Phase I Dose-Escalation Trial of BI 2536, a Polo-Like Kinase 1 Inhibitor, in Relapsed and Refractory Non-Hodgkin’s Lymphoma

<jats:title>Abstract</jats:title> <jats:p>Background: BI 2536 is a highly potent, selective inhibitor of Polo-like kinase 1 (Plk1), a key regulator of mitotic progression. BI 2536 has demonstrated favorable tolerability and antitumor activity in Phase I trials in patients with solid tumors. Antitumor activity of BI 2536 was also shown in preclinical non-Hodgkin’s lymphoma (NHL) models. We determined the maximum tolerated dose (MTD), overall safety, pharmacokinetics (PK) and efficacy of BI 2536 given as an intravenous infusion once every 3 weeks in patients with relapsed or refractory aggressive NHL of T- or B-cell origin.</jats:p> <jats:p>Methods: Sequential cohorts of 3–6 patients with relapsed or refractory aggressive NHL received 1-hour infusions of BI 2536 following a toxicity-guided Phase 1 doseescalation design. Patients relapsed after peripheral stem cell transplantation and transplantation-naive patients were entered into different strata and the respective MTD determined independently. A single administration was given every 21 days. Patients with clinical benefit were eligible for further treatment courses after recovery from toxicity after a 3-week observation period. A total of 41 patients were entered into the trial: 24 patients in the transplant-naive (non-tr) stratum; and 17 patients in the transplant-failure (tr) stratum. Patients were treated at dose levels from 50 to 200 mg.</jats:p> <jats:p>Results: The safety profile was similar in both strata with the MTD determined independently at 175 mg for both non-tr and tr patients. Neutropenia (tot: 33%; CTCAE Grade (gr)3/4: 21%), anemia (tot: 29%; gr3: 4%), thrombocytopenia (tot: 29%; gr3/4: 17%), fatigue (tot: 25%; gr3: 4%) and nausea (tot=gr1/2: 25%) were the most frequent adverse events in non-tr; and thrombocytopenia (tot: 59%; gr3/4: 41%), anemia (tot=gr1/2: 41%), fatigue (tot=gr1/2: 41%) and neutropenia (tot: 41%; gr3/4: 21%) were most frequent in tr patients. Dose-limiting toxicities (DLTs) consisted of reversible thrombocytopenia (six patients) and neutropenia (three patients). No relevant non-specific toxicity was observed. Pharmacokinetic analysis showed dose proportionality of Cmax and AUC0–∞ with a high clearance (~1,400 mL/min) and a high volume of distribution (&gt;1,000 L). Patients were treated for up to 6 courses without evidence of cumulative toxicity. Three complete responses (CRs) and one partial response were observed. Stable disease as best response was noted in three (18%) of tr patients and nine (38%) of non-tr patients. All responders had relapsed after prior peripheral stem cell transplants and were treated at doses of 150–200 mg. Three of the four responders had a peripheral T-cell lymphoma (PTCL) NHL; one CR was observed in a patient with diffuse large B-cell lymphoma. The overall response rate (ORR) in the tr stratum was 23.5%; in the aggregate of both tr and non-tr, the ORR amounted to 9.7%. With three out of five patients responding, an ORR of 60% was observed in the T-cell subset. However, the responses were of short duration.</jats:p> <jats:p>Conclusion: BI 2536 has a favorable safety and PK profile in patients with NHL. Safety profile and PK properties are comparable to data obtained in solid tumor patient populations. Encouraging, albeit transient, anti-lymphoma efficacy was observed in patients suffering from PTCL after autologous stem-cell transplantation.</jats:p>