A Phase I New Approaches to Neuroblastoma Therapy Study of Buthionine Sulfoximine and Melphalan With Autologous Stem Cells for Recurrent/Refractory High-Risk Neuroblastoma.
Myeloablative therapy for high-risk neuroblastoma commonly includes melphalan. Increased cellular glutathione (GSH) can mediate melphalan resistance. Buthionine sulfoximine (BSO), a GSH synthesis inhibitor, enhances melphalan activity against neuroblastoma cell lines, providing the rationale for a Phase 1 trial of BSO-melphalan.



Patients with recurrent/resistant high-risk neuroblastoma received BSO (3 gram/m(2) bolus, then 24 grams/m(2) /day infusion days -4 to -2), with escalating doses of intravenous melphalan (20-125 mg/m(2) ) days -3 and -2, and autologous stem cells day 0 using 3 + 3 dose escalation.



Among 28 patients evaluable for dose escalation, one dose-limiting toxicity occurred at 20 mg/m(2) melphalan (grade 3 aspartate aminotransferase/alanine aminotransferase) and one at 80 mg/m(2) (streptococcal bacteremia, grade 4 hypotension/pulmonary/hypocalcemia) without sequelae. Among 25 patients evaluable for response, there was one partial response (PR) and two mixed responses (MRs) among eight patients with prior melphalan exposure; one PR and three MRs among 16 patients without prior melphalan; one stable disease with unknown melphalan history. Melphalan pharmacokinetics with BSO were similar to reports for melphalan alone. Melphalan Cmax for most patients was below the 10 μM concentration that showed neuroblastoma preclinical activity with BSO.



BSO (75 gram/m(2) ) with melphalan (125 mg/m(2) ) is tolerable with stem cell support and active in recurrent/refractory neuroblastoma. Further dose escalation is feasible and may increase responses.
Department of Pediatrics, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, California.
Judith G
JG
Villablanca
Department of Pediatrics, University of Chicago Comprehensive Cancer Center, Chicago, Illinois.
Samuel L
SL
Volchenboum
Cancer Center and Departments of Cell Biology & Biochemistry, Pediatrics, and Medicine, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas.
Hwangeui
H
Cho
Cancer Center and Departments of Cell Biology & Biochemistry, Pediatrics, and Medicine, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas.
Min H
MH
Kang
Department of Pediatrics, University of Chicago Comprehensive Cancer Center, Chicago, Illinois.
Susan L
SL
Cohn
City of Hope National Medical Center, Duarte, California.
Clarke P
CP
Anderson
Department of Pediatrics, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, California.
Araz
A
Marachelian
Department of Preventative Medicine Statistics, Keck School of Medicine, University of Southern California, Los Angeles, California.
Susan
S
Groshen
Department of Preventative Medicine Statistics, Keck School of Medicine, University of Southern California, Los Angeles, California.
Denice
D
Tsao-Wei
Department of Pediatrics, University of California San Francisco, San Francisco, California.
Katherine K
KK
Matthay
Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
John M
JM
Maris
Department of Pediatrics, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, California.
Charlotte E
CE
Hasenauer
Department of Pediatrics, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, California.
Scarlett
S
Czarnecki
Department of Radiology, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, California.
Hollie
H
Lai
Department of Radiology, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, California.
Fariba
F
Goodarzian
Department of Pathology and The Saban Research Institute, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, California.
Hiro
H
Shimada
Cancer Center and Departments of Cell Biology & Biochemistry, Pediatrics, and Medicine, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas.
Charles Patrick
CP
Reynolds
D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019328:Buthionine Sulfoximine / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004357:Drug Synergism; D005260:Female; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors; D005978:Glutathione / Q000627:therapeutic use; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D008297:Male; D008558:Melphalan / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019653:Myeloablative Agonists / Q000627:therapeutic use*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D009447:Neuroblastoma / Q000188:drug therapy*
D000964:Antimetabolites, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D019653:Myeloablative Agonists; D019328:Buthionine Sulfoximine; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D008558:Melphalan
Phase 1; buthionine sulfoximine; melphalan; neuroblastoma; transplant