Results from three clinical trials involving the inves­ti­ga­tional drug filanesib were presented at the American Society of Hematology (ASH) annual meeting earlier this month.

The trials evaluated the efficacy of filanesib (ARRY-520) alone and in com­bi­na­tion with other agents as potential treat­ments for re­lapsed and refractory multiple myeloma patients.

Overall, the trial results presented at ASH con­firm existing impressions of filanesib as a promising potential myeloma ther­apy.

Results of a Phase 2 trial of filanesib with or without low-dose dex­a­meth­a­sone (Decadron) show that 16 per­cent of patients who had received a median of six prior ther­a­pies responded to single-agent filanesib.

The trial results also indicate that the amount of a specific protein, known as alpha 1-acid glycoprotein (AAG), in a patient's blood may be a useful predictor of whether or not the patient will benefit from treat­ment with filanesib.

Studies of filanesib in com­bi­na­tion with the proteasome inhibitors Velcade (bor­tez­o­mib) and Kyprolis (car­filz­o­mib) were also presented. The results from both of these studies show that filanesib in com­bi­na­tion with either proteasome inhibitor led to response rates of 30 per­cent to 40 per­cent in heavily pretreated patients who were Velcade-refractory.

A preclinical trial investigating filanesib in com­bi­na­tion with Pomalyst (poma­lido­mide, Imnovid) (abstract; full poster [PDF]) also was presented at ASH. The study showed that filanesib plus Pomalyst had higher anti-tumor activity than either drug alone.  This finding may lead to clinical trials testing filanesib in com­bi­na­tion with either Pomalyst or Revlimid (lena­lido­mide), which is in the same broad class of drugs as Pomalyst.

A High-Level View Of The Filanesib ASH Results

The trial results presented at ASH suggest that filanesib is highly active against multiple myeloma as a single agent.  The over­all response rates for the drug when used alone, or in com­bi­na­tion with dex­a­meth­a­sone, may seem low at first glance (15 to 20 per­cent).  However, patients in the relevant trial were very heavily pretreated, with a median of six to eight prior ther­a­pies.

Thus, at this point, it appears that filanesib has single-agent activity against myeloma com­parable to some of the newest myeloma ther­a­pies, such as Kyprolis.

Moreover, the single-agent activity is probably higher than the newest myeloma ther­a­pies when filanesib is used only in patients with low levels of AAG in their blood.

The drug does not appear to be as active as a single agent, however, as the CD38 mono­clonal anti­bodies, such as daratumumab and SAR650984, that also are under devel­op­ment as potential new myeloma ther­a­pies.

In addi­tion, the ASH results raise questions about how much filanesib's single-agent activity helps when the drug is com­bined with other myeloma ther­a­pies.  The response rates seen at the meeting for filanesib in com­bi­na­tion with Velcade or Kyprolis do not seem quite as high as one might have ex­pec­ted given filanesib's efficacy on its own.

True, the com­bi­na­tion trials were Phase 1 studies, exploring a range of different dose levels.  In addi­tion, the patients in the trials were more heavily pretreated than what is usually seen in such trials, making com­par­i­sons even more difficult.

Yet, even with those caveats in mind, there still seem to be hints in the ASH results that filanesib's activity as a single agent may not contribute as much to the activity of com­bi­na­tion regi­mens as one would typically ex­pec­t.

Another factor that may complicate filanesib's future use in com­bi­na­tion regi­mens – and which also needs to be kept in mind generally when thinking about filanesib as a potential myeloma ther­apy – is filanesib's tendency to suppress white blood cell counts.  Indeed, in all the filanesib trials discussed at ASH, patients were given injections of granulocyte colony-stimulating factor (G-CSF, Neupogen) to prevent low white blood cell counts from developing.

Details from the clinical studies involving filanesib that were presented at ASH are summarized below.

Background

Filanesib is a novel anti-myeloma drug that is being developed by Array BioPharma (NASDAQ: ARRY). It is in a distinct class of drugs known as kinesin spindle protein (KSP) inhibitors, which work against myeloma by disrupting cell division.

Prior preclinical studies have shown additive anti-myeloma effects resulting from the com­bi­na­tion of filanesib and a proteasome inhibitor, such as Velcade or Kyprolis.

Initial clinical trial results for filanesib started being presented in research posters at least three years ago. It was not until last year's ASH meeting, however, that filanesib clinical trial results were featured in an oral presentation during the meeting (see related Beacon news).

Filanesib With Or Without Dexamethasone: Phase 2 Results

Researchers at this year's ASH meeting presented results from a Phase 2 study of filanesib with or without low-dose dex­a­meth­a­sone in 87 patients with re­lapsed and refractory myeloma (abstract, slide deck [PDF]).

The first group of patients (37 per­cent of the study participants) received filanesib alone. Filanesib was ad­min­is­tered at 1.5 mg/m² per day on days 1 and 2 every two weeks.  Patients in this group had received a median of six pre­vi­ous ther­a­pies; 41 per­cent of the patients were resistant (refractory) to Velcade, Revlimid, and dex­a­meth­a­sone.

The second group of patients (63 per­cent) received filanesib using the same dosing schedule as patients in group 1 plus 40 mg of dex­a­meth­a­sone weekly.  Patients in this group had received a median of eight pre­vi­ous ther­a­pies; 96 per­cent were refractory to Velcade, Revlimid, and dex­a­meth­a­sone.

To prevent low white blood cell counts from occurring, patients in both groups also received injections of G-CSF on days 3 through 7 of every two-week cycle.

The over­all response rates were similar for both treat­ment groups: 16 per­cent for the first group and 15 per­cent for the second.

The results also showed that filanesib was active in patients who had pre­vi­ously received newer myeloma drugs. The over­all response rate was 21 per­cent for patients who had pre­vi­ously received Pomalyst, Kyprolis, and/or ixazomib (MLN9708).

The researchers found that patients with low levels of alpha 1-acid glycoprotein (AAG), which binds to filanesib, were more likely to respond to filanesib ther­apy. None of the approx­i­mately one-third of the patients with high levels of AAG re­sponded to ther­apy.

Despite similar response rates across the two treat­ment groups, the median duration of response was longer for patients in the first group than in the second group (8.6 months versus 5.1 months, re­spec­tive­ly).

Overall survival was also significantly longer for patients in the first group compared to patients in the second group (19 months versus 11 months, re­spec­tive­ly). The results also showed that low levels of AGG were asso­ci­ated with longer survival.

According to the researchers, filanesib was well tolerated.  They point out that the rate of non-blood-related side effects was low, and that blood-related side effects were generally reversible and not cumulative.

Filanesib Plus Velcade And Dexamethasone: Phase 1 Results

One poster at this year’s ASH meeting summarized the initial results from a Phase 1 study of filanesib in com­bi­na­tion with Velcade and low-dose dex­a­meth­a­sone in re­lapsed and refractory myeloma patients (abstract; full poster [PDF]).

So far, 28 patients with a median age of 64 years have been enrolled in the study. They received one of two 28-day treat­ment regi­mens.

In Schedule 1, patients received varying doses of filanesib on days 1, 2, 15, and 16; 1.3 mg/m² of Velcade plus low-dose dex­a­meth­a­sone on days 1, 8, and 15; and G-CSF.  The 19 patients on Schedule 1 had re­ceived a median of five prior ther­a­pies. All of them had pre­vi­ously received Velcade, and 42 per­cent were refractory to prior Velcade.

In Schedule 2, patients received varying doses of filanesib on days 1 and 15; 1.3 mg/m² of Velcade plus low-dose dex­a­meth­a­sone on days 1, 8, and 15; and G-CSF. The 9 patients on Schedule 2 had received a me­di­an of four prior ther­a­pies. All of them had pre­vi­ously received Velcade, and none of them were refractory to Velcade.

The initial results show that 42 per­cent of patients who received higher doses of filanesib using Schedule 1 responded to treat­ment, with 5 per­cent achieving a very good partial response and 37 per­cent a partial re­sponse. Notably, 30 per­cent of patients who were refractory to prior Velcade or Kyprolis responded to treat­ment.

Response rates for patients on Schedule 2 were not reported.

According to the investigators, the com­bi­na­tion had an acceptable safety profile. The most common side effects were blood-related.  Non-blood-related side effects were mild to mod­er­ate in nature.

The maximum tolerated dose for Schedule 1 was established at 1.5 mg/m² of filanesib.  The maximum tolerated dose for Schedule 2 was established at 3 mg/m² of filanesib.  These doses are being tested fur­ther in the expansion stage of the trial.

Filanesib Plus Kyprolis: Phase 1 Results

Another poster showed the results from a Phase 1 study of filanesib plus Kyprolis in re­lapsed and refractory myeloma patients (abstract; full poster [PDF]).

The study included 20 patients with a median age of 61 years who had received a median of four prior lines of ther­apy. All patients had pre­vi­ously received Velcade and were refractory to it.

Patients received varying doses of filanesib on days 1, 2, 15, and 16, and 27 mg/m² of Kyprolis on days 1, 2, 8, 9, 15, and 16 of a 28-day treat­ment cycle.

Patients also received 4 mg of dex­a­meth­a­sone on the days of their Kyprolis infusions, and injections of G-CSF on days 3 through 7 and 17 through 21 of the treat­ment cycle.

Overall, 37 per­cent of patients responded to treat­ment, with 5 per­cent achieving a near com­plete response and 32 per­cent a partial response.

According to the researchers, the com­bi­na­tion was well tolerated with minimal non-blood-related side ef­fects. Blood-related side ef­fects were transient and non-cumulative.

The maximum tolerated dose was established at 1.5 mg/m² of filanesib.  This dose com­bined with a dose of 27 mg/m² of Kyprolis is the recommended dose for future trials.

For more in­­for­ma­tion about the myeloma-related studies presented at this year’s ASH meeting, please see the Beacon’s ASH 2013 Myeloma Gateway.