Safety and Efficacy of Filanesib in Combination with Pomalidomide and Dexamethasone in Refractory MM Patients. Phase Ib/II Pomdefil Clinical Trial Conducted By the Spanish MM Group

Background

Filanesib (ARRY-520) is a kinesin spindle protein inhibitor, with clinical activity in monotherapy in heavily pretreated MM patients (Lonial ASH 2013). We have previously demonstrated the preclinical synergy of this compound with pomalidomide and dexamethasone (Hernandez-García ASH 2015 & EHA 2016), the basis for the present trial.

Material and Methods

MM patients relapsing after at least two prior lines of therapy including bortezomib and lenalidomide, who were refractory or intolerant to lenalidomide and refractory to the last line of therapy were treated until progression with 28-day cycles of filanesib iv on days 1, 2, 15 & 16, + pomalidomide po days 1-21 + dexamethasone at a fixed dose of 40 mg po days 1, 8, 15 & 22. Mandatory primary prophylaxis with G-CSF comprised two 7-days courses starting at day +3 and day +17. A Phase Ib was initially conducted to evaluate the maximum tolerated dose (MTD) of the combination, using a modified 3+3 dose-escalating algorithm and once the MTD was determined, the Phase II part of the trial was activated in order to evaluate the activity and further define the toxicity of the combination at this dose.

Results

The phase Ib part of the trial included 14 patients with a median of 3.5 prior lines of treatment (range: 2-6); 11 (79%) were refractory to bortezomib; 13 (93%) refractory to lenalidomide, nine of them (64%) Len-refractory in the last line of therapy; 10 (71%) were double refractory to PI and lenalidomide; and 13 (93%) had received a prior ASCT.

Out of these 14 patients, 7 were included in DL1 (pomalidomide 4 mg and filanesib 1 mg/m²) and the other 7 in DL2 (pomalidomide 4 mg and filanesib 1.25 mg/m²). None of the patients in DL1, experienced DLTs; and there was 1 DLT (G3 diarrhea lasting >7 days) in 1 out of the 6 evaluable patients in DL2.

The most frequent treatment-related AEs were hematological: Anemia in 50% patients (36% G3 and 14% G4); neutropenia in 93% (21% G2, 21% G3 and 50% G4); and thrombocytopenia in 78% (50% G1/2, 14% G3 and 14% G4). Non hematological related AEs were mainly low grades, the most frequent-ones being diarrhea (28% G1/2 and 7% G3), asthenia in 36% (all of them G1/2) and infections. Most infections were upper respiratory tract and grades 1/2 (43%). Three patients presented with pneumonia (1 G2 and 2 G3), 1 patient each with sepsis and febrile neutropenia (both G3) and 1 patient died due to an Influenza A pneumonia. In order to maintain a good safety profile, although no formal MTD could be established based on DLTs, DL2 was defined as the recommended dose to proceed to the phase 2.

As far as efficacy was concerned, 1 patient (7%) achieved VGPR and 6 (43%) PR for an overall response rate (ORR) of 50%; 1 additional patient (7%) achieved MR and the disease was stabilized in the remaining 6 patients (43%) (lasting for at least 3 cycles) accounting for a disease control rate (DCR) of 100%. Median time to response was 3 months. Remarkably, responses were not different in the nine patients refractory to lenalidomide in the last line of therapy (4 PR (44%) and 1 MR (11%)). After a median follow-up of 7 months, the median PFS was 7 months (CI95 3.3-10.6). Only 3 patients have died due to influenza A (n=1) and progressive disease (n=2).

Conclusion

The recommended dose of the combination was defined as pomalidomide 4 mg + filanesib 1.25 mg/m². The main toxicity was hematological but manageable; and the efficacy, with 50% overall response rate and 100% disease control rate in refractory patients, clinically confirms the synergy observed in the preclinical setting and supports the use of filanesib as a good partner for combination with pomalidomide and dexamethasone. Phase II is ongoing and updated results will be presented at the meeting.