Combination Chemotherapy in Treating Children With Relapsed Acute Lymphoblastic Leukemia

Leukemia Clinical Trial

Official title:

EXTRAMEDULLARY RELAPSE AND OCCULT BONE MARROW INVOLVEMENT IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA: A PHASE III GROUP-WIDE STUDY

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00002816
• Other study ID #: 1951
• Secondary ID: CCG-1951CDR00000
• Status: Completed
• Phase: Phase 3
• First received: November 1, 1999
• Last updated: August 21, 2013
• Start date: December 1996
• Est. completion date: April 2006

Study information

• Verified date: August 2013
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die.

PURPOSE: Phase III trial to compare the effectiveness of combination chemotherapy in treating children who have relapsed acute lymphoblastic leukemia.

Description:

OBJECTIVES: I. Improve the outcome in children with first isolated central nervous system (CNS), testicular, or ocular relapse of acute lymphoblastic lymphoma (ALL), and increase the knowledge of the characteristics of extramedullary and subsequent relapses of ALL. II. Quantitate, by current molecular biologic techniques, occult systemic leukemia in cases of conventional isolated extramedullary relapse, and examine the relationship between this assessment and subsequent clinical outcome, particularly overt marrow relapse. III. Quantitate occult systemic leukemia in subsets of extramedullary relapse that include site (CNS, testis, or eye), time of relapse (early or late), initial risk group, immunophenotype, DNA index and karyotype, gender (for CNS and eye), and ethnicity, and assess the response to therapy in patients entered on companion protocol CCG-B958. IV. Compare the relative sensitivities of two quantitative in vitro assays for occult systemic leukemia (fluorescence-activated cell sorter/leukemic progenitor cell clonogenic assay vs. polymerase chain reaction-based clonospecific assay), correlate the assays with clinical outcome, and assess other biologic studies of leukemic cells (e.g., neurotropic potential in the SCID mouse xenograft model and methotrexate sensitivity). V. Determine the event-free survival (EFS) and pattern of failure in children with first isolated CNS, testicular, or ocular relapse after treatment that includes intensive systemic chemotherapy. VI. Correlate EFS in patients with CNS and ocular relapse with sex, and in patients with relapse at all three sites with ethnicity. VII. Evaluate the impact of combined chemotherapy and radiotherapy on health status in survivors at two and four years after extramedullary relapse and study entry.

OUTLINE: All patients receive induction chemotherapy over 5 weeks with: etoposide, ifosfamide/mesna, dexamethasone, vincristine, and pegaspargase (if pegaspargase is not available, E. coli asparaginase may be substituted throughout study); then dexamethasone, vincristine, pegaspargase (or E. coli asparaginase), and high-dose methotrexate with leucovorin rescue; and triple intrathecal chemotherapy (TIT). Following induction chemotherapy, all patients receive two 6-week courses of intensification therapy with intermittent TIT; each course consists of dexamethasone, vincristine, high-dose methotrexate/leucovorin, thioguanine, cytarabine, etoposide, and pegaspargase (or E. coli asparaginase) followed by dexamethasone, vincristine, high-dose methotrexate/leucovorin, thioguanine, ifosfamide/mesna, and idarubicin. Patients receive 2 additional courses of intensification chemotherapy followed by four 12-week courses of maintenance chemotherapy with vincristine and methotrexate every 2 weeks and daily oral thioguanine. Total duration of therapy is 78 weeks. Patients with isolated ocular relapse receive local radiotherapy prior to initiation of induction chemotherapy; those who also have CNS leukemia begin TIT with the radiotherapy. Patients with CNS relapse receive craniospinal irradiation during the first month of maintenance therapy, with the dose and fields based on whether they will receive TBI and whether they have had CNS irradiation previously. Patients with testicular relapse receive bilateral testicular irradiation during the first 3 weeks of intensification therapy. Patients are followed every 3 months for 3 years, every 6 months for 3 years, and yearly thereafter, or upon relapse, second malignancy, loss to follow up, or death. All patients undergo quality-of-life assessment at entry and 2 and 4 years after entry.

PROJECTED ACCRUAL: Approximately 120 patients will be accrued for this study.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 120
• Est. completion date: April 2006
• Est. primary completion date: November 2002
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 20 Years

Eligibility

DISEASE CHARACTERISTICS: Acute lymphoblastic leukemia (ALL) with isolated extramedullary relapse Relapse occurred during or following front-line therapy for ALL Initial diagnosis of more than 25% blasts of L1 or L2 morphology No leukemic marrow (M1) by conventional assessment Patients with B precursor ALL must also be enrolled on study CCG-B958 Relapse occurred in the CNS, testis, or eye Ocular relapse confirmed by an ophthalmologist and by cytology or iris biopsy Combined CNS and ocular relapse eligible Down Syndrome patients not eligible No prior bone marrow transplantation in first remission No prior toxicity from any study drugs Patient age: Under 21

PATIENT CHARACTERISTICS: See General Eligibility Criteria

Study Design

Primary Purpose: Treatment

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Lymphoid
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Drug:
• cytarabine
Given IV
• dexamethasone
Given IV
• etoposide
Given IV
• idarubicin
Given IV
• ifosfamide
Given IV
• leucovorin calcium

• mesna
Given IV
• pegaspargase
Given IV
• therapeutic hydrocortisone

• thioguanine

• vincristine sulfate
Given IV

Radiation:
• low-LET cobalt-60 gamma ray therapy

• low-LET electron therapy

• low-LET photon therapy

Drug:
• Methotrexate
Given IV

Locations

Country	Name	City	State
Australia	Princess Margaret Hospital for Children	Perth	Western Australia
Canada	IWK Grace Health Centre	Halifax	Nova Scotia
Canada	British Columbia Children's Hospital	Vancouver	British Columbia
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	Lineberger Comprehensive Cancer Center, UNC	Chapel Hill	North Carolina
United States	University of Chicago Cancer Research Center	Chicago	Illinois
United States	Children's Hospital Medical Center - Cincinnati	Cincinnati	Ohio
United States	Ireland Cancer Center	Cleveland	Ohio
United States	Children's Hospital of Columbus	Columbus	Ohio
United States	Children's Hospital of Denver	Denver	Colorado
United States	Indiana University Cancer Center	Indianapolis	Indiana
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	Children's Mercy Hospital - Kansas City	Kansas City	Missouri
United States	Long Beach Memorial Medical Center	Long Beach	California
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Jonsson Comprehensive Cancer Center, UCLA	Los Angeles	California
United States	University of Wisconsin Comprehensive Cancer Center	Madison	Wisconsin
United States	University of Minnesota Cancer Center	Minneapolis	Minnesota
United States	Vanderbilt Cancer Center	Nashville	Tennessee
United States	Herbert Irving Comprehensive Cancer Center	New York	New York
United States	Kaplan Cancer Center	New York	New York
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Children's Hospital of Orange County	Orange	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania
United States	Doernbecher Children's Hospital	Portland	Oregon
United States	Mayo Clinic Cancer Center	Rochester	Minnesota
United States	Huntsman Cancer Institute	Salt Lake City	Utah
United States	UCSF Cancer Center and Cancer Research Institute	San Francisco	California
United States	Children's Hospital and Regional Medical Center - Seattle	Seattle	Washington
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Children's Oncology Group	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Australia,  Canada, 

References & Publications (2)

Uckun FM, Gaynon PS, Stram DO, Sensel MG, Sarquis MB, Lazarus KH, Willoughby M. Paucity of leukemic progenitor cells in the bone marrow of pediatric B-lineage acute lymphoblastic leukemia patients with an isolated extramedullary first relapse. Clin Cancer — View Citation

Uckun FM, Gaynon PS, Stram DO, Sensel MG, Sarquis MB, Willoughby M. Bone marrow leukemic progenitor cell content in pediatric T-lineage acute lymphoblastic leukemia patients with an isolated extramedullary first relapse. Leuk Lymphoma. 2001 Jan;40(3-4):27 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Event Free Survival	The evaluation of the relationship between prognostic or treatment factors and EFS		Yes