Phase I Trial of G3139, a bcl-2 antisense oligonucleotide, combined with doxorubicin and cyclophosphamide in children with relapsed solid tumors: a Children's Oncology Group Study.
OBJECTIVE
To determine the maximum-tolerated dose, toxicity, pharmacokinetics, and biologic effects of G3139 when administered with doxorubicin and cyclophosphamide to children with relapsed solid tumors.


METHODS
Patients received a 7-day continuous infusion of 3, 5, or 7 mg/kg/d of G3139 every 21 days. Doxorubicin, cyclophosphamide, and dexrazoxane were administered on days 5 and 6 of the infusion. Pharmacokinetics and biology studies were performed during the first course.


RESULTS
Thirty-seven patients, median age 14 years (range, 1 to 19 years), were enrolled, of whom 29 were fully assessable for toxicity. Because of dose-limiting neutropenia, doses of doxorubicin 30 mg/m2/d for 2 days, dexrazoxane 300 mg/m2/d for 2 days, and cyclophosphamide 500 mg/m2/d for 2 days were reduced initially, but with the addition of granulocyte colony-stimulating factor (GCSF), could be re-escalated to starting doses. At the 7 mg/kg/d dose level, only one of six patients experienced DLT (neutropenia > 7 days). At this dose, the average (+/- standard deviation) steady-state G3139 concentration was 2.04 +/- 1 microg/mL, a concentration associated with biologic activity. Eleven of 15 patients had reduced bcl-2 expression in peripheral-blood mononuclear cells at the first assessable time point of G3139 exposure, and in eight of 14 patients with serial specimens this reduction persisted through day 6.


CONCLUSIONS
The recommended phase II dose of G3139 is 7 mg/kg/d as a 7-day continuous infusion, with cyclophosphamide 500 mg/m2/d and doxorubicin 30 mg/m2/d on days 5 and 6, followed by GCSF. G3139 may accentuate the myelosuppressive effects of doxorubicin and cyclophosphamide. Evidence for biologic effects of G3139 was demonstrated.
Rheingold
Susan R
SR
Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Hogarty
Michael D
MD
Blaney
Susan M
SM
Zwiebel
James A
JA
Sauk-Schubert
Calies
C
Chandula
Reddy
R
Krailo
Mark D
MD
Adamson
Peter C
PC
D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006776:Hospitals, Pediatric; D006801:Humans; D007223:Infant; D008297:Male; D020714:Maximum Tolerated Dose; D008495:Medical Oncology; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000009:adverse effects; D018570:Risk Assessment; D016019:Survival Analysis; D013873:Thionucleotides / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D004317:Doxorubicin; C408162:oblimersen; D003520:Cyclophosphamide