Pre-reinductive Decitabine and Vorinostat in Relapsed Lymphoblastic Lymphoma or Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Decitabine and vorinostat may alter the cancer cells by reversing the cancer pathways needed for cell growth. Giving more than one drug (combination chemotherapy) together with decitabine and vorinostat may kill more cancer cells than with chemotherapy alone. PURPOSE: This phase II trial is studying how well giving decitabine and vorinostat together with combination chemotherapy works in treating patients with acute lymphoblastic leukemia or lymphoblastic lymphoma that has relapsed or not responded to treatment.

Detailed Description
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OBJECTIVES: Primary Patients undergo blood and bone marrow sample collection at baseline, on day 5, Day 19 and at the end of study treatment for correlative laboratory studies. Samples are analyzed for hypermethylation at diagnosis and demethylation post-exposure with decitabine and vorinostat using LINE methylation. OUTLINE: Patients receive decitabine IV over 1 hour and oral vorinostat twice daily on days 1-4; vincristine sulfate IV on days 5, 12, 19, and 26; oral prednisone twice daily on days 5-33; doxorubicin hydrochloride IV over 15 minutes and cytarabine intrathecally (IT) on day 5; pegaspargase IV or intramuscularly on days 6, 12, 19, and 26; and methotrexate* IT on days 12 and 33. Patients with Philadelphia chromosome-positive disease may also receive oral imatinib mesylate once daily on days 5-33. NOTE: *Patients with central nervous system (CNS)-positive disease also receive methotrexate IT on days 19 and 26. Patients undergo blood and bone marrow sample collection at baseline, on day 5, Day 19 and at the end of study treatment for correlative laboratory studies. After completion of study treatment, patients are followed for 60 days.

Official Title
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A Therapeutic Trial of Decitabine and Vorinostat in Combination With Chemotherapy (Vincristine, Prednisone, Doxorubicin and PEG-Asparaginase) for Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LL)

Conditions
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Leukemia, Lymphoma

Intervention / Treatment
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* Drug: cytarabine
* Drug: decitabine
* Drug: doxorubicin hydrochloride
* Drug: imatinib mesylate
* Drug: methotrexate
* Drug: pegaspargase
* Drug: prednisone
* Drug: vincristine sulfate
* Drug: vorinostat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of lymphoblastic lymphoma or acute lymphoblastic leukemia with ≥ 5% blasts in the bone marrow (M2/M3) (with or without extramedullary disease) that meets 1 of the following criteria: Refractory disease/induction failure (failure to achieve initial remission after 2 lines of induction therapy) Relapsed disease (in first relapse or higher) Central nervous system (CNS)-positive disease allowed Karnofsky performance status (PS) 50-100% (for patients ≥ 16 years of age) OR Lansky PS 50-100% (for patients < 16 years of age) Life expectancy ≥ 8 weeks Creatinine clearance ≥ 70 mL/min OR maximum serum creatinine based on age/gender as follows: 0.4 mg/dL (for patients 1 to 5 months of age) 0.5 mg/dL (for patients 6 to 11 months of age) 0.6 mg/dL (for patients 1 year of age) 0.8 mg/dL (for patients 2 to 5 years of age) 1.0 mg/dL (for patients 6 to 9 years of age) 1.2 mg/dL (for patients 10 to 12 years of age) 1.5 mg/dL (males) or 1.4 mg/dL (females) (for patients 13 to 15 years of age) 1.7 mg/dL (males) or 1.4 mg/dL (females) (for patients ≥ 16 years of age) ALT < 5 times upper limit of normal (ULN) Total bilirubin ≤ 1.5 times ULN for age LVEF ≥ 40% by ECHO/MUGA scan Shortening fraction > 29% by ECHO/MUGA scan Able to swallow capsules Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 2 months after completion of study treatment No untreated positive blood cultures or progressive infections as assessed by radiographic studies No known allergy to any of the agents or their ingredients used in this study Patients with clinically significant prior allergies to pegaspargase may be treated with asparaginase-Erwinia, if available Patients who cannot receive asparaginase on this study (e.g., due to prior pancreatitis, stroke, or other toxicity) are eligible provided they meet all other inclusion/exclusion criteria Recovered from prior therapy (defined as CTCAE v3.0 toxicity ≤ grade 1) More than 3 weeks since prior chemotherapy for cancer other than hydroxyurea for patients with WBC > 10,000/mm³ At least 7 days since prior hematopoietic growth factors (14 days for pegfilgrastim) At least 1 month since prior biologic therapy, such as monoclonal antibodies At least 3 months since prior hematopoietic stem cell transplantation Exclusion Criteria: Evidence of graft-versus-host disease Concurrent valproic acid Concurrent coumadin/warfarin other than a short course administered in a prophylactic setting

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 60 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: Decitabine / Vorinostat<br>This is a therapeutic trial investigating the combination of decitabine 15 mg/m2 and vorinostat 230 mg/m2 (maximum daily dose not to exceed 400 mg) in relapsed/refractory ALL/LL patients prior to induction chemotherapy. | Drug: cytarabine<br>* At baseline when peripheral blood draw and bone marrow aspirate performed. *Intrathecal Cytarabine administered dependent upon age - ranging from 30 mg to 70 mg.<br>* Other names: cytosine arabinoside;Drug: decitabine<br>* Days 1-4, 15 mg/m^2 intravenously (IV) over 1 hour<br>* Other names: Dacogen(R);Drug: doxorubicin hydrochloride<br>* Day 5, 60 mg/m^2 intravenously (IV) over 15 minutes<br>* Other names: Doxorubicin;Drug: imatinib mesylate<br>* 340 mg/m2 by mouth every day (rounded to the nearest 100 mg) for age <18 years and 400 mg orally every day for >18 years on Days 5-33.<br>* Other names: Gleevec(R);Drug: methotrexate<br>* **Intrathecal Methotrexate administered dependent upon age - ranging from 8 mg to 15 mg.<br>* Other names: MTX;Drug: pegaspargase<br>* 2,500 IU/m2 IM or IV q week (days 6, 12, 19, 26)<br>* Other names: PEG asparaginase;Drug: prednisone<br>* 40mg/m2/day divided BID (days 5 - 33)<br>Drug: vincristine sulfate<br>* 1.5mg/m2 (max 2 mg) iv push q week (days 5, 12, 19, 26)<br>* Other names: Oncovin(R);Drug: vorinostat<br>* Days 1-4, (230 mg/m2)orally divided twice a day (max dose 400 mg daily)<br>* Other names: suberoylanilide hydroxamic acid (SAHA);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response to Treatment | Response includes both complete remission (defined as <5% leukemic blasts in the bone marrow) and partial remission (defined as a greater than 35% reduction in the bone marrow leukemia blast percentage at day 33) | Day 33 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Level of Methylation | the percentage of methylated DNA | Day 0 | 
| Level of Methylation | the percentage of methylated DNA | Day 5 | 
| Level of Methylation | the percentage of methylated DNA | Day 33 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent adult lymphoblastic lymphoma, recurrent childhood lymphoblastic lymphoma, recurrent adult acute lymphoblastic leukemia, recurrent childhood acute lymphoblastic leukemia