Personalised Cancer Medicine
in Phase 1 Cancer Research
at Rigshospitalet
Ulrik Lassen
MD, PH.D
Phase 1 Unit
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
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
Titel/beskrivelse (Sidehoved/fod)
Non-small cell lung cancer - subtyping
Erlotinib, gefitinib
crizotinib
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
Mab og TKI
UL/2012
100
75
%Change From Baseline
(Sum of Lesion Size)
Phase 1 trial:
• Partial remission
in 81% of patients
with Braf-V600E+
melanoma
(960 mg BID)
50
25
0
-25
-50
-75
-100
• Investigator assessments
• Includes confirmed & unconfirmed responses
New track for early clinical trials
Schedule of assessments:
Differential timing of dosing, PD biopsy, and imaging
End of
Cycle 2
Scans
Schedule A: QW
FDG PET
Tumor Bx
RG7212
dosing
Cycle 1
Scr
D1
D2
D3
D4
D8
D15 D17 Cycle 2
D1
D2
D4
D8
D15
…
RG7212
dosing
Tumor Bx
FDG PET
Schedule B: Q3W
End of
Cycle 2
Scans
Both schedules: blood samples taken at multiple time points for PK and PD assessments
9
Titel/beskrivelse (Sidehoved/fod)
Navn (Sidehoved/fod)
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
Titel/beskrivelse (Sidehoved/fod)
Navn (Sidehoved/fod)
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
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
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 highthroughput 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
List of first line therapeutic targets
DHFR
EGFR
EPHA3
EPHA5
EPHB6
ERBB2
ERBB3
ERBB4
ERG
FAK
FAM123B
FBXW7
FGFR1
FGFR2
FGFR3
FGFR4
FHIT
FKBP9
FLCN
FLT1
FLT3
FLT4
FRAP1
GATA1
GNA11
GNAS/Q
GUCY1A2
HDAC1
HDAC2
HNF1A
HRAS
HSP90AA1
IDH1
IDH2
IGF1R
IKBKE
IKZF1
JAK2
JAK3
JNK
KDR
KEAP1
KIAA0774
KIAA1303
KIF11
KIT
KRAS
MAP2K1
MAP2K2
MAP2K4
MCL1
MDM2
MDM4
MEN1
MET
MITF
MLH1
MLL
MPL
MRE11A
MSH2
MSH6
MYC
MYCL1
MYCN
NF1
NF2
NFKB1
NKX2-1
NOTCH1
NOTCH2
NOTCH3
NOTCH4
NPM1
NRAS
NTRK1
NTRK2
NTRK3
PAX5
PDGFRA
PDGFRB
PDPK1
PIK3CA
PIK3R1
PLK1
PLK2
PLK3
PRKAA1
PRKAA2
PRKAb1
PTCH1
PTEN
PTK2B
PTPN11
PTPRD
RAF1
RARA
RARB
RARG
RB1
REL
RET
ROS1
RPS6KA
RUNX1
RUNX1T1
RXRa
RXRb
RXRg
SMAD2
SMAD3
SMAD4
SMARCA4
SMARCB1
SMO
SOCS1
SRC
STK11
TCF4
TERT
TET2
TGFBR2
TNF
TNFAIP3
TOP1
TOP2A
TP53
TSC1
TSC2
TSHR
VHL
WT1
Whole exome ~23,000 genes (research))
ABL1
ABL2
AKT1
AKT2
AKT3
ALK
ANDR
APC
ATM
AURKA
BCL2
BRAF
BRCA1
BRCA2
BTK
CCND1
CCNE1
CDC73
CDH1
CDK4
CDK6
CDK8
CDKN1A
CDKN2A
CEBPA
CHEK1
CHEK2
CREBBP
CRKL
CRTC1
CRTC2
CSF1R
CTNNB1
First line gene targets are sequenced to a coverage above 500 - 1000x (labelled in RED (n=48)).
Second line genes labelled in BLACK (n=117) and whole exome (n=23.000) are sequenced to an
average coverage of 50-100x.
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
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