title: Phase 1 and pharmacodynamic studies of G3139, a Bcl-2 antisense oligonucleotide, in combination with chemotherapy in refractory or relapsed acute leukemia.
abstract: Overexpression of Bcl-2 is a potential mechanism for chemoresistance in acute leukemia and has been associated with unfavorable clinical outcome. We hypothesized that down-regulation of Bcl-2 would restore chemosensitivity in leukemic cells. To test this hypothesis, we performed a phase 1 study of G3139 (Genasense, Genta, Berkeley Heights, NJ), an 18-mer phosphorothioate Bcl-2 antisense, with fludarabine (FL), cytarabine (ARA-C), and granulocyte colony-stimulating factor (G-CSF) (FLAG) salvage chemotherapy in patients with refractory or relapsed acute leukemia. Twenty patients with refractory or relapsed acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) were enrolled. G3139 was delivered by continuous infusion on days 1 to 10. FLAG chemotherapy was administered on days 5 to 10. Common side effects of this combination included fever, nausea, emesis, electrolyte imbalance, and fluid retention that were not dose limiting. Plasma pharmacokinetics of G3139 demonstrated steady-state concentration (Css) within 24 hours. Of the 20 patients, 9 (45%) had disease response, 6 (5 AML, 1 ALL) with complete remission (CR) and 3 (2 AML and 1 ALL) with no evidence of disease but failure to recover normal neutrophil and/or platelet counts or to remain in remission for at least 30 days (incomplete remission). Bcl-2 mRNA levels were down-regulated in 9 of the 12 (75%) evaluable patients. This study demonstrates that G3139 can be administered safely with FLAG chemotherapy and down-regulate its target, Bcl-2. The encouraging clinical and laboratory results justify the current plans for a phase 3 study in previously untreated high-risk AML (ie, age at least 60 years).
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, and the Comprehensive Cancer Center, Ohio State University, Columbus 43210, USA. marcucci-1@medctr.osu.edu
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Guowei
authors.initials: G
authors.lastname: Dai
authors.forename: Marko I
authors.initials: MI
authors.lastname: Klisovic
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Kourlas
authors.forename: Donn C
authors.initials: DC
authors.lastname: Young
authors.forename: Spero R
authors.initials: SR
authors.lastname: Cataland
authors.forename: Diane B
authors.initials: DB
authors.lastname: Fisher
authors.forename: David
authors.initials: D
authors.lastname: Lucas
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Chan
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Porcu
authors.forename: Zhong-Pin
authors.initials: ZP
authors.lastname: Lin
authors.forename: Sherif F
authors.initials: SF
authors.lastname: Farag
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Frankel
authors.forename: James A
authors.initials: JA
authors.lastname: Zwiebel
authors.forename: Eric H
authors.initials: EH
authors.lastname: Kraut
authors.forename: Stanley P
authors.initials: SP
authors.lastname: Balcerzak
authors.forename: Clara D
authors.initials: CD
authors.lastname: Bloomfield
authors.forename: Michael R
authors.initials: MR
authors.lastname: Grever
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000633:toxicity*; D003561:Cytarabine / Q000008:administration & dosage; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D019254:Genes, bcl-2 / Q000187:drug effects*; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D007938:Leukemia / Q000150:complications / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D012074:Remission Induction / Q000379:methods; D016879:Salvage Therapy; D013873:Thionucleotides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; C408162:oblimersen; D014740:Vidarabine