Phase II randomised discontinuation trial of brivanib in patients with advanced solid tumours.

Background: Brivanib is a selective inhibitor of vascular endothelial growth factor and fibroblast growth factor (FGF) signalling. We performed a phase II randomised discontinuation trial of brivanib in 7 tumour types (soft-tissue sarcomas [STS], ovarian cancer, breast cancer, pancreatic cancer, non-small-cell lung cancer [NSCLC], gastric/esophageal cancer and transitional cell carcinoma [TCC]).

Patients And Methods: During a 12-week open-label lead-in period, patients received brivanib 800 mg daily and were evaluated for FGF2 status by immunohistochemistry.

Results of a prospective phase 2 study of pazopanib in patients with surgically unresectable or metastatic chondrosarcoma.

Background: This single-arm, multicenter, phase 2 study evaluated the safety and antitumor activity of pazopanib in patients with unresectable or metastatic conventional chondrosarcoma.

Methods: Eligible patients had conventional chondrosarcoma of any grade with measurable tumors that were unresectable or metastatic. Patients with mesenchymal, dedifferentiated, and extraskeletal myxoid chondrosarcoma subtypes and patients who received prior tyrosine kinase inhibitor therapy were excluded.

An Evaluation of Psychosocial and Religious Belief Differences in a Diverse Racial and Socioeconomic Urban Cancer Population.

Despite years of research aimed at decreasing the cancer mortality rates, the disparity between African-Americans and whites continues to grow. The fundamental psychosocial and belief differences that may mediate these disparities are poorly studied and rarely disentangle race versus specific socioeconomic status (SES) effects. In this study, breast, colon, and lung cancer patients presenting for their first oncology appointment completed a self-administered survey utilizing previously validated instruments regarding psychosocial and belief factors.

First-in-human, phase I study of elisidepsin (PM02734) administered as a 30-min or as a 3-hour intravenous infusion every three weeks in patients with advanced solid tumors.

This first-in-human, phase I clinical trial was designed to determine the dose-limiting toxicities (DLTs) and the dose for phase II trials (P2D) of elisidepsin (PM02734) administered as a 30-min or as a 3-h intravenous infusion every 3 weeks (q3wk). Between March 2006 and April 2011, 53 patients with advanced malignant solid tumors were enrolled and treated with elisidepsin on the two different q3wk infusion schedules: 22 (30-min) and 31 (3-h), respectively. Doses evaluated ranged from 0.

Dose-finding and pharmacokinetic study to optimize the dosing of irinotecan according to the UGT1A1 genotype of patients with cancer.

Purpose: The risk of severe neutropenia from treatment with irinotecan is related in part to UGT1A1*28, a variant that reduces the elimination of SN-38, the active metabolite of irinotecan. We aimed to identify the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of irinotecan in patients with advanced solid tumors stratified by the *1/*1, *1/*28, and *28/*28 genotypes.

Patients And Methods: Sixty-eight patients received an intravenous flat dose of irinotecan every 3 weeks.

A pharmacogenetic study of aldehyde oxidase I in patients treated with XK469.

XK469 (NSC 697887) is a selective topoisomerase II β inhibitor eliminated mainly by aldehyde oxidase I (AOX1). We performed a candidate gene study to investigate whether AOX1 genetic variation contributes to interindividual variability in XK469 clearance. Forty-one AOX1 single nucleotide polymorphisms (SNPs) and seven liver expression quantitative trait loci were genotyped in White patients with advanced refractory solid tumors (n=59) and leukemia (n=33).

Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma: a multicentre, open-label, phase 2 trial.

Background: Preclinical studies have shown synergistic antitumour activity by inhibition of insulin-like growth factor-1 receptor (IGF-1R) and mTOR. The expression of IGF-1R seems to be crucial for this effect. We investigated the safety and efficacy of the combination of the IGF-1R antibody cixutumumab and the mTOR inhibitor temsirolimus in patients with chemotherapy-refractory bone and soft-tissue sarcomas according to IGF-1R expression by immunohistochemistry.

Phase I studies of sirolimus alone or in combination with pharmacokinetic modulators in advanced cancer patients.

Purpose: Sirolimus is the eponymous inhibitor of the mTOR; however, only its analogs have been approved as cancer therapies. Nevertheless, sirolimus is readily available, has been well studied in organ transplant patients, and shows efficacy in several preclinical cancer models.

Experimental Design: Three simultaneously conducted phase I studies in advanced cancer patients used an adaptive escalation design to find the dose of oral, weekly sirolimus alone or in combination with either ketoconazole or grapefruit juice that achieves similar blood concentrations as its intravenously administered and approved prodrug, temsirolimus.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for the treatment of peritoneal sarcomatosis.

Background: The prognosis of peritoneal sarcomatosis is generally poor and conventional treatments for this disease process are mostly ineffective. The use of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) as an aggressive locoregional treatment option remains controversial.

Methods: We reviewed 13 patients with peritoneal sarcomatosis who underwent CRS and closed-abdomen HIPEC with cisplatin and doxorubicin between March 2007 and March 2010.

Two drug interaction studies of sirolimus in combination with sorafenib or sunitinib in patients with advanced malignancies.

Purpose: Sirolimus is the prototypical mTOR inhibitor. Sorafenib and sunitinib are small molecule inhibitors of multiple kinases including VEGF receptor (VEGFR) kinases. These agents have different mechanisms of action, providing a strong rationale for combination.

Phase I study of dose-escalated busulfan with fludarabine and alemtuzumab as conditioning for allogeneic hematopoietic stem cell transplant: reduced clearance at high doses and occurrence of late sinusoidal obstruction syndrome/veno-occlusive disease.

Disease recurrence after allogeneic hematopoietic cell transplant (alloHCT) remains common, making improvements in conditioning regimens desirable. A dose-response relationship between busulfan exposure and outcome is known. Using individual real-time monitoring of the busulfan area under the curve (AUC), we aimed to determine the maximum-tolerated busulfan AUC in a conditioning regimen with fludarabine/alemtuzumab.

The quinoxaline anti-tumor agent (R+)XK469 inhibits neuroblastoma tumor growth.

The quinoxaline anti-tumor agent (R+)XK469 mediates its effects by topoisomerase IIB inhibition. This report describes a 14-year old with relapsed neuroblastoma who experienced disease stabilization for 14 months while receiving (R+)XK469 monotherapy. Due to this favorable response, laboratory studies were undertaken to determine efficacy in the preclinical setting.

A phase I study of continuous infusion cilengitide in patients with solid tumors.

Background: Cilengitide (EMD121974) is a cyclized pentapeptide that is a potent and selective integrin antagonist which has shown activity in malignant gliomas. In all previous studies, cilengitide has been administered in an intermittent fashion. However, cilengitide has a short half-life of 3-5 h with no evidence of drug accumulation.

Ambulatory monitoring detects sorafenib-induced blood pressure elevations on the first day of treatment.

Purpose: Hypertension is a mechanism-based toxicity of sorafenib and other cancer therapeutics that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. This prospective, single-center, cohort study characterized ambulatory blood pressure monitoring as an early pharmacodynamic biomarker of VEGF signaling pathway inhibition by sorafenib.

Experimental Design: Fifty-four normotensive advanced cancer patients underwent 24-hour ambulatory blood pressure monitoring before and between days 6 and 10 of sorafenib therapy.

Primary tumor necrosis predicts distant control in locally advanced soft-tissue sarcomas after preoperative concurrent chemoradiotherapy.

Purpose: Various neoadjuvant approaches have been evaluated for the treatment of locally advanced soft-tissue sarcomas. This retrospective study describes a uniquely modified version of the Eilber regimen developed at the University of Chicago.

Methods And Materials: We treated 34 patients (28 Stage III and 6 Stage IV) with locally advanced soft-tissue sarcomas of an extremity between 1995 and 2008.

R(+)XK469 inhibits hydroxylation of S-warfarin by CYP2C9.

Introduction: XK469 is a novel topoisomerase II inhibitor structurally akin to several propionic acid derivatives, such as ibuprofen and diclofenac, which are metabolised by CYP2C9. We report eight subjects who experienced significant elevation of INR while receiving concomitant R(+)XK469 and warfarin. The aim of the study is to investigate whether R(+)XK469 interacts with S-warfarin by inhibition of CYP2C9.

Phase II study of sorafenib in patients with metastatic or recurrent sarcomas.

PURPOSE Since activity of sorafenib was observed in sarcoma patients in a phase I study, we performed a multicenter phase II study of daily oral sorafenib in patients with recurrent or metastatic sarcoma. PATIENTS AND METHODS We employed a multiarm study design, each representing a sarcoma subtype with its own Simon optimal two-stage design. In each arm, 12 patients who received 0 to 1 prior lines of therapy were treated (0 to 3 for angiosarcoma and malignant peripheral-nerve sheath tumor).

A phase I and pharmacokinetic study of the quinoxaline antitumour Agent R(+)XK469 in patients with advanced solid tumours.

Purpose: To investigate the safety and pharmacokinetics of R(+)XK469, a quinoxaline analogue, in patients with advanced refractory solid tumours. Preclinical studies suggested that efficacy was independent of schedule but that toxicity was decreased by dividing the dose.

Methods: R(+)XK469 was initially administered as a 30 min intravenous infusion on days 1-5 of a 21-d cycle.

A phase I and pharmacokinetic study of XK469R (NSC 698215), a quinoxaline phenoxypropionic acid derivative, in patients with refractory acute leukemia.

A phase I study was performed to determine the safety and pharmacokinetics of XK469R in patients with refractory acute leukemia. The study aimed to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of XK469R given intravenously over 30 to 60 min on days 1, 3, and 5 of a 21 day cycle. Patients were treated in successive cohorts of six until DLT was observed.

Histologic response of dose-intense chemotherapy with preoperative hypofractionated radiotherapy for patients with high-risk soft tissue sarcomas.

Background: The authors studied a dose-intense regimen of epirubicin and ifosfamide with hypofractionated preoperative radiotherapy for high-risk soft tissue sarcomas. The primary objective was estimation of the rate of >or=95% pathologic necrosis.

Methods: Twenty-five patients with intermediate-grade or high-grade, localized soft tissue sarcomas of the extremity or body wall measuring >5 cm were treated with epirubicin at a dose of 30 mg/m(2)/day on Days 1 to 4 and ifosfamide at a dose of 2.

A phase II study of ixabepilone (BMS-247550) in metastatic renal-cell carcinoma.

Introduction: Ixabepilone (BMS-247550) is a semi-synthetic analog of epothilone B that has been characterized as a microtubule stabilizing agent with a mechanism of action distinct from taxanes. Suggestion of activity in renal cell carcinoma (RCC) has been seen in early clinical studies.

Methods: Eligible patients had metastatic RCC as well as ECOG performance status 0-2 and normal organ function.

Spinal cord metastasis of a non-neurofibromatosis type-1 malignant peripheral nerve sheath tumor: an unusual manifestation of a rare tumor.

Malignant peripheral nerve sheath tumors are rare spindle-cell sarcomas derived from Schwann cells or pluripotent cells of the neural crest. They arise from the spinal roots, peripheral nerves, brachial and lumbosacral plexi, cranial nerves and terminal nerve fibers within soft tissue, intestine, lung and bone. These tumors recur either locally, or metastasize distally.

Pharmacokinetic variability of anticancer agents.

The translation of advances in cancer biology to drug discovery can be complicated by pharmacokinetic variation between individuals and within individuals, and this can result in unpredictable toxicity and variable antineoplastic effects. Previously unrecognized variables (such as genetic polymorphisms) are now known to have a significant impact on drug disposition. How can the pharmacokinetic variability of anticancer agents be reduced? This will require the understanding of correlations between pharmacokinetics and treatment outcomes, the identification of relevant patient parameters, mathematical modelling of individual and population pharmacokinetics, and the development of algorithms that will tailor doses to the individual patient.

A phase I trial of pharmacologic modulation of irinotecan with cyclosporine and phenobarbital.

The anticancer agent irinotecan has been demonstrated to improve the survival rate in patients with metastatic colorectal cancer. Its usage has been limited by severe toxicity. To modulate irinotecan pharmacokinetics and reduce the prevalence of severe toxicity, patients were treated with cyclosporine (INN, ciclosporin) and the irinotecan dose was increased from 25 to 72 mg/m2 weekly.

Phase I clinical trial of CEP-2563 dihydrochloride, a receptor tyrosine kinase inhibitor, in patients with refractory solid tumors.

CEP-2563 dihydrochloride (CEP-2563) is a soluble lysinyl-beta-alanyl ester of CEP-751, a potent inhibitor of the trk family of receptor tyrosine kinases and the platelet-derived growth factor (PDGF) receptor tyrosine kinase. CEP-2563 was developed because of the limited aqueous solubility of CEP-751. Preclinical models have demonstrated that both CEP-751 and CEP-2563 have antitumor activity in a variety of tumors.