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Poster Display session 3

1945 - Randomized Phase II Study of Trabectedin/Olaparib Compared to Physician’s Choice in Subjects with Previously Treated Advanced or Recurrent Solid Tumors Harboring DNA Repair Deficiencies.

Date

30 Sep 2019

Session

Poster Display session 3

Topics

Translational Research

Tumour Site

Presenters

Christoph Heilig

Citation

Annals of Oncology (2019) 30 (suppl_5): v760-v796. 10.1093/annonc/mdz268

Authors

C.E. Heilig1, D. Hübschmann2, H. Kopp3, K.H. Metzeler4, S. Richter5, B. Hermes6, N. von Bubnoff7, T. Kindler8, J. Siveke9, S. Wagner10, S. Ochsenreither11, H. Süße12, B. Brors13, A. Benner14, D. Jäger15, C. Von Kalle16, H. Glimm1, S. Gröschel17, S. Fröhling1, R.F. Schlenk18

Author affiliations

  • 1 Department Of Translational Medical Oncology, Nationales Zentrum für Tumorerkrankungen (NCT), 69120 - Heidelberg/DE
  • 2 Division Of Stem Cells And Cancer, German Cancer Research Center (DKFZ), 69120 - Heidelberg/DE
  • 3 Oncology/hematology, Robert-Bosch-Krankenhaus, 70376 - Stuttgart/DE
  • 4 Hematololy/oncology, Ludwig Maximilians University - Grosshadern, 81377 - Munich/DE
  • 5 Medizinische Klinik I, Universitätsklinikum Dresden, 01307 - Dresden/DE
  • 6 Hematology/oncology, Universitätsklinikum Tübingen Medizinische Universitätsklinik, 72076 - Tübingen/DE
  • 7 Innere Medizin I, Universitätsklinikum Freiburg, 79106 - Freiburg/DE
  • 8 University Cancer Center Of Mainz, Universitätsmedizin Mainz, 55131 - Mainz/DE
  • 9 Westdeutsches Tumorzentrum, University Hospital Essen, 45122 - Essen/DE
  • 10 Medizinische Klinik Ii, Hämatologie/onkologie, Universitätsklinikum Frankfurt, 60590 - Frankfurt/DE
  • 11 Hämatologie, Onkologie Und Tumorimmunologie, Charite-Universitätsmedizin Berlin, 13353 - Berlin/DE
  • 12 Trial Center, National Center for Tumor Diseases (NCT), 69120 - Heidelberg/DE
  • 13 Division Applied Bioinformatics, German Cancer Research Center (DKFZ), 69120 - Heidelberg/DE
  • 14 Department Of Biostatistics, German Cancer Research Center (DKFZ), 69120 - Heidelberg/DE
  • 15 Medical Oncology, Nationales Zentrum für Tumorerkrankungen (NCT), 69120 - Heidelberg/DE
  • 16 Department Of Translational Oncology, German Cancer Research Center, 69120 - Heidelberg/DE
  • 17 Internal Medicine 5, Heidelberg University Hospital, 69120 - Heidelberg/DE
  • 18 Clinical Trial Center, Nationales Zentrum für Tumorerkrankungen (NCT), 69120 - Heidelberg/DE

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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.

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