ARIEL2 and ARIEL3: An integrated clinical trial

ARIEL2 and ARIEL3: An integrated clinical trial program to
assess activity of rucaparib in ovarian cancer and to identify
tumor molecular characteristics predictive of response
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1. University of Washington School of Medicine, Seattle, WA; 2. Institute of Cancer Sciences, University of Glasgow,
Glasgow, UK; 3. The University of Texas MD Anderson Cancer Center, Houston, TX; 4. Cancer Research UK Cambridge
Institute, Cambridge, UK; 5. Mayo Clinic, Rochester, MN; 6. Clovis Oncology, Inc., San Francisco, CA and Boulder, CO;
7. UCL Cancer Institute, University College London, London, UK
BACKGROUND
ARIEL2 STUDY OVERVIEW (NCT01891344)
• Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are active in patients with
mutations in BRCA1 and BRCA2, critical components of homologous recombination
(HR) repair
Half of high-grade serous ovarian cancers may be
deficient in homologous recombination2
• PARPi activity extends beyond BRCA1/2 mutations1, most likely in tumors with other
genetic defects leading to homologous recombination deficiency (HRD)
8%
• Approximately 50% of women with high-grade serous ovarian cancer (HGSOC) have
either a BRCA1/2 mutation or other defects in DNA repair in their tumor2
• Germline
~25%
BRCAmut
• Non-BRCA HRD
Progression-free survival (PFS) in molecularly
defined HRD subgroups
600 mg BID
rucaparib
continuously until
disease
progression by
RECIST v1.1
• High-grade serous or endometrioid
epithelial ovarian, fallopian tube, or
primary peritoneal cancer
• ≥1 prior platinum-based regimen &
last treatment platinum-based
Secondary:
Clinic visits
Q2–4wks
• Overall response rate (ORR) and duration of
response (DOR) (RECIST v1.1 and/or GCIG
CA-125 criteria)
• Safety
• Trough (Cmin) level rucaparib PK
CT scans
Q8wks
Exploratory:
• Platinum-sensitive, relapsed disease
• HR
proficient
~50%
• ARIEL, a novel, integrated translational-clinical program, is now underway to
identify patients who may benefit from rucaparib treatment
• Adequate tumor tissue (archival and
fresh biopsy)
• Efficacy in HRD subgroups defined by
alternative HRD algorithms
• Measurable disease
• Adequate organ function; ECOG 0–1
HRD signature is comprised of BRCA and genomic LOH
• BROCA-HRD NGS panel testing of tumor
and blood
• No prior PARPi
• Molecular profile of tumor over time
Other HR defects
Homozygous deletions
Gene expression
miRNA
Planned analyses
Primary:
Key eligibility:
• Somatic BRCAmut
15%
• Rucaparib, an oral PARPi being developed for high-grade ovarian cancer associated
with HRD and pancreatic cancer associated with a BRCA mutation, has consistent
and predictable exposure, is well tolerated, and has demonstrated RECIST and
CA-125 responses in BRCAmut pancreatic, ovarian, and breast cancer in an ongoing
Phase 1/2 study (NCT01482715)3
HR genetic defects
Rucaparib treatment phase
(known gBRCAmut limited to 15)
• Next-generation sequencing (NGS) analysis of tumor tissue can identify germline and
somatic BRCA mutations (BRCAmut), as well as other gene alterations in the DNA
repair pathway, and may therefore be a superior method for selection of patients for
PARPi therapy
Multiple mechanisms result in HRD and genomic scarring
Screening phase
N=180 patients
• Platinum sensitivity, often used as a surrogate predictive indicator for PARPi
response, does not adequately identify all patients likely to respond; the best
molecular predictors of PARPi response are currently unknown
Mutations
Abstract
TPS5619
Elizabeth M. Swisher1, Iain A. McNeish2, Robert L. Coleman3, James D. Brenton4, Scott H. Kaufmann5,
Andrew R. Allen6, Mitch Raponi6, Kevin K. Lin6, Heidi Giordano6, Lara Maloney L6, Jeffrey Isaacson6,
Jonathan A. Ledermann7
• Mechanisms of resistance
• Gene mutations in ctDNA as longitudinal
monitoring of patient response
Methylation
• Gene expression signatures related to
patient outcome
Defective HR protein
Defective HR pathway expression
Ovarian
cancer
HR deficiency
ARIEL3 STUDY DESIGN (NCT01968213)
• A large proportion of HGSOC has genomic loss of heterozygosity (LOH)3
• Most, but not all, BRCA1/2 mutant tumors exhibit high genomic LOH
Genomic scarring
Screening phase
Blinded treatment phase
Planned analyses
NEXT-GENERATION SEQUENCING CAN IDENTIFY TUMORS WITH HRD-PHENOTYPE
NGS platform detects genetic alterations
and the genomic scarring phenotype (LOH)
LOH approach identifies HGSOC patients in TCGA
with better outcome to platinum-based chemotherapy2
100
Deletions
Mutations
(eg, BRCA)
Translocations
Amplifications
LOH
Next Generation
Sequencing
Overall survival (probability)
Examples of DNA
aberration
“genomic scars”
80
•
•
•
•
HRD specifically leads to genomic LOH – a “BRCAness” phenotype
NGS platform sequences single nucleotide polymorphisms (SNPs)
SNP analysis identifies and quantifies genomic LOH
NGS platform also sequences BRCA1/2 genes in tumor
Log-rank: P=0.000059
HR=0.54
40
• ≥2 prior platinum regimens; up to
1 non-platinum permitted
Median OS: 54.4 vs 36.1 months
20
0
25
50
75
100
125
150
175
Overall survival (months)
• TCGA SNP6 data from 309 HGSOC patients was analyzed using the
HRD algorithm
• An optimized cut-off for genomic LOH was applied to the dataset
DEFINITION AND APPLICATION OF HRD TEST IN ARIEL CLINICAL TRIALS
HRD algorithm = BRCA status + genomic LOH
• Sensitive to penultimate platinum
regimen (i.e., radiologic disease
progression >6 months after last
dose of platinum)
• CR or PR (RECIST or GCIG
CA-125 criteria) to most recent
platinum regimen (≥4 cycles)
AND CA-125 ≤ ULN
• Available archival tumor tissue
Rucaparib response signature will be optimized
in ARIEL2 and prospectively validated in ARIEL3
Primary:
N=540 patients
• High-grade serous or
endometrioid epithelial ovarian,
fallopian tube, or primary
peritoneal cancer
60
0
Rucaparib
(known gBRCAmut limited to 150;
tBRCAmut limited to 200)
BRCA or high genomic LOH (n=139)
Non-BRCA and low genomic LOH (n=170)
Normal chromosomes
Key eligibility:
• Adequate organ function and
ECOG PS 0–1
2:1
Stratify:
• HRD
classification
• Response to
platinum
regimen
• Progressionfree interval
after
penultimate
platinum
R
A
N
D
O
M
I
Z
A
T
I
O
N
Study drug
BID until
disease
progression
by RECIST
Clinic visits
Q4wks
Genomic LOH low
BRCApositive
ARIEL2
study
•
•
•
•
Patient-reported outcome (FOSI-18)
Overall survival
Safety
Population PK
Long-term
FU Q12wks
Exploratory:
• CA-125 levels
Placebo
• PFS2 (time to next event of disease
progression)
• ORR and DOR
• Patient reported outcome on EQ-5D
• PK, PD, and safety correlation
ARIEL3
analysis
SUMMARY
HRD-negative
ARIEL3 study
References
1.
2.
3.
• PFS by independent radiology
Optimized
HRD
signature
ARIEL2
analysis
BRCAnegative
• The HRD algorithm is comprised of two elements
– Tumor BRCA1/2 mutation
– Genomic LOH
• A tumor is defined as HRD-negative if it is BRCAwt with low genomic LOH
Secondary:
CT scans
Q12wks
• No prior PARPi
Genomic LOH high
PFS in molecularly-defined
HRD subgroups
Ledermann J et al. N Engl J Med 2012;366:1382–1392.
Cancer Genome Atlas Research Network. Nature 2011;474:609–615.
Kristeleit R et al. ASCO 2014;abstr 2573.
Presented at the American Society of Clinical Oncology (ASCO) 50th Annual Meeting, Chicago, IL, USA, May 30–June 3, 2014
• Molecular analysis of tumor tissue to assess BRCA1/2 mutations as well as LOH, a phenotypic
endpoint of HRD, could be a more inclusive method for selection of patients for PARPi therapy
• ARIEL, an ongoing, novel, integrated translational-clinical program, employs a unique strategy of
conducting two key trials in parallel
• The final HRD test will be defined in the Phase 2 study (ARIEL2) and prospectively validated in the
“all-comer” Phase 3 randomized pivotal trial (ARIEL3)
For more information on the ARIEL studies, please visit: www.arielstudy.com
or contact Clovis Oncology Medical Information at: [email protected]

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