Initial results from a Phase 1 clin­i­cal trial show prom­ise for SAR650984 as a thera­peutic option for heavily pre­treated multiple myeloma patients.

SAR650984 is one of several poten­tial new anti-myeloma agents for which clin­i­cal results were first pre­sented at the American Society of Hematology (ASH) meeting last week.

The results were pre­sented by Dr. Joseph Mikhael from the Mayo Clinic in Scottsdale, Arizona, who told The Beacon, “This drug was hands down the most promising new agent at ASH for myeloma.”

Dr. Mikhael further ex­plained, “The re­sponse­ rates were impressive, especially in a group of heavily pre­treated patients.  There was minimal toxicity – only in­fusional reac­tions that could be con­trolled – and no severe or life-threatening blood-related side effects.”

Based on these findings, Dr. Mikhael concluded, “The re­sponse­ and safety lends to SAR650984’s use alone and in com­bi­na­tion with other myeloma agents.”

Background

SAR650984 ^[1] is being devel­oped by the pharma­ceu­tical com­pany Sanofi (NYSE:SNY).  It belongs to the same broad class of drugs as elo­tu­zu­mab ^[2], daratumumab ^[3], and IPH2101 ^[4], called mono­clonal anti­bodies. Mono­clon­al anti­bodies work by identifying proteins on the surface of myeloma cells and signal­ing for the im­mune sys­tem to destroy the cancer cells.

SAR650984, dara­tu­mu­mab, and another mono­clonal anti­body known as MOR202 ^[5] target cancer cells that have a protein called CD38 on their surface.  Previous re­search has shown that 80 per­cent to 100 per­cent of all myeloma cells have this protein on their surface, making it a good target for anti-myeloma ther­apy.

Preclinical studies have shown that SAR650984 has anti-myeloma activity and that its activity is further en­hanced when admin­istered in com­bi­na­tion with Velcade ^[6] (bor­tez­o­mib), Revlimid ^[7] (lena­lido­mide), Kyprolis ^[8] (car­filz­o­mib), or melphalan ^[9] (Alkeran).

Study Design

Investigators from through­out the United States in­ves­ti­gated the safety and efficacy of SAR650984 at dif­fer­en­t dose and dosing-frequency com­bi­na­tions in a Phase 1 study.

The study in­cluded 39 blood cancer patients with a median age of 65 years.  Most of the study par­tic­i­pants (87 per­cent) were diag­nosed with multiple myeloma.  The myeloma patients had re­ceived a median of six prior lines of ther­apy.

The initial phase of the study was called an ac­cel­er­ated escalation phase, in which one patient was treated with each dose level from 0.0001 mg/kg to 0.1 mg/kg of SAR650984 to verify that there were no dose-limiting side effects at those doses.

During the basic escalation phase, two to six patients were treated at each dose level from 0.3 mg/kg to 20 mg/kg of SAR650984 to find the maximum tolerated dose.

During the final ex­pan­sion phase of the study – which has yet to start – all patients will re­ceive the maxi­mum tolerated dose of SAR650984.

SAR650984 was admin­istered as a single agent, although patients re­ceiv­ing SAR650984 doses of 3 mg/kg or higher also re­ceived 100 mg of pred­ni­sone during their SAR650984 in­fusions to prevent in­fusion-related side effects.  (One hundred milligrams of pred­ni­sone is equivalent to about 16 mg of dexa­meth­a­sone; in­fused pred­ni­sone, how­ever, as long acting as dexa­meth­a­sone.)

All myeloma patients treated with at least 0.3 mg/kg of SAR650984 had pre­vi­ously been treated with both Revlimid and Velcade, and 69 per­cent of those treated with at least 10 mg/kg of the study drug had previ­ous­ly been treated with Kyprolis and/or Pomalyst ^[10] (poma­lido­mide, Imnovid).

Study Results

Among the myeloma patients treated with at least 1 mg/kg of SAR650984, 25 per­cent responded to treat­ment, with 8 per­cent achieving a com­plete re­sponse­ and 17 per­cent achieving a partial re­sponse­.  Nearly a third (29 per­cent) of patients treated at those doses remain on ther­apy.

The re­sponse­ rate was higher (31 per­cent) among those treated with at least 10 mg/kg of SAR650984, with 15 per­cent achieving a com­plete re­sponse­ and 15 per­cent a partial re­sponse­.

The median time to initial re­sponse­ was 6 weeks, and the median duration of re­sponse­ was 5 months.

The over­all re­sponse­ rate of 31 per­cent seen with SAR650984 at its higher dose levels compares favorably to those for the newest anti-myeloma ther­a­pies, Kyprolis and Pomalyst.  The latter drugs have single-agent re­sponse­ rates of no more than 20 per­cent to 25 per­cent in patients with the same number of pre­vi­ous ther­a­pies as those in the SAR650984 trial.

The SAR650984 re­sponse­ rate is somewhat lower, how­ever, than was seen in a trial of dara­tu­mu­mab with patients who had a similar number of prior ther­a­pies as those in the SAR650984 trial. In the dara­tu­mu­mab trial, the over­all re­sponse­ rate was 42 per­cent for patients who re­ceived higher doses of the drug (see re­lated Beacon ^[11] news article).

Overall, 46 per­cent of the patients in the SAR650984 trial ex­peri­enced a serious side effect, but no specific type of side effect was particularly common.  The most fre­quent serious side effects were low platelet counts (8 per­cent), low red blood cell counts (5 per­cent), high cal­cium levels (5 per­cent), and low potassium levels (5 per­cent).

In addi­tion, 36 per­cent of patients in the trial had mild or mod­er­ate in­jec­tion site reac­tions during the first treat­ment cycle.  Only 4 per­cent had a mild in­jec­tion site reac­tion in sub­se­quent cycles.

Dr. Mikhael reported that the maximum tolerated dose of SAR650984 has not yet been reached, and a de­ci­sion is still pend­ing as to what dose will be tested during the final ex­pan­sion phase of the trial.

For more in­for­ma­tion, please refer to ASH abstract 284 ^[12] as well as Dr. Mikhael’s presentation slides ^[13], which he has made avail­able for download and viewing as a courtesy to The Beacon’s readers.