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

• ClinicalTrials.gov Identifier: NCT01483690
• Recruitment Status: Terminated
• First Posted: December 1, 2011
• Last Update Posted: November 24, 2015
• Sponsor: Therapeutic Advances in Childhood Leukemia Consortium
• Information provided by (Responsible Party): Therapeutic Advances in Childhood Leukemia Consortium

Tracking Information

• First Submitted Date: November 29, 2011
• First Posted Date: December 1, 2011
• Last Update Posted Date: November 24, 2015
• Study Start Date: December 2011
• Actual Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 30, 2011)

Number of participants with adverse events. [ Time Frame: 6 weeks ]

To evaluate the side effects of giving decitabine and vorinostat before and during chemotherapy using the standard drugs vincristine, dexamethasone, PEG-asparaginase and mitoxantrone.

• Original Primary Outcome Measures: Same as current
• Change History: Complete list of historical versions of study NCT01483690 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: March 12, 2013)

• Disease response rate after treatment. [ Time Frame: 6 weeks ]
  The study will assess whether the patient's acute lymphoblastic leukemia goes into remission after treatment.
• Gene-specific methylation profiles [ Time Frame: 2 years ]
  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 ]
  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 ]
  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.

Original Secondary Outcome Measures (submitted: November 30, 2011)

• Disease response rate after treatment. [ Time Frame: 6 weeks ]
  The study will assess whether the patient's acute lymphoblastic leukemia goes into remission after treatment.
• Gene-specific methylation profiles [ Time Frame: 2 years ]
  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 ]
  To assess the biological activity of vorinostat by comparing pre- and post-treatment blodd 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 ]
  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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Pilot Study of Decitabine and Vorinostat With Chemotherapy for Relapsed ALL
• Official Title: A Pilot Study of Decitabine and Vorinostat With Chemotherapy for Relapsed ALL
• Brief Summary: 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: 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.
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Acute Lymphoblastic Leukemia
• Precursor B-Cell Lymphoblastic Leukemia
• Precursor T-Cell Lymphoblastic Leukemia

Intervention

• 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

• Study Arms: Not Provided
• Publications *: Raetz EA, Bhatla T. Where do we stand in the treatment of relapsed acute lymphoblastic leukemia? Hematology Am Soc Hematol Educ Program. 2012;2012:129-36. doi: 10.1182/asheducation-2012.1.129. Review.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: November 20, 2015): 23
• Original Estimated Enrollment (submitted: November 30, 2011): 16
• Study Completion Date: Not Provided
• Actual Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)

Eligibility 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 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 1 Year to 21 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, United States
• Removed Location Countries: Canada

Administrative Information

• NCT Number: NCT01483690
• Other Study ID Numbers: T2009-003
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Therapeutic Advances in Childhood Leukemia Consortium
• Study Sponsor: Therapeutic Advances in Childhood Leukemia Consortium
• Collaborators: Not Provided

Investigators

• Study Chair: Michael Burke, MD; Medical College of Wisconsin

• PRS Account: Therapeutic Advances in Childhood Leukemia Consortium
• Verification Date: September 2015