Phase I study of valspodar (PSC-833) with mitoxantrone and etoposide in refractory and relapsed pediatric acute leukemia: a report from the Children's Oncology Group.
BACKGROUND
Valspodar, a non-immunosuppressive analog of cylosporine, is a potent P-glycoprotein (MDR1) inhibitor. As MDR1-mediated efflux of chemotherapeutic agents from leukemic blasts may contribute to drug resistance, a phase 1 study of valspodar combined with mitoxantrone and etoposide in pediatric patients with relapsed or refractory leukemias was performed.


METHODS
Patients received a valspodar-loading dose (2 mg/kg) followed by a 5-day continuous valspodar infusion (8, 10, 12.5, or 15 mg/kg/day) combined with lower than standard doses of mitoxantrone and etoposide. The valspodar dose was escalated using a standard 3 + 3 phase I design.


RESULTS
Twenty-one patients were evaluable for toxicity and 20 for response. The maximum tolerated dose (MTD) of valspodar was 12.5 mg/kg/day, combined with 50% dose-reduced mitoxantrone and etoposide. The clearance of mitoxantrone and etoposide was decreased by 64% and 60%, respectively, when combined with valspodar. Dose-limiting toxicities included stomatitis, ataxia, and bone marrow aplasia. Three of 11 patients with acute lymphoblastic leukemia (ALL) had complete responses while no patient with acute myeloid leukemia (AML) had an objective response. In vitro studies demonstrated P-glycoprotein expression on the blasts of 5 of 14 patients, although only 1 had inhibition of rhodamine efflux by valspodar.


CONCLUSIONS
While this regimen was tolerable, responses in this heavily pretreated population were limited to a subset of patients with ALL.
O'Brien
Maureen M
MM
Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA, USA.
Lacayo
Norman J
NJ
Lum
Bert L
BL
Kshirsagar
Smita
S
Buck
Steven
S
Ravindranath
Yaddanapudi
Y
Bernstein
Mark
M
Weinstein
Howard
H
Chang
Myron N
MN
Arceci
Robert J
RJ
Sikic
Branimir I
BI
Dahl
Gary V
GV
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000097:blood; D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D003524:Cyclosporins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018432:Drug Resistance, Multiple; D064420:Drug-Related Side Effects and Adverse Reactions; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008942:Mitoxantrone / Q000008:administration & dosage; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D012008:Recurrence; D016879:Salvage Therapy; D055815:Young Adult
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D005047:Etoposide; D008942:Mitoxantrone; C070272:valspodar