Filanesib combination therapy in multiple myeloma
Overview of the Study
Filanesib is a kinesin spindle protein inhibitor that’s recently proposed as a cancer treatment for multiple myeloma. In this study of the first dose-escalation phase, the researchers tried to understand the maximum tolerated dose of two schedules of filanesib, bortezomib, and dexamethasone plus a subsequent dose-expansion phase using maximum tolerated doses.
Multiple Myeloma and Kinesin Spindle Protein
Multiple myeloma treatment has undergone improvements thanks to the introduction of immunomodulating agents (MiDs), proteasome inhibitors (PIs), and monoclonal antibody therapy. Despite this, the disease still remains incurable. A new treatment involving the use of agents such as kinesin spindle protein inhibitors (KSP) is believed to have been delivering promising results.
So, how does it do that? Essentially, KSP is a mitotic spindle motor protein that’s essential for mitosis. KSP inhibitors produce prolonged mitotic arrest during which protein synthesis is halted, leading to depletion of proteins such as the apoptosis inhibitor myeloid cell leukemia 1 (MCL- 1). Neoplastic plasma cells depend on MCL- 1 as a survival signal and undergo apoptosis when treated with KSP inhibitors.
Using this MTD in phase 2, the investigators confirmed the presence of modest single-agent activity with an overall response rate (ORR) of 16% and clinical benefit rate (CBR, responses of ≥ minimal response, MR) of23% in patients with a median of over six previous lines of therapy.
Methods
Study Design
The study is a phase 1 multicenter study with a dose-escalation phase and a subsequent dose-expansion phase. The dose-escalation phase determined the MTD of two schedules of filanesib and bortezomib with and without dexamethasone. The dose-expansion phase was planned to obtain preliminary estimates of the efficacy.
The design was motivated by the operating characteristics when using a Simon two-stage design with a null hypothesis of >50% ORR (85% power, α = 0.15). With such a design, 21 evaluable patients would be needed for the first stage with >7 responders needed to move to stage 2.
The development plan contemplated conducting the stage 2 portion as a separate study. Additional objectives were to further evaluate the drug combination’s safety to assess pharmacokinetic interactions between filanesib and bortezomib and to explore possible biomarkers of response including AAG. Data analyses focused on the previously unreported dose-expansion phase with secondary analyses of the composite of patients from both phases treated with therapeutic doses of study drugs.
Patients
Patients that are allowed for participation were aged 18 or above with measurable RRMM or plasma cell leukemia. Patients in the dose-escalation phase had received two or more lines of prior treatment including an IMiD and a PI, with the progression of disease (PD) during the last prior regimen or after. Patients in the dose-expansion phase had received between one and three lines of prior treatment, but patients with the bortezomib-refractory disease were excluded.
In the dose-expansion phase, 7 patients in schedule 1 and 21 in schedule 2 were enrolled and dosed between November 5, 2013, and December 3, 2014, at six centers in the United States.
Enrollment began with schedule 2 due to ease of dosing. After 21 patients were accrued, schedule 1 enrollment began. Due to slowing enrollment at this time, enrollment was closed after seven patients. With a total of 28 patients between the two schedules, it was determined that estimates of response rates would not be meaningfully affected.
At the time of data cut-off (November 21, 2016), four patients who were responding to treatment at study closure were transitioned to a rollover study to continue receiving the combination.
Schedules of Treatment
Schedule 1
1.50 mg/m2/day of filanesib was administered on days 1, 2, 15, and 16 of 28- day cycles with 1.3 mg/m2/day dose of bortezomib subcutaneously and 40 mg/day of dexamethasone orally on days 1, 8, and 15 with prophylactic G- CSF for 5– 7 days on day 3 or 4 and day 17 or 18.
Schedule 2
3.0 mg/m2/day of filanesib was administered on days 1 and 15 of each cycle with 1.3 mg/m2of bortezomib plus 40 mg/day of dexamethasone orally on days 1, 8, and 15 with prophylactic G- CSF for 5– 7 days on day 2 or 3 and day 16 or 17.
In both schedules, bortezomib could be administered intravenously if investigators believed it was in the patient’s best interest. In both schedules, patients ≥75 years were given 20 mg/day of dexamethasone. Patients continued to receive study therapy in repeating cycles until unacceptable toxicity or PD as long as the investigator deemed it appropriate for the patient’s care.
Statistical Analysis
In the expansion phase, cohorts of up to approximately 21 evaluable patients were anticipated to be enrolled. Continuous variables were summarized by the median (range: minimum-maximum) and categorical variables by N(%).
Patients were evaluable for safety and efficacy if they received at least 1 dose of filanesib. The Kaplan– Meier method was utilized to estimate PFS and DOR with patients censored at the last date known to be alive and progression-free.
No formal comparisons were planned or performed. To assess for drug interactions, comparisons of plasma drug concentrations of filanesib and bortezomib were as-sessed as geometric mean ratios by patient and day. Results for ratios were presented for each patient and summarized using descriptive statistics. The effects of concomitant bortezomib administration on filanesib concentrations and vice-versa were assessed using analysis of variance. SAS 9.4 was used for statistical tests.
Results
During the dose-expansion phase, a total of 28 patients were evaluated for safety and efficacy.
The most common grade ≥3 adverse events were neutropenia (21%) and anemia (18%), which were noncumulative and reversible, and hypertension (18%). The overall response rate was 43% with the median duration of response not yet reached (range, 2.8– 23.7+ months) with a median follow-up of 6.3 months.
A post hoc analysis incorporated 29 dose-escalation phase patients who received therapeutic filanesib doses, with an overall response rate of 39% and median duration of response of 18.0 months among the 57 total patients with median progression-free survival of 8.5 months. Notably, the PFS of high-risk patients was comparable at 8.5 months, driven by the patients with 1q21 gain, characterized by increased MCL 1 expression, with a PFS of 9.1 months versus 3.5 months for the remainder of high-risk patients.
Patients with t(11;14) also had an encouraging PFS of 15.0 months. The combination of filanesib, bortezomib, and dexamethasone continues to show safety and encouraging activity in relapsed/refractory multiple myeloma, particularly in those patients with 1q21 gain and t(11;14).
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