Abstract 1945
Background
Genomic aberrations affecting the repair of DNA double-strand breaks by homologous recombination (HR) are found in various cancers and result in sensitivity to inhibitors of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP). DNA double-strand breaks and activation of PARP can be induced by trabectedin, a cytotoxic agent used in soft-tissue sarcoma. In HR-deficient cancers that depend on PARP activity, trabectedin may thus increase the effect of PARP inhibitors such as olaparib. Next-generation sequencing techniques allow rapid identification of mutations in DNA repair pathways and mutational signatures that are generated by these aberrations.
Trial design
We present a randomized phase II trial comparing a combination of trabectedin and olaparib with treatment of physician’s choice in adult patients with advanced or metastatic tumors with genomic imprints of defective HR DNA repair (“BRCAness”), as determined by whole-exome or genome sequencing. A dedicated BRCAness score incorporates germline and somatic mutations in HR-relevant genes, mutational signatures, and measures of genomic instability; scores equal or above 3 allow for inclusion. Main exclusion criteria are hematologic and primary brain cancers, progressive/symptomatic brain metastases, ECOG PS > 1, severe organ insufficiencies, and prior treatment with a PARP inhibitor. Patients are randomized 1:1 to treatment with trabectedin (day 1) and olaparib (days 1-21) in a 21-day cycle vs. physician’s choice, both until disease progression. Cross-over upon disease progression is allowed. The primary endpoint is disease control (including CR, PR and SD according to RECIST v1.1) after 16 weeks. Secondary endpoints are tumor response, PFS, OS and quality of life. Efficacy evaluation involves a 2-group comparison between treatment arms in 102 patients. The statistical test used is a one-sided test of differences in disease control rates (alpha = 0.025). An interim analysis for futility will be conducted after 30% of patients are evaluable for the primary endpoint. The trial is active within the German Cancer Consortium, and thus far nine patients have been randomized.
Clinical trial identification
EudraCT: 2017-001755-31; NCT03127215.
Editorial acknowledgement
Legal entity responsible for the study
Heidelberg University Hospital, Heidelberg, Germany.
Funding
AstraZeneca, ParmaMar and German Cancer Research Center (DKFZ).
Disclosure
C.E. Heilig: Honoraria (self), Travel / Accommodation / Expenses: PharmaMar; Travel / Accommodation / Expenses: Teva; Honoraria (institution), Travel / Accommodation / Expenses: Lilly; Travel / Accommodation / Expenses: Celgene; Travel / Accommodation / Expenses: Novartis. H. Kopp: Advisory / Consultancy: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck-MSD; Advisory / Consultancy: Sanofi; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: Boehringer-Ingelheim. K.H. Metzeler: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Celgene; Advisory / Consultancy: Novartis; Advisory / Consultancy: Jazz; Research grant / Funding (institution): Agios. S. Richter: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (self), Travel / Accommodation / Expenses: Lilly. B. Hermes: Travel / Accommodation / Expenses: PharmaMar; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Lilly. N. von Bubnoff: Honoraria (self): AstraZeneca; Honoraria (self): Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self): BMS. T. Kindler: Advisory / Consultancy: Novartis; Travel / Accommodation / Expenses: PharmaMar. J. Siveke: Advisory / Consultancy: Baxalta; Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Celgene; Advisory / Consultancy, Travel / Accommodation / Expenses: Shire; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Research grant / Funding (self), Travel / Accommodation / Expenses: BMS. S. Wagner: Advisory / Consultancy: Takeda. S. Ochsenreither: Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: BMS; Advisory / Consultancy: AstraZeneca. B. Brors: Research grant / Funding (institution): SAP. D. Jäger: Advisory / Consultancy: Amgen; Advisory / Consultancy: Bayer; Advisory / Consultancy: CureVac; Advisory / Consultancy: Definiens; Advisory / Consultancy: Roche; Advisory / Consultancy: BMS. C. Von Kalle: Advisory / Consultancy: Roche; Advisory / Consultancy: Genentech; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Shareholder / Stockholder / Stock options: Genewerk. H. Glimm: Honoraria (self), Research grant / Funding (self): Bayer. S. Fröhling: Honoraria (self), Travel / Accommodation / Expenses: Amgen; Honoraria (self), Travel / Accommodation / Expenses: PharmaMar; Honoraria (self), Travel / Accommodation / Expenses: Lilly; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Bayer. R.F. Schlenk: Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Novartis; Research grant / Funding (institution): Pfizer; Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Daiichi Synkyo. All other authors have declared no conflicts of interest.
Resources from the same session
2316 - A 3D co-culture platform of breast cancer and patient derived immune cells to analyse the response to chemotherapy and immunotherapies
Presenter: Diana Saraiva
Session: Poster Display session 3
Resources:
Abstract
4290 - Characterization of the mechanism of action and efficacy of MEN1611 (PA799), a novel PI3K inhibitor, in breast cancer preclinical models.
Presenter: Alessio Fiascarelli
Session: Poster Display session 3
Resources:
Abstract
2167 - Neat-1: culprit lnRNA tying PIG-C, MSLN, CD80 in TNBC
Presenter: Nada Hussein
Session: Poster Display session 3
Resources:
Abstract
1829 - A novel RAF/MEK inhibitor CH5126766 in phase 1 clinical trial has an effectiveness in the combination with eribulin for the treatment of triple negative breast cancer
Presenter: Hisako Ono
Session: Poster Display session 3
Resources:
Abstract
4357 - Identification of a stemness-related gene panel associated with BET inhibition in triple negative breast cancer
Presenter: Eva Galan-Moya
Session: Poster Display session 3
Resources:
Abstract
5163 - Preclinical Evaluation targeting both IGF1R and IR in Triple Negative Breast Cancer
Presenter: Alex Eustace
Session: Poster Display session 3
Resources:
Abstract
832 - Monospecific antibody targeting of CDH11 inhibits epithelial-to-mesenchymal transition and represses cancer stem cell-like phenotype by up-regulating miR-335 in metastatic breast cancer, in vitro and in vivo.
Presenter: Jia-Hong Chen
Session: Poster Display session 3
Resources:
Abstract
3781 - Pharmacological screening with Chk1 inhibitors identify synergistic agents to overcome resistance to platinums in basal breast and ovarian cancer
Presenter: Ana Lucia Sanabria
Session: Poster Display session 3
Resources:
Abstract
3275 - Comparison of 11 circulating miRNAs and CA125 kinetics in ovarian cancer during first line treatment: data from the randomized CHIVA trial (a GINECO-GCIG study)
Presenter: Patrick Robelin
Session: Poster Display session 3
Resources:
Abstract
3391 - Inhibiting Ehmt2 and Ezh2 histone methyltransferases alters the immune microenvironment in a Trp53-/- murine ovarian cancer model
Presenter: Pavlina Spiliopoulou
Session: Poster Display session 3
Resources:
Abstract