ARRY-520 is one of several potential new anti-myeloma agents that was highlighted at the American Society of Hematology (ASH) annual meeting earlier this week.

Initial results from two clinical trials show promise for ARRY-520 ^[1] (filanesib ^[2]), alone or in com­bi­na­tion with other myeloma drugs, as a thera­peutic option for heavily pretreated multiple myeloma patients.

“ARRY-520 shows promising activity in com­bi­na­tion with dexa­meth­a­sone in heavily pretreated myeloma patients,” said Dr. Jatin Shah, from the MD Anderson Cancer Center in Houston and lead investigator of both studies.

Based on their findings, the study investigators believe that ARRY-520 warrants further investigation in patients with re­lapsed and refractory (treatment resistant) myeloma.

A third study related to ARRY-520 focused on the use of alpha-1-acid glycoprotein levels for identifying patients who are more likely to benefit from treat­ment with the drug.

ARRY-520 ^[3] is being developed by Array BioPharma (NASDAQ: ARRY). It inhibits kinesin spindle protein, which plays an important role in actively dividing cells. According to Dr. Shah, ARRY-520 is expected to have low cross-resistance with other current myeloma treat­ments.

Details of the oral presentation and two poster presentations related to ARRY-520 that were presented at ASH are summarized below.

ARRY-520 Alone Or With Low-Dose Dexamethasone: Phase 2 Trial Results

On Monday, Dr. Shah presented the results of a Phase 2 clinical trial comparing the efficacy and safety of ARRY-520 alone and in com­bi­na­tion with low-dose dexamethasone ^[4] (Decadron) in re­lapsed and refractory myeloma patients who were heavily pre-treated with Velcade ^[5] (bor­tez­o­mib) and Revlimid ^[6] (lena­lido­mide).

Prior preclinical studies have shown that the addi­tion of dexa­meth­a­sone enhances the effect of ARRY-520 in myeloma cells.

The study included two sets of patient groups. The first group included 32 patients with a median age of 65 years who had received a median of six prior treat­ment regi­mens. These patients were treated with ARRY-520 alone.

The second group included 18 patients with a median age of 67 years who had received a median of 10 prior ther­a­pies. All patients in the second group were refractory to Revlimid, Velcade, and dexa­meth­a­sone. These patients were treated with a com­bi­na­tion of ARRY-520 and low-dose dexa­meth­a­sone.

All patients had received prior Revlimid, and almost all had received prior Velcade (91 per­cent in group 1 and 100 per­cent in group 2). In addi­tion, most patients had undergone an au­tol­o­gous stem cell trans­plant (81 per­cent in group 1 and 89 per­cent in group 2).

During the course of the study, every patient received 1.5 mg/m² of ARRY-520 on days 1 and 2 every two weeks. Additionally, the patients in group 2 received 40 mg of dexa­meth­a­sone weekly.

Of the patients treated with ARRY-520 alone, 16 per­cent achieved a partial response. Of those treated with ARRY-520 plus low-dose dexa­meth­a­sone, 22 per­cent achieved a partial response.

The median duration of response was 8.6 months for ARRY-520 alone and 5.4 months for ARRY-520 plus dexa­meth­a­sone.

Dr. Shah and his colleagues also found that levels of the protein alpha-1-acid glycoprotein before treat­ment with ARRY-520 had an effect on response.  In particular, patients who responded to the ARRY-520-based ther­apy had low levels of a protein called apha-1-acid glycoprotein in the blood compared to patients who did not respond to treat­ment (see details of a related study below).

According to Dr. Shah, ARRY-520 has a favorable side effect profile. He pointed out, in particular, that ARRY-520 was asso­ci­ated with a low rate of non-blood-related side effects.

Common severe side effects of ARRY-520 were low white blood cell counts (47 per­cent), low platelet counts (47 per­cent), low red blood cell counts (37 per­cent), fatigue (15 per­cent), low potassium levels (6 per­cent), and back pain (6 per­cent).

Dr. Shah said that blood-related side effects are generally reversible and that, in general, there was no cumulative toxicity with long-term admin­istra­tion.

Additional severe side effects appeared with the addi­tion of dexa­meth­a­sone, including pneu­monia (20 per­cent), joint pain (5 per­cent), and upper res­pira­tory tract in­fec­tion (5 per­cent).

No treat­ment-related periph­eral neu­rop­athy (pain, tingling, and loss of sensation in the extremities) was observed in either group. Dr. Shah pointed out that only 9 per­cent of patients in group 1 and 11 per­cent of patients in group 2 dis­con­tinued the study due to side effects.

Given that patients who received the com­bi­na­tion regi­men were more heavily pretreated and nevertheless dem­onstrated a higher response rate, Dr. Shah recommended that the com­bi­na­tion of ARRY-520 and dexa­meth­a­sone should be further studied in the context of re­lapsed and refractory myeloma patients.

He added that two Phase 1 trials (ARRY-520 in com­bi­na­tion with Velcade and ARRY-520 in com­bi­na­tion with Kyprolis ^[7] (car­filz­o­mib)) are cur­rently ongoing.

ARRY-520 Plus Kyprolis: Phase 1 Trial Results

Dr. Shah and his colleagues also presented via a poster the initial results from a Phase 1 clinical trial of ARRY-520 plus Kyprolis in re­lapsed and refractory multiple myeloma patients.

Preclinical studies have also shown additive anti-myeloma effects resulting from the com­bi­na­tion of a proteasome inhibitor, such as Velcade or Kyprolis, and a kinesin spindle protein inhibitor, such as ARRY-520.

In this study, researchers sought to determine the efficacy and safety of ARRY-520 in com­bi­na­tion with Kyprolis.

So far, nine patients have been enrolled in the study.  The patients had a median age of 67 years and had been treated with a median of four prior ther­a­pies. All patients were either refractory to or intolerant of Velcade.  In addi­tion, all patients had pre­vi­ously been treated with Revlimid, and all had received a stem cell trans­plant.

During the trial, patients are receiving one of four doses of ARRY-520, ranging from 0.75 mg/m² to  1.5 mg/m², on days 1, 2, 15, and 16 of a 28-day cycle.

Additionally, they are being treated with dexa­meth­a­sone (4 mg) and Kyprolis on days 1, 2, 8, 9, 15, and 16.  Patients start at 20 mg/m² of Kyprolis for the first two doses and then 27 mg/m² for all later doses.

To date, 22 per­cent of patients have responded to the com­bi­na­tion ther­apy, with 11 per­cent reaching a complete response and 11 per­cent reaching a partial response.  An addi­tional 33 per­cent have achieved a minor response.

According to the investigators, the com­bi­na­tion was well-tolerated. Common severe side effects included low white blood cell counts (22 per­cent), lung in­fec­tions (22 per­cent), low red blood cell counts (11 per­cent), and diarrhea (11 per­cent).

AAG Levels And Response To ARRY-520

The second poster about ARRY-520 presented findings from a study investigating the rela­tion­ship between alpha-1-acid glycoprotein (AAG) levels and patients' responses to treat­ment with ARRY-520.

Patient data was obtained from three clinical trials of ARRY-520, including a Phase 1 study in patients with solid tumors, a Phase 1/2 study in patients with acute myeloid leukemia, and a Phase 1/2 study in patients with multiple myeloma.

In each of these studies, investigators took blood samples from patients before and after they were treated with ARRY-520. They sub­se­quently measured the concentrations of several proteins, including AAG, and the inter­actions of these proteins with ARRY-520.

A total of 72 patients were included in the analysis. Among these patients, 26 per­cent had more than 1.1 g/L of AAG, while the remaining patients had AAG levels that fell below this cutoff point.

Notably, none of the patients who had levels more than 1.1 g/L of AAG responded to treat­ment. On the other hand, 23 per­cent of patients who had lower levels of AAG achieved at least a partial response.

Patients with higher AAG levels also dem­onstrated a decreased median time on the study compared to those with lower AAG levels (1.5 months versus 4.7 months).

The researchers found that AAG binds to ARRY-520.  Therefore, the amount of ARRY-520 available to be effective against tumors is reduced in patients with high levels of AAG.

Thus, the study investigators suggest that AAG levels could be used to identify and exclude patients who are unlikely to benefit from treat­ment with ARRY-520.

For more in­­for­ma­tion, please see abstract 449 ^[8], abstract 4082 ^[9], and abstract 1868 ^[10] on the ASH 2012 Annual Meeting website.

Also, Dr. Shah has made the slides from his oral presentation available ^[11] for download and viewing as a courtesy to The Beacon’s readers