloacetic transaminase (SGOT) or serum glutamate pyruvate transaminase (SGPT) less than or equal to 4 x upper limit of normal (ULN) Serum creatinine less than or equal to 2.0 mg/dL unless considered due to involvement by tumor when an upper limit of 2.5 mg/dL is acceptable Exclusion Criteria: Pregnant or nursing women
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 (nelarabine and combination chemotherapy)<br>See Detailed Description | Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Cytarabine<br>* Given IV<br>* Other names: WR-28453;Drug: Dexamethasone<br>* Given IV or PO<br>* Other names: ZoDex;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Drug: Mercaptopurine<br>* Given PO<br>* Other names: WR-2785;Drug: Methotrexate<br>* Given IV and PO<br>* Other names: WR-19039;Drug: Nelarabine<br>* Given IV<br>* Other names: GW506U78;Drug: Pegaspargase<br>* Given IV<br>* Other names: Polyethylene Glycol-L-Asparaginase;Drug: Prednisone<br>* Given PO<br>* Other names: SK-Prednisone;Drug: Venetoclax<br>* Given PO<br>* Other names: Venclyxto;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 |
| --- | --- | --- |
| Complete remission rate | The sample size will provide an estimate of relapse rate at 3 years with a 95% confidence interval of width +/- 10%. | 3 years | 
| Duration of remission | Duration of remission will be evaluated. | Up to 9 years | 
| Progression-free survival | Progression-free survival will be estimated. | 3 years | 
| Overall survival | Overall survival will be estimated. | 3 years |