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

Primary Purpose

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

Status
Terminated
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Decitabine
Vorinostat
Vincristine
Dexamethasone
Mitoxantrone
Pegaspargase
Methotrexate
Sponsored by
Therapeutic Advances in Childhood Leukemia Consortium
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Lymphoblastic Leukemia focused on measuring Relapse, Lymphoblastic, Leukemia, Decitabine, Vorinostat, Refractory, Acute, Childhood, Pediatric, ALL

Eligibility Criteria

1 Year - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Childrens Hospital Los Angeles
  • CHOC
  • UCSF School of Medicine
  • The Children's Hospital, University of Colorado
  • Children's National Medical Center
  • University of Miami Cancer Center
  • Children's Healthcare of Atlanta, Emory University
  • Lurie Children's Hospital
  • Johns Hopkins University
  • Dana Farber
  • C.S. Mott Children's Hospital
  • Childrens Hospital & Clinics of Minnesota
  • University of Minnesota Children's Hospital
  • Children's Mercy Hospitals and Clinics
  • New York University Medical Center
  • Children's Hospital New York-Presbyterian
  • Levine Children's Hospital at Carolinas Medical Center
  • Nationwide Childrens Hospital
  • Oregon Health and Science University
  • Children's Hospital of Philadelphia
  • St. Jude
  • Vanderbilt Children's Hospital
  • University of Texas at Southwestern
  • Cook Children's Medical Center
  • Seattle Children's Hospital
  • Children's Hospital at Westmead
  • Royal Children's Hospital
  • Sydney Children's Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Initial Dose Level

Modified Dose Level

Arm Description

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

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

Full Information

First Posted
November 29, 2011
Last Updated
October 5, 2020
Sponsor
Therapeutic Advances in Childhood Leukemia Consortium
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1. Study Identification

Unique Protocol Identification Number
NCT01483690
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
Study Type
Interventional

2. Study Status

Record Verification Date
October 2020
Overall Recruitment Status
Terminated
Why Stopped
Toxicity
Study Start Date
December 2011 (undefined)
Primary Completion Date
July 31, 2015 (Actual)
Study Completion Date
July 31, 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Therapeutic Advances in Childhood Leukemia Consortium

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Lymphoblastic Leukemia, Precursor B-Cell Lymphoblastic Leukemia, Precursor T-Cell Lymphoblastic Leukemia
Keywords
Relapse, Lymphoblastic, Leukemia, Decitabine, Vorinostat, Refractory, Acute, Childhood, Pediatric, ALL

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
23 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Initial Dose Level
Arm Type
Experimental
Arm Description
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
Arm Title
Modified Dose Level
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Decitabine
Other Intervention Name(s)
Dacogen
Intervention Description
10 mg/m2/day given IV over 1 hour on days 1 through 5 and days 15 through 19.
Intervention Type
Drug
Intervention Name(s)
Vorinostat
Other Intervention Name(s)
Zolinza, suberoylanilide hydroxamic acid (SAHA)
Intervention Description
180 mg/m2/day (Max dose=400mg daily) given orally on days 2 through 7 and days 16 through 21.
Intervention Type
Drug
Intervention Name(s)
Vincristine
Other Intervention Name(s)
Oncovin, Vincasar PFS, Vincrex, vincristine sulfate, VCR
Intervention Description
1.5 mg/m2/day (Max dose 2 mg) given IV push on days 10, 17, 24 and 31.
Intervention Type
Drug
Intervention Name(s)
Dexamethasone
Other Intervention Name(s)
Decadron, Dexamethasone Intensol, dexamethasone acetate, dexamethasone sodium phosphate
Intervention Description
20 mg/m2/day divided BID given orally on days 8 through 12 and 22 through 26.
Intervention Type
Drug
Intervention Name(s)
Mitoxantrone
Other Intervention Name(s)
Novantrone, DHAD, DHAQ
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Pegaspargase
Other Intervention Name(s)
Oncospar, PEG-L-asparaginase
Intervention Description
2500 international units/m2/day IM or IV on days 10 and 24.
Intervention Type
Drug
Intervention Name(s)
Methotrexate
Other Intervention Name(s)
Folex, Mexate, MTX, Methotrex
Intervention Description
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
Primary Outcome Measure Information:
Title
Number of Participants Who Experienced a Dose Limiting Toxicity (DLT).
Description
To evaluate the side effects of giving decitabine and vorinostat before and during chemotherapy using the standard drugs vincristine, dexamethasone, PEG-asparaginase and mitoxantrone.
Time Frame
6 weeks
Secondary Outcome Measure Information:
Title
Disease Response Rate After Treatment.
Description
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.
Time Frame
6 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michael Burke, MD
Organizational Affiliation
Medical College of Wisconsin
Official's Role
Study Chair
Facility Information:
Facility Name
Childrens Hospital Los Angeles
City
Los Angeles
State/Province
California
ZIP/Postal Code
90027
Country
United States
Facility Name
CHOC
City
Orange
State/Province
California
Country
United States
Facility Name
UCSF School of Medicine
City
San Francisco
State/Province
California
ZIP/Postal Code
94143-0106
Country
United States
Facility Name
The Children's Hospital, University of Colorado
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Children's National Medical Center
City
Washington
State/Province
District of Columbia
Country
United States
Facility Name
University of Miami Cancer Center
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
Children's Healthcare of Atlanta, Emory University
City
Atlanta
State/Province
Georgia
Country
United States
Facility Name
Lurie Children's Hospital
City
Chicago
State/Province
Illinois
Country
United States
Facility Name
Johns Hopkins University
City
Baltimore
State/Province
Maryland
Country
United States
Facility Name
Dana Farber
City
Boston
State/Province
Massachusetts
Country
United States
Facility Name
C.S. Mott Children's Hospital
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109-0914
Country
United States
Facility Name
Childrens Hospital & Clinics of Minnesota
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55404-4597
Country
United States
Facility Name
University of Minnesota Children's Hospital
City
Minneapolis
State/Province
Minnesota
Country
United States
Facility Name
Children's Mercy Hospitals and Clinics
City
Kansas City
State/Province
Missouri
ZIP/Postal Code
64108
Country
United States
Facility Name
New York University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
Children's Hospital New York-Presbyterian
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Levine Children's Hospital at Carolinas Medical Center
City
Charlotte
State/Province
North Carolina
ZIP/Postal Code
28203
Country
United States
Facility Name
Nationwide Childrens Hospital
City
Columbus
State/Province
Ohio
Country
United States
Facility Name
Oregon Health and Science University
City
Portland
State/Province
Oregon
Country
United States
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
St. Jude
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105-3678
Country
United States
Facility Name
Vanderbilt Children's Hospital
City
Nashville
State/Province
Tennessee
Country
United States
Facility Name
University of Texas at Southwestern
City
Dallas
State/Province
Texas
Country
United States
Facility Name
Cook Children's Medical Center
City
Fort Worth
State/Province
Texas
ZIP/Postal Code
76104
Country
United States
Facility Name
Seattle Children's Hospital
City
Seattle
State/Province
Washington
ZIP/Postal Code
98105
Country
United States
Facility Name
Children's Hospital at Westmead
City
Westmead
State/Province
New South Wales
Country
Australia
Facility Name
Royal Children's Hospital
City
Brisbane
State/Province
Queensland
Country
Australia
Facility Name
Sydney Children's Hospital
City
Sydney
Country
Australia

12. IPD Sharing Statement

Citations:
PubMed Identifier
31969338
Citation
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.
Results Reference
derived
PubMed Identifier
23233571
Citation
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.
Results Reference
derived
Links:
URL
http://www.tacl.us
Description
Therapeutic Advances in Childhood Leukemia & Lymphoma Consortium web site.

Learn more about this trial

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

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