ABSTRACT
BACKGROUND: Molecular alterations of the PI3K and Ras pathways often occur in human cancer. In this trial, the pharmacokinetics, toxicity, and activity of two drugs inhibiting these pathways-everolimus and sorafenib-were investigated. METHODS: Thirteen patients with progressing solid tumors were treated with everolimus and sorafenib, according to a 3+3 scheme. Patients were selected on the basis of immunohistochemical expression of tumor molecular targets, including phospho-AKT, -p70S6K, and -ERK1/2. RESULTS: The daily recommended dose identified was 2.5 mg of everolimus and 600 mg of sorafenib. Dose-limiting toxicities included grade 3 asthenia and hand-foot skin reaction. No grade 4 adverse events were observed. The most frequent grade 3 toxicities were hypophosphatemia (30.8%), alanine aminotransferase level increase, asthenia, and anorexia (14%). No pharmacokinetic interactions were identified between everolimus and sorafenib. Of 12 evaluable patients, we observed 2 partial responses, with greater than 10% shrinkage in an additional 5 patients. Objective responses were observed in one patient with a thymoma and in one patient with a lung adenocarcinoma. Tumor shrinkage that did not qualify as a partial response was seen in an abdominal leiomyosarcoma and in adenoid cystic carcinomas. CONCLUSION: The combination of everolimus and sorafenib is safe. The tumor activity observed in different tumor types could be the result of the combined action of these drugs as well as the molecular selection of the treated population. Further research is warranted to better investigate drugs simultaneously blocking the PI3K and the Ras pathways and to refine patient selection.
Subject(s)
Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy , Niacinamide/analogs & derivatives , Phenylurea Compounds/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Sirolimus/analogs & derivatives , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Everolimus , Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors , Humans , Niacinamide/adverse effects , Niacinamide/pharmacokinetics , Niacinamide/therapeutic use , Phenylurea Compounds/adverse effects , Phenylurea Compounds/pharmacokinetics , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacokinetics , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Sirolimus/adverse effects , Sirolimus/pharmacokinetics , Sirolimus/therapeutic use , Sorafenib , ras Proteins/antagonists & inhibitorsABSTRACT
BACKGROUND: In vitro data suggest that panobinostat (LBH589), a pan-deacetylase inhibitor, may add therapeutic benefit in the treatment of small-cell lung cancer (SCLC) with regression of tumors. METHODS: This multicenter, nonrandomized phase 2 trial was designed to evaluate antitumor activity of LBH589 in patients with previously treated SCLC. Patients received LBH589 administered intravenously at a dose of 20 mg/mq (days 1-8) every 21 days. RESULTS: A total of 21 patients with extensive- or limited-stage SCLC were enrolled. Patients received a median of two cycles (range, 1-6). LBH589 was well tolerated, and the most common toxicities were grade 1 to 2 gastrointestinal disorders (nausea 38%, diarrhea 24%, vomiting 19%), grade 1 to 2 thrombocytopenia (14.3%). Of 19 patients evaluable for efficacy, two cases showed shrinkages more than 30% at first assessment, with time to progression of 14 and 21 weeks, respectively, and there were three long disease stabilizations of 12, 10, and 13 weeks. The study was prematurely closed because of a lack of activity. CONCLUSION: This is the first report of a pan-deacetylase inhibitor inducing tumor shrinkage and sustained stable disease in SCLC. We believe that although the trial was prematurely discontinued, modest clinical activity of LBH589 combined with a favorable safety profile in pretreated SCLC patients was observed, which warrants further exploration of the potential contribution of LBH589 in other trials.
Subject(s)
Antineoplastic Agents/therapeutic use , Histone Deacetylase Inhibitors/therapeutic use , Hydroxamic Acids/therapeutic use , Indoles/therapeutic use , Lung Neoplasms/drug therapy , Small Cell Lung Carcinoma/drug therapy , Aged , Antineoplastic Agents/adverse effects , Female , Histone Deacetylase Inhibitors/adverse effects , Humans , Hydroxamic Acids/adverse effects , Indoles/adverse effects , Male , Middle Aged , PanobinostatABSTRACT
BACKGROUND: The broad spectrum of antitumor activity of the oral platinum satraplatin (S) and vinorelbine (V) were the rationale for performing a phase I trial to define the maximum tolerated (MTD) and the recommended (RD) dose in adult patients with advanced solid tumors. PATIENTS AND METHODS: 4 dose levels (DLs) of S (mg/m(2)/day, days 1-5) and V (mg/m(2)/day, days 1, 8, 15, and 22) every 28 days were explored: S60/V60 on days 1, 8 and 15 only; S60/V60; S70/V60; and S80/V60. Subsequently, 3 further DLs were evaluated with V omitted on day 22: S70/V60, S80/V60, and S80/V80. RESULTS: Treating 27 patients, the MTD was S80/V80 on days 1, 8, and 15, with 2 dose-limiting toxicities in 2 patients (nausea and vomiting grade (G) 3 with skipping of V on day 15, and neutropenia G4 with infection). The RD was S80/V60 on days 1, 8, and 15. The most frequent toxicities (any G) were nausea (70%), diarrhea (59%), anorexia (37%), vomiting (33%), asthenia (26%), constipation (26%), and paresthesia (18%). Partial responses were observed in 2 platinum-sensitive ovarian cancer patients and in 1 prostate cancer patient. CONCLUSION: The combination of S and V is tolerable at a DL of S80/V60 on days 1, 8, and 15; further evaluations in platinum- and V-sensitive tumor types would be of interest.
