Ixazomib in combination with carboplatin in pretreated women with advanced triple-negative breast cancer, a phase I/II trial of the AGMT (AGMT MBC-10 trial)

Gabriel Rinnerthaler, Simon Peter Gampenrieder, Andreas Petzer, Sonja Burgstaller, David Fuchs, Dieter Rossmann, Marija Balic, Daniel Egle, Holger Rumpold, Christian F Singer, Rupert Bartsch, Edgar Petru, Thomas Melchardt, Hanno Ulmer, Brigitte Mlineritsch, Richard Greil, Gabriel Rinnerthaler, Simon Peter Gampenrieder, Andreas Petzer, Sonja Burgstaller, David Fuchs, Dieter Rossmann, Marija Balic, Daniel Egle, Holger Rumpold, Christian F Singer, Rupert Bartsch, Edgar Petru, Thomas Melchardt, Hanno Ulmer, Brigitte Mlineritsch, Richard Greil

Abstract

Background: Triple-negative breast cancer (TNBC) comprises a heterogeneous group of diseases which are generally associated with poor prognosis. Up to now, no targeted treatment beyond anti-VEGF therapy has been approved for TNBC and cytotoxic agents remain the mainstay of treatment. Ixazomib is a selective and reversible inhibitor of the proteasome, which has been mainly investigated in the treatment of multiple myeloma. In a preclinical study TNBC cells were treated with the first-generation proteasome inhibitor bortezomib in combination with cisplatin and synergistic efficacy was demonstrated. Clinical data are available for carboplatin plus bortezomib in metastatic ovarian and lung cancers showing remarkable antitumor activity and good tolerability (Mol Cancer 11:26 2012, J Thorac Oncol 4:87-92 2009, J Thorac Oncol 7:1032-1040, 2012). Based on this evidence, the phase I/II MBC-10 trial will evaluate the toxicity profile and efficacy of the second-generation proteasome inhibitor ixazomib in combination with carboplatin in patients with advanced TNBC.

Methods: Patients with metastatic TNBC pretreated with at least one prior line of chemotherapy for advanced disease with a confirmed disease progression and measurable disease according to RECIST criteria 1.1 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 utilizes an alternate dose escalation accelerated titration design. After establishing the maximum tolerated dose (MTD), the efficacy and safety of the combination will be further evaluated (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 progression-free survival, safety, and quality of life. This trial is open for patient enrollment since November 2016 in six Austrian cancer centers. Accrual is planned to be completed within 2 years.

Discussion: Based on preclinical and clinical findings an ixazomib and carboplatin combination is thought to be effective in metastatic TNBC patients. 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.

Trial registration: EudraCT Number: 2016-001421-13 received on March 31, 2016, ClinicalTrials.gov Identifier: NCT02993094 first posted on December 15, 2016. This trial was registered prospectively.

Keywords: Breast cancer; Carboplatin; Ixazomib; Platinum; Proteasome inhibitor; Triple-negative.

Conflict of interest statement

Ethics approval and consent to participate

This study is conducted under the principles of the Declaration of Helsinki and International Conference on Harmonisation E6 Good Clinical Practice (ICH E6 GCP) guidelines. The study protocol has been approved by the independent medical ethics committee of the Province of Salzburg (Ethikkommission des Landes Salzburg, Austria, EC number 415-E/2067/16–2016) and the Austrian regulatory authority (9308458). The study protocol has been registered on an international primary trial register (Consent for publication

Not applicable.

Competing interests

Conflicts of Interest with Takeda®: Employment or Leadership Position: none; Consultant or Advisory Role: Andreas Petzer, Richard Greil; Fees for non-CME services received directly from commercial interest or their agents none; Contracted Research: Richard Greil; Ownership Interest: none; Traveler Grants: none; Marija Balic is on the Editorial Board of BMC Cancer.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Accelerated titration design of the phase I part of the trial. Illustration of the accelerated titration design of the phase I part of the trial. Each box outlined in bold represents a cohort containing the indicated number of patients treated at a given dose level. Ixazomib will be administrated orally on days 1, 8, and 15 and carboplatin intravenously on days 1, 8, and 15 of a 4-week cycle. Drug dosages per dose level are given on the left side of the graph. DLT = dose-limiting toxicity; AUC = area under the curve

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