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Acute Lymphoblastic LeukemiaPhase 1/2NCT01483690

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

A Phase 1/2 study testing Decitabine, Vorinostat and Vincristine in people with Acute Lymphoblastic Leukemia and Precursor B-Cell Lymphoblastic Leukemia, run by Therapeutic Advances in Childhood Leukemia Consortium at 28 sites in 2 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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). Read more about this study

Who is it for?
Ages 1 year to 21 years
What is being tested?
Decitabine, Vorinostat and Vincristine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
23 participants
Where
28 sitesin 2 countries
Study dates
Dec 2011to 31 Jul 2015
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 1 year to 21 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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
Show all 27Show fewer
  • 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.

Who cannot join

  • 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.

Trial locations and contacts

28 sites in 2 countries.

28 sites in 2 countries

United States25 sites

  • C.S. Mott Children's Hospital

    Ann Arbor, Michigan, 48109-0914

  • Children's Healthcare of Atlanta, Emory University

    Atlanta, Georgia

  • The Children's Hospital, University of Colorado

    Aurora, Colorado, 80045

  • Johns Hopkins University

    Baltimore, Maryland

  • Dana Farber

    Boston, Massachusetts

  • Levine Children's Hospital at Carolinas Medical Center

    Charlotte, North Carolina, 28203

  • Lurie Children's Hospital

    Chicago, Illinois

  • Nationwide Childrens Hospital

    Columbus, Ohio

  • University of Texas at Southwestern

    Dallas, Texas

  • Cook Children's Medical Center

    Fort Worth, Texas, 76104

  • Children's Mercy Hospitals and Clinics

    Kansas City, Missouri, 64108

  • Childrens Hospital Los Angeles

    Los Angeles, California, 90027

  • St. Jude

    Memphis, Tennessee, 38105-3678

  • University of Miami Cancer Center

    Miami, Florida, 33136

  • Childrens Hospital & Clinics of Minnesota

    Minneapolis, Minnesota, 55404-4597

  • University of Minnesota Children's Hospital

    Minneapolis, Minnesota

  • Vanderbilt Children's Hospital

    Nashville, Tennessee

  • New York University Medical Center

    New York, New York, 10016

  • Children's Hospital New York-Presbyterian

    New York, New York, 10032

  • CHOC

    Orange, California

  • Children's Hospital of Philadelphia

    Philadelphia, Pennsylvania, 19104

  • Oregon Health and Science University

    Portland, Oregon

  • UCSF School of Medicine

    San Francisco, California, 94143-0106

  • Seattle Children's Hospital

    Seattle, Washington, 98105

  • Children's National Medical Center

    Washington D.C., District of Columbia

Other trials in United States

Australia3 sites

  • Royal Children's Hospital

    Brisbane, Queensland

  • Sydney Children's Hospital

    Sydney

  • Children's Hospital at Westmead

    Westmead, New South Wales

Other trials in Australia

About this study

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).

Read the 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.

Being tested
Decitabine, Vorinostat, Vincristine, Dexamethasone, Mitoxantrone
Keywords
Relapse, Lymphoblastic, Leukemia, Decitabine, Vorinostat, Refractory, Acute, Childhood, Pediatric, ALL
Medical subject headings
Precursor Cell Lymphoblastic Leukemia-Lymphoma, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Recurrence, Leukemia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • DecitabineDrug

    Also called Dacogen

    10 mg/m2/day given IV over 1 hour on days 1 through 5 and days 15 through 19.

  • VorinostatDrug

    Also called Zolinza, suberoylanilide hydroxamic acid (SAHA)

    180 mg/m2/day (Max dose=400mg daily) given orally on days 2 through 7 and days 16 through 21.

  • VincristineDrug

    Also called Oncovin, Vincasar PFS, Vincrex, vincristine sulfate

    1.5 mg/m2/day (Max dose 2 mg) given IV push on days 10, 17, 24 and 31.

  • DexamethasoneDrug

    Also called Decadron, Dexamethasone Intensol, dexamethasone acetate, dexamethasone sodium phosphate

    20 mg/m2/day divided BID given orally on days 8 through 12 and 22 through 26.

  • MitoxantroneDrug

    Also called Novantrone, DHAD, DHAQ

    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

  • PegaspargaseDrug

    Also called Oncospar, PEG-L-asparaginase

    2500 international units/m2/day IM or IV on days 10 and 24.

  • MethotrexateDrug

    Also called Folex, Mexate, MTX, Methotrex

    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

Study groups in NCT01483690
Study groupRoleWhat they receive
Initial Dose LevelExperimentalDecitabine 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
Receives: Drug: Decitabine; Drug: Vorinostat; Drug: Vincristine; Drug: Dexamethasone; Drug: Mitoxantrone; Drug: Pegaspargase; Drug: Methotrexate
Modified Dose LevelExperimentalDecitabine 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
Receives: Drug: Decitabine; Drug: Vorinostat; Drug: Vincristine; Drug: Dexamethasone; Drug: Mitoxantrone; Drug: Pegaspargase; Drug: Methotrexate

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 6 weeks

Secondary outcomes (1)

  1. 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.

    Measured: 6 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 Dec 2011 (estimated)
  2. Study startDec 2011
  3. Primary completion31 Jul 2015
  4. Study completion31 Jul 2015

Why it stopped: Toxicity

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
23 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01483690
Sponsor's protocol ID
T2009-003
Status last verified
Oct 2020
First submitted
29 Nov 2011
Last updated
27 Oct 2020
Data monitoring committee
Yes

Publications

  • Burke MJ, Kostadinov R, Sposto R, Gore L, Kelley SM, Rabik C, Trepel JB, Lee MJ, Yuno A, Lee S, Bhojwani D, Jeha S, Chang BH, Sulis ML, Hermiston ML, Gaynon P, Huynh V, Verma A, Gardner R, Heym KM, Dennis RM, Ziegler DS, Laetsch TW, Oesterheld JE, Dubois SG, Pollard JA, Glade-Bender J, Cooper TM, Kaplan JA, Farooqi MS, Yoo B, Guest E, Wayne AS, Brown PA. Decitabine and Vorinostat with Chemotherapy in Relapsed Pediatric Acute Lymphoblastic Leukemia: A TACL Pilot Study. Clin Cancer Res. 2020 May 15;26(10):2297-2307. doi: 10.1158/1078-0432.CCR-19-1251. Epub 2020 Jan 22.

    PubMed 31969338

  • 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.

    PubMed 23233571

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Decitabine, Vorinostat and Vincristine in people with Acute Lymphoblastic Leukemia and Precursor B-Cell Lymphoblastic Leukemia, run by Therapeutic Advances in Childhood Leukemia Consortium at 28 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 27 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 27 Oct 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 28 sites in United States, Australia. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 27 Oct 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants Who Experienced a Dose Limiting Toxicity (DLT). (time frame: 6 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01483690, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Oct 2020.

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