Abstract CT160: Ixazomib in combination with carboplatin in pretreated women with advanced triple negative breast cancer, an ongoing phase I/II trial (AGMT MBC-10 trial)
Authors: Rinnerthaler Gabriel , Gampenrieder Simon P. , Petzer Andreas , Pusch Renate , Voskova Daniela , Rossmann Dieter , Balic Marija , Egle Daniel , Rumpold Holger , Singer Christian F. , Melchardt Thomas , Ulmer Hanno , Mlineritsch Brigitte , Greil Richard 
Published: August 2018

Background: Triple-negative breast cancer (TNBC) comprises a heterogeneous group of diseases which are generally associated with poor prognosis. Recently, the PARP inhibitor olaparib was approved as first targeted treatment beyond antiVEGF therapy for the BRCA1/2 mutated subgroup of TNBC. However, cytotoxic agents still remain the mainstay of treatment for this breast cancer subtype. Ixazomib is a selective and reversible inhibitor of the proteasome, which has been mainly investigated as treatment of multiple myeloma. In a preclinical cell line model for TNBC the first-generation proteasome inhibitor bortezomib showed synergistic efficacy with cisplatin. Clinical data are available for carboplatin plus bortezomib in metastatic ovarian and lung cancers showing remarkable antitumor activity (47% and 38% response rate, respectively) and good tolerability. In solid tumors cytotoxic effect of proteasome inhibitors is thought to be mediated through different mechanisms: (1) Inhibition of the Fanconi Anemia and BRCA1 DNA repair mechanism (2) Inhibition of p53 degradation (3) Inhibition of NF-kappa B signaling cascade. Based on this evidence, the phase I/II MBC-10 trial will evaluate the toxicity profile and efficacy of the oral second-generation proteasome inhibitor ixazomib in combination with carboplatin in patients with advanced TNBC.

Trial Design: Patients with metastatic TNBC pretreated with at least one prior line of chemotherapy for advanced disease with a confirmed disease progression and measurable disease are eligible for this study. Patients will receive ixazomib in combination with carboplatin on days 1, 8, and 15 in a 28-day cycle. The phase I part of this study uses an alternate dose escalation accelerated titration design. After establishing the maximum tolerated dose (MTD), accrual continues to evaluate the efficacy and safety of the combination (phase II, including 41 evaluable patients). All patients will continue on study drugs until disease progression, unacceptable toxicity or discontinuation for any other reason. Primary endpoint of the phase II is overall response rate, secondary endpoints include safety profile, progression-free survival and quality of life. The MBC-10 trial is accompanied by a broad biomarker program investigating predictive biomarkers for treatment response and potential resistance mechanisms to the investigational drug combination. This trial is open for patient enrollment since November 2016 in six Austrian cancer centers. Accrual is planned to be completed within two years. ClinicalTrials.gov Identifier: NCT02993094

Citation Format: Gabriel Rinnerthaler, Simon P. Gampenrieder, Andreas Petzer, Renate Pusch, Daniela Voskova, Dieter Rossmann, Marija Balic, Daniel Egle, Holger Rumpold, Christian F. Singer, Thomas Melchardt, Hanno Ulmer, Brigitte Mlineritsch, Richard Greil. Ixazomib in combination with carboplatin in pretreated women with advanced triple negative breast cancer, an ongoing phase I/II trial (AGMT MBC-10 trial) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT160.