Combination Chemotherapy and Radiation Therapy in Treating Patients With Acute Lymphoblastic Leukemia That Has Relapsed in the CNS or Testes

Leukemia Clinical Trial

Official title:

Treatment of Late Isolated Extramedullary Relapse From Acute Lymphoblastic Leukemia (ALL) (Initial CR1≥ 18 Months)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00096135
• Other study ID #: AALL02P2
• Secondary ID: COG-AALL02P2NCI-
• Status: Active, not recruiting
• Phase: N/A
• First received: November 9, 2004
• Last updated: February 9, 2016
• Start date: November 2004

Study information

• Verified date: July 2015
• 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 work in different ways to stop cancer cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage cancer cells. Giving combination chemotherapy together with radiation therapy may kill more cancer cells.

PURPOSE: This clinical trial is studying how well giving chemotherapy together with radiation therapy works in treating patients with acute lymphoblastic leukemia that has relapsed in the CNS and/or testes.

Description:

OBJECTIVES:

Primary

• Determine the efficacy of intensified systemic chemotherapy with reduced-dose CNS radiotherapy in patients with acute lymphoblastic leukemia and late isolated CNS relapse.

• Determine the efficacy of intensive systemic chemotherapy without testicular radiotherapy in patients with acute lymphoblastic leukemia and late isolated testicular relapse.

• Determine the toxicity of these regimens in these patients.

Secondary

• Determine whether bone marrow involvement is present at the time of extramedullary relapse in patients treated with these regimens.

• Correlate pretreatment minimal residual disease with outcomes in patients treated with these regimens.

• Correlate the role of host gene polymorphisms with toxicity of these regimens and incidence and outcome in these patients.

• Determine the neuropsychological sequelae associated with isolated CNS relapse and these treatment regimens in these patients.

OUTLINE: This is a pilot, multicenter study. All patients receive common induction, consolidation, re-induction, and intensification chemotherapy. Patients are stratified to maintenance therapy according to site of extramedullary relapse (CNS vs testicular).

• Induction therapy (weeks 1-4): Patients receive vincristine IV on days 1, 8, 15, and 22; oral dexamethasone twice daily on days 1-28; daunorubicin* IV over 15 minutes on days 1, 8, and 15; and intrathecal triple therapy** (ITT) comprising methotrexate, hydrocortisone, and cytarabine on days 1, 8, 15, and 22.

NOTE: *The total dose of anthracyclines on this study is capped at 450 mg/m2. Once this dose is reached, all subsequent doses of daunorubicin are omitted.

NOTE: **Patients with isolated testicular relapse receive ITT on day 1 only.

In addition to the above, patients with isolated testicular relapse also receive high-dose methotrexate IV continuously over 24 hours on day -14. Patients with clinical signs of disease at the end of induction undergo testicular biopsy.

Patients with CNS disease who do not achieve CNS remission after induction therapy receive additional ITT as above on days 29 and 36.

• Consolidation therapy (weeks 5-10): Patients receive high-dose cytarabine IV over 3 hours twice daily on days 1-2 and 22-23 and pegaspargase intramuscularly (IM) on days 2 and 23. Patients also receive filgrastim (G-CSF) subcutaneously (SC) beginning on days 3 and 24 and continuing until blood counts recover.

Patients with isolated testicular relapse with positive biopsy results at the end of induction undergo testicular radiotherapy once daily for a total of 12 fractions during consolidation therapy.

• Intensification I (weeks 11-22): Patients receive high-dose methotrexate with leucovorin calcium rescue IV over 24 hours on days 1, 22, 43, and 64 and oral mercaptopurine once daily on days 2-6, 23-27, 44-48, and 65-69. Patients also receive etoposide IV over 1 hour and cyclophosphamide IV over 15-30 minutes on days 8, 29, 50, and 71. Patients receive ITT* on days 15, 36, 57, and 78.

NOTE: *Patients with isolated testicular relapse receive ITT on days 36 and 78 only.

• Reinduction therapy (weeks 23-26): Patients receive vincristine IV on days 1, 8, 15, and 22; oral dexamethasone twice daily on days 1-7 and 15-21, and daunorubicin IV over 15 minutes on days 1, 8, and 15.

• Intensification II (weeks 27-50): Patients receive high-dose cytarabine IV over 3 hours twice daily on days 1-2, 43-44, 85-86, and 127-128; pegaspargase IM on days 2, 44, 86, and 128; ITT* on days 22, 64, 106, and 148; high-dose methotrexate IV continuously over 24 hours on days 29, 71, 113, and 155; oral mercaptopurine on days 30-34, 72-76, 114-118, and 156-160; and etoposide IV over 1 hour and cyclophosphamide IV over 15-30 minutes on days 36, 78, 120, and 162. Patients also receive G-CSF SC beginning on days 3, 45, 87, and 129 and continuing until blood counts recover.

NOTE: *Patients with isolated testicular relapse receive ITT on days 22 and 106 only.

• Chemotherapy and radiotherapy (weeks 51-54): Patients receive oral dexamethasone twice daily on days 1-7 and 15-21, vincristine IV on days 1, 8, and 15, and pegaspargase IM on days 1 and 15.

Patients with isolated CNS relapse also undergo cranial radiotherapy once daily, 5 days a week, for a total of 12 fractions.

• Maintenance therapy for isolated CNS relapse: (weeks 55-104): Patients receive dexamethasone PO orIV twice daily on days 1-5; oral mercaptopurine once daily on days 1-42; methotrexate IM on days 1, 8, 15, 22, 29, and 36; and vincristine IV and cyclophosphamide IV over 1 hour on days 43, 50, 57, and 64. Treatment repeats every 10 weeks for 5 courses.

• Maintenance therapy for isolated testicular relapse:

• (Weeks 55-74): Patients receive ITT on day 1 and dexamethasone, mercaptopurine, methotrexate, vincristine, and cyclophosphamide as in maintenance therapy for isolated CNS relapse. Treatment repeats every 10 weeks for 2 courses.

• (Weeks 75-106): Patients receive vincristine IV on day 1; dexamethasone orally or IV on days 1-5; oral mercaptopurine on days 1-28; and methotrexate IM on days 1, 8, 15, and 22. Treatment repeats every 28 days for 8 courses. Patients also receive ITT on day 1 every 12 weeks for 3 doses.

Patients with combined testicular and CNS relapse receive high-dose methotrexate IV continuously over 24 hours on day -14 in addition to the same chemotherapy and radiotherapy administered during the induction, consolidation, intensification I, reinduction, intensification II, and maintenance phases of therapy as isolated CNS relapse patients.

All patients undergo neuropsychological assessment within 3 months after completion of induction therapy (before cranial radiotherapy) and at 2 years after completion of treatment.

Patients are followed for survival.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 168
• Est. primary completion date: September 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Months to 29 Years

Eligibility

DISEASE CHARACTERISTICS:

• Diagnosis of acute lymphoblastic leukemia (ALL)

• B-precursor lineage (T-precursor lineage closed to accrual as of 05/20/10)

• In first bone marrow remission (M1 by morphology) AND duration of first complete remission = 18 months from time of initial diagnosis

• First isolated CNS and/or testicular relapse

• Isolated CNS relapse, as defined by 1 of the following:

• WBC = 5/mm^3 in cerebrospinal fluid (CSF) with blasts present on cytospin

• Any number of WBC in CSF with immunophenotypic proof of leukemic relapse, defined by the following:

• Identifiable blasts AND 1 of the following:

• B-lineage (TdT OR CD-10-positive on 2 consecutive CSF samples obtained 4 weeks apart)

• T-lineage (TdT AND CD-7 OR TdT positivity alone on 2 consecutive CSF samples obtained 4 weeks apart) (Closed to accrual as of 05/20/10)

• Isolated testicular relapse, defined as biopsy proven testicular involvement

• No Down syndrome

• No T-cell ALL or T-cell non-Hodgkin lymphoma

• No known optic nerve and/or retinal involvement

PATIENT CHARACTERISTICS:

Age

• 18 months to 29 years at relapse

Performance status

• Karnofsky 30-100% (for patients > 16 years of age) OR

• Lansky 30-100% (for patients = 16 years of age)

Life expectancy

• Not specified

Hematopoietic

• Not specified

Hepatic

• Not specified

Renal

• Creatinine adjusted according to age as follows:

• No greater than 0.4 mg/dL (= 5 months)

• No greater than 0.5 mg/dL (6 months -11 months)

• No greater than 0.6 mg/dL (1 year-23 months)

• No greater than 0.8 mg/dL (2 years-5 years)

• No greater than 1.0 mg/dL (6 years-9 years)

• No greater than 1.2 mg/dL (10 years-12 years)

• No greater than 1.4 mg/dL (13 years and over [female])

• No greater than 1.5 mg/dL (13 years to 15 years [male])

• No greater than 1.7 mg/dL (16 years and over [male]) OR

• Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min

Cardiovascular

• Shortening fraction = 27% by echocardiogram OR

• Ejection fraction = 50% by MUGA

Other

• Not pregnant or nursing

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No prior bone marrow transplantation

Chemotherapy

• Prior total anthracycline dosage = 360 mg/m^2

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• No prior systemic therapy for concurrent extramedullary relapse

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

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

Intervention

Biological:
• filgrastim
given subcutaneously (SC)

Drug:
• cyclophosphamide
IV over 15-30 minutes
• cytarabine
IV over 3 hours twice daily
• daunorubicin hydrochloride
IV over 15 minutes
• dexamethasone
oral twice daily
• etoposide
IV over 1 hour
• leucovorin calcium
rescue IV over 24 hours
• mercaptopurine
oral
• methotrexate
intramuscularly (IM)
• pegaspargase
intramuscularly (IM)
• therapeutic hydrocortisone

• vincristine sulfate
given IV

Radiation:
• radiation therapy
Patients with isolated testicular relapse will start Induction with a single dose of high-dose methotrexate (HDMTX) and will not receive either testicular or cranial radiation. Patients with isolated CNS relapse will NOT receive the initial dose of HDMTX prior to Induction, but will receive 1200 cGy of cranial radiation after completing the initial 12 months of intensive systemic chemotherapy.

Locations

Country	Name	City	State
Australia	Princess Margaret Hospital for Children	Perth	Western Australia
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	IWK Health Centre	Halifax	Nova Scotia
Canada	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario
Canada	Cancer Centre of Southeastern Ontario at Kingston General Hospital	Kingston	Ontario
Canada	Hopital Sainte Justine	Montreal	Quebec
Canada	Children's Hospital of Eastern Ontario	Ottawa	Ontario
Canada	Centre Hospitalier Universitaire de Quebec	Quebec
Canada	Allan Blair Cancer Centre at Pasqua Hospital	Regina	Saskatchewan
Canada	Saskatoon Cancer Centre at the University of Saskatchewan	Saskatoon	Saskatchewan
Canada	Janeway Children's Health and Rehabilitation Centre	St. John's	Newfoundland and Labrador
Canada	Children's & Women's Hospital of British Columbia	Vancouver	British Columbia
Canada	CancerCare Manitoba	Winnipeg	Manitoba
New Zealand	Starship Children's Health	Auckland
New Zealand	Christchurch Hospital	Christchurch
Switzerland	Swiss Pediatric Oncology Group Bern	Bern
Switzerland	Swiss Pediatric Oncology Group Geneva	Geneva
Switzerland	Swiss Pediatric Oncology Group Lausanne	Lausanne
United States	Akron Children's Hospital	Akron	Ohio
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	Texas Tech University Health Sciences Center School of Medicine - Amarillo	Amarillo	Texas
United States	C.S. Mott Children's Hospital at University of Michigan Medical Center	Ann Arbor	Michigan
United States	AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus	Atlanta	Georgia
United States	Children's Hospital Center for Cancer and Blood Disorders	Aurora	Colorado
United States	Alvin and Lois Lapidus Cancer Institute at Sinai Hospital	Baltimore	Maryland
United States	CancerCare of Maine at Eastern Maine Medical Center	Bangor	Maine
United States	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania
United States	UAB Comprehensive Cancer Center	Birmingham	Alabama
United States	Mountain States Tumor Institute at St. Luke's Regional Medical Center	Boise	Idaho
United States	Floating Hospital for Children at Tufts - New England Medical Center	Boston	Massachusetts
United States	Albert Einstein Cancer Center at Albert Einstein College of Medicine	Bronx	New York
United States	Brooklyn Hospital Center	Brooklyn	New York
United States	Maimonides Cancer Center at Maimonides Medical Center	Brooklyn	New York
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Fletcher Allen Health Care - University Health Center Campus	Burlington	Vermont
United States	Hollings Cancer Center at Medical University of South Carolina	Charleston	South Carolina
United States	West Virginia University Health Sciences Center - Charleston	Charleston	West Virginia
United States	Blumenthal Cancer Center at Carolinas Medical Center	Charlotte	North Carolina
United States	Presbyterian Cancer Center at Presbyterian Hospital	Charlotte	North Carolina
United States	T.C. Thompson Children's Hospital	Chattanooga	Tennessee
United States	University of Illinois Cancer Center	Chicago	Illinois
United States	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio
United States	Rainbow Babies and Children's Hospital	Cleveland	Ohio
United States	Ellis Fischel Cancer Center at University of Missouri - Columbia	Columbia	Missouri
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Driscoll Children's Hospital	Corpus Christi	Texas
United States	Medical City Dallas Hospital	Dallas	Texas
United States	Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas	Dallas	Texas
United States	Geisinger Cancer Institute at Geisinger Health	Danville	Pennsylvania
United States	Dayton Children's - Dayton	Dayton	Ohio
United States	Presbyterian - St. Luke's Medical Center	Denver	Colorado
United States	Blank Children's Hospital	Des Moines	Iowa
United States	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan
United States	Southern California Permanente Medical Group	Downey	California
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Duke Comprehensive Cancer Center	Durham	North Carolina
United States	Inova Fairfax Hospital	Falls Church	Virginia
United States	CCOP - MeritCare Hospital	Fargo	North Dakota
United States	Hurley Medical Center	Flint	Michigan
United States	Broward General Medical Center Cancer Center	Fort Lauderdale	Florida
United States	Lee Cancer Care of Lee Memorial Health System	Fort Myers	Florida
United States	Cook Children's Medical Center - Fort Worth	Fort Worth	Texas
United States	University of Florida Shands Cancer Center	Gainesville	Florida
United States	Butterworth Hospital at Spectrum Health	Grand Rapids	Michigan
United States	St. Vincent Hospital Regional Cancer Center	Green Bay	Wisconsin
United States	Greenville Hospital Cancer Center	Greenville	South Carolina
United States	Van Elslander Cancer Center at St. John Hospital and Medical Center	Grosse Pointe Woods	Michigan
United States	Hackensack University Medical Center Cancer Center	Hackensack	New Jersey
United States	Connecticut Children's Medical Center	Hartford	Connecticut
United States	Penn State Children's Hospital	Hershey	Pennsylvania
United States	Memorial Cancer Institute at Memorial Regional Hospital	Hollywood	Florida
United States	Cancer Research Center of Hawaii	Honolulu	Hawaii
United States	Baylor University Medical Center - Houston	Houston	Texas
United States	Indiana University Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	St. Vincent Indianapolis Hospital	Indianapolis	Indiana
United States	Holden Comprehensive Cancer Center at University of Iowa	Iowa City	Iowa
United States	University of Mississippi Cancer Clinic	Jackson	Mississippi
United States	Nemours Children's Clinic	Jacksonville	Florida
United States	CCOP - Kalamazoo	Kalamazoo	Michigan
United States	Children's Mercy Hospital	Kansas City	Missouri
United States	Kansas Masonic Cancer Research Institute at the University of Kansas Medical Center	Kansas City	Kansas
United States	East Tennessee Children's Hospital	Knoxville	Tennessee
United States	Gundersen Lutheran Center for Cancer and Blood	La Crosse	Wisconsin
United States	Breslin Cancer Center at Ingham Regional Medical Center	Lansing	Michigan
United States	CCOP - Nevada Cancer Research Foundation	Las Vegas	Nevada
United States	Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire
United States	Lucille P. Markey Cancer Center at University of Kentucky	Lexington	Kentucky
United States	Arkansas Cancer Research Center at University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Loma Linda University Cancer Institute at Loma Linda University Medical Center	Loma Linda	California
United States	Jonathan Jaques Children's Cancer Center at Miller Children's Hospital	Long Beach	California
United States	Childrens Hospital Los Angeles	Los Angeles	California
United States	Jonsson Comprehensive Cancer Center at UCLA	Los Angeles	California
United States	Kosair Children's Hospital	Louisville	Kentucky
United States	Children's Hospital Central California	Madera	California
United States	Marshfield Clinic - Marshfield Center	Marshfield	Wisconsin
United States	Cardinal Bernardin Cancer Center at Loyola University Medical Center	Maywood	Illinois
United States	Baptist-South Miami Regional Cancer Program	Miami	Florida
United States	Miami Children's Hospital	Miami	Florida
United States	University of Miami Sylvester Comprehensive Cancer Center - Miami	Miami	Florida
United States	Midwest Children's Cancer Center at Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	Winthrop University Hospital	Mineola	New York
United States	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota
United States	Mary Babb Randolph Cancer Center at West Virginia University Hospitals	Morgantown	West Virginia
United States	Overlook Hospital	Morristown	New Jersey
United States	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee
United States	Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School	New Brunswick	New Jersey
United States	Saint Peter's University Hospital	New Brunswick	New Jersey
United States	Schneider Children's Hospital	New Hyde Park	New York
United States	Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center	New York	New York
United States	NYU Cancer Institute at New York University Medical Center	New York	New York
United States	Newark Beth Israel Medical Center	Newark	New Jersey
United States	Keyser Family Cancer Center at Advocate Hope Children's Hospital	Oak Lawn	Illinois
United States	Children's Hospital and Research Center Oakland	Oakland	California
United States	Oklahoma University Cancer Institute	Oklahoma City	Oklahoma
United States	Children's Hospital of Orange County	Orange	California
United States	Florida Hospital Cancer Institute at Florida Hospital Orlando	Orlando	Florida
United States	M.D. Anderson Cancer Center at Orlando	Orlando	Florida
United States	Nemours Children's Clinic - Orlando	Orlando	Florida
United States	Lucile Packard Children's Hospital at Stanford University Medical Center	Palo Alto	California
United States	Advocate Lutheran General Cancer Care Center	Park Ridge	Illinois
United States	St. Joseph's Hospital and Medical Center	Paterson	New Jersey
United States	Sacred Heart Cancer Center at Sacred Heart Hospital	Pensacola	Florida
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	St. Christopher's Hospital for Children	Philadelphia	Pennsylvania
United States	Phoenix Children's Hospital	Phoenix	Arizona
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Knight Cancer Institute at Oregon Health and Science University	Portland	Oregon
United States	Legacy Emanuel Hospital and Health Center and Children's Hospital	Portland	Oregon
United States	Rhode Island Hospital Comprehensive Cancer Center	Providence	Rhode Island
United States	Carilion Medical Center for Children at Roanoke Community Hospital	Roanoke	Virginia
United States	James P. Wilmot Cancer Center at University of Rochester Medical Center	Rochester	New York
United States	Mayo Clinic Cancer Center	Rochester	Minnesota
United States	Kaiser Permanente Medical Center - Oakland	Sacramento	California
United States	Sutter Cancer Center	Sacramento	California
United States	All Children's Hospital	Saint Petersburg	Florida
United States	Primary Children's Medical Center	Salt Lake City	Utah
United States	Methodist Children's Hospital of South Texas	San Antonio	Texas
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California
United States	Sanford Cancer Center at Sanford USD Medical Center	Sioux Falls	South Dakota
United States	Providence Cancer Center at Sacred Heart Medical Center	Spokane	Washington
United States	Simmons Cooper Cancer Institute	Springfield	Illinois
United States	Stony Brook University Cancer Center	Stony Brook	New York
United States	SUNY Upstate Medical University Hospital	Syracuse	New York
United States	St. Joseph's Cancer Institute at St. Joseph's Hospital	Tampa	Florida
United States	Medical University of Ohio Cancer Center	Toledo	Ohio
United States	Arizona Cancer Center at University of Arizona Health Sciences Center	Tucson	Arizona
United States	New York Medical College	Valhalla	New York
United States	Children's National Medical Center	Washington	District of Columbia
United States	Kaplan Cancer Center at St. Mary's Medical Center	West Palm Beach	Florida
United States	Alfred I. duPont Hospital for Children	Wilmington	Delaware
United States	Wake Forest University Comprehensive Cancer Center	Winston-Salem	North Carolina
United States	Tod Children's Hospital	Youngstown	Ohio

Sponsors (2)

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

Countries where clinical trial is conducted

United States,  Australia,  Canada,  New Zealand,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Event-free Survival	Monitoring of efficacy results will be performed in comparison with historical results.	3 years	No