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).

Antisense and nonantisense effects of antisense Bcl-2 on multiple roles of Bcl-2 as a chemosensitizer in cancer therapy

“…Based on several phase I/II clinical trials of AS Bcl-2, which were conducted to assess its safety, tolerance and therapeutic efficacy [23][24][25][26][27][28][29] on hematological malignancies and solid tumors, the first randomized phase III trial has been conducted for metastatic melanoma. The results were compared with dacarbazine and AS Bcl-2/dacarbazine.…”

“…In fact, previous studies indicated that treatment with AS Bcl-2 decreased Bcl-2 mRNA and/or protein levels up to 75% in different malignancies. 23,24,32,34 Others however have cited the fact that although downregulation of Bcl-2 was not observed, growth was inhibited 40 or that Bcl-2 expression in diagnostic tumor specimens was not predictive of Effects of antisense Bcl-2 on multiple roles of Bcl-2 R Kim et al response to this therapy. 24 In some of these reports, the assessment of Bcl-2 mRNA was more sensitive and reliable than the protein level.…”

“…11,18 Several preclinical and clinical studies showed that the combination treatment with antisense Bcl-2 (AS Bcl-2) and an anticancer drug increased the chemotherapeutic effect in various types of cancers. [19][20][21][22][23][24][25][26][27][28][29] Nevertheless, despite the fact that in some clinical trials combination therapy with AS Bcl-2 and anticancer drug increased the response rate for metastatic melanoma and chronic lymphocytic lymphoma (CLL), 30,31 downregulation of Bcl-2 was observed in 10-50% of tumor samples. 32 The low frequency of downregulation of Bcl-2 in clinical samples does not necessarily diminish its therapeutic value against cancer cells.…”

New agents in acute myeloid leukemia and other myeloid disorders

“…G3139 has been administered safely in combination with fludarabine, cytarabine, plus granulocytecolony stimulating factor (FLAG) to 20 patients with refractory AML or acute lymphoblastic leukemia (ALL). 77 Tolerable nausea, emesis, fever, fluid retention, and electrolyte imbalances were the main side effects encountered. bcl-2 mRNA levels were downregulated in 9 of 12 patients evaluated (75%); the CR rate was 35%.…”

“…bcl-2 mRNA levels were downregulated in 9 of 12 patients evaluated (75%); the CR rate was 35%. 77 Apoptosis also may be enhanced by activating the caspase cascade through blockade of the IAPs and through inhibition of the nuclear factor B (NF B) pathway (using I B kinase inhibitors or proteasome inhibitors) and the PI3K pathway (using kinase inhibitors). 78 IAPs, including the X-linked inhibitor of apoptosis (XIAP), can block apoptosis through interaction with members of caspase family.…”