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

October 5, 2020 updated by: Therapeutic Advances in Childhood Leukemia Consortium
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).

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

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

Enrollment (Actual)

23

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Australia
      • Sydney, Australia
        • Sydney Children's Hospital
    • New South Wales
      • Westmead, New South Wales, Australia
        • Children's Hospital at Westmead
    • Queensland
      • Brisbane, Queensland, Australia
        • Royal Children's Hospital
  • United States
    • California
      • Los Angeles, California, United States, 90027
        • Childrens Hospital Los Angeles
      • Orange, California, United States
        • CHOC
      • San Francisco, California, United States, 94143-0106
        • UCSF School of Medicine
    • Colorado
      • Aurora, Colorado, United States, 80045
        • The Children's Hospital, University of Colorado
    • District of Columbia
      • Washington, District of Columbia, United States
        • Children's National Medical Center
    • Florida
      • Miami, Florida, United States, 33136
        • University of Miami Cancer Center
    • Georgia
      • Atlanta, Georgia, United States
        • Children's Healthcare of Atlanta, Emory University
    • Illinois
      • Chicago, Illinois, United States
        • Lurie Children's Hospital
    • Maryland
      • Baltimore, Maryland, United States
        • Johns Hopkins University
    • Massachusetts
      • Boston, Massachusetts, United States
        • Dana Farber
    • Michigan
      • Ann Arbor, Michigan, United States, 48109-0914
        • C.S. Mott Children's Hospital
    • Minnesota
      • Minneapolis, Minnesota, United States, 55404-4597
        • Childrens Hospital & Clinics of Minnesota
      • Minneapolis, Minnesota, United States
        • University of Minnesota Children's Hospital
    • Missouri
      • Kansas City, Missouri, United States, 64108
        • Children's Mercy Hospitals and Clinics
    • New York
      • New York, New York, United States, 10016
        • New York University Medical Center
      • New York, New York, United States, 10032
        • Children's Hospital New York-Presbyterian
    • North Carolina
      • Charlotte, North Carolina, United States, 28203
        • Levine Children's Hospital at Carolinas Medical Center
    • Ohio
      • Columbus, Ohio, United States
        • Nationwide Childrens Hospital
    • Oregon
      • Portland, Oregon, United States
        • Oregon Health and Science University
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • Children's Hospital of Philadelphia
    • Tennessee
      • Memphis, Tennessee, United States, 38105-3678
        • St. Jude
      • Nashville, Tennessee, United States
        • Vanderbilt Children's Hospital
    • Texas
      • Dallas, Texas, United States
        • University of Texas at Southwestern
      • Fort Worth, Texas, United States, 76104
        • Cook Children's Medical Center
    • Washington
      • Seattle, Washington, United States, 98105
        • Seattle Children's Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 year to 21 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Initial Dose Level

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
10 mg/m2/day given IV over 1 hour on days 1 through 5 and days 15 through 19.
Other Names:
  • 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:
  • VCR
  • Oncovin
  • Vincrex
  • Vincasar PFS
  • vincristine sulfate
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 sodium phosphate
  • dexamethasone acetate
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:
  • DHAD
  • DHAQ
  • Novantrone
Drug: Pegaspargase
2500 international units/m2/day IM or IV on days 10 and 24.
Other Names:
  • PEG-L-asparaginase
  • Oncospar
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
Experimental: Modified Dose Level

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
10 mg/m2/day given IV over 1 hour on days 1 through 5 and days 15 through 19.
Other Names:
  • 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:
  • VCR
  • Oncovin
  • Vincrex
  • Vincasar PFS
  • vincristine sulfate
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 sodium phosphate
  • dexamethasone acetate
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:
  • DHAD
  • DHAQ
  • Novantrone
Drug: Pegaspargase
2500 international units/m2/day IM or IV on days 10 and 24.
Other Names:
  • PEG-L-asparaginase
  • Oncospar
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants Who Experienced a Dose Limiting Toxicity (DLT).
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.
6 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Disease Response Rate After Treatment.
Time Frame: 6 weeks
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Therapeutic Advances in Childhood Leukemia Consortium

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

December 1, 2011

Primary Completion (Actual)

July 31, 2015

Study Completion (Actual)

July 31, 2015

Study Registration Dates

First Submitted

November 29, 2011

First Submitted That Met QC Criteria

November 30, 2011

First Posted (Estimate)

December 1, 2011

Study Record Updates

Last Update Posted (Actual)

October 27, 2020

Last Update Submitted That Met QC Criteria

October 5, 2020

Last Verified

October 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • T2009-003

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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