Heat shock protein 90 (Hsp90) is a molecular chaperone with many oncogenic client proteins. The small-molecule Hsp90 inhibitor alvespimycin, a geldanamycin derivative, is being developed for various malignancies. This phase 1 study examined the maximum-tolerated dose (MTD), safety and pharmacokinetic/pharmacodynamic profiles of alvespimycin in patients with advanced acute myeloid leukemia (AML). Patients with advanced AML received escalating doses of intravenous alvespimycin (8-32 mg/m 2 ), twice weekly, for 2 of 3 weeks. Dose-limiting toxicities (DLTs) were assessed during cycle 1. A total of 24 enrolled patients were evaluable for toxicity. Alvespimycin was well tolerated; the MTD was 24 mg/m 2 twice weekly. Common toxicities included neutropenic fever, fatigue, nausea and diarrhea. Cardiac DLTs occurred at 32 mg/m 2 (elevated troponin and myocardial infarction). Pharmacokinetics revealed linear increases in C max and area under the curve (AUC) from 8 to 32 mg/m 2 and minor accumulation upon repeated doses. Pharmacodynamic analyses on day 15 revealed increased apoptosis and Hsp70 levels when compared with baseline within marrow blasts. Antileukemia activity occurred in 3 of 17 evaluable patients (complete remission with incomplete blood count recovery). The twiceweekly administered alvespimycin was well tolerated in patients with advanced AML, showing linear pharmacokinetics, target inhibition and signs of clinical activity. We determined a recommended phase 2 dose of 24 mg/m 2 .

Purpose: CT-2106 is a 20(S)-camptothecin poly-L-glutamate conjugate. This linkage stabilizes the active lactone form of camptothecin and enhances aqueous solubility. In addition, poly-Lglutamate is postulated to increase tumor delivery of the active compound through enhanced permeability and retention effect in tumor. We studied a weekly schedule of CT-2106 in patients with refractory solid tumor malignancies. Experimental Design: CT-2106 was infused (10 min i.v. infusion) on days 1, 8, and 15 of each 28-day cycle. Plasma and urine were analyzed for total and unconjugated camptothecin by highperformance liquid chromatography equipped with a fluorescence detector.Toxicity and response assessments were done with Common Toxicity Criteria for Adverse Events version 3 and Response Evaluation Criteria in Solid Tumors, respectively. Results: Twenty-six patients were enrolled. Median age was 58 years (range, 36-83) and median number of doses was 6 (range, 1-9). The most frequent tumor type (50%) was melanoma. Dose limiting toxicities were thrombocytopenia and fatigue. A weekly dose of 25 mg/m 2 given every 3 of 4 weeks was the maximum tolerated dose. The majority of grade 3 and 4 toxicities were hematologic. The pharmacokinetic profile of conjugated and unconjugated camptothecin showed a polyexponential decline with similar terminal half life (t 1/2 range was 44-63 and 31-48 h for conjugated and unconjugated, respectively). Pharmacokinetics of conjugated and unconjugated camptothecin were dose and time independent in the tested dose range. Urinary excretion of conjugated and unconjugated camptothecin accounted for about 30% and 4% of the administered dose, respectively. Conclusions: CT-2106 has a more manageable toxicity profile compared with unconjugated camptothecin. The maximum tolerated dose is 25 mg/m 2 weekly given 3 of 4 weeks. This compound results in prolonged release of unconjugated camptothecin.

Purpose: Endothelins and their cell membrane receptors (ET A R and ET B R) are implicated in neoplastic pathogenesis. Atrasentan, a potent, selective ET A R antagonist, has a direct effect on tumor proliferation, apoptosis, and angiogenesis.This study was designed to assess the influence of atrasentan on paclitaxel pharmacokinetics and to determine the safety and efficacy of atrasentan in combination with paclitaxel-carboplatin. Experimental Design: Chemonaive patients with stage IIIB (malignant pleural effusion) and IV non^small cell lung cancer were enrolled. Toxicity and response were determined using the National Cancer Institute CommonToxicity Criteria version 2.0 and Response Evaluation Criteria in Solid Tumors criteria, respectively. Treatment consisted of paclitaxel (225 mg/m 2 ) and carboplatin (area under the curve, 6) administered on day 1every 3 weeks. A fixed 10 mg daily oral dose of atrasentan was administered continuously, starting on day 4 of cycle 1. Paclitaxel clearance was calculated during the first two cycles (pre-and post-atrasentan) in the first 10 patients. Results: All 44 patients were evaluable for survival, toxicity, and response. No significant change in mean paclitaxel clearance was detected (mean F SD, 21.2 F 4.5 L/h versus 21.3 F 4.9 L/h) for pre-and post-atrasentan values, respectively (P = 0.434). Grade 3/4 toxicities z10% were lymphopenia (22.7%), neutropenia (20.5%), dyspnea (11.4%), and hyperglycemia (11.4%). Response rate was 18.2%, with progression-free survival of 4.2 months, median survival of 10.6 months, and 1-year survival of 43%. Conclusion: Atrasentan plus paclitaxel-carboplatin was safe and well tolerated, with no apparent paclitaxel-atrasentan pharmacokinetic interaction. Efficacy and survival in advanced non^small cell lung cancer were comparable with studies of chemotherapy alone.In 2006, lung cancer remains the most frequent cause of cancer mortality in the United States (1). More than 80% of patients have non -small cell lung cancer (NSCLC) and half of them have advanced disease at diagnosis (2). In these cases, treatment mostly consists of chemotherapy with a platinumbased doublet (3). Chemotherapy, however, has reached an efficacy plateau, and newer therapies are needed (4,5). Improved understanding of the molecular biology of NSCLC (signaling pathways, etc.) has opened a whole new field of therapeutic options, where development of many new agents targets these pathways (6, 7), such as the endothelin axis pathway (8).The endothelins include three 21 -amino acid isopeptides (ET-1, ET-2, and ET-3) characterized by a single a-helix and two disulfide bridges. They exert their effects by binding to two cell surface receptors (ET A R and ET B R), which belong to the G protein -linked family of receptors (8,9). The binding of ET-1 to ET A R exerts pleiotropic biological effects that influence cell survival and proliferation (through activation of various kinases, namely, protein kinase C, epidermal growth factor, and insulin-like growth factor), apoptosis (b...

Akt, a serine/threonine protein kinase, is constitutively phosphorylated and hyperactivated in multiple cancers, including acute myeloid leukemia. High levels are linked to poor survival and inferior responses to chemotherapy, making Akt inhibition an attractive therapeutic target. In this phase I/II study of TCN-PM, a small-molecule Akt inhibitor, TCN-PM therapy was well tolerated in patients with advanced hematological malignancies, and reduced levels of phosphorylation of Akt and its substrate Bad were shown, consistent with inhibition of this survival pathway and induction of cell death. Further investigation of TCN-PM alone or in combination in patients with high Akt levels is warranted.

We have investigated the ability of several cytokine combinations to improve retrovirus-mediated transduction of human primitive hematopoietic progenitors (PHPs) from mobilized peripheral blood (MPB). Retroviral infection of CD34+ cells was performed by culture on fibronectin fragment CH-296 (RetroNectin, RN), using the truncated human nerve growth factor receptor (NGFR) as the transgene reporter. Transgene expression among progeny of PHPs was assayed by FACS analysis after long-term stromal culture (LTC). Transgene delivery to PHPs was assessed by PCR of individual stromal culture-derived methylcellulose colonies (LTC-CFCs). Compared with interleukin 3 (IL-3), IL-6, and leukemia inhibitory factor (LIF), the combination of thrombopoietin (TPO), Flt3 ligand (FL), and Kit ligand (KL) effected a 73-fold increase in NGFR expression among CD34+ cells (to 14%) and a 14-fold increase in NGFR expression among total cells (to 10%) after LTC. In addition, a 2.4-fold increase in neo gene marking of LTC-CFCs was observed. A preclinical study comparing the effect of high-speed centrifugation ("spinoculation") or culture on RN during exposure to retroviral particles in teflon cell culture bags showed no difference in the efficiency of transduction of PHPs between these two methods.