Pernas S, et al. - The safety, tolerability, pharmacokinetics, and preliminary phase 1 activity of the C-X-C chemokine receptor type 4 (CXCR4) antagonist, balixafortide, in combination with eribulin chemotherapy were determined in patients with heavily pretreated, relapsed metastatic breast cancer. As per outcomes, balixafortide plus eribulin seemed to have similar safety and tolerability profile as that of eribulin or balixafortide monotherapy. The preliminary activity of the combination appeared promising in patients with HER-negative metastatic breast cancer. Results suggest balixafortide plus eribulin have potential for providing a new therapeutic option in heavily pretreated patients with metastatic breast cancer.

Methods

• Researchers performed a single-arm, dose-escalation, phase 1 trial enrolling patients at 11 sites in Spain and the USA.
• For this study, eligible patients were women aged 18 years or older who had histologically confirmed HER2-negative metastatic breast cancer, evidence of tumour cell CXCR4 expression, an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received between one and three chemotherapy regimens for metastatic breast cancer, and at least one endocrine therapy if they had hormone receptor-positive disease, unless they were considered unsuitable for endocrine therapy.
• They used a standard 3+3 dose-escalation design, followed by an expanded cohort at the established maximum tolerated dose or highest dose if no dose-limiting toxicity was observed for the combination.
• A protocol amendment modified the study design to be done in two parts after a treatment-related fatal adverse event in the first cohort who received 21-day cycles of treatment with eribulin and balixafortide.
• Patients enrolled to part 1 were administered an initial 28-day run-in cycle, with some cohorts were administered de-escalated doses of eribulin plus balixafortide to determine the safety and pharmacokinetics of the combination.
• Any dose-limiting toxicities or eribulin–balixafortide interactions were not confirmed in part 1; therefore, patients in part 2 were administered eribulin at the originally planned dose of 1·4 mg/m² on days 2 and 9 of a 21-day cycle and balixafortide from a starting dose of 2 mg/kg with dose increments of 0·5 or 1 mg/kg on days 1–3 and 8–10 of the 21-day cycle.
• Administration of both drugs as intravenous infusions was perfomed.
• Treatment was provided to all patients until disease progression or unacceptable toxicity.
• The primary endpoints included dose-limiting toxicities and adverse events, and the establishment of a maximum tolerated dose or recommended phase 2 dose, and pharmacokinetic parameters.
• All patients who received at least one dose of study treatment underwent safety analysis.
• All patients who received at least one full cycle of study treatment were analyzed for antitumour activity.

Results

• The trial included 56 patients from Jan 28, 2014, to Oct 4, 2016.
• Findings confirmed no dose-limiting toxicities; the maximum tolerated dose was not reached.
• In this study, the highest dose was noted as eribulin 1·4 mg/m² on days 2 and 9, and balixafortide 5·5 mg/kg on days 1–3 and 8–10 of the 21-day cycle.
• In 16 (30%; 95% CI 18–44) of 54 patients who were evaluable for antitumour activity, objective responses (all partial responses) were noted.
• Fatigue (44 [79%] of 56 patients), neutropenia (32 [57%]), infusion-related reactions (27 [48%]), alopecia (26 [46%]), constipation (26 [46%]), and nausea (25 [45%]) were noted as the most common treatment-emergent adverse events.
• Serious adverse events were encountered in 21 (38%) of 56 patients; these included febrile neutropenia in five (9%) of 56 patients, neutrophil count decrease in two (4%) patients, constipation in two (4%) patients, pneumonia in two (4%) patients, and urinary tract infection in three (5%) patients.
• Death of 2 (4%) of 56 patients was reported while receiving study treatment; one from septic shock and one from pneumonia.