Combination Chemotherapy Plus PSC-833 in Treating Children With Refractory or Relapsed Acute Leukemia

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Completed

CT.gov ID

NCT00002912

Collaborator

(none)

Enrollment

Locations

Arm

0.1

Patients Per Site

Study Details

Study Description

Brief Summary

Phase I trial to study the effectiveness of PSC-833 plus etoposide and mitoxantrone in treating children who have refractory or relapsed acute leukemia. Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Some cancers become resistant to chemotherapy drugs. Combining PSC-833 with chemotherapy may reduce resistance to the drug and allow more cancer cells to be killed.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: etoposide Drug: mitoxantrone hydrochloride Drug: valspodar	Phase 1

Detailed Description

OBJECTIVES:

Determine the maximum tolerated dose of PSC-833 in combination with mitoxantrone and etoposide in children with refractory or relapsed acute leukemia.
Determine the effects of PSC-833 on mitoxantrone and etoposide pharmacokinetics.
Quantify MDR1 gene expression and MDR1 P-glycoprotein expression and function in patient-derived leukemia cells.

OUTLINE: This is a dose escalation study of PSC-833.

Patients undergo induction therapy consisting of etoposide IV and mitoxantrone IV on days 1-5. Patients then receive PSC-833 IV over 124 hours beginning on day 2. A second course is administered no sooner than 21 days from the start of the first course if the marrow is hypocellular after the first course. Patients with persistent disease after 2 induction courses are removed from the study. Patients receive a total of 3 courses of etoposide/mitoxantrone. Patients who achieve complete remission after 1 induction course receive 2 courses of etoposide/mitoxantrone with PSC-833 as consolidation, beginning within 4 weeks of attainment of complete remission. Patients who achieve complete remission after 2 induction courses receive 1 course of etoposide/mitoxantrone with PSC-833 as consolidation. Cohorts of 3-6 patients receive escalating doses of PSC-833 until the maximum tolerated dose is determined. Patients are followed every 6 months.

Study Design

Study Type:

Interventional

Actual Enrollment :

3 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A PHASE I COOPERATIVE AGREEMENT PEDIATRIC TRIAL OF MITOXANTRONE, ETOPOSIDE AND PSC-833 (PSC-ME) THERAPY IN PATIENTS WITH RELAPSED AND REFRACTORY ACUTE LEUKEMIA

Study Start Date :

Jan 1, 1997

Actual Primary Completion Date :

Mar 1, 2006

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I Patients undergo induction therapy consisting of etoposide IV and mitoxantrone IV on days 1-5. Patients then receive PSC-833 IV over 124 hours beginning on day 2. A second course is administered no sooner than 21 days from the start of the first course if the marrow is hypocellular after the first course. Patients with persistent disease after 2 induction courses are removed from the study. Patients receive a total of 3 courses of etoposide/mitoxantrone. Patients who achieve complete remission after 1 induction course receive 2 courses of etoposide/mitoxantrone with PSC-833 as consolidation, beginning within 4 weeks of attainment of complete remission. Patients who achieve complete remission after 2 induction courses receive 1 course of etoposide/mitoxantrone with PSC-833 as consolidation. Cohorts of 3-6 patients receive escalating doses of PSC-833 until the maximum tolerated dose is determined. Patients are followed every 6 months.	Drug: etoposide Drug: mitoxantrone hydrochloride Drug: valspodar

Arm

Intervention/Treatment

Experimental: Arm I

Drug: etoposide

Drug: mitoxantrone hydrochloride

Drug: valspodar

Outcome Measures

Primary Outcome Measures

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Acute myeloid leukemia (AML) in one of the following categories:
First relapse if initial CR less than 6 months
Refractory to first or second induction with daunomycin, cytarabine, and thioguanine (DAT) or other anthracycline-containing regimens
Relapse following bone marrow transplantation provided good trilineage engraftment followed transplant and greater than 6 months since transplant
Presentation with secondary AML or AML evolving from myelodysplastic syndrome --Acute lymphocytic leukemia in one of the following categories:
In second or subsequent relapse or failed second or later induction attempts regardless of prior remissions
Relapsed following bone marrow transplantation provided good trilineage engraftment followed transplant and greater than 6 months since transplant
No isolated CNS or extramedullary relapse

PATIENT CHARACTERISTICS:

Age: Under 22 at diagnosis
Performance status: Karnofsky 50-100% (ECOG 0-2)
Lansky 40-100% (in patients under 12 years of age)
Life expectancy: At least 8 weeks
Bilirubin less than 1.5 mg/dL
ALT less than twice normal
Creatinine normal for age (within 2 standard deviations) OR glomular filtration rate at least 70 mL/min
Albumin at least 3 g/dL
Ejection fraction greater than 50% at rest or with 5% increase with exercise OR shortening fraction greater than 27% by echocardiogram
No history of clinical heart failure
No uncontrolled infection
No anticonvulsant therapy
No history of allergic reactions or anaphylaxis to etoposide not remediable by premedication
Not pregnant or nursing
Fertile patients must use effective contraception
Third percentile weight for height

PRIOR CONCURRENT THERAPY:

At least 4 weeks since chemotherapy and recovered
Prior cumulative anthracycline dose no greater than 360 mg per square meter
Hydroxyurea therapy allowed just prior to study for rapidly rising blast count

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
2	University of California San Diego Cancer Center	La Jolla	California	United States	92093-0658
3	Children's Hospital Los Angeles	Los Angeles	California	United States	90027-0700
4	Jonsson Comprehensive Cancer Center, UCLA	Los Angeles	California	United States	90095-1781
5	City of Hope National Medical Center	Los Angeles	California	United States	91010
6	Children's Hospital of Orange County	Orange	California	United States	92668
7	UCSF Cancer Center and Cancer Research Institute	San Francisco	California	United States	94115-0128
8	Stanford University Medical Center	Stanford	California	United States	94305-5408
9	Children's National Medical Center	Washington	District of Columbia	United States	20010-2970
10	University of Florida Health Science Center	Gainesville	Florida	United States	32610-0296
11	Emory University Hospital - Atlanta	Atlanta	Georgia	United States	30322
12	Robert H. Lurie Comprehensive Cancer Center, Northwestern University	Chicago	Illinois	United States	60611
13	Children's Memorial Hospital, Chicago	Chicago	Illinois	United States	60614
14	Indiana University Cancer Center	Indianapolis	Indiana	United States	46202-5265
15	University of Kansas Medical Center	Kansas City	Kansas	United States	66160-7357
16	Johns Hopkins Oncology Center	Baltimore	Maryland	United States	21231
17	Boston Floating Hospital Infants and Children	Boston	Massachusetts	United States	02111
18	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
19	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109-0752
20	Children's Hospital of Michigan	Detroit	Michigan	United States	48201
21	University of Minnesota Cancer Center	Minneapolis	Minnesota	United States	55455
22	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905
23	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216-4505
24	Children's Mercy Hospital	Kansas City	Missouri	United States	64108
25	Cardinal Glennon Children's Hospital	Saint Louis	Missouri	United States	63104
26	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
27	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
28	Cancer Institute of New Jersey	New Brunswick	New Jersey	United States	08901
29	Roswell Park Cancer Institute	Buffalo	New York	United States	14263-0001
30	NYU School of Medicine's Kaplan Comprehensive Cancer Center	New York	New York	United States	10016
31	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10021
32	Columbia Presbyterian Hospital	New York	New York	United States	10032
33	State University of New York - Upstate Medical University	Syracuse	New York	United States	13210
34	Duke Comprehensive Cancer Center	Durham	North Carolina	United States	27710
35	Children's Hospital Medical Center - Cincinnati	Cincinnati	Ohio	United States	45229-3039
36	Children's Hospital of Columbus	Columbus	Ohio	United States	43205-2696
37	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73190
38	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
39	Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213
40	Medical University of South Carolina	Charleston	South Carolina	United States	29425-0721
41	Vanderbilt Cancer Center	Nashville	Tennessee	United States	37232-6838
42	Simmons Cancer Center - Dallas	Dallas	Texas	United States	75235-9154
43	Cook Children's Medical Center - Fort Worth	Fort Worth	Texas	United States	76104
44	Texas Children's Cancer Center	Houston	Texas	United States	77030-2399
45	University of Texas - MD Anderson Cancer Center	Houston	Texas	United States	77030-4009
46	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78284-7811
47	Primary Children's Medical Center	Salt Lake City	Utah	United States	84113
48	Children's Hospital and Regional Medical Center - Seattle	Seattle	Washington	United States	98105
49	University of Wisconsin Comprehensive Cancer Center	Madison	Wisconsin	United States	53792
50	Midwest Children's Cancer Center	Milwaukee	Wisconsin	United States	53226
51	Royal Children's Hospital	Parkville	Victoria	Australia	3052
52	Princess Margaret Hospital for Children	Perth	Western Australia	Australia	6001
53	Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8
54	Montreal Children's Hospital	Montreal	Quebec	Canada	H3H 1P3
55	Hopital Sainte Justine	Montreal	Quebec	Canada	H3T 1C5