Genomic correlates of clinical outcome in advanced prostate cancer.

Heterogeneity in the genomic landscape of metastatic prostate cancer has become apparent through several comprehensive profiling efforts, but little is known about the impact of this heterogeneity on clinical outcome. Here, we report comprehensive genomic and transcriptomic analysis of 429 patients with metastatic castration-resistant prostate cancer (mCRPC) linked with longitudinal clinical outcomes, integrating findings from whole-exome, transcriptome, and histologic analysis. For 128 patients treated with a first-line next-generation androgen receptor signaling inhibitor (ARSI; abiraterone or enzalutamide), we examined the association of 18 recurrent DNA- and RNA-based genomic alterations, including androgen receptor (AR) variant expression, AR transcriptional output, and neuroendocrine expression signatures, with clinical outcomes. Of these, only RB1 alteration was significantly associated with poor survival, whereas alterations in RB1, AR, and TP53 were associated with shorter time on treatment with an ARSI. This large analysis integrating mCRPC genomics with histology and clinical outcomes identifies RB1 genomic alteration as a potent predictor of poor outcome, and is a community resource for further interrogation of clinical and molecular associations.

Advanced solid tumors treated with cediranib: comparison of dynamic contrast-enhanced MR imaging and CT as markers of vascular activity.

PURPOSE: To assess baseline reproducibility and compare performance of dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging versus DCE computed tomographic (CT) measures of early vascular response in the same patients treated with cediranib (30 or 45 mg daily). MATERIALS AND METHODS: After institutional review board approval, written informed consent was obtained from 29 patients with advanced solid tumors who had lesions 3 cm or larger and in whom simultaneous imaging of an adjacent artery was possible. Two baseline DCE MR acquisitions and two baseline DCE CT acquisitions 7 days or fewer apart (within 14 days of starting treatment) and two posttreatment acquisitions with each modality at day 7 and 28 (±3 days) were obtained. Nonmodeled and modeled parameters were derived (measured arterial input function [AIF] for CT, population-based AIF for MR imaging; temporal sampling rate of 0.5 second for CT, 3-6 seconds for MR imaging). Baseline variability was assessed by using intra- and intersubject analysis of variance and Bland-Altman analysis; a paired t test assessed change from baseline to after treatment. RESULTS: The most reproducible parameters were DCE MR imaging enhancement fraction (baseline intrapatient coefficient of variation [CV]=8.6%), volume transfer constant (CV=13.9%), and integrated area under the contrast agent uptake curve at 60 seconds (CV=15.5%) and DCE CT positive enhancement integral (CV=16.0%). Blood plasma volume was highly variable and the only parameter with CV greater than 30%. Average reductions (percentage change) from baseline were consistently observed for all DCE MR imaging and DCE CT parameters at day 7 and 28 for both starting-dose groups (45 and 30 mg), except for DCE CT mean transit time. Percentage change from baseline for parameters reflecting blood flow and permeability were comparable, and reductions from baseline at day 7 were maintained at day 28. CONCLUSION: DCE MR imaging and DCE CT can depict vascular response to antiangiogenic agents with response evident at day 7. Improved reproducibility with MR imaging favors its use in trials with small patient numbers.

Two-stage phase I dose-escalation study of intratumoral reovirus type 3 dearing and palliative radiotherapy in patients with advanced cancers.

PURPOSE: To determine the safety and feasibility of combining intratumoral reovirus and radiotherapy in patients with advanced cancer and to assess viral biodistribution, reoviral replication in tumors, and antiviral immune responses. EXPERIMENTAL DESIGN: Patients with measurable disease amenable to palliative radiotherapy were enrolled. In the first stage, patients received radiotherapy (20 Gy in five fractions) plus two intratumoral injections of RT3D at doses between 1 x 10(8) and 1 x 10(10) TCID(50). In the second stage, the radiotherapy dose was increased (36 Gy in 12 fractions) and patients received two, four, or six doses of RT3D at 1 x 10(10) TCID(50). End points were safety, viral replication, immunogenicity, and antitumoral activity. RESULTS: Twenty-three patients with various solid tumors were treated. Dose-limiting toxicity was not seen. The most common toxicities were grade 2 (or lower) pyrexia, influenza-like symptoms, vomiting, asymptomatic lymphopenia, and neutropenia. There was no exacerbation of the acute radiation reaction. Reverse transcription-PCR (RT-PCR) studies of blood, urine, stool, and sputum were negative for viral shedding. In the low-dose (20 Gy in five fractions) radiation group, two of seven evaluable patients had a partial response and five had stable disease. In the high-dose (36 Gy in 12 fractions) radiation group, five of seven evaluable patients had partial response and two stable disease. CONCLUSIONS: The combination of intratumoral RT3D and radiotherapy was well tolerated. The favorable toxicity profile and lack of vector shedding means that this combination should be evaluated in newly diagnosed patients receiving radiotherapy with curative intent.

Phase I safety, pharmacokinetic, and pharmacogenomic trial of ES-285, a novel marine cytotoxic agent, administered to adult patients with advanced solid tumors.

A dose-escalation, phase I study evaluated the safety, pharmacokinetics, pharmacogenomics, and efficacy of ES-285, a novel agent isolated from a marine mollusc, in adult cancer patients. Patients received a 24-hour i.v. infusion of ES-285 once every 3 weeks until disease progression or unacceptable toxicity. The starting dose was 4 mg/m(2). Dose escalation in cohorts of at least three patients proceeded according to the worst toxicity observed in the previous cohort. Twenty-eight patients were treated with 72 courses of ES-285 across eight dose levels. No dose-limiting toxicities were seen between 4 and 128 mg/m(2). Two of four patients treated at 256 mg/m(2) had dose-limiting reversible grade 3 transaminitis; one patient at 256 mg/m(2) also had transient grade 3 central neurotoxicity. One of three patients subsequently treated at 200 mg/m(2) died following drug-related central neurotoxicity. Other toxicities included phlebitis, nausea, fatigue, and fever. Pharmacokinetic studies indicated dose proportionality with high volume of distribution (median V(ss) at 256 mg/m(2) was 2,389 liters; range, 1,615-4,051 liters) and long elimination half life (median t(1/2) at 256 mg/m(2) was 28 h; range, 21-32 h). The three patients with dose-limiting toxicity had the highest drug exposure. Pharmacogenomic studies of paired surrogate tissue samples identified changes in gene expression following treatment that correlated with increasing dose. Disease stabilization for 6 to 18 weeks was recorded in nine patients. Using this schedule, 128 mg/m(2) was considered safe and feasible. At this dose, pharmacologically relevant concentrations of the drug were safely achieved with pharmacogenomic studies indicating changes in the expression of genes of potential mechanistic relevance.

Phase I and pharmacokinetic study of XRP6258 (RPR 116258A), a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid tumors.

PURPOSE: To assess the feasibility of administering XRP6258, a new taxane with a low affinity for the multidrug resistance 1 protein, as a 1-hour i.v. infusion every 3 weeks. The study also sought to determine the maximum tolerated dose and the recommended dose, to describe the pharmacokinetic (PK) behavior of the compound, and to seek preliminary evidence of anticancer activity. EXPERIMENTAL DESIGN: Twenty-five patients with advanced solid malignancies were treated with 102 courses of XRP6258 at four dose levels ranging from 10 to 25 mg/m(2). Dose escalation was based on the occurrence of dose-limiting toxicity (DLT) at each dose level, provided that PK variables were favorable. The maximum tolerated dose was defined as the dose at which at least two patients developed a DLT at the first course. RESULTS: Neutropenia was the principal DLT, with one patient experiencing febrile neutropenia and two others showing prolonged grade 4 neutropenia at the 25 mg/m(2) dose level. Nonhematologic toxicities, including nausea, vomiting, diarrhea, neurotoxicity, and fatigue, were generally mild to moderate in severity. XRP6258 exhibited dose-proportional PK, a triphasic elimination profile, a long terminal half-life (77.3 hours), a high clearance (mean CL, 53.5 L/h), and a large volume of distribution (mean V(ss), 2,034 L/m(2)). Objective antitumor activity included partial responses in two patients with metastatic prostate carcinoma, one unconfirmed partial response, and two minor responses. CONCLUSION: The recommended phase II dose of XRP6258 on this schedule is 20 mg/m(2). The general tolerability and encouraging antitumor activity in taxane-refractory patients warrant further evaluations of XRP6258.

A phase I study of intravenous oncolytic reovirus type 3 Dearing in patients with advanced cancer.

PURPOSE: To determine the safety and feasibility of daily i.v. administration of wild-type oncolytic reovirus (type 3 Dearing) to patients with advanced cancer, assess viral excretion kinetics and antiviral immune responses, identify tumor localization and replication, and describe antitumor activity. EXPERIMENTAL DESIGN: Patients received escalating doses of reovirus up to 3 x 10(10) TCID(50) for 5 consecutive days every 4 weeks. Viral excretion was assessed by reverse transcription-PCR and antibody response by cytotoxicity neutralization assay. Pretreatment and post-treatment tumor biopsies were obtained to measure viral uptake and replication. RESULTS: Thirty-three patients received 76 courses of reovirus from 1 x 10(8) for 1 day up to 3 x 10(10) TCID(50) for 5 days, repeated every four weeks. Dose-limiting toxicity was not seen. Common grade 1 to 2 toxicities included fever, fatigue, and headache, which were dose and cycle independent. Viral excretion at day 15 was not detected by reverse transcription-PCR at 25 cycles and only in 5 patients at 35 cycles. Neutralizing antibodies were detected in all patients and peaked at 4 weeks. Viral localization and replication in tumor biopsies were confirmed in 3 patients. Antitumor activity was seen by radiologic and tumor marker (carcinoembryonic antigen, CA19.9, and prostate-specific antigen) evaluation. CONCLUSIONS: Oncolytic reovirus can be safely and repeatedly administered by i.v. injection at doses up to 3 x 10(10) TCID(50) for 5 days every 4 weeks without evidence of severe toxicities. Productive reoviral infection of metastatic tumor deposits was confirmed. Reovirus is a safe agent that warrants further evaluation in phase II studies.

Reovirus therapy in cancer: has the orphan virus found a home?

There has been great interest in the development of oncolytic viruses - viruses that selectively destroy tumour cells - as cancer therapeutics. Reovirus holds great promise as an anticancer therapy, not just because it is a wild type virus that inherently displays selective tumour cytotoxicity in cancers with active Ras signalling pathways but also because it results only in relatively benign infections with few minor symptoms. As many tumours have an activated Ras pathway, the potential for utilizing reovirus as an effective anticancer agent is substantial. The several challenges that need to be overcome in the development of oncolytic viruses as anticancer agents, including issues of systemic toxicity, tumour selectivity and immune response, are addressed in this review. Clinical studies with the objective of developing Reolysin (human reovirus serotype 3 Dearing) as a human cancer therapeutic are currently underway. The first human Phase I study with intravenous Reolysin has now been completed and further studies, including Phase I and II clinical trials using Reolysin alone and in combination with radiation or chemotherapy, delivered via local or systemic intravenous administration, have commenced.

A phase 1 pharmacokinetic and pharmacodynamic study of the histone deacetylase inhibitor belinostat in patients with advanced solid tumors.

PURPOSE: To determine the safety, dose-limiting toxicity, maximum tolerated dose, and pharmacokinetic and pharmacodynamic profiles of the novel hydroxamate histone deacetylase inhibitor belinostat (previously named PXD101) in patients with advanced refractory solid tumors. EXPERIMENTAL DESIGN: Sequential dose-escalating cohorts of three to six patients received belinostat administered as a 30-min i.v. infusion on days 1 to 5 of a 21-day cycle. Pharmacokinetic variables were evaluated at all dose levels. Pharmacodynamic measurements included acetylation of histones extracted from peripheral blood mononuclear cells, caspase-dependent cleavage of cytokeratin-18, and interleukin-6 levels. RESULTS: Forty-six patients received belinostat at one of six dose levels (150-1,200 mg/m(2)/d). Dose-limiting toxicities were grade 3 fatigue (one patient at 600 mg/m(2); one patient at 1,200 mg/m(2)), grade 3 diarrhea combined with fatigue (one patient at 1,200 mg/m(2)), grade 3 atrial fibrillation (one patient at 1,200 mg/m(2); one patient at 1,000 mg/m(2)), and grade 2 nausea/vomiting leading to inability to complete a full 5-day cycle (two patients at 1,000 mg/m(2)). The maximum tolerated dose was 1,000 mg/m(2)/d. I.v. belinostat displayed linear pharmacokinetics with respect to C(max) and AUC. The intermediate elimination half-life was 0.3 to 1.3 h and was independent of dose. Histone H4 hyperacetylation was observed after each infusion and was sustained for 4 to 24 h in a dose-dependent manner. Increases in interleukin-6 levels were detected following belinostat treatment. Stable disease was observed in a total of 18 (39%) patients, including 15 treated for > or =4 cycles, and this was associated with caspase-dependent cleavage of cytokeratin-18. Of the 24 patients treated at the maximum tolerated dose (1,000 mg/m(2)/d), 50% achieved stable disease. CONCLUSIONS: I.v. belinostat is well tolerated, exhibits dose-dependent pharmacodynamic effects, and has promising antitumor activity.

Phase I and pharmacokinetic study of tasidotin hydrochloride (ILX651), a third-generation dolastatin-15 analogue, administered weekly for 3 weeks every 28 days in patients with advanced solid tumors.

PURPOSE: To determine the safety, tolerability, and pharmacokinetics and to seek preliminary evidence of anticancer activity of tasidotin (ILX651), a novel dolastatin analogue, when administered as a 30-minute i.v. infusion weekly for 3 weeks every 4 weeks. EXPERIMENTAL DESIGN: Thirty patients with advanced solid malignancies were treated with 82 courses at six dose levels ranging from 7.8 to 62.2 mg/m2 weekly, initially according to an accelerated dose-escalation scheme, which evolved into a Fibonacci scheme as a relevant degree of toxicity was observed. Plasma and urine were sampled to characterize the pharmacokinetic behavior of tasidotin. RESULTS: A high incidence of neutropenia complicated by fever (one patient), or precluding treatment on day 15 (three patients), was the principal toxicity of tasidotin, at doses above 46.8 mg/m2. At all dose levels, nonhematologic toxicities were generally mild to moderate and manageable. Grade 3 toxicities included diarrhea and vomiting (one patient each). Drug-induced neurosensory symptoms were mild and there was no evidence of cardiovascular toxicity, which has been previously associated with other dolastatins. Tasidotin pharmacokinetics were mildly nonlinear, whereas metabolite kinetics were linear. A patient with non-small cell lung carcinoma experienced a minor response, and a patient with hepatocellular carcinoma had stable disease lasting 11 months. CONCLUSIONS: The recommended dose for phase II studies of tasidotin administered on this schedule is 46.8 mg/m2. The mild myelosuppression and manageable nonhematologic toxicities at the recommended dose, the evidence of antitumor activity, and the unique mechanistic aspects of tasidotin warrant further disease-directed evaluations on this and alternative schedules.