Clinical trial NCT00003700: Combination Chemotherapy in Treating Patients With Untreated Acute Lymphoblastic Leukemia
Official title: Phase II Study in Adults With Untreated Acute Lymphoblastic Leukemia Testing Increased Doses of Daunorubicin During Induction, and Cytarabine During Consolidation, Followed by High-Dose Methotrexate and Intrathecal Methotrexate in Place of Cranial Irradiation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Leukemia
Keywords: untreated adult acute lymphoblastic leukemia
L1 adult acute lymphoblastic leukemia
L2 adult acute lymphoblastic leukemia
Lead sponsor: Alliance for Clinical Trials in Oncology
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2004-05-20
Enrollment: 163
Sex: ALL
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining more than one drug may kill more cancer cells.

PURPOSE: Phase II trial to study the effectiveness of combination chemotherapy in treating patients who have untreated acute lymphoblastic leukemia.

Detailed description: OBJECTIVES:

* Determine the complete response rate and toxicity of escalating doses of daunorubicin in patients under 60 years old with untreated acute lymphoblastic leukemia (ALL).
* Determine the complete response rate and toxicity of a constant dose of daunorubicin in patients at least 60 years old with untreated ALL.
* Determine the toxicity of high dose cytarabine during postremission therapy in these patients.
* Determine the CNS relapse rate of ALL when prophylactic intrathecal methotrexate and high-dose intravenous chemotherapy replace cranial irradiation.

OUTLINE:

* Course I: Patients are assigned to 1 of 2 induction treatment groups based on age.

  * Group 1 (under age 60): Patients receive cyclophosphamide IV over 15-30 minutes on day 1, escalating doses of daunorubicin IV over 5-10 minutes on days 1-3, vincristine IV on days 1, 8, 15, and 22, oral prednisone on days 1-21, asparaginase intramuscularly on days 5, 8, 11, 15, 18, and 22, and filgrastim (G-CSF) subcutaneously (SC) beginning on day 4 and continuing for at least 7 days and then until blood counts recover.
  * Group 2 (age 60 and over): Patients receive vincristine, asparaginase, cyclophosphamide, and G-CSF as in group 1, fixed dose daunorubicin IV over 5-10 minutes on days 1-3, and oral prednisone on days 1-7.

Patients are then evaluated for bone marrow cellularity on day 29. Those with M0, M1, or M2 cellularity proceed to course II. Patients with M3 cellularity may proceed to course II or be removed from study.

* Course II (early intensification): Patients receive intrathecal methotrexate and cyclophosphamide IV over 15-30 minutes on day 1, cytarabine IV over 3 hours on days 1-3, and G-CSF SC beginning on day 4.

Bone marrow is again examined on day 29. Patients with M0 or M1 cellularity after course I and no sign of relapse after course II proceed to course III. Patients with M2 or M3 cellularity after course I must have M0 or M1 cellularity after course II to proceed to course III. Patients with M2 or M3 cellularity after course II are removed from study.

* Course III: Patients receive intrathecal methotrexate, vincristine IV, and methotrexate IV over 3 hours on days 1, 8, and 15 and oral methotrexate every 6 hours for 4 doses beginning 6 hours after starting methotrexate IV on days 1, 2, 8, 9, 15, and 16. Patients receive leucovorin calcium IV 6 hours after the last oral methotrexate dose on days 2, 9, and 16 and oral leucovorin calcium beginning 12 hours after leucovorin calcium IV for at least 4 doses on days 3, 4, 10, 11, 17, and 18.

Patients must be off leucovorin calcium for a minimum of 3 days before beginning days 8 and 15 of treatment. Patients who maintain M0 or M1 cellularity on day 29 of course III continue therapy. Those with M2 or M3 cellularity after course III are removed from the study.

* Course IV (Late intensification): Repeat course I.
* Course V (Late intensification): Repeat course II.
* Course VI (CNS intensification): Repeat course III.
* Course VII (Prolonged maintenance): Patients receive oral mercaptopurine daily, vincristine IV once every 4 weeks, oral prednisone on days 1-5, and oral methotrexate on days 1, 8, 15, and 22. Courses repeat every 4 weeks for up to 18 months.

Patients with testicular disease receive gonadal radiotherapy anytime after course I. Chemotherapy is not halted during radiotherapy.

Patients are followed every 3 months for 1 year, every 6 months for 2 years, and then annually for 10 years.

PROJECTED ACCRUAL: A total of 140 patients will be accrued for this study within 15 months.

Eligibility criteria: 1. Any other serious illnesses which would limit survival to \<2 years, or psychiatric condition which would prevent compliance with treatment or informed consent.
2. Uncontrolled or severe cardiovascular disease.
3. History of pancreatitis or overt coagulopathy (prior cerebrovascular accident or hemorrhage, transient ischemic attack or deep venous thrombosis).
4. Elevations in bilirubin, creatinine, or amylase that may suggest impaired hepatic, renal, or pancreatic function must be considered as potentially serious obstacles for safe tolerance of the therapy prescribed in this protocol.
5. Prior use of the agents administered in this protocol for other non-malignant disease may reduce the likelihood of beneficial outcome, and should also be considered prior to enrolling patients.
6. Treatment under this protocol would expose an unborn child to significant risks.

   Women and men of reproductive potential should agree to use an effective means of birth control.
7. Unequivocal histologic diagnosis of Acute Lymphoblastic leukemia (ALL), FAB L1-or L2 or Acute Undifferentiated Leukemia (AUL).
8. Age ≥ 15 years
9. Prior Treatment: No prior treatment for leukemia, with three permissible exceptions:

   i. emergency leukapheresis; ii. emergency treatment for hyperleukocytosis with hydroxyurea; iii. cranial RT for CNS leukostasis (one dose only).

Primary outcomes:
measure: Complete Response
timeFrame: 6 months post treatment
Secondary outcomes:
measure: Toxicity
timeFrame: prior to ea tx and ea maintenance course
measure: CNS relapse rate
timeFrame: before ea tx, q 3 mon for 1 yr, q 6 mon for 2 yrs, then yrly up to 10 yrs
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Veterans Affairs Medical Center - Birmingham
state: Alabama
city: La Jolla
country: United States
facility: University of California San Diego Cancer Center
state: California
city: San Francisco
country: United States
facility: UCSF Cancer Center and Cancer Research Institute
state: California
city: San Francisco
country: United States
facility: Veterans Affairs Medical Center - San Francisco
state: California
city: Wilmington
country: United States
facility: CCOP - Christiana Care Health Services
state: Delaware
city: Washington
country: United States
facility: Lombardi Cancer Center, Georgetown University
state: District of Columbia
city: Washington
country: United States
facility: Walter Reed Army Medical Center
state: District of Columbia
city: Miami Beach
country: United States
facility: CCOP - Mount Sinai Medical Center
state: Florida
city: Chicago
country: United States
facility: University of Illinois at Chicago Health Sciences Center
state: Illinois
city: Chicago
country: United States
facility: Veterans Affairs Medical Center - Chicago (Westside Hospital)
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Cancer Research Center
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Togus
country: United States
facility: Veterans Affairs Medical Center - Togus
state: Maine
city: Baltimore
country: United States
facility: Marlene & Stewart Greenebaum Cancer Center, University of Maryland
state: Maryland
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts Memorial Medical Center
state: Massachusetts
city: Minneapolis
country: United States
facility: Veterans Affairs Medical Center - Minneapolis
state: Minnesota
city: Columbia
country: United States
facility: Veterans Affairs Medical Center - Columbia (Truman Memorial)
state: Missouri
city: Columbia
country: United States
facility: Ellis Fischel Cancer Center - Columbia
state: Missouri
city: Saint Louis
country: United States
facility: Barnes-Jewish Hospital
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Las Vegas
country: United States
facility: CCOP - Southern Nevada Cancer Research Foundation
state: Nevada
city: Lebanon
country: United States
facility: Norris Cotton Cancer Center
state: New Hampshire
city: Camden
country: United States
facility: Cooper Cancer Institute
state: New Jersey
city: Livingston
country: United States
facility: St. Barnabas Medical Center
state: New Jersey
city: Paterson
country: United States
facility: St. Joseph's Hospital and Medical Center
state: New Jersey
city: Buffalo
country: United States
facility: Veterans Affairs Medical Center - Buffalo
state: New York
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Manhasset
country: United States
facility: CCOP - North Shore University Hospital
state: New York
city: Manhasset
country: United States
facility: North Shore University Hospital
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: New York
country: United States
facility: New York Presbyterian Hospital - Cornell Campus
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Center, NY
state: New York
city: Syracuse
country: United States
facility: CCOP - Syracuse Hematology-Oncology Associates of Central New York, P.C.
state: New York
city: Syracuse
country: United States
facility: State University of New York - Upstate Medical University
state: New York
city: Syracuse
country: United States
facility: Veterans Affairs Medical Center - Syracuse
state: New York
city: Chapel Hill
country: United States
facility: Lineberger Comprehensive Cancer Center, UNC
state: North Carolina
city: Durham
country: United States
facility: Veterans Affairs Medical Center - Durham
state: North Carolina
city: Durham
country: United States
facility: Duke Comprehensive Cancer Center
state: North Carolina
city: Winston-Salem
country: United States
facility: CCOP - Southeast Cancer Control Consortium
state: North Carolina
city: Winston-Salem
country: United States
facility: Comprehensive Cancer Center of Wake Forest University Baptist Medical Center
state: North Carolina
city: Columbus
country: United States
facility: Arthur G. James Cancer Hospital - Ohio State University
state: Ohio
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Memphis
country: United States
facility: University of Tennessee, Memphis Cancer Center
state: Tennessee
city: Memphis
country: United States
facility: Veterans Affairs Medical Center - Memphis
state: Tennessee
city: Burlington
country: United States
facility: Vermont Cancer Center
state: Vermont
city: White River Junction
country: United States
facility: Veterans Affairs Medical Center - White River Junction
state: Vermont
city: Richmond
country: United States
facility: Veterans Affairs Medical Center - Richmond
state: Virginia
city: Richmond
country: United States
facility: MBCCOP - Massey Cancer Center
state: Virginia
Study officials:
affiliation: University of Chicago
name: Wendy Stock, MD
role: STUDY_CHAIR
References:
citation: Stock W, Yu D, Johnson J, et al.: Intensified Daunorubicin during induction and post-remission therapy of adult acute lymphoblastic leukemia (ALL): results of CALGB 19802. [Abstract] Blood 102 (11 Pt 1): A-1375, 2003.
citation: Stock W, Dodge RK, Vardiman JW, et al.: Treatment of adult acute lymphoblastic leukemia (ALL): phase II trial of dose intensification of Daunorubicin and Cytarabine followed by high-dose Methotrexate and intrathecal Methotrexate in place of cranial irradiation (CALGB 19802). [Abstract] Blood 98 (11 Pt 1): A-2472, 2001.