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A phase 1 dose-escalation study of filanesib plus bortezomib and dexamethasone in patients with recurrent/refractory
Ajai Chari1, Myo Htut2, Jeffrey A Zonder3
1Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York. ajai.chari@mssm.edu.
Background:
Filanesib is a kinesin spindle protein inhibitor that has demonstrated encouraging activity in patients with recurrent/refractory multiple myeloma. Preclinical synergy with bortezomib was the rationale for the current phase 1 study.
Methods:
The current study was a multicenter study with an initial dose-escalation phase to determine the maximum tolerated dose of 2 schedules of filanesib plus bortezomib with and without dexamethasone, followed by a dose-expansion phase.
Results:
With the addition of prophylactic filgastrim, the maximum planned dose was attained: 1.3 mg/m2 /day of bortezomib plus 40 mg of dexamethasone on days 1, 8, and 15 of a 28-day cycle, with filanesib given intravenously either at a dose of 1.5 mg/m2 /day (schedule 1: days 1, 2, 15, and 16) or 3 mg/m2 /day (schedule 2: days 1 and 15). The most common adverse events (assessed for severity using version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events) were transient, noncumulative neutropenia and thrombocytopenia with grade 3/4 events reported in 44% (16% in cycle 1 with filgastrim) and 29% of patients, respectively. A low (≤11%) overall rate of nonhematological grade 3/4 toxicity was observed. With a median of 3 prior lines of therapy and 56% of patients with disease that was refractory to proteasome inhibitors, the overall response rate was 20% (55 patients), and was 29% in 14 patients with proteasome inhibitors-refractory disease receiving filanesib at a dose of ≥1.25 mg/m2 (duration of response, 5.2 to ≥21.2 months).
Conclusions:
The current phase 1 study established a dosing schedule for the combination of these agents that demonstrated a favorable safety profile with a low incidence of nonhematologic toxicity and manageable hematologic toxicity. The combination of filanesib, bortezomib, and dexamethasone appears to have durable activity in patients with recurrent/refractory multiple myeloma. Cancer 2016;122:3327-3335. © 2016 American Cancer Society.
Insights
Filanesib combined with bortezomib and dexamethasone shows durable activity in recurrent/refractory multiple myeloma. This phase 1 study established a safe dosing schedule with manageable side effects.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Filanesib, a kinesin spindle protein inhibitor, exhibits activity in relapsed/refractory multiple myeloma.
- Preclinical studies indicated synergy between filanesib and bortezomib, justifying this clinical investigation.
Purpose of the Study:
- To determine the maximum tolerated dose (MTD) of two filanesib dosing schedules combined with bortezomib and dexamethasone.
- To evaluate the safety and efficacy of this combination therapy in patients with recurrent/refractory multiple myeloma.
Main Methods:
- A multicenter, phase 1 dose-escalation and dose-expansion study.
- Patients received escalating doses of filanesib with bortezomib and dexamethasone, with filgastrim prophylaxis.
- Adverse events were assessed using NCI Common Terminology Criteria for Adverse Events v4.0.
Main Results:
- The MTD was determined, with filanesib administered at 1.5 mg/m²/day or 3 mg/m²/day.
- Common toxicities included transient neutropenia (44%) and thrombocytopenia (29%), with low nonhematologic toxicity (≤11%).
- An overall response rate of 20% was observed, with 29% response in patients refractory to proteasome inhibitors.
Conclusions:
- A safe and tolerable dosing schedule for filanesib, bortezomib, and dexamethasone was established.
- The combination demonstrated durable activity in patients with recurrent/refractory multiple myeloma.
- This regimen offers a promising option for patients with relapsed or refractory disease.
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