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.
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
- Conditions the study is for
- Acute Lymphoblastic Leukemia, Precursor B-Cell Lymphoblastic Leukemia, Precursor T-Cell Lymphoblastic Leukemia
- What is being tested?
- Decitabine, Vorinostat and Vincristine
- Type of treatment
- Pill or oral medicine, Injection or infusion
- 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
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
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- 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
Australia3 sites
Royal Children's Hospital
Brisbane, Queensland
Sydney Children's Hospital
Sydney
Children's Hospital at Westmead
Westmead, New South Wales
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.
- Conditions
- Acute Lymphoblastic Leukemia, Precursor B-Cell Lymphoblastic Leukemia, Precursor T-Cell 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 group | Role | What they receive |
|---|---|---|
| Initial Dose Level | Experimental | 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 Receives: Drug: Decitabine; Drug: Vorinostat; Drug: Vincristine; Drug: Dexamethasone; Drug: Mitoxantrone; Drug: Pegaspargase; Drug: Methotrexate |
| Modified Dose Level | Experimental | 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 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.
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)
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.
- First posted1 Dec 2011 (estimated)
- Study startDec 2011
- Primary completion31 Jul 2015
- Study completion31 Jul 2015
Why it stopped: Toxicity
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Acute Lymphoblastic LeukemiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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)
Sponsor and investigators
- Lead sponsor
- Therapeutic Advances in Childhood Leukemia Consortium
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Michael Burke, MD, Study chair, Medical College of Wisconsin
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
- Results posted
- Yes, on ClinicalTrials.gov
- 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 31969338Raetz 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