Safety and Biologic Activity of Intravenous BCL-2 Antisense Oligonucleotide (G3139) and Taxane Chemotherapy in Patients With Advanced Cancer

Abstract

G3139 is a BCL-2 antisense oligonucleotide whose antitumor effects in preclinical models are enhanced when combined with taxane-based chemotherapy. This trial determined the safety and biologic activity of G3139 given with paclitaxel and docetaxel for the treatment of progressive solid tumors. Three cohorts of patients received weekly paclitaxel 100 mg/m2 on days 1, 8, and 15 concurrently with a 21-day continuous infusion of G3139 at 4.1, 5.3, and 6.9 mg/kg/d, depending on the cohort. Two subsequent cohorts received docetaxel (75 mg/m2) on day 5 of a 5-day infusion of G3139 at 5 or 7 mg/kg/d. Bcl-2 protein levels in peripheral blood mononuclear cells (PBMCs) were assayed on an exploratory basis. Fifteen patients were treated. Eight received a total of 14 cycles of G3139 and paclitaxel; seven received a total of 22 cycles of G3139 and docetaxel. Eight patients required dose modifications for either grade 4 neutropenia (6 patients) or grade 1-2 reversible transaminitis (2 patients). No radiographic responses were seen, although two of the six taxane-naive prostate cancer patients exhibited a prostate-specific antigen decline greater than 50%. Bcl-2 protein levels in PBMCs declined with treatment as assessed by immunohistochemistry. The authors conclude that G3139, whether given as a 5- or 21-day infusion, is well tolerated with taxane chemotherapy and is biologically active by immunohistochemistry at doses up to and including 7 mg/kg/d, using weekly paclitaxel (100 mg/m2) or docetaxel every 3 weeks (75 mg/m2). These data support the dose selection of ongoing phase 2 studies of G3139 at 7 mg/kg/d and docetaxel 75 mg/m2.

Circulating Tumor Cell Analysis in Patients with Progressive Castration-Resistant Prostate Cancer

“…It should be noted that CTCs can be enumerated in all patients, even when cell counts are too low to allow molecular characterization by FISH or immunofluorescence (20). This rate of retrieval of cancer cells was significantly higher than the 10% rate we obtained historically using iliac crest bone marrow biopsies in a similar patient group (2). Although the diagnostic yield is increased when computed tomography -guided biopsies of fluorodeoxyglucose-avid lesions are done, the latter are invasive, costly, difficult to schedule, and much slower to provide results.…”

“…Such guidance is particularly important in prostate cancer management because the factors contributing to tumor cell growth and survival change over time as a result of both the intrinsic biology of the tumor and the specific therapies under which it had progressed (1). Our ability to profile recurrent metastatic prostate cancers is limited because a repeat biopsy is not part of the routine management of the disease, and when it is attempted, the frequency that tumor material is obtained is low (2). Consequently, treatment decisions are often made without current knowledge of whether the tumor expresses the putative targets of the drugs under consideration.…”

Death receptors in chemotherapy and cancer

“…Antisense approaches targeting Bcl-2 by, for example, G3139 (Genasense), an antisense phosphothiorate oligonucleotide that suppresses Bcl-2 expression have been evaluated experimentally and also in clinical studies. Bcl-2 antisense therapy is well tolerated and preclinical studies have also shown that G313 may increase the anticancer effect of several cytotoxic drugs (Cotter et al, 1994;Webb et al, 1997;Ziegler et al, 1997;Waters et al, 2000;Banerjee, 2001;Chi et al, 2001;Morris et al, 2002;Olie et al, 2002;Rudin et al, 2002;Marcucci et al, 2003). After completion of the phase I study in patients with nonHodgkin's lymphoma, partial response rates and stable disease have been reported in 14 or 43% of the patients, respectively (Waters et al, 2000).…”

Down-regulation of Polo-like Kinase 1 Elevates Drug Sensitivity of Breast Cancer CellsIn vitroandIn vivo

“…Several phosphorothioate ASOs are currently being evaluated in patients suffering from different types of cancer such as ovarian, colon, prostate, lymphoma, non-small-cell lung cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, and melanomas (1), suggesting ASOs as valuable agents for therapeutic approaches. Furthermore, various investigations used first-and secondgeneration ASOs targeted against different cancer-relevant genes in combination with traditional chemotherapeutic agents in vitro and in clinical trials to enhance the chemosensitivity to various anticancer drugs (2)(3)(4)(5).…”