Combination Chemotherapy in Treating Patients With Untreated Acute Lymphoblastic Leukemia

Sponsor

Alliance for Clinical Trials in Oncology (Other)

Overall Status

Completed

CT.gov ID

NCT00003700

Collaborator

National Cancer Institute (NCI) (NIH)

163

Enrollment

Locations

Arm

132

Duration (Months)

3.3

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Biological: G-CSF Drug: asparaginase Drug: cyclophosphamide Drug: cytarabine Drug: daunorubicin hydrochloride Drug: leucovorin calcium Drug: mercaptopurine Drug: methotrexate Drug: prednisone Drug: vincristine sulfate Drug: Allopurinol	Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

163 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 Start Date :

Jan 1, 1999

Actual Primary Completion Date :

Feb 1, 2004

Actual Study Completion Date :

Jan 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Daunorubicin, ara-C, & MTX Therapy daunorubicin during induction, increasing doses of cytarabine during consolidation followed by methotrexate in place of cranial irradiation for treatment of ALL	Biological: G-CSF Courses I, II, IV, V: 5 ug/kg/d subQ injection Day 4 until ANC > 5,000 uL after nadir: 7 day minimum for Courses I & IV Other Names: filgrastim Drug: asparaginase 6000 U/sq m subQ or IM injection 2X/wk for 6 doses starting on Day 5: Courses I & IV Drug: cyclophosphamide 1200 mg/sq m IV infusion over 15-30 min Day 1 Courses I & IV (pts < 60y/o) 1000 mg/sq m IV infusion over 15-30 min Day 1 Courses II & V Drug: cytarabine 2000 mg/sq m IV infusion over 3 hrs Days 1,2, & 3: Courses II & V Other Names: ara-C Drug: daunorubicin hydrochloride 80mg/sq m (pts<60y/o)OR 60mg/sq m (pts =/>60y/o) IV infusion over 5-10 min Days 1,2,& 3: Courses I & IV Drug: leucovorin calcium Courses III & VI: 25mg/sq m IV infusion Days 2, 9, and 16 5mg/sq m PO q 6 hr for 8 doses or until serum MTX <0.05 uM after ea IV dose Drug: mercaptopurine 60mg/sq m/d PO every day Course VII Drug: methotrexate 15mg intrathecal Day 1 Courses II & V 1000mg/sq m IV infusion over 3 hrs Days 1, 8, & 15 and 25mg/sq m PO q 6hr x 4 doses after ea IV dose: Courses III & VI. Drug: prednisone 60mg/sq m/day PO Days 1-21 (pts<60y/o) OR Days 1-7 (pts >/= 60y/o) Courses I & IV and Days 1-5 of ea 4 cycle in Course VII Drug: vincristine sulfate 2 mg total IV infusion Days 1,8,15,& 22 Courses I & IV and Days 1, 8, & 15 Courses III & VI, and Day 1 of ea 4 wk cycle in Course VII Drug: Allopurinol 300mg PO q day Days 1-14 Course I

Arm

Intervention/Treatment

Experimental: Daunorubicin, ara-C, & MTX Therapy

daunorubicin during induction, increasing doses of cytarabine during consolidation followed by methotrexate in place of cranial irradiation for treatment of ALL

Biological: G-CSF

Courses I, II, IV, V: 5 ug/kg/d subQ injection Day 4 until ANC > 5,000 uL after nadir: 7 day minimum for Courses I & IV

Other Names:

filgrastim

Drug: asparaginase

6000 U/sq m subQ or IM injection 2X/wk for 6 doses starting on Day 5: Courses I & IV

Drug: cyclophosphamide

1200 mg/sq m IV infusion over 15-30 min Day 1 Courses I & IV (pts < 60y/o) 1000 mg/sq m IV infusion over 15-30 min Day 1 Courses II & V

Drug: cytarabine

2000 mg/sq m IV infusion over 3 hrs Days 1,2, & 3: Courses II & V

Other Names:

ara-C

Drug: daunorubicin hydrochloride

80mg/sq m (pts<60y/o)OR 60mg/sq m (pts =/>60y/o) IV infusion over 5-10 min Days 1,2,& 3: Courses I & IV

Drug: leucovorin calcium

Courses III & VI: 25mg/sq m IV infusion Days 2, 9, and 16 5mg/sq m PO q 6 hr for 8 doses or until serum MTX <0.05 uM after ea IV dose

Drug: mercaptopurine

60mg/sq m/d PO every day Course VII

Drug: methotrexate

15mg intrathecal Day 1 Courses II & V 1000mg/sq m IV infusion over 3 hrs Days 1, 8, & 15 and 25mg/sq m PO q 6hr x 4 doses after ea IV dose: Courses III & VI.

Drug: prednisone

60mg/sq m/day PO Days 1-21 (pts<60y/o) OR Days 1-7 (pts >/= 60y/o) Courses I & IV and Days 1-5 of ea 4 cycle in Course VII

Drug: vincristine sulfate

2 mg total IV infusion Days 1,8,15,& 22 Courses I & IV and Days 1, 8, & 15 Courses III & VI, and Day 1 of ea 4 wk cycle in Course VII

Drug: Allopurinol

300mg PO q day Days 1-14 Course I

Outcome Measures

Primary Outcome Measures

Complete Response [6 months post treatment]

Secondary Outcome Measures

Toxicity [prior to ea tx and ea maintenance course]
CNS relapse rate [before ea tx, q 3 mon for 1 yr, q 6 mon for 2 yrs, then yrly up to 10 yrs]

Eligibility Criteria

Criteria

Ages Eligible for Study:

15 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Any other serious illnesses which would limit survival to <2 years, or psychiatric condition which would prevent compliance with treatment or informed consent.
Uncontrolled or severe cardiovascular disease.
History of pancreatitis or overt coagulopathy (prior cerebrovascular accident or hemorrhage, transient ischemic attack or deep venous thrombosis).
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.
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.
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.

Unequivocal histologic diagnosis of Acute Lymphoblastic leukemia (ALL), FAB L1-or L2 or Acute Undifferentiated Leukemia (AUL).
Age ≥ 15 years
Prior Treatment: No prior treatment for leukemia, with three permissible exceptions:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Veterans Affairs Medical Center - Birmingham	Birmingham	Alabama	United States	35233
2	University of California San Diego Cancer Center	La Jolla	California	United States	92093-0658
3	UCSF Cancer Center and Cancer Research Institute	San Francisco	California	United States	94115-0128
4	Veterans Affairs Medical Center - San Francisco	San Francisco	California	United States	94121
5	CCOP - Christiana Care Health Services	Wilmington	Delaware	United States	19899
6	Lombardi Cancer Center, Georgetown University	Washington	District of Columbia	United States	20007
7	Walter Reed Army Medical Center	Washington	District of Columbia	United States	20307-5000
8	CCOP - Mount Sinai Medical Center	Miami Beach	Florida	United States	33140
9	University of Illinois at Chicago Health Sciences Center	Chicago	Illinois	United States	60612
10	Veterans Affairs Medical Center - Chicago (Westside Hospital)	Chicago	Illinois	United States	60612
11	University of Chicago Cancer Research Center	Chicago	Illinois	United States	60637
12	University of Iowa Hospitals and Clinics	Iowa City	Iowa	United States	52242
13	Veterans Affairs Medical Center - Togus	Togus	Maine	United States	04330
14	Marlene & Stewart Greenebaum Cancer Center, University of Maryland	Baltimore	Maryland	United States	21201
15	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
16	University of Massachusetts Memorial Medical Center	Worcester	Massachusetts	United States	01655
17	Veterans Affairs Medical Center - Minneapolis	Minneapolis	Minnesota	United States	55417
18	Veterans Affairs Medical Center - Columbia (Truman Memorial)	Columbia	Missouri	United States	65201
19	Ellis Fischel Cancer Center - Columbia	Columbia	Missouri	United States	65203
20	Barnes-Jewish Hospital	Saint Louis	Missouri	United States	63110
21	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198-3330
22	CCOP - Southern Nevada Cancer Research Foundation	Las Vegas	Nevada	United States	89106
23	Norris Cotton Cancer Center	Lebanon	New Hampshire	United States	03756
24	Cooper Cancer Institute	Camden	New Jersey	United States	08103
25	St. Barnabas Medical Center	Livingston	New Jersey	United States	07039
26	St. Joseph's Hospital and Medical Center	Paterson	New Jersey	United States	07503
27	Veterans Affairs Medical Center - Buffalo	Buffalo	New York	United States	14215
28	Roswell Park Cancer Institute	Buffalo	New York	United States	14263-0001
29	CCOP - North Shore University Hospital	Manhasset	New York	United States	11030
30	North Shore University Hospital	Manhasset	New York	United States	11030
31	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10021
32	New York Presbyterian Hospital - Cornell Campus	New York	New York	United States	10021
33	Mount Sinai Medical Center, NY	New York	New York	United States	10029
34	CCOP - Syracuse Hematology-Oncology Associates of Central New York, P.C.	Syracuse	New York	United States	13210
35	State University of New York - Upstate Medical University	Syracuse	New York	United States	13210
36	Veterans Affairs Medical Center - Syracuse	Syracuse	New York	United States	13210
37	Lineberger Comprehensive Cancer Center, UNC	Chapel Hill	North Carolina	United States	27599-7295
38	Veterans Affairs Medical Center - Durham	Durham	North Carolina	United States	27705
39	Duke Comprehensive Cancer Center	Durham	North Carolina	United States	27710
40	CCOP - Southeast Cancer Control Consortium	Winston-Salem	North Carolina	United States	27104-4241
41	Comprehensive Cancer Center of Wake Forest University Baptist Medical Center	Winston-Salem	North Carolina	United States	27157-1082
42	Arthur G. James Cancer Hospital - Ohio State University	Columbus	Ohio	United States	43210
43	Rhode Island Hospital	Providence	Rhode Island	United States	02903
44	Medical University of South Carolina	Charleston	South Carolina	United States	29425-0721
45	University of Tennessee, Memphis Cancer Center	Memphis	Tennessee	United States	38103
46	Veterans Affairs Medical Center - Memphis	Memphis	Tennessee	United States	38104
47	Vermont Cancer Center	Burlington	Vermont	United States	05401-3498
48	Veterans Affairs Medical Center - White River Junction	White River Junction	Vermont	United States	05009
49	Veterans Affairs Medical Center - Richmond	Richmond	Virginia	United States	23249
50	MBCCOP - Massey Cancer Center	Richmond	Virginia	United States	23298-0037