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
5760 - Landscape of PD-L1 expression status in Chinese solid tumor patients.
Presenter: Yi Zhong
Session: Poster Display session 3
Resources:
Abstract
3733 - Anti-cancer and immunomodulatory effects of cobimetinib in triple negative breast cancer
Presenter: Chun-Yu Liu
Session: Poster Display session 3
Resources:
Abstract
4426 - Differential expression of immunoregulatory molecules and highly-associated cancer genes may provide novel insights into strategic trial design for therapeutics
Presenter: Jacob Adashek
Session: Poster Display session 3
Resources:
Abstract
2752 - Insights into the Tumor Immune Microenvironment using Tissue Phenomics to Drive Cancer Immunotherapy
Presenter: Martin Groher
Session: Poster Display session 3
Resources:
Abstract
5713 - Immune competent somatic mosaic model of colorectal cancer
Presenter: Stefania Napolitano
Session: Poster Display session 3
Resources:
Abstract
1898 - Genomic correlates of response to anti-PDL1 Atezolizumab in non-small-cell lung cancer OAK and POPLAR trials
Presenter: Hari Singhal
Session: Poster Display session 3
Resources:
Abstract
3246 - Erdafitinib (erda) versus available therapies in advanced urothelial cancer: A matching adjusted indirect comparison
Presenter: Yohann Loriot
Session: Poster Display session 3
Resources:
Abstract
3311 - High level of activity of Nivolumab anti-PD-1 immunotherapy and favorable outcome in metastatic/refractory MSI-H non-colorectal cancer: Results of the MSI cohort from the French AcSé program
Presenter: Christophe Tournigand
Session: Poster Display session 3
Resources:
Abstract
2314 - TP53 and ATM Co-mutation Predicts Response to Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer
Presenter: Yu Chen
Session: Poster Display session 3
Resources:
Abstract
4692 - Immune cell biomarkers on neo-adjuvant chemo-immunotherapy treatment for resectable stage IIIA NSCLC patients
Presenter: Raquel Laza-Briviesca
Session: Poster Display session 3
Resources:
Abstract