Personalised Cancer Medicine in Phase 1 Cancer Research at Rigshospitalet

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Personalised Cancer Medicinein Phase 1 Cancer
Research at Rigshospitalet

• Ulrik Lassen
• MD, PH.D
• Phase 1 Unit

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Background

• New targeted therapy is selected according to
  specific molecular alterations in the tumors
• Determination 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 therapy
• Also EGFR and ALK mutations in lung cancer

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Tumor regression was seen in 30 of patients with
mutations, compared to 10 of patients without
mutations. There may be an advantage by
selecting patients
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Non-small cell lung cancer - subtyping
Erlotinib, gefitinib
crizotinib
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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 2011

Kwak EL et al, N Engl J Med 2010
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• Phase 1 trial
• Partial remissionin 81 of patients with
  Braf-V600E melanoma (960 mg BID)

• Investigator assessments
• Includes confirmed unconfirmed responses

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New track for early clinical trials
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Schedule of assessmentsDifferential timing of
dosing, PD biopsy, and imaging
End of Cycle 2 Scans
Schedule A QW
FDG PET
Tumor Bx
RG7212 dosing

Scr
D1
D2
D8
D15
Cycle 1
D1
D2
Cycle 2
D4
D8
D15
D3
D4
D17
RG7212 dosing
Tumor Bx
FDG PET
End of Cycle 2 Scans
Schedule B Q3W
Both schedules blood samples taken at multiple
time points for PK and PD assessments
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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 considered
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Also in Denmark?

• Patients with good performance status and tumor
  lesions assessable for biopsy are included in a
  study of genomic characterization
• A collaboration between the Phase 1 Unit,
  Pathology, Genomic Medicine, Clinical Genetics,
  Diagnostic Radiology and Bioinformatics
• Important for drug development, attracting new
  studies and allocating patients for studies
• We are part of an European network and hope to be
  able to distribute patients for enrichment of
  studies in the future

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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 informed
  
• Eligible 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

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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

www.rhmicroarray.com
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List of first line therapeutic targets
Whole exome 23,000 genes (research))
First line gene targets are sequenced to a
coverage above 500 - 1000x (labelled in RED
(n48)). Second line genes labelled in BLACK
(n117) and whole exome (n23.000) are sequenced
to an average coverage of 50-100x.
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Status

• 1 breast cancer patient with ROS1 mutation -
  offered crizotinib
• Several patients with either BRCA-mut, low p53 or
  ATM allocated to PARP-inhibitors
• Several patients with FGF-ligand overexpression
  -allocated for studies with FGFR-modifying
  agents
• No specific pattern allocated to other Phase 1
  studies

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The perspectives of gene profiling

• Enrichment of population for phase 1 studies
• Attracting more studies and offering personalized
  therapy for the patients
• Recruiting patients
• Referring patients for appropriate studies
  locally and globally
• Offering treatment with selected marketed
  targeted agents