Phase 1 Study of the Novel Kinesin Spindle Protein Inhibitor Filanesib + Carfilzomib in Patients with Relapsed and/or Refractory Multiple Myeloma (RRMM)

Background: Filanesib (ARRY-520), a kinesin spindle protein (KSP) inhibitor, has demonstrated promising clinical activity, both as a single agent and combined with dexamethasone in patients (pts) with bortezomib/carfilzomib/lenalidomide and pomalidomide-refractory MM. Carfilzomib (car), an irreversible proteasome inhibitor (PI), also has demonstrated single agent activity in RRMM at 27 mg/m² as well as at 56 mg/m² in combination with dexamethasone. Part A of the phase 1 trial previously presented demonstrated Car 20/27mg/m² can be safely combined with filanesib 1.5 mg/m². We subsequently enrolled and now present additional pts in Part A dose expansion with a cohort of Car naïve and Car refractory pts; we also continued in Part B of the trial with subsequent dose escalation of Car to 56 mg/m².

Methods: The primary objective was to determine the MTD and the safety/tolerability of Car and filanesib in RRMM. Secondary objectives were to determine efficacy as measured by the overall response rate (ORR), time to progression, progression free survival and time to next therapy. Pts had to be ineligible for autologous stem cell transplant (ASCT), have disease refractory/intolerant to bortezomib and have had prior lenalidomide exposure. Filanesib was administered intravenously (iv) on days 1, 2, 15 and 16; car was administered intravenously on days 1, 2, 8, 9, 15 and 16 of a 28 day cycle. All pts received growth factor support in cycle 1. Dose-escalation used a standard 3+3 schema with dose-limiting toxicities (DLTs) assessed during cycle 1. Adverse events (AEs) were graded by NCI-CTCAE v4, while responses were assessed by the modified International Uniform Response Criteria.

Results: 51 pts were enrolled in the study (20 patients in Part A dose escalation; 15 carfilzomib-naïve pts in Part A dose expansion; 7 carfilzomib-refractory pts in Part A dose expansion; 9 pts in Part B dose escalation). The median age was 63 (range 41-84); 18 females; 32 males. Of the 15 car-naïve pts dosed in the Part A dose expansion: 1 patient was non-compliant/lost to followup after 2 cycles and inevaluable for response. The ORR (≥ PR) was 36% (5/14; 4 pts with PR and 1 with VGPR). With the addition of 19/20 carfilzomib naïve patients from the Part A dose escalation phase, a total of 33 evaluable pts were dosed who were Car-naïve; 27/33 pts were lenalidomide refractory/intolerant and all pts were bortezomib refractory/intolerant. The ORR (≥PR) was 42% (14/33) and clinical benefit rate (≥MR) was 52% (17/33). 8 pts remain on therapy.

In the dose expansion with 7 patients with car refractory disease in Part A, the best response observed was SD in 2 pts dosed for 5 and 6 cycles.

In Part B, car was escalated in 3 cohorts to 36 mg/m², 45 mg/m² and 56 mg/m²; the filanesib dose remained at 1.5 mg/m². 9 pts were dosed in the dose escalation. 7/9 pt were lenalidomide refractory; 9/9 pts were refractory to bortezomib; 8/9 pts were refractory to lower doses of carfilzomib. No DLTs were observed in 3 pts dosed in each of the 3 cohorts. The final planned cohort with car 56 mg/m² and filanesib at 1.5 mg/m² is ongoing with additional 3 pts, for a total of 6 patients, to confirm the recommended phase 2 dose.

Hematologic adverse events included: Grade 3/4 (G3/4) anemia in 14/51 pts; G3/4 thrombocytopenia in 20/51 pts; and G3/4 neutropenia in 21/51 pts.

G3/4 non hematologic adverse events were limited and included 1 pt respectively with elevated alanine aminotransferase, aspartate aminotransferase, bacteremia, diarrhea, dizziness, febrile neutropenia, fluid overload, fever, mucositis, peripheral neuropathy, sepsis; 2 pt with dyspnea, sinusitis; 3 pt with elevated creatinine, myalgia and elevated serum lipase; 5 pts with fatigue ; 8 pts with lung infection.

Treatment emergent SAEs among all 51 pts included 11 pts with lung infection; 4 pts with renal dysfunction (G2, G3, G3, and G5 each); 3 pts with febrile neutropenia G3 (n=2) and G5 FN (n=1); 2 pts with heart failure; and 1 patient each with G3 bacteremia, G2 lethargy, G2 sinusitis, G3 diarrhea.

Conclusions: Full dose filanesib, 1.5 mg/m²,can be safely combined with Carfilzomib 27 mg/m², in a steroid sparing regimen, with an ORR of 42% and CBR of 52% in bortezomib-refractory patients. The preliminary data from ongoing part B dose escalation supports full dose filanesib can also be combined with carfilzomib 56 mg/m² and is well tolerated with limited hematologic and the final data set to be presented at ASH.