1 Ulrik Lassen MD, PH.D Phase 1 Unit Personalised Cancer Medicine in Phase 1 Cancer Research at RigshospitaletUlrik LassenMD, PH.DPhase 1 Unit
2 BackgroundNew targeted therapy is selected according to specific molecular alterations in the tumorsDetermination of HER2-gene expression in breast cancer is a routine due to treatment with trastuzumab (Herceptin).Analysis af K-ras mutation status is a routine in order to select patients with colorectal cancer for anti-EGFR therapyAlso EGFR and ALK mutations in lung cancer
3 There may be an advantage by selecting patients Tumor regression was seen in 30% of patients with mutations, compared to 10% of patients without mutations.There may be an advantage by selecting patientsTitel/beskrivelse (Sidehoved/fod)
4 Non-small cell lung cancer - subtyping Erlotinib, gefitinibcrizotinib
5 ALK-inhibition in NSCLC 31 heavily pre-treated patients with NSCLC and ALK re-arrangement tested in a Phase 1 trial.20/31 had regression, (including 1 CR; and long-term regression - median 24 weeks)The fusion gene was first identified in NSCLC in 2007, clinical activity seen in 2009 – and crizotinib was FDA-approved in 2011Kwak EL et al, N Engl J Med 2010Mab og TKIUL/2012
6 Phase 1 trial:Partial remission in 81% of patients with Braf-V600E+ melanoma (960 mg BID)Enlarge and brighten title and authors of phase ! expansionInvestigator assessmentsIncludes confirmed & unconfirmed responses6
9 Schedule of assessments: Differential timing of dosing, PD biopsy, and imaging Schedule A: QWEnd of Cycle 2 ScansFDG PETTumor BxRG7212 dosing…Cycle 1ScrD1D2D3D4D8D15D17Cycle 2D1D2D4D8D15RG7212 dosingTumor BxFDG PETEnd of Cycle 2 ScansSchedule B: Q3WBoth schedules: blood samples taken at multiple time points for PK and PD assessments
10 Titel/beskrivelse (Sidehoved/fod) Navn (Sidehoved/fod)
11 The most important finding at the moment is the feasibility of performing complex molecular characterization in daily clinical practice. A hundred patients were enrolled in seven months. For some patients, the results of the analyses changes the phase 1 trials and treatments for which they were being consideredTitel/beskrivelse (Sidehoved/fod)Navn (Sidehoved/fod)
12 Also in Denmark?Patients with good performance status and tumor lesions assessable for biopsy are included in a study of genomic characterizationA collaboration between the Phase 1 Unit, Pathology, Genomic Medicine, Clinical Genetics, Diagnostic Radiology and BioinformaticsImportant for drug development, attracting new studies and allocating patients for studiesWe are part of an European network and hope to be able to distribute patients for enrichment of studies in the future
13 Complete genomic profile of phase 1 population Up to 200 patients are referred to the Phase 1 Unit every year.Every patient will be asked for a signed informedEligible patients are required to fulfill normal criteria for entering early phase studies, including normal organ function and adequate performance status, as well as measurable disease.Most patient fulfill these criteria, and it is anticipated that 500 patients will be eligible during the project period (5 years).Patients will be referred for ultrasound-guided tumor biopsies with 18 Gauge needle.Biopsies snap-frozen/RNA-later and paraffin-embedded as well as verified for their representativeness, tumor cell content, and suitability for molecular analysis at the Department of Pathology
14 Genome-wide technologies and identification of tumor specific genetic changes The Center for Genomic Medicine functions as core facility for array and NGS technologies and covers all necessary high-throughput analyses from microarray-based transcriptome profiling to analysis of SNP arrays (Affymetrix) as well as NGS (Illumina and Roche platforms).The pipeline from biopsy to isolation of DNA and RNA is firmly established as part of our front-line work-up of carcinoma of unknown origin and childhood solid tumours, which are subject to array analysis and exome sequencing, respectively.All samples are handled according to standard operation procedures and quality control parameters according to MIAME and Tumor Analysis Best Practices Working Group
16 List of first line therapeutic targets Whole exome ~23,000 genes (research))First line gene targets are sequenced to a coverage above x (labelled in RED (n=48)).Second line genes labelled in BLACK (n=117) and whole exome (n=23.000) are sequenced to anaverage coverage of x.
17 Status1 breast cancer patient with ROS1 mutation: - offered crizotinibSeveral patients with either BRCA-mut, low p53 or ATM – allocated to PARP-inhibitorsSeveral patients with FGF-ligand overexpression - allocated for studies with FGFR-modifying agentsNo specific pattern – allocated to other Phase 1 studies
18 The perspectives of gene profiling Enrichment of population for phase 1 studiesAttracting more studies and offering personalized therapy for the patientsRecruiting patientsReferring patients for appropriate studies locally and globallyOffering treatment with selected marketed targeted agents
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