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

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2014 by Therapeutic Advances in Childhood Leukemia Consortium
Sponsor:
Information provided by (Responsible Party):
Therapeutic Advances in Childhood Leukemia Consortium
ClinicalTrials.gov Identifier:
NCT01483690
First received: November 29, 2011
Last updated: January 31, 2014
Last verified: January 2014
  Purpose

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).


Condition Intervention Phase
Acute Lymphoblastic Leukemia
Precursor B-Cell Lymphoblastic Leukemia
Precursor T-Cell Lymphoblastic Leukemia
Drug: Decitabine
Drug: Vorinostat
Drug: Vincristine
Drug: Dexamethasone
Drug: Mitoxantrone
Drug: Pegaspargase
Drug: Methotrexate
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pilot Study of Decitabine and Vorinostat With Chemotherapy for Relapsed ALL

Resource links provided by NLM:


Further study details as provided by Therapeutic Advances in Childhood Leukemia Consortium:

Primary Outcome Measures:
  • Number of participants with adverse events. [ Time Frame: 6 weeks ] [ Designated as safety issue: Yes ]
    To evaluate the side effects of giving decitabine and vorinostat before and during chemotherapy using the standard drugs vincristine, dexamethasone, PEG-asparaginase and mitoxantrone.


Secondary Outcome Measures:
  • Disease response rate after treatment. [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]
    The study will assess whether the patient's acute lymphoblastic leukemia goes into remission after treatment.

  • Gene-specific methylation profiles [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    To assess the biologic activity of decitabine by comparing pre and post-treatment marrow samples for global and gene-specific methylation profiles using HELP and methylation-specific PCR.

  • Global histone acetylation and histone modifications [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    To assess the biological activity of vorinostat by comparing pre- and post-treatment blood and bone marrow samples for global histone acetylation (using acetyl-H3 Western blotting), and for gene-specific histone modifications (using H3K9/14Ac ChIP-chip and ChIP-qPCR).

  • Gene expression profiles [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    To determine the impact of combined epigenetic therapy on the expression of epigenetically-regulated genes by comparing pre and post-treatment marrow samples for gene expression profiles (using microarrays), and correlating these with the methylation and histone modification assays.


Estimated Enrollment: 16
Study Start Date: December 2011
Estimated Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Decitabine
    10 mg/m2/day given IV over 1 hour on days 1 through 5 and days 15 through 19.
    Other Name: Dacogen
    Drug: Vorinostat
    180 mg/m2/day (Max dose=400mg daily) given orally on days 2 through 7 and days 16 through 21.
    Other Names:
    • Zolinza
    • suberoylanilide hydroxamic acid (SAHA)
    Drug: Vincristine
    1.5 mg/m2/day (Max dose 2 mg) given IV push on days 10, 17, 24 and 31.
    Other Names:
    • Oncovin
    • Vincasar PFS
    • Vincrex
    • vincristine sulfate
    • VCR
    Drug: Dexamethasone
    20 mg/m2/day divided BID given orally on days 8 through 12 and 22 through 26.
    Other Names:
    • Decadron
    • Dexamethasone Intensol
    • dexamethasone acetate
    • dexamethasone sodium phosphate
    Drug: Mitoxantrone
    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
    Other Names:
    • Novantrone
    • DHAD
    • DHAQ
    Drug: Pegaspargase
    2500 international units/m2/day IM or IV on days 10 and 24.
    Other Names:
    • Oncospar
    • PEG-L-asparaginase
    Drug: Methotrexate

    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

    Other Names:
    • Folex
    • Mexate
    • MTX
    • Methotrex
Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   1 Year to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 unable to swallow capsules.
  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01483690

Contacts
Contact: Jeannette van der Giessen 323-361-8725 jvandergiessen@chla.usc.edu
Contact: Elena Eckroth 323-361-5429 eeckroth@chla.usc.edu

  Show 29 Study Locations
Sponsors and Collaborators
Therapeutic Advances in Childhood Leukemia Consortium
Investigators
Study Chair: Michael Burke, MD University of Minnesota Children's Hospital
  More Information

Additional Information:
No publications provided by Therapeutic Advances in Childhood Leukemia Consortium

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Therapeutic Advances in Childhood Leukemia Consortium
ClinicalTrials.gov Identifier: NCT01483690     History of Changes
Other Study ID Numbers: T2009-003
Study First Received: November 29, 2011
Last Updated: January 31, 2014
Health Authority: United States: Food and Drug Administration
Australia: Department of Health and Ageing Therapeutic Goods Administration
Canada: Health Canada

Keywords provided by Therapeutic Advances in Childhood Leukemia Consortium:
Relapse
Lymphoblastic
Leukemia
Decitabine
Vorinostat
Refractory
Acute
Childhood
Pediatric
ALL

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphoid
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
BB 1101
Decitabine
Dexamethasone
Dexamethasone 21-phosphate
Dexamethasone acetate
Methotrexate
Mitoxantrone
Pegaspargase
Vincristine
Vorinostat
Abortifacient Agents
Abortifacient Agents, Nonsteroidal
Analgesics
Anti-Inflammatory Agents
Antiemetics
Antimetabolites
Antimetabolites, Antineoplastic
Antimitotic Agents
Antineoplastic Agents

ClinicalTrials.gov processed this record on October 21, 2014