Clinical Efficacy of TroVax in the Treatment of Progressive Castration-resistant Prostate Cancer

With approximately 240,890 new cases expected in 2011, prostate cancer remains the leading cause of non-melanoma cancer deaths in men. Immunotherapies using viral vector-based delivery systems targeting tumor-specific antigens are being studied. Viral vector-based delivery systems present tumor-targeted antigens (TAAs) to the immune system while breaking self-tolerance. Modified vaccinia ankara has been combined with the oncofetal antigen 5T4 to create TroVax for the treatment of castration-resistant prostate cancer (CRPC). The 5T4 antigen is highly expressed in a large number of carcinomas, including prostate cancer, but is rarely expressed in healthy tissue. TroVax has been demonstrated to be safe and highly immunogenic, both as monotherapy and in combination with other standard of care therapies in colorectal, renal cell, and prostate cancer. With minimal side effects and the ability to produce a strong immunogenic response, TroVax (MVA-5T4) is a viable addition to the treatment of prostate cancer

Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel

A major use of the 1000 Genomes Project (1000GP) data is genotype imputation in genome-wide association studies (GWAS). Here we develop a method to estimate haplotypes from low-coverage sequencing data that can take advantage of single-nucleotide polymorphism (SNP) microarray genotypes on the same samples. First the SNP array data are phased to build a backbone (or 'scaffold') of haplotypes across each chromosome. We then phase the sequence data 'onto' this haplotype scaffold. This approach can take advantage of relatedness between sequenced and non-sequenced samples to improve accuracy. We use this method to create a new 1000GP haplotype reference set for use by the human genetic community. Using a set of validation genotypes at SNP and bi-allelic indels we show that these haplotypes have lower genotype discordance and improved imputation performance into downstream GWAS samples, especially at low-frequency variants. © 2014 Macmillan Publishers Limited. All rights reserved

911PD - A first-in-human phase I/II trial of the oral HIF-2a inhibitor PT2977 in patients with advanced RCC

Hypoxia-inducible factor (HIF)-2α is a transcription factor that is a key oncogenic driver in renal cell carcinoma (RCC). PT2977 is a potent and selective small molecule HIF-2α inhibitor that prevents HIF-2α from heterodimerizing with HIF-1β, blocking the expression of HIF-2α target genes in tumour cells, and inducing regressions in mouse xenograft RCC models. Patients with advanced solid tumours were treated with PT2977 in a dose-escalation design to determine the recommended Phase 2 dose (RP2D). Patients with advanced clear cell RCC who had received at least one prior therapy were enrolled in an expansion cohort at the RP2D of 120mg orally once daily. 55 pts were treated with PT2977 120mg (three in dose escalation; 52 in expansion). Median number of prior therapies was 3 (1-9). 73% of patients were intermediate risk and 18% were poor risk by IMDC criteria. As of March 15, 2019, the most common all-grade, all-cause adverse events (AEs) > 25% are anemia (75%), fatigue (64%), dyspnea (44%), nausea (33%), peripheral edema (29%) and cough (27%). Anemia (20%) and hypoxia (11%) are the most common Grade 3 AEs and on-target effects of HIF2α inhibition. Discontinuation due to a treatment-related AE was reported in 2 patients (4%). 13 patients (24%) experienced a confirmed PR and 30 patients (54%) had SD, with a clinical benefit rate of 78%. Follow-up for all patients has been at least 40 weeks and the probability of PFS at 40 weeks is 50.1%. PT2977 is well tolerated and has a favorable safety profile. The clinical activity of PT2977 shows promise for the treatment of RCC. A PT2977 monotherapy Phase 3 trial in previously treated advanced RCC patients is planned. NCT02974738. Peloton Therapeutics, Inc. Peloton Therapeutics, Inc. E. Jonasch: Advisory / Consultancy, Research grant / Funding (self): Exelixis; Research grant / Funding (institution): Peloton Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Eisai; Advisory / Consultancy: Genentech; Advisory / Consultancy: Ipsen. E.R. Plimack: Research grant / Funding (institution): Peloton Therapeutics; Research grant / Funding (institution): Astellas; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Incyte; Advisory / Consultancy: Janssen; Advisory / Consultancy: AstraZeneca. T. Bauer: Research grant / Funding (institution): Peloton Therapeutics; Research grant / Funding (institution): ARMO Biosciences; Research grant / Funding (institution): Foundation Medicine; Research grant / Funding (institution): Phosplatin Therapeutics; Research grant / Funding (institution): Karyopharm Therapeutics; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Loxo; Research grant / Funding (institution): Top Alliance BioScience; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): Sanofi; Advisory / Consultancy, Research grant / Funding (institution): Moderna Therapeutics; Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Pfizer; Research grant / Funding (institution): Aileron Therapeutics; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Calithera Biosciences; Advisory / Consultancy, Research grant / Funding (institution): Ignyta; Research grant / Funding (institution): Immugen. J.R. Merchan: Research grant / Funding (institution): Peloton Therapeutics; Advisory / Consultancy: Exelixis; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Tocagen; Research grant / Funding (institution): Vyriad; Research grant / Funding (institution): Silagen; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Corvus; Research grant / Funding (institution): RepImmune; Research grant / Funding (institution): Rexahn. K.P. Papadopoulos: Research grant / Funding (institution): Peloton Therapeutics; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): ADC Therapeutics; Research grant / Funding (institution): ARMO Biosciences; Advisory / Consultancy, Research grant / Funding (institution): ArQule; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Calithera Biosciences; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): 3D Medicines; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Syros Pharmaceuticals; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Jounce Therapeutics; Research grant / Funding (institution): MabSpace Biosciences; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Mersana; Research grant / Funding (institution): Regereron; Research grant / Funding (institution): Sanofi. D.F. McDermott: Advisory / Consultancy, Research grant / Funding (institution): Peloton Therapeutics; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Exelixis; Honoraria (self), Advisory / Consultancy: Array BioPharm; Honoraria (self), Advisory / Consultancy: Genentech; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: EMD Serono; Research grant / Funding (institution): Prometheus Laboratories; Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self): Jounce Therapeutics. M.D. Michaelson: Research grant / Funding (institution): Peloton Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Merck; Advisory / Consultancy: Exelixis. L.J. Appleman: Research grant / Funding (institution): Peloton Therapeutics; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Acerta; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Agensys; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Tokai; Research grant / Funding (institution): AVEO; Research grant / Funding (institution): Calithera; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Inovio; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Eli Lilly. S. Thamake: Shareholder / Stockholder / Stock options, Full / Part-time employment: Peloton Therapeutics. N. Zojwalla: Shareholder / Stockholder / Stock options, Full / Part-time employment: Peloton Therapeutics. T.K. Choueiri: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Peloton Therapeutics; Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Tracon; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Eisai; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Foundation Medicine; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Exelixis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Ipsen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Genentech; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): GlaxoSmithKline; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / F