A phase I study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in solid tumor malignancies

Abstract

Purpose-To establish the safety, maximum tolerated dose (MTD), recommended phase II dose, and preliminary anti-tumor activity of obatoclax mesylate (GX15-070MS), a Bcl-2 antagonist, in combination with topotecan in patients with solid tumor malignancies.Patients and methods-Patients with solid tumor malignancies for whom topotecan was an appropriate treatment were administered obatoclax mesylate and topotecan on a 3-week cycle in a pre-defined, standard 3 + 3 dose escalation scheme. The starting dose for obatoclax mesylate was 14 mg/m 2 by 3-h intravenous (IV) infusion. Topotecan 1.25 mg/m 2 was given concurrently as an IV infusion on days 1-5 of each cycle.Results-Fourteen patients received 40 cycles of obatoclax mesylate at the following doses: 14 mg/m 2 on day 1, 14 mg/m 2 on days 1 and 3, and 20 mg/m 2 on day 1. The most common toxicities related to obatoclax were neurologic, including ataxia, mood alterations, somnolence, and cognitive dysfunction. The majority of these were grades 1 and 2 (88%). Two of five patients experienced dose-limiting grade 3 neurologic toxicity at a dose of 20 mg/m 2 ; no patients experienced grade 4 neurologic toxicities, and no other patients experienced grade 3 neurologic toxicity. Of the patients who experienced grade 3 neurologic events, one later developed febrile neutropenia, which was also a dose-limiting toxicity (DLT). After an additional three patients were treated without DLT at the previously tolerated dose of 14 mg/m 2 on day 1, the level was escalated to 14 mg/m 2 on days 1 and 3. Three patients were treated at this dose and, with none experiencing a DLT, 14 mg/m 2 on days 1 and 3 was defined as the recommended phase II dose. Two patients with small-cell lung cancer (SCLC) achieved partial responses and four patients had stable disease. Median time to progression (TTP) was 12 weeks.Conclusion-Obatoclax mesylate administered at 14 mg/m 2 IV on days 1 and 3 is safe and well tolerated when given in combination with topotecan 1.25 mg/m 2 IV on days 1-5 of an every 3-week cycle. A phase II trial to assess the efficacy of this combination for patients with relapsed SCLC is currently accruing patients.

Apoptosis-Modulating Drugs for Improved Cancer Therapy

“…These so-called BH3 mimetics directly interfere with the protein structure of Bcl-2, Bcl-xL, Bcl-w or Mcl-1 and thus inhibit the antiapoptotic function of these molecules [124]. Among them, the preclinically most intensively studied compound obatoclax (GX15–070) [135,136,137] and gossypol (AT-101) [138,139,140] showed very promising results and are currently undergoing clinical testing. ABT-737 and its orally available derivative navitoclax (ABT-263) bind to Bcl-2, Bcl-xL and Bcl-w and sequester proapoptotic BH3 domain proteins, which promotes the oligomerization of proapoptotic Bax and Bak [141].…”

Mitochondrial targeted peptides for cancer therapy

“…Added to carboplatin/etoposide chemotherapy as initial treatment for extensive-stage small-cell lung cancer [43,44] TLSGA-FELSRDK (TLS) In vivo (SKOV3 ovarian cancer) Induces early-stage apoptosis [45] See text for abbreviation definitions ex vivo treatment of AML cell lines and AML primary patient samples in clinical trials [26,42].…”

“…Obatoclax is currently undergoing evaluation in phase I/II clinical trials for patients with hematologic malignancies and can overcome the resistance to apoptosis conferred by MCL-1. It can be used alone or in combination with other anti-cancer drugs, for treating a variety of hematological malignancies such as leukemia, lymphoma, and solid tumor malignancies [43,44].…”

Have chemosensitizing strategies for multidrug-resistant childhood acute lymphoblastic leukemia come of age?

“…ABT-263 is currently evaluated in adults [20]. Based on interesting preclinical data by the PPTP consortium [35], this agent should also be evaluated in refractory childhood ALL. We expect the Phase I study by the Dana Farber Cancer Institute (NCT00874562), which assesses the biological response to rapamycin in combination with steroids in relapsed ALL, to stimulate further clinical evaluation.…”

“…Thus, it is likely that we will achieve biologically active drug levels in pediatric patients at a tolerable dose level. Dose-limiting toxicity in adults was mostly infusion related and resulted in reversible neurologic symptoms [34][35][36]. Our secondary objective will be to obtain evidence for biological activity in vivo by monitoring treatment response at the single-cell level by flow cytometry, and by detection of characteristic necroptotic cell-death features using electron microscopy.…”