SYNERGY: Phase I and randomized phase II trial to investigate the addition of the anti-CD73 antibody oleclumab to durvalumab, paclitaxel and carboplatin for previously untreated, locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC)
Authors: C. Maurer, D. Eiger, C. Velghe, P.G. Aftimos, M. Maetens, J. Gaye, M. Paesmans, M. Ignatiadis, M. Piccart, L. Buisseret
Journal: Annals of Oncology (2019)

Background: The combination of immune checkpoint blockade and chemotherapy has improved overall survival in a limited subset of patients (pts) with metastatic TNBC. The ectoenzyme CD73 found on the surface of tumor and stromal cells has immunosuppressive functions and is associated with poor prognosis in TNBC, thus blocking it with the monoclonal antibody oleclumab might enhance antitumor response of combined immunotherapy and chemotherapy. Trial design: The phase I studies the safety of the combination of paclitaxel (P; 80 mg/m2 IV weekly [Q1W] x 12), carboplatin (C; AUC 2 IV Q1W x 12), durvalumab (D; 1500 mg IV Q4W) and oleclumab (O; IV Q2W x 5, then Q4W; D/O until disease progression or unacceptable toxicity). The phase I will follow a de-escalation, modified 3 + 3 design testing 3 dose levels (DL0, -1, -2) of O in order to define the recommended phase 2 dose (RP2D). Starting doses were selected following the results of a phase I study in pts with metastatic solid tumors that determined a recommended dose of O both as monotherapy and in combination with D (corresponds to DL0). The RP2D of O will be used in combination with P, C and D in the phase 2 part. Regardless of the RP2D, DL0 of O will be used from week 17 onwards. The phase II openly randomizes pts in a 1:1 ratio to D, P and C with or without O. For D, P and C, the same doses and schedules as in the phase I will be used. The primary objective compares the efficacy of the two treatment arms by studying the clinical benefit rate (CBR; pts with complete/partial response and stable disease) at week 24. Sample size was planned assuming a CBR of 40% in the O-free arm (based on a phase Ib trial) and a CBR of 60% (as clinically meaningful benefit) in the O arm, requiring 68 pts/treatment arm (one-sided α = 0.1, 80% power). Assuming a 10% drop-out rate, 150 pts will be randomized. The trial has a translational research component with the collection of several blood/ tissue samples aiming at understanding mechanisms of sensitivity/resistance to D and O in TNBC. Recruitment for the phase I trial started in Jan 2019 with 3 pts enrolled so far. Clinical trial information: NCT03616886. Clinical trial identification: Sponsor Protocol Number: IJB-SYNERGY-012017, Issue date 30/06/2018. Legal entity responsible for the study: Institut Jules Bordet, Bruxelles. Funding: AstraZeneca/MedImmune. Disclosure: C. Maurer: Travel grants: Mundipharma, Amgen. P.G. Aftimos: Honoraria: Synthon, Amgen, Novartis; Consulting/advisory role: Roche, Novartis, Macrogenics, Boehringer Ingelheim, Amcure; Travel grants: MSD, Roche, Amgen, Pfizer. M. Ignatiadis: Consultant/advisory role (honoraria): Celgene, Novartis, Pfizer, Roche, Seattle Genetics, Tesaro; Research grants to my Institute: Roche, Menarini Silicon Biosystems, Janssen Diagnostics, Pfizer; Travel grants: Pfizer. M. Piccart: Consultant/advisory role (honoraria): AstraZeneca; Research grants to my institute: AstraZeneca, Medimmune. All other authors have declared no conflicts of interest.