Chiappori A.,H. Lee Moffitt Cancer Center and Research Institute |
Williams C.,Arlington Cancer Center |
Northfelt D.W.,Mayo Clinic Arizona |
Adams J.W.,Arlington Cancer Center |
And 6 more authors.
Journal of Thoracic Oncology | Year: 2014
INTRODUCTION: The proapoptotic small-molecule pan-Bcl-2 inhibitor obatoclax mesylate (GX15-070) may enhance the cytotoxicity of chemotherapy in relapsed/refractory non-small-cell lung cancer (NSCLC). METHODS: Obatoclax was administered with docetaxel in patients with relapsed or refractory NSCLC - docetaxel as a 1-hour infusion on day 1 and obatoclax as a 24-hour infusion on days 1 and 2 - every 3 weeks for up to eight cycles. Four dose levels were evaluated in phase 1 (level 1: docetaxel 55 mg/m × 1 and obatoclax 30 mg × 2; levels 2-4: docetaxel 75 mg/m and obatoclax 30 mg, 45 mg, or 60 mg × 2) to identify dose-limiting toxicity and a phase 2 dose. In phase 2, response and tolerability were evaluated. RESULTS: Eighteen patients were included in phase 1. Two dose-limiting toxicities occurred during cycle 1: one febrile neutropenia each at dose levels 3 and 4. Maximum tolerated dose was not reached; 32 patients (including 3 from phase 1) were treated in phase 2 with docetaxel 75 mg/m and obatoclax 60 mg (median 2 cycles). Three patients (11%) had partial responses in phase 2; two demonstrated stable disease lasting 12 weeks or more. Median duration of response was 4.8 months. Overall, median progression-free survival was 1.4 months. Neutropenia (31%), febrile neutropenia (16%), and dyspnea (19%) were the most common grade 3/4 adverse events observed. CONCLUSIONS: Combined obatoclax mesylate plus docetaxel is tolerable in patients with NSCLC, but response was minimal and neutropenia was a common adverse event. Copyright © 2013 by the International Association for the Study of Lung Cancer.
Alavian K.N.,Yale University |
Li H.,Yale University |
Collis L.,Biocurrents Research Center |
Bonanni L.,University of Chieti Pescara |
And 17 more authors.
Nature Cell Biology | Year: 2011
Anti-apoptotic Bcl2 family proteins such as Bcl-x L protect cells from death by sequestering apoptotic molecules, but also contribute to normal neuronal function. We find in hippocampal neurons that Bcl-x L enhances the efficiency of energy metabolism. Our evidence indicates that Bcl-x L interacts directly with the β-subunit of the F1 FO ATP synthase, decreasing an ion leak within the F1 FO ATPase complex and thereby increasing net transport of H + by F1 FO during F1 FO ATPase activity. By patch clamping submitochondrial vesicles enriched in F 1 FO ATP synthase complexes, we find that, in the presence of ATP, pharmacological or genetic inhibition of Bcl-xL activity increases the membrane leak conductance. In addition, recombinant Bcl-x L protein directly increases the level of ATPase activity of purified synthase complexes, and inhibition of endogenous Bcl-xL decreases the level of F1 FO enzymatic activity. Our findings indicate that increased mitochondrial efficiency contributes to the enhanced synaptic efficacy found in Bcl-x L-expressing neurons. © 2011 Macmillan Publishers Limited. All rights reserved.
Gemin X Pharmaceuticals, Geminx Pharmaceuticals Canada Inc. and Gemin X Biotechnologies Inc. | Date: 2011-07-26
Hwang J.J.,Lombardi Cancer Center |
Kuruvilla J.,Princess Margaret Hospital |
Mendelson D.,Premiere Oncology of Arizona |
Pishvaian M.J.,Lombardi Cancer Center |
And 5 more authors.
Clinical Cancer Research | Year: 2010
Purpose: Two phase I, single-agent studies were conducted to determine the dose and regimen of obatoclax, an antagonist of all BCL-2 antiapoptotic proteins, for evaluation in phase II trials. The two studies, GX001 and GX005, evaluated the safety and tolerability of weekly 1-hour and 3-hour infusions of obatoclax, respectively. Experimental Design: Eligible patients in both studies were adults with solid tumor or lymphoma and performance status 0-1 for whom standard therapies were not appropriate. In the GX001 study an accelerated dose titration design was initially used with subsequent cohorts of three to six patients with 40% dose increments between levels. In the GX005 study three to six patients entered at each dose level with 40% dose increments between levels. Results: Thirty-five patients were enrolled in studies GX001 (n = 8) and GX005 (n = 27). Clinically significant central nervous system (CNS) toxicity was observed using the 1-hour infusion schedule. The obatoclax maximum tolerated dose (MTD) in GX001 was 1.25 mg/m2 due to these infusional CNS events. The 3-hour infusion schedule studied in GX005 had improved tolerability, and the obatoclax MTD was 20 mg/m2. One patient in GX005 with relapsed non-Hodgkin's lymphoma achieved partial response of 2 months' duration, and one patient with relapsed non-Hodgkin's lymphoma had stable disease for 18 months. Conclusions: The 1-hour infusion schedule of obatoclax was associated with neuropsychiatric doselimiting toxicities at relatively low doses (MTD, 1.25 mg/m2). The 3-hour i.v. infusion of obatoclax administered once weekly to patients with solid tumors was better tolerated (MTD, 20 mg/m 2), and evidence of clinical activity was observed. ©2010 AACR.
Chiappori A.A.,H. Lee Moffitt Cancer Center and Research Institute |
Schreeder M.T.,Clearview Cancer Institute |
Moezi M.M.,Integrated Community Oncology Network |
Stephenson J.J.,Institute for Translational Oncology Research |
And 7 more authors.
British Journal of Cancer | Year: 2012
Background: Bcl-2 family genes are frequently amplified in small cell lung cancer (SCLC). A phase I trial was conducted to evaluate the safety of obatoclax, a Bcl-2 family inhibitor, given in combination with standard chemotherapy. Methods: Eligible patients (3-6 per cohort) had extensive-stage SCLC, measurable disease, 1 before therapy, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate organ function. Patients were treated with escalating doses of obatoclax, either as a 3-or 24-h infusion, on days 1-3 of a 21-day cycle, in combination with carboplatin (area under the curve 5, day 1 only) and etoposide (100 mg m 2, days 1-3). The primary endpoint was to determine the maximum tolerated dose of obatoclax.Results:Twenty-five patients (56% male; median age 66 years) were enrolled in three dose cohorts for each schedule. Maximum tolerated dose was established with the 3-h infusion at 30 mg per day and was not reached with the 24-h infusion. Compared with the 24-h cohorts, the 3-h cohorts had higher incidence of central nervous system (CNS) adverse events (AEs); dose-limiting toxicities were somnolence, euphoria, and disorientation. These CNS AEs were transient, resolving shortly after the end of infusion, and without sequelae. The response rate was 81% in the 3-h and 44% in the 24-h infusion cohorts. Conclusion: Although associated with a higher incidence of transient CNS AEs than the 24-h infusion, 3-h obatoclax infusion combined with carboplatin-etoposide was generally well tolerated at doses of 30 mg per day. Though patient numbers were small, there was a suggestion of improved efficacy in the 3-h infusion group. Obatoclax 30 mg infused intravenously over 3 h on 3 consecutive days will be utilised in future SCLC studies. © 2012 Cancer Research UK All rights reserved.
Wei Y.,University of Texas M. D. Anderson Cancer Center |
Kadia T.,University of Texas M. D. Anderson Cancer Center |
Tong W.,University of Texas M. D. Anderson Cancer Center |
Zhang M.,University of Texas M. D. Anderson Cancer Center |
And 7 more authors.
Clinical Cancer Research | Year: 2010
Purpose: Single-agent histone deacetylase inhibitors (HDACi) have limited clinical activity in human leukemia. Although the way HDACi exert their antileukemia effect is not fully understood, it is accepted that induction of apoptosis is important. We hypothesized, therefore, that combination of an HDACi with a proapoptotic agent, such as the Bcl-2 homology domain-3 mimetic GX15-070, could result in enhanced antileukemia activity. Experimental Design: We analyzed the cellular and molecular effects of two different HDACi (MGCD0103 and vorinostat) in combination with GX15-070 in leukemia cell lines and primary acute myelogenous leukemia cells. Results: We showed that the combination had synergistic antileukemia effect both in leukemia cell lines and in primary acute myelogenous leukemia cells. Using molecular markers and electron microscopy, we observed that in addition to apoptosis, autophagy accounts for the nonapoptotic decrease in cell viability, an effect that could be inhibited by chloroquine, an inhibitor of autophagy. Finally, we established a role for calpain activity in the induction of both autophagy and apoptosis by this combination. Conclusions: The combination of an HDACi and GX15-070 has synergistic antileukemia activity, and the effect is mediated by induction of apoptosis and autophagy. The combination should be studied in clinical trials of leukemia and the role of autophagy in leukemia therapy needs to be better understood. ©2010 AACR.
Dean E.J.,Paterson Institute for Cancer Research |
Cummings J.,Paterson Institute for Cancer Research |
Roulston A.,Gemin X Pharmaceuticals |
Berger M.,Gemin X Pharmaceuticals |
And 4 more authors.
Neoplasia | Year: 2011
Small cell lung cancer (SCLC) is an aggressive disease in which, after initial sensitivity to platinum/etoposide chemotherapy, patients frequently relapse with drug-resistant disease. Deregulation of the Bcl-2 pathway is implicated in the pathogenesis of SCLC, and early phase studies of Bcl-2 inhibitors have been initiated in SCLC. Obatoclax is a small-molecule drug designed to target the antiapoptotic Bcl-2 family members to a proapoptotic effect. Preclinical studies were conducted to clarify the kinetics of obatoclax-induced apoptosis in a panel of SCLC cell lines to assist with the interpretation of biomarker data generated during early phase clinical trials. In vitro, obatoclax was synergistic with cisplatin and etoposide, and "priming" cells with obatoclax before the cytotoxics maximized tumor cell death. Peak levels of apoptosis, reflected by cleaved cytokeratin 18 (CK18) levels (M30 ELISA) and caspase activity (SR-DEVD-FMK), occurred 24 hours after obatoclax treatment. A phase 1b-2 trial of obatoclax administered using two infusion regimens in combination with carboplatin and etoposide has been completed in previously untreated patients with extensive-stage SCLC. Circulating pharmacodynamic biomarkers of cell death, full-length and/or cleaved CK18, and oligonucleosomal DNA were studied in the phase 1b trial. All SCLC patients classified as "responders" after two cycles of treatment showed significantly increased levels of full-length and cleaved CK18 (M65 ELISA) on day 3 of study. However, the preclinical data and the absence of a peak in circulating caspasecleaved CK18 in trial patients suggest suboptimal timing of blood sampling, which will need refinement in future trials incorporating obatoclax. © 2011 Neoplasia Press, Inc.
Goy A.,Hackensack University Medical Center |
Hernandez-Ilzaliturri F.J.,Roswell Park Cancer Institute |
Kahl B.,University of Wisconsin - Madison |
Ford P.,Hackensack University Medical Center |
And 2 more authors.
Leukemia and Lymphoma | Year: 2014
Obatoclax, a BH3 mimetic inhibitor of anti-apoptotic Bcl-2 proteins, demonstrates synergy with bortezomib in preclinical models of mantle cell lymphoma (MCL). This phase I/II study assessed obatoclax plus bortezomib in patients with relapsed/refractory MCL. Twenty-three patients received obatoclax 30 or 45 mg plus bortezomib 1.0 or 1.3 mg/m2, administered intravenously on days 1, 4, 8 and 11 of a 21-day cycle. In phase I, the combination was feasible at all doses. Obatoclax 45 mg plus bortezomib 1.3 mg/m2 was selected for phase II study. Common adverse events were somnolence (87%), fatigue (61%) and euphoric mood (57%), all primarily grade 1/2. Grade 3/4 events included thrombocytopenia (21%), anemia (13%) and fatigue (13%). Objective responses occurred in 4/13 (31%) evaluable patients (three complete and one partial response). Six patients (46%) had stable disease lasting ≥ 8 weeks. Obatoclax plus bortezomib was feasible, but the synergy demonstrated in preclinical models was not confirmed. © 2014 Informa UK, Ltd.
Arellano M.L.,Emory University |
Borthakur G.,University of Texas M. D. Anderson Cancer Center |
Berger M.,Gemin X Pharmaceuticals |
Luer J.,Powered Inc. |
Raza A.,Columbia University
Clinical Lymphoma, Myeloma and Leukemia | Year: 2014
Curative therapies are lacking for older patients with myelodysplastic syndrome (MDS). In this small phase II study, the B-cell lymphoma 2 (Bcl-2) inhibitor obatoclax (60 mg over 24 hours every 2 weeks) was feasible and relatively well tolerated, but had limited first-line activity in MDS.Background: Obatoclax mesylate is a small-molecule Bcl-2 homology domain-3 mimetic that neutralizes antiapoptotic Bcl-2erelated proteins. We evaluated obatoclax in untreated MDS patients with anemia/thrombocytopenia .Patients and Methods: Twenty-four patients with a bone marrow blast count of ≤ 10% and anemia (hemoglobin level < 10 g/dL) or thrombocytopenia (platelet count < 50 × 109/L) were eligible to receive intravenous obatoclax 60 mg over 24 hours every 2 weeks .Results: Response rate was 8% (2 patients; hematologic improvement). Disease stabilization/response was maintained ≥ 12 weeks in 50% (12 patients). Because the response rate was below a predetermined threshold, the study was terminated. Adverse events (any grade) included euphoric mood (63%; 15 patients), nausea (38%; 9 patients), and diarrhea (25%; 6 patients); Grade 3/4 adverse events included anemia (21%; 5 patients), thrombocytopenia (13%; 3 patients), and pneumonia (13%; 3 patients) .Conclusions: Obatoclax 60 mg every 2 weeks was feasible, but had limited first-line activity in MDS . © 2014 Elsevier Inc. All rights reserved.