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

Acute Lymphoblastic Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01483690
• Other study ID #: T2009-003
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: December 2011
• Est. completion date: July 31, 2015

Study information

• Verified date: October 2020
• Source: Therapeutic Advances in Childhood Leukemia Consortium
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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).

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 23
• Est. completion date: July 31, 2015
• Est. primary completion date: July 31, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 21 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia
• Leukemia
• Leukemia, Lymphoid
• Precursor B-Cell Lymphoblastic Leukemia
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Precursor T-Cell Lymphoblastic Leukemia
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Drug:
• 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=400mg daily) given orally on days 2 through 7 and days 16 through 21.
• Vincristine
1.5 mg/m2/day (Max dose 2 mg) given IV push on days 10, 17, 24 and 31.
• Dexamethasone
20 mg/m2/day divided BID given orally on days 8 through 12 and 22 through 26.
• 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
• Pegaspargase
2500 international units/m2/day IM or IV on days 10 and 24.
• 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

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Therapeutic Advances in Childhood Leukemia Consortium

Countries where clinical trial is conducted

United States,  Australia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	6 weeks
Secondary	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.	6 weeks

External Links

•   Therapeutic Advances in Childhood Leukemia & Lymphoma Consortium web site.