BACKGROUND The transcription factor, WT1, is highly overexpressed in malignant pleural mesothelioma (MPM) and immunohistochemical stains for WT1 are used routinely to aid in its diagnosis. Using computer prediction analysis we designed analog peptides derived from WT1 sequences by substituting amino acids at key HLA-A0201 binding positions. We tested the safety and immunogenicity of a WT1 vaccine comprised of four class 1 and class 2 peptides in patients with thoracic neoplasms expressing WT1. METHODS Therapy consisted of six subcutaneous vaccinations administered with Montanide adjuvant on weeks 0, 4, 6, 8, 10, and 12, with 6 additional monthly injections for responding patients. Injection sites were pre-stimulated with GM-CSF (70mcg). Immune responses were evaluated by DTH, CD4 T-cell proliferation, CD8 T-cell interferon gamma release, intracellular cytokine staining, WT1 peptide MHC-tetramer staining, and cytotoxicity against WT1 positive tumor cells. RESULTS Nine patients with MPM and 3 with NSCLC were vaccinated, with 8 patients receiving at least 6 vaccinations; in total, 10 patients were evaluable for immune response. Six out of nine patients tested demonstrated CD4 T-cell proliferation to WT1 specific peptides, and five of the six HLA-A0201 patients tested mounted a CD8 T-cell response. Stimulated T cells were capable of cytotoxicity against WT-1 positive cells. Vaccination also induced polyfunctional CD8 T cell responses. CONCLUSIONS This multivalent WT1 peptide analog vaccine induces immune responses in a high proportion of patients with thoracic malignancies with minimal toxicity. A randomized trial testing this vaccine as adjuvant therapy in MPM is planned.

Introduction We previously reported data on the safety, tolerability, and recommended phase II dose of obatoclax mesylate in conjunction with topotecan in patients with advanced solid tumor malignancies. Preliminary efficacy data suggested activity in patients with recurrent small cell lung cancer (SCLC). Based on these data, we performed a phase II study of obatoclax mesylate plus topotecan in patients with relapsed SCLC to assess efficacy. Methods This was an open-label, single-arm, phase II extension of obatoclax mesylate plus topotecan in patients with relapsed SCLC. Obatoclax mesylate was given intravenously (IV) at a dose of 14 mg/m2 on days 1 and 3 with IV topotecan at 1.25 mg/m2 on days 1–5 of an every 3-week cycle. The primary end-point of this study was overall response rate. Results Nine patients with recurrent SCLC were enrolled into the first stage of the study. Patients received a median of 2 cycles of treatment. All patients were evaluable for the primary end-point of overall response. There were no partial or complete responses. Five patients (56%) had stable disease. The remaining four patients (44%) developed progressive disease. The most common grade 3 or 4 adverse events included thrombocytopenia (22%), anemia (11%), neutropenia (11%), and ataxia (11%). Conclusion Obatoclax mesylate added to topotecan does not exceed the historic response rate seen with topotecan alone in patients with relapsed SCLC following the first-line platinum-based therapy.

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.

Background: Direct-acting oral anticoagulants are indicated for the treatment of nonvalvular atrial fibrillation, but their use in patients after undergoing cardiac surgery is poorly defined despite a high prevalence of postoperative atrial fibrillation in this population. Methods: Patients diagnosed with postoperative atrial fibrillation were prospectively randomized to warfarin or apixaban. Safety, efficacy, and economic outcomes were evaluated until their 4- to 6-week postoperative appointment. Results: While this pilot study was not powered to determine a difference in safety or efficacy, adverse event rates were similar to the published literature. It was noted that a patient’s course of therapy when utilizing apixaban was significantly less costly than warfarin when including medication, bridging, and laboratory expenses. Conclusion: Apixaban and warfarin both appeared to be safe and effective for anticoagulation throughout the duration of this pilot study in treating postoperative atrial fibrillation after coronary artery bypass grafting. Apixaban was associated with significantly less expense when bridging and monitoring costs were included in addition to medication expense.