Download A phase III randomized trial of niraparib versus physician`s

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Abstract # TPS659
A phase III randomized trial of niraparib versus physician’s choice in
previously- treated, HER2 negative, germline- BRCA mutated breast cancer
patients: An EORTC-BIG intergroup study
Tryfonidis K. , Bogaerts J. ,Balmana J. , Audeh W. , Sledge G. , Martell R. , Deleersnijder A. , Favorito F. ,
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Agarwal S. , Rizzetto G. , Messina C. , Slaets L. , Goulioti T. , Tutt A. , Cameron D. , Turner N.
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EORTC Headquarters, Brussels, BE • 2Vall d’Hebron, University Hospital, Barcelona, ES • 3Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, US •
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Stanford University, Palo Alto, CA, US • 5TESARO, Inc, Waltham, MA, US • 6 Breast International Group, Brussels, BE •
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Research Oncology, Division of Cancer Studies, School of Medicine, King’s College, London, GB • 8University of Edinburgh, Edinburgh, GB • 9The Royal Marsden NHS Foundation Trust, London, GB
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SCIENTIFIC BACKGROUND
ENDPOINTS
Germline mutations of BRCA1 and BRCA2 genes are found in the majority of patients with hereditary
breast or ovarian cancer. The overall prevalence of a BRCA mutation in patients with a family history of
breast or ovarian cancer is 15%, and in patients without a family history of breast cancer the prevalence
is reduced to 5%. However data regarding the impact of BRCA mutational status on treatment of breast
cancer are currently inconclusive and thus these genes do not currently affect the decision making
process regarding the type of systemic treatment. The poly (ADP-ribose) polymerases (PARP) family of
enzymes play a crucial role in DNA repair. Upon formation of stalling DNA replication forks or singlestrand DNA breaks, PARP binds DNA strands resulting in efficient repair of DNA breaks. Cells that are
not able to repair these defects , such as those with malfunctioning base excision repair pathway, or
those treated with PARP inhibitors accumulate defects that ultimately lead to their apoptosis. Niraparib
is a potent and selective PARP-1 and PARP-2 inhibitor, that has demonstrated selective anti-proliferative
activity for cancer cell lines that have been mutated for BRCA1 or BRCA2. The final results of a phase
I trial of niraparib in 100 patients with various solid tumors (49 ovarian, 23 CRPC, 12 breast and 16
others) established the maximum tolerated dose at 300mg/day while the most common dose-limiting
toxic effects reported in the first cycle were grade 3 fatigue, grade 3 anemia, and grade 3 and 4
thrombocytopenia.
The primary endpoint is to compare PFS as assessed by blinded, central review between patients
randomized to niraparib versus physician’s choice according RECIST v.1.1
Secondary Endpoints include:
• Overall Survival
• Safety
• PFS according local investigator assessment
• Time to treatment failure
• Response rate and duration of response
• Tests in order to determine concordance for the development of a companion diagnostic test
• HQoL assessments
STATISTICS
To compare progression-free survival (PFS) as assessed by blinded central review between patients
randomized to niraparib versus physician’s choice (eribulin or capecitabine or gemcitabine or vinorelbine).
Overall 306 patients will be randomized on niraparib versus physician’s choice arm. Sample size
calculation is based on Overall Survival (OS). The hypothesized median PFS improvement is 6 versus
3 months (hazard ratio=0.5) for niraparib versus physician’s of choice. The study has 99.6% power for
the primary PFS analysis at a 1- sided alpha of 0.025. Assuming an increase in overall survival from 9
to 13 months (hazard ratio=0.69), the study has 80% power for the OS comparison at a 1-sided alpha
of 0.025.
TREATMENT SCHEDULE AND STUDY DESIGN
TRANSLATIONAL RESEARCH
PRIMARY OBJECTIVE AND KEY SECONDARY OBJECTIVE
This study is a randomized, open-label, multicenter, controlled trial to compare niraparib versus physician’s
choice, in patients with germline BRCA mutations who have advanced HER2- negative breast cancer.
Eligible patients will be randomized to 2:1 for receiving niraparib orally at a dose of 300 mg QD on
a continuous dosing regimen or physician’s choice amongst one of the following four single agents
(eribulin, vinorelbine, gemcitabine or capecitabine).
Eligible patients
A. Concordance of the companion diagnostic test for determination of germline BRCA1/2 mutations
B. Evaluation of predictive biomarkers related to efficacy of niraparib that includes:
1. Tumor biomarkers
2. Assessment of circulating plasma DNA
3. Humoral immune response monitoring
4. Peripheral Blood Mononuclear Cells (PBMC)
Open Label, randomization (ratio: 2/1)
No cross overto niraparib is allowed
Niraparib
Total Daily Dose
300 mg
Stratifications factors:
• Visceral disease (yes or no)
• Histology (TNBC vs ER/PR positive)
• Number of lines of prior cytotoxic chemotherapy
for MBC (0-1 vs 2)
STATUS
Physician’s choice
The study opened for recruitment in US on November 2013 and in EU on March 2014. Overall 14
countries will participate, including countries from Europe but also North America, Canada and Israel.
Eribulin or
Vinorelbine or
Gemcitabine or
Capecitabine
MAIN INCLUSION CRITERIA
• Patients that have a germline BRCA1 or BRCA2 mutation which is considered deleterious or suspected
deleterious and may be performed at any time prior to randomization. BRCA mutations will be
centrally assessed .
• Metastatic or locally advanced HER2 negative breast cancer patients pretreated with up to two (2)
prior cytotoxic regimens for their metastatic disease.
• Patients with no prior cytotoxic regimens for advanced or metastatic disease will only be allowed
if they relapsed during or within 12 months of (neo-) adjuvant cytotoxic therapy.
• Previous therapy should have included a taxane and/or an anthracycline. Platinum pretreated patients
are allowed only if they are not considered as platinum resistant (relapsed during or within 6 months
of completion of prior platinum treatment).
• Patients with hormone-receptor positive disease must also have progressed during at least 1 prior
hormonal therapy for which chemotherapy is indicated.
• Patients should have measurable disease by RECIST v 1.1 or no measurable but clinically evaluable
(sclerotic only bone disease patients will be excluded.
For more information please contact [email protected]
Clinical trial registry number: NCT01905592
References:
1. Hartman AR, Kaldate RR, Sailer LM, et al. Prevalence of BRCA mutations in an unselected population of triple-negative
breast cancer. Cancer 118:2787-2795,2012
2. Frankish H: BRCA1 has a pivotal role in repairing DNA. Lancet 357:1678,2001
3. Lakhani SR, Gusterson BA, Jacquemier J, et al: The pathology of familial breast cancer: histological features of cancers in
families not attributable to mutations in BRCA1 or BRCA2. Clin Cancer Res 6:782-789, 2000
4. Curtin NJ: DNA repair dysregulation from cancer driver to therapeutic target. Nat Rev Cancer 12:801-817, 2012
5. Patel AG, Sarkaria JN, Kaufmann SH: Non- homologous end joining drives poly (ADP- ribose) polymerase (PARP) inhibitor
lethality in homologous recombination- deficient cells. Proc Natl Acad Sci USA 108:3406-3411, 2011
6. Bryant HE, Schultz N, Thomas HD, et al: Specific killing of BRCA2-deficient tumors with inhibitors of poly (ADP- ribose)
polymerase. Nature 434:913-917, 2005
7. Sandhu KS,Schelman RW,Wilding G” The poly(-ADP ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation
carriers and patients with sporadic cancer: a phase 1, dose-escalation trial. The Lancet Oncology, Volume 14, Issue 9, 882892, August 2013.
Poster design: Sonia Pazos, EORTC Headquarters, Brussels, Belgium