gx-15-070 and Small-Cell-Lung-Carcinoma

This randomized phase II study assessed the efficacy and safety of obatoclax mesylate, a small-molecule Bcl-2 inhibitor, added to carboplatin/etoposide chemotherapy as initial treatment for extensive-stage small-cell lung cancer (ES-SCLC).. Chemotherapy-naïve subjects with ES-SCLC and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2 received carboplatin/etoposide with (CbEOb) or without (CbE) obatoclax for up to six cycles. Responders to CbEOb could receive maintenance obatoclax until disease progression. The primary endpoint was objective response rate (ORR).. 155 subjects (median age 62, 58% male, 10% ECOG PS 2) were treated with CbEOb (n=77) or CbE (n=78); 65% and 59% of subjects, respectively, completed six cycles. ORR was 62% with CbEOb versus 53% with CbE (1-sided p=0.143). Clinical benefit (ORR+ stable disease) trended better with CbEOb (81% versus 68%; p=0.054). Median progression-free survival (PFS) and overall survival (OS) were 5.8 months (95% confidence interval [CI]: 5.3-6.5) and 10.5 months (8.9-13.8) with CbEOb and 5.2 months (95% CI: 4.1-5.7) and 9.8 months (7.2-11.2) with CbE. Median OS was 10.5 months (95% CI: 8.9-13.8) and 9.8 months (7.2-11.2) with a nonsignificant hazard ratio for OS, 0.823; 1-sided p=0.121. Grade 3/4 adverse events (AEs) were primarily hematologic and similar in frequency between treatment arms. Obatoclax-related somnolence and euphoria were grade 1/2, transient, and did not require treatment discontinuation.. Obatoclax was well tolerated when added to carboplatin/etoposide in first-line treatment of ES-SCLC, but failed to significantly improve ORR, PFS, or OS.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Comorbidity; Etoposide; Female; Humans; Indoles; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Pyrroles; Small Cell Lung Carcinoma; Treatment Outcome

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.. 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.. 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.. 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.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Central Nervous System; Drug Administration Schedule; Etoposide; Female; Humans; Indoles; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Small Cell Lung Carcinoma

Proteasome inhibitors, bortezomib (BTZ), and carfilzomib (CFZ) are approved drugs for hematological malignancies, but lack anticancer activities against most solid tumors. Small cell lung cancer (SCLC) is a very aggressive neuroendocrine carcinoma of the lungs demanding effective therapy. In this study we investigated whether BTZ or CFZ combined with obatoclax (OBX), an antagonist for MCL-1 and a pan-BCL family inhibitor, could cause synergistic growth inhibition of SCLC cells. We showed that combined application of BTZ or CFZ with OBX caused synergistic growth inhibition of human SCLC cell lines (H82, H526, DMS79, H196, H1963, and H69) than single agent alone. Both BTZ-OBX and CFZ-OBX combinations displayed marked synergism on inducing apoptosis (~50% increase vs BTZ or CFZ alone). A comprehensive proteomics analysis revealed that BTZ preferentially induced the expression of MCL-1, an antiapoptotic protein, in SCLC cells. Thus, proteasome inhibitor-OBX combinations could specifically induce massive growth inhibition and apoptosis in SCLC cells. Subsequent proteome-wide profiling analysis of activated transcription factors suggested that BTZ- or CFZ-induced MCL-1 upregulation was transcriptionally driven by FOXM1. In nude mice bearing in SCLC H82 xenografts, both BTZ-OBX, and CFZ-OBX combinations exhibited remarkable antitumor activities against SCLC tumors evidenced by significant reduction of tumor size and the proliferation marker Ki-67 signals in tumor tissues as compared with single agent alone. Thus, proteasome inhibitor-OBX combinations are worth immediate assessments for SCLC in clinical settings.

Topics: Animals; Antineoplastic Agents; Apoptosis; Bortezomib; Cell Line, Tumor; Drug Synergism; Forkhead Box Protein M1; HEK293 Cells; Humans; Indoles; Lung Neoplasms; Mice, Nude; Myeloid Cell Leukemia Sequence 1 Protein; Oligopeptides; Proteasome Inhibitors; Pyrroles; Small Cell Lung Carcinoma; Up-Regulation; Xenograft Model Antitumor Assays

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 caspase-cleaved CK18 in trial patients suggest suboptimal timing of blood sampling, which will need refinement in future trials incorporating obatoclax.

Topics: Antineoplastic Agents; Biomarkers, Tumor; Blood Chemical Analysis; Calibration; Cell Death; Cell Line, Tumor; Cell Proliferation; Cisplatin; Clinical Trials, Phase I as Topic; Drug Synergism; Etoposide; Humans; Indoles; Lung Neoplasms; Prognosis; Pyrroles; Small Cell Lung Carcinoma