A Pilot Study of Decitabine and Vorinostat With Chemotherapy for Relapsed ALL

Study Overview
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Brief Summary
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This is a pilot study using decitabine and vorinostat before and during chemotherapy with vincristine, dexamethasone, mitoxantrone, and peg-asparaginase in pediatric patients with acute lymphoblastic leukemia (ALL).

Detailed Description
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Decitabine is a demethylating agent and vorinostat is a HDAC inhibitor. The use of demethylating agents and HDAC inhibitors in combination have been previously shown to have synergistic effects in altering neoplastic pathways of cancer cells and be well tolerated in human clinical studies. With the ability of decitabine and vorinostat to alter the abnormal cellular pathways of leukemic blasts and essentially turn off anti-apoptotic proteins, the leukemia cells have become primed for cytotoxic cell kill via chemotherapeutic agents. This study will ask the question as to whether or not the combination of decitabine and vorinostat followed by chemotherapy is feasible and whether it can positively impact outcome in patients with relapsed or refractory acute lymphoblastic leukemia.

Official Title
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A Pilot Study of Decitabine and Vorinostat With Chemotherapy for Relapsed ALL

Conditions
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Acute Lymphoblastic Leukemia, Precursor B-Cell Lymphoblastic Leukemia, Precursor T-Cell Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: Decitabine
* Drug: Vorinostat
* Drug: Vincristine
* Drug: Dexamethasone
* Drug: Mitoxantrone
* Drug: Pegaspargase
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be ≥1 and ≤ 21 years of age when originally diagnosed with ALL. Diagnosis Patients must have a diagnosis of acute lymphoblastic leukemia (ALL) with ≥ 25% blasts in the bone marrow (M3), with or without extramedullary disease. Patients may have CNS 1, 2 or 3 disease. Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for patients ≤ 16 years of age. Prior Therapy Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. Patients must have had 2 or more prior therapeutic attempts defined as: Relapse after going into remission from re-induction for the first or subsequent relapse (ie: 2nd , 3rd, 4th…relapse), OR Refractory disease after first or greater relapse and a re-induction attempt, OR Failing to go into remission from original diagnosis after 2 previous induction attempts. Hematopoietic Stem Cell Transplant: Patients who have experienced their relapse after a HSCT are eligible, provided they have no evidence of Graft-versus-Host Disease (GVHD) and are at least 60 days post-transplant at the time of enrollment. Prior anthracycline exposure: Patients must have less than 400 mg/m2 lifetime exposure of anthracycline chemotherapy. (See Appendix II for calculation worksheet) Hematopoietic grow factors: It must have been at least 7 days since the completion of therapy with GCSF or other growth factors at the time of enrollment. It must have been at least 14 days since the completion of therapy with pegfilgrastim (Neulasta®). Biologic (anti-neoplastic) therapy: It must be at least 7 days after last does of biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair Monoclonal antibodies: At least 3 half-lives of the antibody must have elapsed after the last dose of monoclonal antibody. (ie. Rituximab=66 days, Epratuzumab=69 days) Immunotherapy: At least 42 days after the completion of any type of immunotherapy, e.g. tumor vaccines. Renal and Hepatic Function Patient's serum creatinine must be ≤ 1.5 x institutional upper limit of normal (ULN) according to age. If the serum creatinine is greater than 1.5 times normal, the patient must have a calculated creatinine clearance or radioisotope GRF ≥ 70mL/min/1.73m2. Patient's ALT and AST must be < 5 x institutional upper limit of norm ULN. The hepatic requirements are waived for patients with known or suspected liver involvement who would otherwise be eligible after consultation with the Study Chair or Vice Chair. Patient's total bilirubin must be ≤ 1.5 x ULN. The hepatic requirements are waived for patients with known or suspected liver involvement who would otherwise be eligible. Cardiac Function: Patient must have a shortening fraction ≥ 27% by Echo or an ejection fraction ≥ 50% by MUGA. Reproductive Function Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed prior to enrollment. Female patients with infants must agree not to breastfeed their infants while on this study. Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study. Exclusion Criteria: Patients will be excluded if they are receiving Valproic Acid (VPA) therapy. Patients will be excluded if they have a known allergy to any of the drugs used in the study. Patients will be excluded if they have a systemic fungal, bacterial, viral or other infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment. Patients will be excluded if there is a plan to administer non-protocol chemotherapy, radiation therapy, or immunotherapy during the study period. Patients will be excluded if they have significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance with the protocol treatment or procedures, interfere with consent, study participation, follow up, or interpretation of study results. Patients will be excluded if they have had any positive fungal culture in the last 30 days prior to enrollment.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 21 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Initial Dose Level<br>Decitabine 15 mg/m2/day given IV over 1 hour on days 1 through 7 and days 15 through 21. Vorinostat: 180 mg/m2/day (Max dose=400 mg daily) given orally on days 3 through 10 and days 17 through 24 | Drug: Decitabine<br>* 10 mg/m2/day given IV over 1 hour on days 1 through 5 and days 15 through 19.<br>* Other names: Dacogen;Drug: Vorinostat<br>* 180 mg/m2/day (Max dose=400mg daily) given orally on days 2 through 7 and days 16 through 21.<br>* Other names: suberoylanilide hydroxamic acid (SAHA);Drug: Vincristine<br>* 1.5 mg/m2/day (Max dose 2 mg) given IV push on days 10, 17, 24 and 31.<br>* Other names: VCR;Drug: Dexamethasone<br>* 20 mg/m2/day divided BID given orally on days 8 through 12 and 22 through 26.<br>* Other names: dexamethasone sodium phosphate;Drug: Mitoxantrone<br>* 10 mg/m2/day given on days 8 and 9 as a short IV infusion over 5-15 minutes; do not infuse over less than 3 minutes<br>* Other names: DHAQ;Drug: Pegaspargase<br>* 2500 international units/m2/day IM or IV on days 10 and 24.<br>* Other names: PEG-L-asparaginase;Drug: Methotrexate<br>* Given intrathecally to all patients the dose defined by age below. 8 mg for patients age 1-1.99 10 mg for patients age 2-2.99 12 mg for patients 3-8.99 years of age 15 mg for patients >9 years of age CNS 1 or 2 patients get doses on day 8, 22 and 35 and CNS 3 patients should get doses on day 8, 15, 22, 29 and 35<br>* Other names: Methotrex;|
| Experimental: Modified Dose Level<br>Decitabine 10 mg/m2/day given IV over 1 hour on days 1 through 5 and days 15 through 19. Vorinostat: 180 mg/m2/day (Max dose=400 mg daily) given orally on days 2 through 7 and days 16 through 21 | Drug: Decitabine<br>* 10 mg/m2/day given IV over 1 hour on days 1 through 5 and days 15 through 19.<br>* Other names: Dacogen;Drug: Vorinostat<br>* 180 mg/m2/day (Max dose=400mg daily) given orally on days 2 through 7 and days 16 through 21.<br>* Other names: suberoylanilide hydroxamic acid (SAHA);Drug: Vincristine<br>* 1.5 mg/m2/day (Max dose 2 mg) given IV push on days 10, 17, 24 and 31.<br>* Other names: VCR;Drug: Dexamethasone<br>* 20 mg/m2/day divided BID given orally on days 8 through 12 and 22 through 26.<br>* Other names: dexamethasone sodium phosphate;Drug: Mitoxantrone<br>* 10 mg/m2/day given on days 8 and 9 as a short IV infusion over 5-15 minutes; do not infuse over less than 3 minutes<br>* Other names: DHAQ;Drug: Pegaspargase<br>* 2500 international units/m2/day IM or IV on days 10 and 24.<br>* Other names: PEG-L-asparaginase;Drug: Methotrexate<br>* Given intrathecally to all patients the dose defined by age below. 8 mg for patients age 1-1.99 10 mg for patients age 2-2.99 12 mg for patients 3-8.99 years of age 15 mg for patients >9 years of age CNS 1 or 2 patients get doses on day 8, 22 and 35 and CNS 3 patients should get doses on day 8, 15, 22, 29 and 35<br>* Other names: Methotrex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced a Dose Limiting Toxicity (DLT). | To evaluate the side effects of giving decitabine and vorinostat before and during chemotherapy using the standard drugs vincristine, dexamethasone, PEG-asparaginase and mitoxantrone. | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Response Rate After Treatment. | Bone marrow evaluation was performed on Day 35 of study to evaluate treatment response. CR defined as attaining M1 marrow (<5% blasts) with no evidence of circulating blasts or extramedullary disease in addition to recovery of peripheral blood counts (ANC >750/uL and platelet count >75,000/uL). CRp was defined as attaining an M1 marrow with no evidence of circulating blasts or extramedullary disease in addition to recovery of ANC but insufficient recovery of platelets. CRi was attaining M1 marrow with no evidence of circulating blasts or extramedullary disease but insufficient recovery of ANC with or without sufficient recovery of platelets. PR was defined as no evidence of circulating blasts and achievement of M2 marrow (5-25% blasts) without new sites of disease and with recovery of ANC. SD is for patients who did not meet the criteria for PR, CR, CRp, or CRi. PD is an increase of at least 25% in the absolute number of leukemia cells or development of new sites. | 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute, Relapse, Lymphoblastic, Leukemia, Decitabine, Vorinostat, Refractory, Childhood, Pediatric, ALL