Abstract
163 Background: Low molecular weight cyclin E (LMW-E) isoforms are overexpressed in a majority (~70%) of triple-negative breast cancers (TNBC). LMW-E isoforms have a role in tumorigenesis, likely mediated through binding and activation of CDK2. The combination of CDK1/CDK2 inhibitors, such as dinaciclib, with an anthracycline was found to be synergistic in decreasing viability of TNBC cell lines. Based on this data, we conducted a phase 1 study aimed to determine the maximum tolerated dose of dinaciclib in combination with epirubicin in patients with metastatic TNBC. Methods: Cohorts of at least 2 patients were treated with escalating doses of dinaciclib (20-50 mg/m2) given on day 1 followed by standard dose of epirubicin (75 mg/m2) given on day 2 of a 21 day cycle. All patients received pegfilagrastim 24-48 hours after chemotherapy. No intra-patient dose escalation was allowed. An adaptive accrual design based upon toxicity during cycle 1 determined entry into therapy cohorts. The target acceptable dose limiting toxicity (DLT) to advance to the next treatment level was 30%. Results: Between 9/18/2012 and 7/18/2013, 9 patients were enrolled and treated at MD Anderson Cancer Center. Patient characteristics are included in the Table. One patient was taken off treatment after 1 cycle due to toxicity. DLTs included febrile neutropenia (grade 3, n=2), syncope (grade 3, n=2) and vomiting (grade 3, n=1). Dose escalation did not proceed past the second cohort due to toxicity. After further accrual, the first dose level was found to be too toxic. Eight patients had disease progression, median number of cycles was 1 (range 1-4), and median time to progression was 1 month (range 1-3). No treatment responses were noted and it was decided to stop accrual rather than explore lower dose levels. Associated with significant toxicities. Conclusions: The combination of dinaciclib and epirubicin does not appear to be an effective treatment option for TNBC, and is associated with significant toxicities. Clinical trial information: NCT01624441. [Table: see text]
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